Noninvasive monitoring of adrenocortical activity in carnivores by fecal glucocorticoid analyses.

PubMed

Young, K M; Walker, S L; Lanthier, C; Waddell, W T; Monfort, S L; Brown, J L

2004-06-01

Measurement of glucocorticoid metabolites in feces has become an accepted method for the noninvasive evaluation of adrenocortical activity. The objective of this study was to determine if a simple cortisol enzyme immunoassay (EIA) was suitable for monitoring adrenocortical activity in a variety of carnivore species. Performance of the cortisol EIA was gauged by comparison to a corticosterone radioimmunoassay (RIA) that has been used for measuring glucocorticoid metabolites in feces of numerous species. Tests for parallelism and extraction efficiency were used to compare the cortisol EIA and corticosterone RIA across eight species of carnivores (Himalayan black bear, sloth bear, domestic cat, cheetah, clouded leopard, black-footed ferret, slender-tailed meerkat, and red wolf). The biological relevance of immunoreactive glucocorticoid metabolites in feces was established for at least one species of each Carnivora family studied with an adrenocorticotropic hormone (ACTH) challenge. High performance liquid chromatography (HPLC) analysis of fecal extracts for each species revealed (1) the presence of multiple immunoreactive glucocorticoid metabolites in feces, but (2) the two immunoassays measured different metabolites, and (3) there were differences across species in the number and polarities of metabolites identified between assay systems. ACTH challenge studies revealed increases in fecal metabolite concentrations measured by the cortisol EIA and corticosterone RIA of approximately 228-1145% and approximately 231-4150% above pre-treatment baseline, respectively, within 1-2 days of injection. Concentrations of fecal glucocorticoid metabolites measured by the cortisol EIA and corticosterone RIA during longitudinal evaluation (i.e., >50 days) of several species were significantly correlated (P<0.0025, correlation coefficient range 0.383-0.975). Adrenocortical responses to physical and psychological stressors during longitudinal evaluations varied with the type of stimulus, between episodes of the same stimulus, and among species. Significant elevations of glucocorticoid metabolites were observed following some potentially stressful situations [anesthesia (2 of 3 subjects), restraint and saline injection (2 of 2 subjects), restraint and blood sampling (2 of 6 episodes), medical treatment (1 of 1 subject)], but not in all cases [e.g., gonadotropin injection (n=4), physical restraint only (n=1), mate introduction/breeding (n=1), social tension (n=1), construction (n=2) or relocation (n=1)]. Results reinforced the importance of an adequate baseline period of fecal sampling and frequent collections to assess adrenocortical status. The corticosterone RIA detected greater adrenocortical responses to exogenous ACTH and stressful exogenous stimuli in the Himalayan black bear, domestic cat (female), cheetah, clouded leopard, slender-tailed meerkat, and red wolf, whereas the cortisol EIA proved superior to resolving adrenocortical responses in the black-footed ferret and domestic cat (male). Overall results suggest the cortisol EIA tested in this study offers a practical method for laboratories restricted in the usage of radioisotopes (e.g., zoological institutions and field facilities) to integrate noninvasive monitoring of adrenocortical activity into studies of carnivore behavior and physiology.

Noninvasive measures of reproductive function and disturbance in the barred owl, great horned owl, and northern spotted owl.

PubMed

Wasser, Samuel K; Hunt, Kathleen E

2005-06-01

There is an urgent need for noninvasive methods to study reproduction and environmental stress in at-risk species such as the northern spotted owl (Strix occidentalis caurina). Two related owl species (barred owl and great horned owl) were used as surrogates to validate hormone assays for fecal metabolites of progesterone, 17beta-estradiol, testosterone, and corticosterone. Infusions of radiolabeled hormones showed that the owls excreted most hormone within 6 h. Feces and urine contained roughly equal amounts of hormone, and most fecal hormone metabolites were quite polar. The testosterone and corticosterone assays in this study bound to the major excreted metabolites of these hormones, but two progesterone assays did not appreciably bind to the major progesterone metabolites. All assays showed excellent parallelism with hydrolyzed and unhydrolyzed samples and with previously dried or undried fecal samples. Thus, samples do not require hydrolysis or prior drying. Samples from a female barred owl had significantly higher fecal estrogen, lower fecal testosterone, and higher fecal estrogen/testosterone ratio than samples from two male barred owls. The fecal estrogen/testosterone ratio was the most accurate predictor of owl gender, particularly if two or more samples are available from the same individual. Fecal corticosterone metabolites also demonstrated considerable utility for wild northern spotted owls. Fecal glucocorticoid levels varied by gender and breeding stage, being highest in male northern spotted owls early in the breeding season and highest in females when nestlings were fledging. Collectively, these studies show that noninvasive fecal hormone measurements show great promise for noninvasive assessment of reproduction and stress in wild owls.

Neonatal handling reduces renal function in adult rats.

PubMed

Donadio, Márcio Vinícius Fagundes; Jacobs, Silvana; Corezola, Kizzy Ludnila; Melo, Denizar Alberto da Silva; Dias, Henrique Bregolin; Reichel, Carlos Luiz; Franci, Celso Rodrigues; Jeckel-Neto, Emilio Antonio; Lulhier, Francisco; Lucion, Aldo Bolten; de Oliveira, Jarbas Rodrigues; Sanvitto, Gilberto Luiz

2009-01-01

To evaluate the effects of neonatal handling on hydroelectrolytic balance in adult rats. The litters were divided into two groups: nonhandled and handled. The procedure consisted of handling the pups for 1 min/day in the first 10 days postnatally. When adults, animals had their body weight verified and were housed in individual metabolic cages. After a 24-hour period, urine samples were collected and the urinary and water intake volumes measured. Blood samples to determine osmolality, aldosterone, corticosterone, angiotensin II, creatinine, urea, sodium and potassium levels were collected. The kidneys were removed for histological assessment. Urinary osmolality, sodium, urea and creatinine were also measured and the creatinine clearance (CC) calculated. No difference between groups was found in the body weight. Handled animals showed a reduction in the total kidney wet weight, water intake, urinary volume, CC, plasma angiotensin II, corticosterone and aldosterone when compared to the nonhandled and an increase in the urinary osmolality and sodium excretion fraction. No differences in serum potassium and no evidence of structural changes were demonstrated by histological analysis. Neonatal handling induced long-lasting effects decreasing renal function without evidence of kidney structural changes. (c) 2009 S. Karger AG, Basel.

Corticosterone stress response and plasma metabolite levels during breeding and molt in a free-living migratory songbird, the wood thrush (Hylocichla mustelina).

PubMed

Done, Tyler; Gow, Elizabeth A; Stutchbury, Bridget J M

2011-04-01

Many birds face energetic trade-offs between different life history stages, such as reproductive effort, feather molt and the non-breeding period. Little is known about how physiological measures of condition (corticosterone, plasma metabolites) in free-living birds change from nesting stages to the post-breeding molt period or whether this is influenced by prior reproductive effort. We evaluated whether corticosterone (CORT) and plasma metabolite levels vary with date, nest stage and sex in a free-living migratory songbird, the wood thrush (Hylocichla mustelina). We also tested whether (1) baseline CORT levels early in the season were predictive of subsequent reproductive success and (2) whether prior reproductive effort influenced CORT levels and blood metabolites during molt. Baseline CORT levels decreased with date during both the incubation stage and nestling stage, but did not vary significantly across stage of breeding season. Stress-induced CORT declined with date during incubation and varied significantly across breeding stage, with lower levels during feather molt. Profiles of the metabolites of β-hydroxybutyrate, glycerol, and triglyceride did not vary significantly with date or breeding stage. Only triglycerides varied significantly with sex, with females having higher levels than males. Reproductive output was highly variable (0-10 fledglings per season) but baseline CORT levels in females during the first incubation period of the season was not related to subsequent reproductive output. Prior reproductive effort, measured as the cumulative number of young hatched during the breeding season, was positively related to stress-induced CORT during molt. High reproductive effort in wood thrush appears to have physiological carry-over effects into the molt period which could potentially affect rate of molt and preparation for fall migration. Copyright © 2011. Published by Elsevier Inc.

Metabolomics Approach to Male Lower Urinary Tract Symptoms: Identification of Possible Biomarkers and Potential Targets for New Treatments.

PubMed

Mitsui, Takahiko; Kira, Satoru; Ihara, Tatsuya; Sawada, Norifumi; Nakagomi, Hiroshi; Miyamoto, Tatsuya; Shimura, Hiroshi; Yokomichi, Hiroshi; Takeda, Masayuki

2018-05-01

We identified metabolites using a metabolomics approach and investigated the association between these metabolites and lower urinary tract symptoms. We used a 24-hour bladder diary and I-PSS (International Prostate Symptom Score) to assess micturition behavior and lower urinary tract symptoms in 58 male patients without apparent neurological disease. Lower urinary tract symptoms were defined as a total I-PSS score of 8 or greater. Patients with a score of 7 or less were placed in the control group. A comprehensive study of plasma metabolites was also performed by capillary electrophoresis time-of-flight mass spectrometry. Metabolites were compared between the lower urinary tract symptoms and control groups using the Mann-Whitney U test. Biomarkers of male lower urinary tract symptoms from the metabolites were analyzed using multivariable logistic regression analysis to determine the OR. Of the 58 men 32 were in the lower urinary tract symptoms group and the remaining 26 were in the control group. The 24-hour bladder diary showed that nocturnal urine volume, 24-hour micturition frequency, nocturnal micturition frequency and the nocturia index were significantly higher in the lower urinary tract symptoms group. Metabolomics analysis identified 60 metabolites from patient plasma. Multivariate analysis revealed that increased glutamate and decreased arginine, asparagine and inosine monophosphate were significantly associated with lower urinary tract symptoms in males. Decreases in citrulline and glutamine could also be associated with male lower urinary tract symptoms. Male lower urinary tract symptoms may develop due to abnormal metabolic processes in some pathways. Potential new treatments for lower urinary tract symptoms can be developed by identifying changes in the amino acid profiles. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Metabolomic study of corticosterone-induced cytotoxicity in PC12 cells by ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry.

PubMed

Zhang, Hongye; Zheng, Hua; Zhao, Gan; Tang, Chaoling; Lu, Shiyin; Cheng, Bang; Wu, Fang; Wei, Jinbin; Liang, Yonghong; Ruan, Junxiang; Song, Hui; Su, Zhiheng

2016-03-01

Glucocorticoids (GCs) have been proved to be an important pathogenic factor of some neuropsychiatric disorders. Usually, a classical injury model based on corticosterone-induced cytotoxicity of differentiated rat pheochromocytoma (PC12) cells was used to stimulate the state of GC damage of hippocampal neurons and investigate its potential mechanisms involved. However, up to now, the mechanism of corticosterone-induced cytotoxicity in PC12 cells was still looking forward to further elucidation. In this work, the metabolomic study of the biochemical changes caused by corticosterone-induced cytotoxicity in differentiated PC12 cells with different corticosterone concentrations was performed for the first time, using the ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS). Partial least squares-discriminate analysis (PLS-DA) indicated that metabolic profiles of different corticosterone treatment groups deviated from the control group. A total of fifteen metabolites were characterized as potential biomarkers involved in corticosterone-induced cytotoxicity, which were corresponding to the dysfunctions of five pathways including glycerophospholipid metabolism, sphingolipid metabolism, oxidation of fatty acids, glycerolipid metabolism and sterol lipid metabolism. This study indicated that the rapid and holistic cell metabolomics approach might be a powerful tool to further study the pathogenesis mechanism of corticosterone-induced cytotoxicity in PC12 cells.

Levels of plasma and fecal glucocorticoid metabolites following an ACTH challenge in male and female coyotes (Canis latrans).

PubMed

Stevenson, Erika T; Gese, Eric M; Neuman-Lee, Lorin A; French, Susannah S

2018-03-01

Knowledge of endocrine stress responses can be advantageous for understanding how animals respond to their environment. One tool in wildlife endocrinology is to measure the adrenocortical activity as a parameter of disturbance of animals. Fecal glucocorticoid metabolites (GCMs) provide a noninvasive assessment of adrenocortical activity. Using an adrenocorticotropic hormone (ACTH) challenge administered to 28 captive coyotes (Canis latrans), we measured the levels of plasma cortisol, and fecal cortisol and corticosterone metabolites (i.e., GCMs). Our goal was to determine the dose-response in the plasma and fecal samples following the injection and determine if there were effects of sex, age, and time of day. Specifically, animals were anesthetized for ~ 90 min with treatment animals intravenously injected with exogenous ACTH and control animals receiving saline. We collected blood samples prior to injection and at 4 different time points post-injection. We also collected fecal samples 2 days pre- and 2 days post-injection to measure fecal GCMs and determine if an endocrine stress response could be detected in fecal samples. We found a definite response in cortisol levels in the plasma for coyotes to the ACTH challenge. There was a response in fecal corticosterone 1 day post-injection, but the control males showed a similar response indicating a handling effect. Fecal cortisol levels did not indicate a response to the ACTH challenge, and were significantly lower than corticosterone concentrations. We also found significant sex, but not age or diurnal, differences in fecal GCMs. Radioimmunoassays for fecal corticosterone levels appeared to be a reliable indicator of physiological stress in coyotes.

Urinary metabolite levels and symptoms in Filipino workers using organic solvents.

PubMed

Cucueco, M T; Espinosa, N C; Villanueva, M B; Castro, F T; Sison, S Y; Ortega, V S; Hisanaga, N

1993-01-01

To compare symptoms with urinary metabolite levels, 900 workers from 7 organic solvent-using industries were studied. Urinary metabolites were determined using a high performance liquid chromatograph. Urinary hippuric acid concentrations exceeding the reference value (2.5 g/g creatinine) were found in 78 (8.7%) workers. However, only 3 (0.3%) and 1 (0.1%) of the participants exceeded the reference value for mandelic (0.8 g/g creatinine) and total methylhippuric acid (1.5 g/g creatinine), respectively. The sum of the values of the ratio of measured urinary metabolite concentration to the corresponding ACGIH's biological exposure indices (BEI) [(HA/BEI of HA + MHA/BEI of MHA + MA/BEI of MA)] exceeded 1.0 in 166 (18.4%) workers. Majority of them were from the footwear manufacturing industry (63/129 or 49.2%). Questionnaire interviews were also administered to determine the prevalence of symptoms while at work (acute symptoms) or within the past 6 months (chronic symptoms). Urinary metabolite levels of individual and mixed solvents were compared with the symptoms of all workers. Analysis using Spearman's rank correlation showed in workers whose urinary hippuric acid exceeded 3.75 g/g creatine (1.5 x BEI), significant correlation between their hippuric acid levels and subjective complaints. Workers whose sum of the values of the ratio of measured urinary metabolite concentration to corresponding BEI exceeded 1.5 were selected and comparing this level with their symptoms, significant correlation was also noted in some complaints.

[Relationship between urinary polycyclic aromatic hydrocarbon metabolite and cell cycle of lymphocyte in coke oven workers].

PubMed

Pan, B L; Zhang, H T; Zhang, H J; Chen, W T; Yang, J

2016-11-20

Objective: To investigate the relationship between urinary polycyclic aromatic hydrocarbon metabolite and cell cycle of lymphocyte in coke oven workers. Methods: 437 coke oven workers and 163 work-ers in water treatment department were recruited in this study. Flow cytometry was used to detect the cell cycle of lymphocyte. For the measurement of urinary metabolites, urine samples were treated with β-glucuronidase and analyzed using HPLC with a fluorescence detector. Results: The concentrations of urinary 2-naphthol, 2-hydroxyfluorene, 9-phenanthrol and 1-hydroxypyrene l in coke oven workers were significantly higher than those in control group ( P <0.01) . The distributions of cell cycle were analyzed in high exposure group (the content of urinary metabolites high than P 75) and low exposure group (the content of urinary metabolites low than P 25) . According to the content of 1-hydroxypyrene, the proportions of S phase in high exposure group were significant-ly higher than those of low exposure group ( Z =-2.496, P =0.013) , but the proportions of G0/G1 phase were sig-nificantly lower than low exposure group ( Z =-2.074, P =0.038) . The similar results were not been found in other hydroxylated metabolites as internal exposure group. Conclusion: Increasing levels of urinary 1-hydroxypyrene might resulting in cell cycle of lymphocyte disorders, mainly for G0/G1 phase shorten and S phase arrest.

Urinary composition and postprandial blood changes in H-secoisolariciresinol diglycoside (SDG) metabolites in rats do not differ between acute and chronic SDG treatments.

PubMed

Rickard, S E; Thompson, L U

2000-09-01

Although chronic exposure to secoisolariciresinol diglycoside (SDG) was shown to alter (3)H-SDG metabolite disposition in rats, the proportion of measured radioactivity attributed to known or unknown SDG metabolites was not determined. Using HPLC and GC-MS, two experiments were conducted to determine the effect of acute (1 d) vs. chronic (10 d) SDG treatment on major urinary metabolites of (3)H-SDG in female, Sprague-Dawley rats (70-72-d-old) over a 48-h period and if new urinary metabolites were detectable in rats fed nonradioactive flaxseed or SDG. A third experiment was conducted to determine changes in postprandial blood levels of (3)H-SDG metabolites over a 24-h period with acute or chronic SDG treatment. Regardless of treatment, enterodiol, enterolactone and secoisolariciresinol accounted for 75-80% of urine radioactivity. Four potential new lignan metabolites, two of which were detected in the urine of rats fed nonradioactive flaxseed or SDG, were found. Type of treatment had no effect on levels of individual urinary metabolites of (3)H-SDG. As observed for plasma lignans in women fed flaxseed, blood radioactivity peaked at 9 h and remained high until 24 h in both treatment groups, suggesting that blood lignan kinetics might be similar with flaxseed or SDG consumption and that they were comparable between humans and rats. In conclusion, the main urinary lignan metabolites were enterodiol, enterolactone and secoisolariciresinol. Urinary composition or blood levels of radioactive lignans were not affected by the duration of SDG exposure. Thus, while chronic SDG exposure alters lignan disposition in rats, it does not change the metabolite profile.

Acute thermal stressor increases glucocorticoid response but minimizes testosterone and locomotor performance in the cane toad (Rhinella marina).

PubMed

Narayan, Edward J; Hero, Jean-Marc

2014-01-01

Climatic warming is a global problem and acute thermal stressor in particular could be considered as a major stressor for wildlife. Cane toads (Rhinella marina) have expanded their range into warmer regions of Australia and they provide a suitable model species to study the sub-lethal impacts of thermal stressor on the endocrine physiology of amphibians. Presently, there is no information to show that exposure to an acute thermal stressor could initiate a physiological stress (glucocorticoid) response and secondly, the possible effects on reproductive hormones and performance. Answering these questions is important for understanding the impacts of extreme temperature on amphibians. In this study, we experimented on cane toads from Queensland, Australia by acclimating them to mildly warm temperature (25°C) and then exposing to acute temperature treatments of 30°, 35° or 40°C (hypothetical acute thermal stressors). We measured acute changes in the stress hormone corticosterone and the reproductive hormone testosterone using standard capture and handling protocol and quantified the metabolites of both hormones non-invasively using urinary enzyme-immunoassays. Furthermore, we measured performance trait (i.e. righting response score) in the control acclimated and the three treatment groups. Corticosterone stress responses increased in all toads during exposure to an acute thermal stressor. Furthermore, exposure to a thermal stressor also decreased testosterone levels in all toads. The duration of the righting response (seconds) was longer for toads that were exposed to 40°C than to 30°, 35° or 25°C. The increased corticosterone stress response with increased intensity of the acute thermal stressor suggests that the toads perceived this treatment as a stressor. Furthermore, the results also highlight a potential trade-off with performance and reproductive hormones. Ultimately, exposure acute thermal stressors due to climatic variability could impact amphibians at multiple eco-physiological levels through impacts on endocrine physiology, performance and potentially fitness traits (e.g. reproductive output).

Acute Thermal Stressor Increases Glucocorticoid Response but Minimizes Testosterone and Locomotor Performance in the Cane Toad (Rhinella marina)

PubMed Central

Narayan, Edward J.; Hero, Jean-Marc

2014-01-01

Climatic warming is a global problem and acute thermal stressor in particular could be considered as a major stressor for wildlife. Cane toads (Rhinella marina) have expanded their range into warmer regions of Australia and they provide a suitable model species to study the sub-lethal impacts of thermal stressor on the endocrine physiology of amphibians. Presently, there is no information to show that exposure to an acute thermal stressor could initiate a physiological stress (glucocorticoid) response and secondly, the possible effects on reproductive hormones and performance. Answering these questions is important for understanding the impacts of extreme temperature on amphibians. In this study, we experimented on cane toads from Queensland, Australia by acclimating them to mildly warm temperature (25°C) and then exposing to acute temperature treatments of 30°, 35° or 40°C (hypothetical acute thermal stressors). We measured acute changes in the stress hormone corticosterone and the reproductive hormone testosterone using standard capture and handling protocol and quantified the metabolites of both hormones non-invasively using urinary enzyme-immunoassays. Furthermore, we measured performance trait (i.e. righting response score) in the control acclimated and the three treatment groups. Corticosterone stress responses increased in all toads during exposure to an acute thermal stressor. Furthermore, exposure to a thermal stressor also decreased testosterone levels in all toads. The duration of the righting response (seconds) was longer for toads that were exposed to 40°C than to 30°, 35° or 25°C. The increased corticosterone stress response with increased intensity of the acute thermal stressor suggests that the toads perceived this treatment as a stressor. Furthermore, the results also highlight a potential trade-off with performance and reproductive hormones. Ultimately, exposure acute thermal stressors due to climatic variability could impact amphibians at multiple eco-physiological levels through impacts on endocrine physiology, performance and potentially fitness traits (e.g. reproductive output). PMID:24643017

Characterization of Train-Induced Vibration and its Effect on Fecal Corticosterone Metabolites in Mice

PubMed Central

Atanasov, Nicholas A; Sargent, Jennifer L; Parmigiani, John P; Palme, Rupert; Diggs, Helen E

2015-01-01

Excessive environmental vibrations can have deleterious effects on animal health and experimental results, but they remain poorly understood in the animal laboratory setting. The aims of this study were to characterize train-associated vibration in a rodent vivarium and to assess the effects of this vibration on the reproductive success and fecal corticosterone metabolite levels of mice. An instrumented cage, featuring a high-sensitivity microphone and accelerometer, was used to characterize the vibrations and sound in a vivarium that is near an active railroad. The vibrations caused by the passing trains are 3 times larger in amplitude than are the ambient facility vibrations, whereas most of the associated sound was below the audible range for mice. Mice housed in the room closest to the railroad tracks had pregnancy rates that were 50% to 60% lower than those of mice of the same strains but bred in other parts of the facility. To verify the effect of the train vibrations, we used a custom-built electromagnetic shaker to simulate the train-induced vibrations in a controlled environment. Fecal pellets were collected from male and female mice that were exposed to the simulated vibrations and from unexposed control animals. Analysis of the fecal samples revealed that vibrations similar to those produced by a passing train can increase the levels of fecal corticosterone metabolites in female mice. These increases warrant attention to the effects of vibration on mice and, consequently, on reproduction and experimental outcomes. PMID:26632783

Characterization of Train-Induced Vibration and its Effect on Fecal Corticosterone Metabolites in Mice.

PubMed

Atanasov, Nicholas A; Sargent, Jennifer L; Parmigiani, John P; Palme, Rupert; Diggs, Helen E

2015-11-01

Excessive environmental vibrations can have deleterious effects on animal health and experimental results, but they remain poorly understood in the animal laboratory setting. The aims of this study were to characterize train-associated vibration in a rodent vivarium and to assess the effects of this vibration on the reproductive success and fecal corticosterone metabolite levels of mice. An instrumented cage, featuring a high-sensitivity microphone and accelerometer, was used to characterize the vibrations and sound in a vivarium that is near an active railroad. The vibrations caused by the passing trains are 3 times larger in amplitude than are the ambient facility vibrations, whereas most of the associated sound was below the audible range for mice. Mice housed in the room closest to the railroad tracks had pregnancy rates that were 50% to 60% lower than those of mice of the same strains but bred in other parts of the facility. To verify the effect of the train vibrations, we used a custom-built electromagnetic shaker to simulate the train-induced vibrations in a controlled environment. Fecal pellets were collected from male and female mice that were exposed to the simulated vibrations and from unexposed control animals. Analysis of the fecal samples revealed that vibrations similar to those produced by a passing train can increase the levels of fecal corticosterone metabolites in female mice. These increases warrant attention to the effects of vibration on mice and, consequently, on reproduction and experimental outcomes.

COMPARISON OF THE URINARY METABOLITES OF RATS, MICE, AND HUMANS AFTER ORAL ARSENIC EXPOSURE FOCUSING ON THIOARSENICALS

EPA Science Inventory

Urinary metabolites of arsenic are useful as biomarkers of exposure because ingested arsenic is excreted primarily in urine1. Complete urinary arsenic speciation can provide insight into possible metabolic pathways as well as potential exposure sources. The pattern of excreted me...

Vinyl flooring in the home is associated with children’s airborne butylbenzyl phthalate and urinary metabolite concentrations

PubMed Central

Just, Allan C.; Miller, Rachel L.; Perzanowski, Matthew S.; Rundle, Andrew G.; Chen, Qixuan; Jung, Kyung Hwa; Hoepner, Lori; Camann, David E.; Calafat, Antonia M.; Perera, Frederica P.; Whyatt, Robin M.

2015-01-01

Prior studies have shown that vinyl flooring, as well as the vinyl-softening plasticizers butylbenzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP), are associated with asthma and airway inflammation. While DEHP exposure is primarily dietary, whether home vinyl flooring contributes to indoor air and urinary metabolite concentrations for these two phthalates is unclear. Exposures to BBzP and DEHP were examined in a prospective birth cohort of New York City children (n=239) using: (1) visual observation of potential phthalate containing flooring, (2) a two-week home indoor air sample, and (3) concurrent urinary metabolites in a subset (n=193). The category “vinyl or linoleum” flooring was observed in 135 (56%) of monitored rooms; these rooms had statistically significantly higher indoor air geometric mean concentrations of BBzP (23.9 ng/m3) than rooms with wood or carpet flooring (10.6 ng/m3). Children from homes with “vinyl or linoleum” flooring also had significantly higher urinary BBzP metabolite concentrations than other children. Indoor air BBzP and urinary metabolite concentrations were correlated positively (Spearman’s rho 0.40). By contrast, indoor air DEHP was not associated with flooring type nor with its urinary metabolite concentrations. Vinyl flooring in the home may be an important source of children’s exposure to BBzP via indoor air. PMID:25690585

Vinyl flooring in the home is associated with children's airborne butylbenzyl phthalate and urinary metabolite concentrations.

PubMed

Just, Allan C; Miller, Rachel L; Perzanowski, Matthew S; Rundle, Andrew G; Chen, Qixuan; Jung, Kyung Hwa; Hoepner, Lori; Camann, David E; Calafat, Antonia M; Perera, Frederica P; Whyatt, Robin M

2015-01-01

Prior studies have shown that vinyl flooring as well as the vinyl-softening plasticizers butylbenzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) are associated with asthma and airway inflammation. Although DEHP exposure is primarily dietary, whether home vinyl flooring contributes to indoor air and urinary metabolite concentrations for these two phthalates is unclear. Exposures to BBzP and DEHP were examined in a prospective birth cohort of New York City children (n=239) using: (i) visual observation of potential phthalate containing flooring, (ii) a 2-week home indoor air sample, and (iii) concurrent urinary metabolites in a subset (n=193). The category "vinyl or linoleum" flooring was observed in 135 (56%) of monitored rooms; these rooms had statistically significantly higher indoor air geometric mean concentrations of BBzP (23.9 ng/m(3)) than rooms with wood or carpet flooring (10.6 ng/m(3)). Children from homes with "vinyl or linoleum" flooring also had significantly higher urinary BBzP metabolite concentrations than other children. Indoor air BBzP and urinary metabolite concentrations were correlated positively (Spearman's rho 0.40). By contrast, indoor air DEHP was not associated with flooring type nor with its urinary metabolite concentrations. Vinyl flooring in the home may be an important source of children's exposure to BBzP via indoor air.

Alterations of urinary metabolite profile in model diabetic nephropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stec, Donald F.; Wang, Suwan; Stothers, Cody

2015-01-09

Highlights: • {sup 1}H NMR spectroscopy was employed to study urinary metabolite profile in diabetic mouse models. • Mouse urinary metabolome showed major changes that are also found in human diabetic nephropathy. • These models can be new tools to study urinary biomarkers that are relevant to human disease. - Abstract: Countering the diabetes pandemic and consequent complications, such as nephropathy, will require better understanding of disease mechanisms and development of new diagnostic methods. Animal models can be versatile tools in studies of diabetic renal disease when model pathology is relevant to human diabetic nephropathy (DN). Diabetic models using endothelialmore » nitric oxide synthase (eNOS) knock-out mice develop major renal lesions characteristic of human disease. However, it is unknown whether they can also reproduce changes in urinary metabolites found in human DN. We employed Type 1 and Type 2 diabetic mouse models of DN, i.e. STZ-eNOS{sup −/−} C57BLKS and eNOS{sup −/−} C57BLKS db/db, with the goal of determining changes in urinary metabolite profile using proton nuclear magnetic resonance (NMR). Six urinary metabolites with significantly lower levels in diabetic compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle and aromatic amino acid catabolism including 3-indoxyl sulfate, cis-aconitate, 2-oxoisocaproate, N-phenyl-acetylglycine, 4-hydroxyphenyl acetate, and hippurate. Levels of 4-hydroxyphenyl acetic acid and hippuric acid showed the strongest reverse correlation to albumin-to-creatinine ratio (ACR), which is an indicator of renal damage. Importantly, similar changes in urinary hydroxyphenyl acetate and hippurate were previously reported in human renal disease. We demonstrated that STZ-eNOS{sup −/−} C57BLKS and eNOS{sup −/−} C57BLKS db/db mouse models can recapitulate changes in urinary metabolome found in human DN and therefore can be useful new tools in metabolomic studies relevant to human pathology.« less

Effects of high-intensity interval versus mild-intensity endurance training on metabolic phenotype and corticosterone response in rats fed a high-fat or control diet

PubMed Central

Shen, Youqing; Huang, Guoyuan; McCormick, Bryan P.; Song, Tao

2017-01-01

The aim of the present study was to compare the effects of high-intensity interval training (HI) to mild-intensity endurance training (ME), combined with a high-fat diet (HFD) or control diet (CD) on metabolic phenotype and corticosterone levels in rats. Fifty-three rats were randomized to 6 groups according to diet and training regimen as follows: CD and sedentary (CS, n = 11), CD and ME (CME, n = 8), CD and HI (CHI, n = 8), HFD and sedentary (HS, n = 10), HFD and ME (HME, n = 8), and HFD and HI (HHI, n = 8). All exercise groups were trained for 10 weeks and had matched running distances. Dietary intake, body composition, blood metabolites, and corticosterone levels were measured. Histological lipid droplets were observed in the livers. The HFD led to hyperglycemia, hyperlipidemia and higher body fat (all, P < 0.01, η2 > 0.06), as well as higher corticosterone levels (P < 0.01, η2 = 0.09) compared with the CD groups. Exercise training improved fat weight, glucose, and lipid profiles, and reduced corticosterone levels (P < 0.01, η2 = 0.123). Furthermore, body and fat weight, serum glucose and triglycerides, lipid content in the liver, and corticosterone levels (P < 0.05) were lower with HI training compared to ME training. Reductions in HFD-induced body weight gain, blood glucose and lipid profiles, and corticosterone levels, as well as improvements in QUICKI were better with HHI compared to HME. Correlation analyses revealed that corticosterone levels were significantly associated with phenotype variables (P < 0.01). Corticosterone level was inversely correlated with QUICKI (r = −0.38, P < 0.01). Altogether, these results indicate that HFD may elicit an exacerbated basal serum corticosterone level and thus producing a metabolic imbalance. Compared with ME training, HI training contributes to greater improvements in metabolic and corticosterone responses, leading to a greater reduction in susceptibility to HFD-induced disorders. PMID:28727846

Effects of high-intensity interval versus mild-intensity endurance training on metabolic phenotype and corticosterone response in rats fed a high-fat or control diet.

PubMed

Shen, Youqing; Huang, Guoyuan; McCormick, Bryan P; Song, Tao; Xu, Xiangfeng

2017-01-01

The aim of the present study was to compare the effects of high-intensity interval training (HI) to mild-intensity endurance training (ME), combined with a high-fat diet (HFD) or control diet (CD) on metabolic phenotype and corticosterone levels in rats. Fifty-three rats were randomized to 6 groups according to diet and training regimen as follows: CD and sedentary (CS, n = 11), CD and ME (CME, n = 8), CD and HI (CHI, n = 8), HFD and sedentary (HS, n = 10), HFD and ME (HME, n = 8), and HFD and HI (HHI, n = 8). All exercise groups were trained for 10 weeks and had matched running distances. Dietary intake, body composition, blood metabolites, and corticosterone levels were measured. Histological lipid droplets were observed in the livers. The HFD led to hyperglycemia, hyperlipidemia and higher body fat (all, P < 0.01, η2 > 0.06), as well as higher corticosterone levels (P < 0.01, η2 = 0.09) compared with the CD groups. Exercise training improved fat weight, glucose, and lipid profiles, and reduced corticosterone levels (P < 0.01, η2 = 0.123). Furthermore, body and fat weight, serum glucose and triglycerides, lipid content in the liver, and corticosterone levels (P < 0.05) were lower with HI training compared to ME training. Reductions in HFD-induced body weight gain, blood glucose and lipid profiles, and corticosterone levels, as well as improvements in QUICKI were better with HHI compared to HME. Correlation analyses revealed that corticosterone levels were significantly associated with phenotype variables (P < 0.01). Corticosterone level was inversely correlated with QUICKI (r = -0.38, P < 0.01). Altogether, these results indicate that HFD may elicit an exacerbated basal serum corticosterone level and thus producing a metabolic imbalance. Compared with ME training, HI training contributes to greater improvements in metabolic and corticosterone responses, leading to a greater reduction in susceptibility to HFD-induced disorders.

Rat urinary metabolites of [9,10-methylene-14C] sterculic acid.

PubMed

Eisele, T A; Yoss, J K; Nixon, J E; PAwlowski, N E; Libbey, L M; Sinnhuber, R O

1977-07-20

1. The metabolism of [9,10-methylene-14C] sterculic acid was studied in corn oil and Stercula foetida oil fed rats. The majority of the radioactivity was excreted into the urine as short chain dicarboxylic acids. The main urinary metabolites were cis-3,4-methylene adipic acid, cis-3,4-methylene suberic acid, trans-3,4-methylene adipic acid, cis-3,4-methylene pimelic acid, and cis-3,4-methylene azelic acid. 2. Formation of these urinary metabolites requires alpha-, beta-, and omega-oxidation plus reduction of the cyclopropene ring to a cyclopropane ring. Sterculic acid must be transported through both mitochondrial and microsomal systems. 3. Other non-radioactive urinary compounds were also identified. A proposed pathway for the metabolism of sterculic acid and possible detrimental effects caused by these metabolites is discussed.

Urinary phthalate metabolites and their biotransformation products: predictors and temporal variability among men and women

PubMed Central

Meeker, John D.; Calafat, Antonia M.; Hauser, Russ

2012-01-01

Most epidemiology studies investigating potential adverse health effects in relation to phthalates measure the urinary concentration of the free plus glucuronidated species of phthalate metabolites (i.e., total concentration) to estimate exposure. However, the free species may represent the biologically relevant dose. In this study, we collected 943 urine samples from 112 men and 157 women and assessed the between- and within-person variability and predictors of a) the free and total urinary concentrations of phthalate metabolites, and b) the percentage of free phthalate metabolites (a potential phenotypic indicator of individual susceptibility). We also explored the proportion of urinary di-(2-ethylhexyl) phthalate (DEHP) metabolites contributed to by the bioactive mono-2-ethylhexyl phthalate (MEHP), considered a possible indicator of susceptibility to phthalate exposure. The percentage of phthalate metabolites present in the free form were less stable over time than the total metabolite concentration, and, therefore, it is not likely a useful indicator of metabolic susceptibility. Thus, the added costs and effort involved in the measurement of free in addition to total metabolite concentrations in large-scale studies may not be justified. Conversely, the proportion of DEHP metabolites contributed to by MEHP was more stable within individuals over time and may be a promising indicator of susceptibility if time of day of sample collection is carefully considered. PMID:22354176

A flexible Bayesian hierarchical approach for analyzing spatial and temporal variation in the fecal corticosterone levels in birds when there is imperfect knowledge of individual identity.

PubMed

Zimmerman, Guthrie S; Millspaugh, Joshua J; Link, William A; Woods, Rami J; Gutiérrez, R J

2013-12-01

Population cycles have long interested biologists. The ruffed grouse, Bonasa umbellus, is one such species whose populations cycle over most of their range. Thus, much effort has been expended to understand the mechanisms that might control cycles in this and other species. Corticosterone metabolites are widely used in studies of animals to measure physiological stress. We evaluated corticosterone metabolites in feces of territorial male grouse as a potential tool to study mechanisms governing grouse cycles. However, like most studies of corticosterone in wild animals, we did not know the identity of all individuals for which we had fecal samples. This presented an analytical problem that resulted in either pseudoreplication or confounding. Therefore, we derived an analytical approach that accommodated for uncertainty in individual identification. Because we had relatively low success capturing birds, we estimated turnover probabilities of birds on territorial display sites based on capture histories of a limited number of birds we captured. Hence, we developed a study design and modeling approach to quantify variation in corticosterone levels among individuals and through time that would be applicable to any field study of corticosterone in wild animals. Specifically, we wanted a sampling design and model that was flexible enough to partition variation among individuals, spatial units, and years, while incorporating environmental covariates that would represent potential mechanisms. We conducted our study during the decline phase of the grouse cycle and found high variation among corticosterone samples (11.33-443.92 ng/g [x=113.99 ng/g, SD=69.08, median=99.03 ng/g]). However, there were relatively small differences in corticosterone levels among years, but levels declined throughout each breeding season, which was opposite our predictions for stress hormones correlating with a declining population. We partitioned the residual variation into site, bird, and repetition (i.e., multiple samples collected from the same bird on the same day). After accounting for years and three general periods within breeding seasons, 42% of the residual variation among observations was attributable to differences among individual birds. Thus, we attribute little influence of site on stress level of birds in our study, but disentangling individual from site effects is difficult because site and bird are confounded. Our model structures provided analytical approaches for studying species having different ecologies. Our approach also demonstrates that even incomplete information on individual identity of birds within samples is useful for analyzing these types of data. Copyright © 2013 Elsevier Inc. All rights reserved.

Corticosterone metabolite concentrations in greater sage-grouse are positively associated with the presence of cattle grazing

USGS Publications Warehouse

Jankowski, M.D.; Russell, Robin E.; Franson, J. Christian; Dusek, Robert J.; Hines, M.K.; Gregg, M.; Hofmeister, Erik K.

2014-01-01

The sagebrush biome in the western United States is home to the imperiled greater sage-grouse (Centrocercus urophasianus) and encompasses rangelands used for cattle production. Cattle grazing activities have been implicated in the range-wide decline of the sage-grouse, but no studies have investigated the relationship between the physiological condition of sage-grouse and the presence of grazing cattle. We sampled 329 sage-grouse across four sites (two grazed and two ungrazed) encompassing 13 600 km2 during the spring and late summer–early autumn of 2005 to evaluate whether demographic factors, breeding status, plasma protein levels, and residence in a cattle-grazed habitat were associated with the stress hormone corticosterone. Corticosterone was measured in feces as immunoreactive corticosterone metabolites (ICM). Males captured during the lekking season exhibited higher ICM levels than all others. Prenesting female sage-grouse captured in a grazed site had higher ICM levels than those in ungrazed sites and prenesting female plasma protein levels were negatively correlated with ICM concentrations. With the use of a small-scale spatial model, we identified a positive correlation between cattle pat count and sage-grouse ICM levels. Our model indicated that ICM levels increased by 2.60 ng · g-1 dry feces for every increase in the number of cow pats found in the vicinity. Management practices will benefit from future research regarding the consistency and mechanism(s) responsible for this association and, importantly, how ICM levels and demographic rates are related in this species of conservation concern.

Urinary Concentrations of Polycyclic Aromatic Hydrocarbon Metabolites in Maté Drinkers in Rio Grande do Sul, Brazil

PubMed Central

Lopes, Antonio Barros; Metzdorf, Marcela; Metzdorf, Luiza; Ramalho, Marcos Paulo; Kavalco, Caroline; Etemadi, Arash; Pritchett, Natalie R.; Murphy, Gwen; Calafat, Antonia M.; Abnet, Christian C.; Dawsey, Sanford M.; Fagundes, Renato Borges

2017-01-01

Background Consumption of maté, an infusion of the herb Ilex paraguariensis (yerba maté), is associated with increased risk of esophageal squamous cell carcinoma (ESCC), but the carcinogenic mechanism is unclear. Commercial brands of yerba maté contain high levels of carcinogenic polycyclic aromatic hydrocarbons (PAHs), which are acquired during the traditional drying process. The purpose of this study was to characterize exposure to PAHs in maté drinkers over a wide range of maté consumption. Methods We recruited 244 adults who answered a questionnaire and collected a fasting spot urine specimen. We quantified urinary concentrations of seven PAH metabolites, and assessed associations between self-reported recent maté consumption and urinary PAH metabolites by multivariate regression. Results Recent maté consumption showed a significant dose-response association with 6 of 7 PAH metabolites in unadjusted models (p-for-trend <0.05). After adjustment for creatinine and potential confounders, concentrations of 2-naphthol, 1-hydroxyphenanthrene, and the sum of 2- and 3-hydroxyphenanthrene remained significantly associated with recent maté intake. The sum of the urinary concentrations of the phenanthrene metabolites was similar or higher among maté drinkers who did not smoke than among smokers who did not drink maté. Conclusions Urinary concentrations of PAH metabolites were significantly associated with self-reported amount of recent maté intake, and drinking maté increased urinary concentrations of some PAH metabolites as much as smoking cigarettes. Impact Drinking maté is a source of exposure to potentially carcinogenic PAHs, consistent with the hypothesis that the PAH content of maté may contribute to the increased risk of ESCC in maté drinkers. PMID:29263183

Urinary Concentrations of Polycyclic Aromatic Hydrocarbon Metabolites in Maté Drinkers in Rio Grande do Sul, Brazil.

PubMed

Lopes, Antonio Barros; Metzdorf, Marcela; Metzdorf, Luiza; Sousa, Marcos Paulo Ramalho; Kavalco, Caroline; Etemadi, Arash; Pritchett, Natalie R; Murphy, Gwen; Calafat, Antonia M; Abnet, Christian C; Dawsey, Sanford M; Fagundes, Renato Borges

2018-03-01

Background: Consumption of maté , an infusion of the herb Ilex paraguariensis (yerba maté) , is associated with increased risk of esophageal squamous cell carcinoma (ESCC), but the carcinogenic mechanism is unclear. Commercial brands of yerba maté contain high levels of carcinogenic polycyclic aromatic hydrocarbons (PAHs), which are acquired during the traditional drying process. The purpose of this study was to characterize exposure to PAHs in maté drinkers over a wide range of maté consumption. Methods: We recruited 244 adults who answered a questionnaire and collected a fasting spot urine specimen. We quantified urinary concentrations of seven PAH metabolites and assessed associations between self-reported recent maté consumption and urinary PAH metabolites by multivariate regression. Results: Recent maté consumption showed a significant dose-response association with 6 of 7 PAH metabolites in unadjusted models ( P trend < 0.05). After adjustment for creatinine and potential confounders, concentrations of 2-naphthol, 1-hydroxyphenanthrene, and the sum of 2- and 3-hydroxyphenanthrene remained significantly associated with recent maté intake. The sum of the urinary concentrations of the phenanthrene metabolites was similar or higher among maté drinkers who did not smoke than among smokers who did not drink maté Conclusions: Urinary concentrations of PAH metabolites were significantly associated with self-reported amounts of recent maté intake, and drinking maté increased urinary concentrations of some PAH metabolites as much as smoking cigarettes. Impact: Drinking maté is a source of exposure to potentially carcinogenic PAHs, consistent with the hypothesis that the PAH content of maté may contribute to the increased risk of ESCC in maté drinkers. Cancer Epidemiol Biomarkers Prev; 27(3); 331-7. ©2017 AACR . ©2017 American Association for Cancer Research.

Urinary Estrogen Metabolites, Active and Sedentary Behaviors, and Breast Cancer Risk

Cancer.gov

A cross-sectional study of approximately 600 postmenopausal controls in the Breast Cancer Case-Control Study in Poland to assess urinary estrogen metabolites in relation to accelerometer-based measures of active and sedentary behaviors

Association of atmospheric concentrations of polycyclic aromatic hydrocarbons with their urinary metabolites in children and adolescents.

PubMed

Poursafa, Parinaz; Amin, Mohammad Mehdi; Hajizadeh, Yaghoub; Mansourian, Marjan; Pourzamani, Hamidreza; Ebrahim, Karim; Sadeghian, Babak; Kelishadi, Roya

2017-07-01

This study aims to determine the atmospheric concentrations of particulate matter 2.5 (PM 2.5 )-bounded polycyclic aromatic hydrocarbons (PAHs) and their association with their urinary metabolites in children and adolescents. This study was conducted from October 2014 to March 2016 in Isfahan, Iran. We measured 16 species of PAHs bounded to PM 2.5 by gas chromatography mass spectrometry (GC/MS) from 7 parts of the city. Moreover, PAH urinary metabolites were measured in 186 children and adolescents, randomly selected from households. Urinary metabolites consisted of 1-hydroxy naphthalene (1-naphthol), 2-hydroxy naphthalene (2-naphthol), 9-hydroxy phenanthrene (9-phenanthrol), and 1-hydroxy pyrene using GC/MS. Considering the short half-lives of PAHs, we measured the metabolites twice with 4 to 6 months of time interval. We found that the ambient concentrations of PAHs were significantly associated with their urinary metabolites. 1-hydroxy naphthalene and 2-hydroxy naphthalene concentrations showed an increase of 1.049 (95% CI: 1.030, 1.069) and 1.047 (95% CI: 1.025, 1.066) for each unit increase (1 ng/m 3 ) in ambient naphthalene. Similarly, 1-hydroxy pyrene showed an increase of 1.009 (95% CI: 1.006-1.011) for each unit increase (1 ng/m 3 ) in ambient pyrene concentration after adjustment for body mass index, physical activity level, urinary creatinine, age, and sex. The association of urinary 9-hydroxyphenanthrene and ambient phenantherene was significant in the crude model; however after adjustment for the abovementioned covariates, it was no more significant. We found significant correlations between exposure to ambient PM 2.5 -bounded PAHs and their urinary excretion. Considering the adverse health effects of PAHs in the pediatric age group, biomonitoring of PAHs should be underscored; preventive measures need to be intensified.

Associations of urinary 5-methyl-2'-deoxycytidine and 5-hydroxymethyl-2'-deoxycytidine with phthalate exposure and semen quality in 562 Chinese adult men.

PubMed

Pan, Yitao; Jing, Jun; Yeung, Leo W Y; Sheng, Nan; Zhang, Hongxia; Yao, Bing; Dai, Jiayin

2016-09-01

5-methyl-2'-deoxycytidine (5mdC) and 5-hydroxymethyl-2'-deoxycytidine (5hmdC), products of DNA methylation and hydroxymethylation processes, have been detected previously in human urine, but their associations with environmental chemicals or healthy outcomes are unclear. The present investigation explored the associations between urinary 5mdC and 5hmdC with phthalate exposure and semen quality. We assessed semen parameters including sperm concentration, motility, and morphology, before measuring urinary 5mdC, 5hmdC and 13 phthalate metabolites among 562 subfertile men from Nanjing, China. Urinary 5mdC and 5hmdC were positively associated with the levels of low molecular weight phthalate metabolites (Low-MWP), high molecular weight phthalate metabolites (High-MWP), and the sum of all phthalate metabolites (ΣPAEs), respectively. Urinary 5mdC was associated with below-reference sperm concentration (odds ratios for increasing quartiles=1.0, 2.2, 3.0, 2.0; p for trend =0.02), sperm motility (1.0, 1.1, 1.9, 1.3; p for trend =0.05), and sperm morphology (1.0, 1.4, 2.3, 1.5; p for trend =0.05). Sperm concentration was associated with the highest quartile of urinary 5hmdC [odds ratio=1.9 (95% CI: 1.1, 3.6)]. Our findings showed significant associations between urinary 5mdC and 5hmdC with phthalate metabolites and semen parameters, which suggested urinary 5mdC and 5hmdC may be promising biomarkers in future epidemiological studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

MODELING OF MACROSCALE AGRICULTURAL ELEMENTS IN PESTICIDE EXPOSURE

EPA Science Inventory

Yuma County, Arizona, is the site of year around agriculture. To understand the role of agricultural pesticide exposures experienced by children, urinary metabolite concentrations were compared with agricultural use of pesticides. The urinary metabolite and household data wer...

[Use of antagonistic Bacillus subtilis bacteria for treatment of nosocomial urinary tract infections].

PubMed

Pushkarev, A M; Tuĭgunova, V G; Zaĭnullin, R R; Kuznetsova, T N; Gabidullin, Iu Z

2007-01-01

Effect of Bactisporin--a probiotic, containing spores of aerobic Bacillus subtilis 3H bacterium--for complex treatment of patients with nosocomial urinary tract infections was studied. 68 Cultures of different species of conditionally pathogenic bacteria were isolated from urine of the patients. Susceptibility of the isolated cultures to antibiotics before and after application of B. subtilis 3H metabolites was determined. The metabolites were accumulated on potato-glucose agar (PGA) while bacterium was cultivated on kapron membranes placed on surface of the medium. Influence of obtained metabolites on isolated strains was assessed by cultivation of each strain in metabolites-rich PGA during 24 h. Metabolites of B. subtilis led to decrease in resistance of isolated uropathogenic microflora to antibiotics. Use of Bactisporin in complex treatment of nosocomial urinary tract infections resulted in accelerated elimination of causative microorganism.

The effect of purified compared with nonpurified diet on bone changes induced by hindlimb suspension of female rats

NASA Technical Reports Server (NTRS)

Tou, Janet C L.; Arnaud, Sara B.; Grindeland, Richard; Wade, Charles

2005-01-01

The purpose of this study was to compare the bone changes induced by unloading in rats fed different diets, because space flight studies use a semipurified diet, whereas space flight simulation studies typically use nonpurified diets. Female Sprague-Dawley rats were fed a purified American Institute of Nutrition (AIN) 93G diet or a standard nonpurified diet and kept ambulatory or subjected to unloading by hindlimb suspension (HLS) for 38 days. Bone mineral content (BMC), mechanical strength, and factors related to the diet that affect bone (i.e., urinary calcium excretion, estradiol, and corticosterone) were measured. Average food intakes (grams per day) differed for diets, but caloric intake (kilocalories per day) and the final body masses of treatment groups were similar. The HLS-induced decrease in femoral BMC was not statistically different for rats fed a nonpurified diet (-8.6%) compared with a purified AIN-93G diet (-11.4%). The HLS-induced decrease in femoral mechanical strength was not statistically different for rats fed a nonpurified diet (-24%) compared with a purified AIN-93G diet (-31%). However, bone lengths were decreased (P < 0.05) in rats fed a nonpurified diet compared with a purified diet. Plasma estradiol levels were lower (P < 0.05) in the HLS/AIN-93G group but similar in the HLS and ambulatory rats fed a nonpurified diet. Plasma estradiol was related to femoral BMC (r = 0.85, P < 0.01). Urinary calcium excretion was higher (P < 0.05) in rats fed a nonpurified diet than those fed a purified AIN-93G diet, which is consistent with the higher level of calcium in the nonpurified diet. Urinary corticosterone levels were higher (P < 0.05) in rats fed a nonpurified diet than rats fed the AIN-93G diet. Although the osteopenia induced by unloading was similar in both diet groups, there were differences in longitudinal bone growth, calcium excretion, plasma estradiol levels, and urinary corticosterone levels. Results indicate that the type of standard diet used is an important factor to consider when measuring bone end points.

Paternal urinary concentrations of organophosphate flame retardant metabolites, fertility measures, and pregnancy outcomes among couples undergoing in vitro fertilization.

PubMed

Carignan, Courtney C; Mínguez-Alarcón, Lidia; Williams, Paige L; Meeker, John D; Stapleton, Heather M; Butt, Craig M; Toth, Thomas L; Ford, Jennifer B; Hauser, Russ

2018-02-01

Use of organophosphate flame retardants (PFRs) has increased over the past decade following the phase out of some brominated flame retardants, leading to increased human exposure. We recently reported that increasing maternal PFR exposure is associated with poorer pregnancy outcomes among women from a fertility clinic. Because a small epidemiologic study previously reported an inverse association between male PFR exposures and sperm motility, we sought to examine associations of paternal urinary concentrations of PFR metabolites and their partner's pregnancy outcomes. This analysis included 201 couples enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. In both the male and female partner, we measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). The sum of the molar concentrations of the urinary PFR metabolites was calculated. We used multivariable generalized linear mixed models to evaluate the association of urinary concentrations of paternal PFR metabolites with IVF outcomes, accounting for multiple in vitro fertilization (IVF) cycles per couple. Models were adjusted for year of IVF treatment cycle, primary infertility diagnosis, and maternal urinary PFR metabolites as well as paternal and maternal age, body mass index, and race/ethnicity. Detection rates were high for paternal urinary concentrations of BDCIPP (84%), DPHP (87%) and ip-PPP (76%) but low for tb-PPP (12%) and zero for BCIPP (0%). We observed a significant 12% decline in the proportion of fertilized oocytes from the first to second quartile of male urinary ΣPFR and a 47% decline in the number of best quality embryos from the first to third quartile of male urinary BDCIPP in our adjusted models. An 8% decline in fertilization was observed for the highest compared to lowest quartile of urinary BDCIPP concentrations (95% CI: 0.01, 0.12, p-trend=0.06). Using IVF as a model to investigate human reproduction and pregnancy outcomes, we found that paternal urinary concentrations of BDCIPP were associated with reduced fertilization. In contrast to previously reported findings for the female partners, the paternal urinary PFR metabolites were not associated with the proportion of cycles resulting in successful implantation, clinical pregnancy, and live birth. These results indicate that paternal preconception exposure to TDCIPP may adversely impact successful oocyte fertilization, whereas female preconception exposure to ΣPFRs may be more relevant to adverse pregnancy outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Monitoring of drugs and metabolites in body fluids by capillary electrophoresis with XeHg lamp-based and laser-induced fluorescence detection.

PubMed

Caslavska, Jitka; Thormann, Wolfgang

2004-06-01

Commercial capillary electrophoresis instrumentation with XeHg lamp-based and laser induced fluorescence (LIF) detection is employed for analysis of urinary 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its major metabolites, urinary metabolites of acetylsalicylic acid, urinary benzoylecgonine in an immunoassay format, and albendazole sulfoxide and albendazole sulfone in plasma. For the examples studied, the data suggest that the lamp-based detector can be employed for the monitoring of pharmacological and toxicological relevant solute concentrations, and thus represents an attractive alternative to LIF detection.

A capillary electrophoresis coupled to mass spectrometry pipeline for long term comparable assessment of the urinary metabolome.

PubMed

Boizard, Franck; Brunchault, Valérie; Moulos, Panagiotis; Breuil, Benjamin; Klein, Julie; Lounis, Nadia; Caubet, Cécile; Tellier, Stéphanie; Bascands, Jean-Loup; Decramer, Stéphane; Schanstra, Joost P; Buffin-Meyer, Bénédicte

2016-10-03

Although capillary electrophoresis coupled to mass spectrometry (CE-MS) has potential application in the field of metabolite profiling, very few studies actually used CE-MS to identify clinically useful body fluid metabolites. Here we present an optimized CE-MS setup and analysis pipeline to reproducibly explore the metabolite content of urine. We show that the use of a beveled tip capillary improves the sensitivity of detection over a flat tip. We also present a novel normalization procedure based on the use of endogenous stable urinary metabolites identified in the combined metabolome of 75 different urine samples from healthy and diseased individuals. This method allows a highly reproducible comparison of the same sample analyzed nearly 130 times over a range of 4 years. To demonstrate the use of this pipeline in clinical research we compared the urinary metabolome of 34 newborns with ureteropelvic junction (UPJ) obstruction and 15 healthy newborns. We identified 32 features with differential urinary abundance. Combination of the 32 compounds in a SVM classifier predicted with 76% sensitivity and 86% specificity UPJ obstruction in a separate validation cohort of 24 individuals. Thus, this study demonstrates the feasibility to use CE-MS as a tool for the identification of clinically relevant urinary metabolites.

[Analysis of laboratory data of 155 patients with pheochromocytoma-paraganglioma syndrome diagnosed during the past 20 years].

PubMed

Balog, Beatrice; Tőke, Judit; Róna, Kálmán; Szücs, Nikolette; Igaz, Péter; Pusztai, Péter; Sármán, Beatrix; Gláz, Edit; Kiss, Róbert; Patócs, Attila; Rácz, Károly; Tóth, Miklós

2015-04-19

Laboratory diagnosis of pheochromocytoma-paraganglioma syndrome has been markedly improved during the past two decades. Retrospective assessment of diagnostic utility of urinary catecholamines and their metabolites as well as serum chromogranin A in 155 patients diagnosed at the 2nd Department of Medicine, Semmelweis University. Urinary catecholamines and metabolites were measured using high-performance liquid chromatography with electrochemical detection in 155 patients with pheochromocytoma-paraganglioma (of whom 28.4% had hereditary background) and in 170 non-pheochromocytoma patients used as controls. Serum chromogranin A was measured by immunoradiometry. Sensitivity (93.2%) and specificity (87.0%) of urinary fractionated metanephrines were higher than those of urinary catecholamines (90.9% vs. 85.7%, respectively) and serum chromogranin A (88.7% and 77.5%, respectively). Urinary normetanephrine and serum chromogranin A correlated positively with tumor size (r = 0.552, p<0.0001 and r = 0.618, p<0.0001, respectively). These data confirm the diagnostic utility of urinary catecholamines and their metabolites. Urinary normetanephrine and serum chromogranin A may help to estimate tumour mass and probably tumour progression.

Changes in Urinary Phthalate Metabolite Levels Before and After the Phthalate Contamination Event and Identification of Exposure Sources in a Cohort of Taiwanese Children.

PubMed

Huang, Chian-Feng; Wang, I-Jen

2017-08-19

In 2011, the Taiwan Food and Drug Administration inadvertently discovered that, for decades, manufacturers had replaced expensive natural emulsifiers in food products with diethylhexyl phthalate (DEHP). We wanted to compare urinary phthalate metabolite levels of children before and after the DEHP food contamination event and identify source(s) of phthalate exposure in addition to the illegal food additives. In the present study, morning urine samples were collected from a cohort of 453 children in 2010 in Taipei. After the DEHP food contamination event, there were 200 cohort children left at follow-up in 2013. The geometric means (GMs) of urinary mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP) levels before and after the event were 9.39 and 13.34 µg/g of creatinine, respectively, with no significant difference ( p = 0.093). After the DEHP food contamination event, we found that urinary phthalate metabolite levels were significantly higher in people who frequently consumed microwave-heated food and used fragrance-containing products ( p < 0.05). In addition, children who did not frequently wash hands before eating had significantly higher urinary phthalate metabolite levels than those who did ( p < 0.05). These results demonstrate that urinary phthalate metabolite levels did not decrease after the DEHP food contamination event, thus, other sources must contribute to phthalate exposure in daily life. Public awareness of approaches to reducing phthalate exposure is necessary.

Effects of invasion history on physiological responses to immune system activation in invasive Australian cane toads

PubMed Central

West, Andrea J.; Brown, Gregory P.; Fanson, Kerry V.; Addison, BriAnne; Rollins, Lee A.; Shine, Richard

2017-01-01

The cane toad (Rhinella marina) has undergone rapid evolution during its invasion of tropical Australia. Toads from invasion front populations (in Western Australia) have been reported to exhibit a stronger baseline phagocytic immune response than do conspecifics from range core populations (in Queensland). To explore this difference, we injected wild-caught toads from both areas with the experimental antigen lipopolysaccharide (LPS, to mimic bacterial infection) and measured whole-blood phagocytosis. Because the hypothalamic-pituitary-adrenal axis is stimulated by infection (and may influence immune responses), we measured glucocorticoid response through urinary corticosterone levels. Relative to injection of a control (phosphate-buffered saline), LPS injection increased both phagocytosis and the proportion of neutrophils in the blood. However, responses were similar in toads from both populations. This null result may reflect the ubiquity of bacterial risks across the toad’s invaded range; utilization of this immune pathway may not have altered during the process of invasion. LPS injection also induced a reduction in urinary corticosterone levels, perhaps as a result of chronic stress. PMID:29018604

Metabonomics Approach to Assessing the Metabolism Variation and Endoexogenous Metabolic Interaction of Ginsenosides in Cold Stress Rats.

PubMed

Zhang, Zhihao; Wang, Xiaoyan; Wang, Jingcheng; Jia, Zhiying; Liu, Yumin; Xie, Xie; Wang, Chongchong; Jia, Wei

2016-06-03

Metabolic profiling technology, a massive information provider, has promoted the understanding of the metabolism of multicomponent medicines and its interactions with endogenous metabolites, which was previously a challenge in clarification. In this study, an untargeted GC/MS-based approach was employed to investigate the urinary metabolite profile in rats with oral administration of ginsenosides and the control group. Significant changes of urinary metabolites contents were observed in the total ginsenosides group, revealing the impact of ginsenosides as indicated by the up- or down-regulation of several pathways involving neurotransmitter-related metabolites, tricarboxylic acid (TCA) cycle, fatty acids β-oxidation, and intestinal microflora metabolites. Meanwhile, a targeted UPLC-QQQ/MS-based metabonomic approach was developed to investigate the changes of urinary ginsenoside metabolites during the process of acute cold stress. Metabolic analysis indicated that upstream ginsenosides (rg1, re, and rf) increased significantly, whereas downstream ginsenosides (ck, ppd, and ppt) decreased correspondingly after cold exposure. Finally, the relationships between ginsenosides and significantly changed metabolites were investigated by correlation analysis.

NON-RESIDENTIAL ORGANOPHOSPHOROUS PESTICIDE USE AS A PREDICTOR OF CHILDREN'S URINARY METABOLITE LEVELS

EPA Science Inventory

NON-RESIDENTIAL ORGANOPHOSPHORUS PESTICIDE USE AS A PREDICTOR OF CHILDREN'S URINARY METABOLITE LEVELS.
Julie A. Baker, Pauline Mendola, Dana Barr, Debra Walsh, John Creason, and Larry Needham. (University at Buffalo, US Environmental Protection Agency, and Centers for Disease ...

Phthalate metabolites in Norwegian mothers and children: Levels, diurnal variation and use of personal care products.

PubMed

Sakhi, Amrit Kaur; Sabaredzovic, Azemira; Cequier, Enrique; Thomsen, Cathrine

2017-12-01

Exposure to phthalates has been associated with reproductive and developmental toxicity. Data on levels of these compounds in the Norwegian population is limited. In this study, urine samples were collected from 48 mothers and their children in two counties in Norway. Eleven different phthalate metabolites originating from six commonly used phthalates in consumer products were determined. Concentrations of phthalate metabolites were significantly higher in children compared to mothers except for mono-ethyl phthalate (MEP). The mothers provided several urine samples during 24hours (h) and diurnal variation showed that the concentrations in the morning urine samples (24-8h) were significantly higher than at other time-periods for most of the phthalate metabolites. Intraclass correlation coefficients (ICCs) for 24-hour time-period were in the range of 0.49-0.81. These moderate to high ICCs indicate that one spot urine sample can be used to estimate the exposure to phthalates. Since a significant effect of time of day was observed, it is still advisable to standardize the collection time point to reduce the variation. For the mothers, the use of personal care products (PCPs) were less associated with morning urine samples than early day (8-12h) and evening (16-24h) urine samples. The use of perfume and hair products were positively associated with the urinary concentrations of low molecular weight phthalates. Use of shower soap and shampoo were positively associated with urinary concentration of di(2-ethylhexyl) phthalate (DEHP) metabolites. For children, face cream use was positively associated with phthalate metabolites in the morning samples, and hand soap use was negatively associated with concentration of urinary DEHP metabolites in afternoon/evening samples. Since different PCPs were associated with the urinary phthalate metabolites in different time-periods during a day, more than one spot urine sample might be required to study associations between urinary phthalate metabolites and the use of PCPs. Copyright © 2017 Elsevier B.V. All rights reserved.

Hormonal modulation of food intake in response to low leptin levels induced by hypergravity

NASA Technical Reports Server (NTRS)

Moran, M. M.; Stein, T. P.; Wade, C. E.

2001-01-01

A loss in fat mass is a common response to centrifugation and it results in low circulating leptin concentrations. However, rats adapted to hypergravity are euphagic. The focus of this study was to examine leptin and other peripheral signals of energy balance in the presence of a hypergravity-induced loss of fat mass and euphagia. Male Sprague-Dawley rats were centrifuged for 14 days at gravity levels of 1.25, 1.5, or 2 G, or they remained stationary at 1 G. Urinary catecholamines, urinary corticosterone, food intake, and body mass were measured on Days 11 to 14. Plasma hormones and epididymal fat pad mass were measured on Day 14. Mean body mass of the 1.25, 1.5, and 2 G groups were significantly (P < 0.05) lower than controls, and no differences were found in food intake (g/day/100 g body mass) between the hypergravity groups and controls. Epididymal fat mass was 14%, 14%, and 21% lower than controls in the 1.25, 1.5, and 2.0 G groups, respectively. Plasma leptin was significantly reduced from controls by 46%, 45%, and 65% in the 1.25, 1.5, and 2 G groups, respectively. Plasma insulin was significantly lower in the 1.25, 1.5, and 2.0 G groups than controls by 35%, 38%, and 33%. No differences were found between controls and hypergravity groups in urinary corticosterone. Mean urinary epinephrine was significantly higher in the 1.5 and 2.0 G groups than in controls. Mean urinary norepinephrine was significantly higher in the 1.25, 1.5 and 2.0 G groups than in controls. Significant correlations were found between G load and body mass, fat mass, leptin, urinary epinephrine, and norepinephrine. During hypergravity exposure, maintenance of food intake is the result of a complex relationship between multiple pathways, which abates the importance of leptin as a primary signal.

Stereoselectivity of the arene epoxide pathway of mephenytoin hydroxylation in man.

PubMed

Küpfer, A; Lawson, J; Branch, R A

1984-02-01

Stereoselective metabolism of mephenytoin has been investigated in four normal subjects by comparing urinary recoveries of hydroxylated metabolites after administration of racemic RS-mephenytoin (1.4 mmol/day) and R-mephenytoin (0.7 mmol/day) on separate occasions. Gas chromatography-mass spectrometry was employed to measure the urinary recovery of 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin (4-OH-M) and mephenytoin catechol, methylcatechol, and dihydrodiol metabolites. Following a single oral dose of racemic mephenytoin, 4-OH-M, mephenytoin catechol, and methylcatechol metabolites were identified in urine mainly as conjugates, whereas the dihydrodiol metabolite was recovered mainly in its unconjugated form. Urinary elimination of each metabolite was similar on days 1 and 10 of chronic racemic mephenytoin administration. Following R-mephenytoin administration, urinary recoveries of hydroxylated metabolites were five to 10 times smaller than after administration of the racemic drug. This implies substrate-stereoselective hydroxylation of the S-enantiomer of mephenytoin. In one subject with a genetic deficiency of aromatic mephenytoin hydroxylation deficiency, the excretion of each hydroxylated mephenytoin metabolite after RS-mephenytoin administration was decreased to 5-15% of the values found in the four extensively hydroxylating study volunteers. The impaired formation of hydroxylated mephenytoin metabolites in genetic hydroxylation deficiency, in conjunction with stereoselective hydroxylation of S-mephenytoin via an extensive NIH shift in normal man, is consistent with the hypothesis that the formation of the S-mephenytoin arene oxide is under genetic control and represents the initial enzymatic reaction of stereoselective aromatic mephenytoin hydroxylation. The formation of this potentially reactive metabolite of S-mephenytoin may have implications in mephenytoin-induced toxicity.

Major urinary metabolites of 6-keto-prostaglandin F2α in mice[S

PubMed Central

Kuklev, Dmitry V.; Hankin, Joseph A.; Uhlson, Charis L.; Hong, Yu H.; Murphy, Robert C.; Smith, William L.

2013-01-01

Western diets are enriched in omega-6 vs. omega-3 fatty acids, and a shift in this balance toward omega-3 fatty acids may have health benefits. There is limited information about the catabolism of 3-series prostaglandins (PG) formed from eicosapentaenoic acid (EPA), a fish oil omega-3 fatty acid that becomes elevated in tissues following fish oil consumption. Quantification of appropriate urinary 3-series PG metabolites could be used for noninvasive measurement of omega-3 fatty acid tone. Here we describe the preparation of tritium- and deuterium-labeled 6-keto-PGF2α and their use in identifying urinary metabolites in mice using LC-MS/MS. The major 6-keto-PGF2α urinary metabolites included dinor-6-keto-PGF2α (∼10%) and dinor-13,14-dihydro-6,15-diketo-PGF1α (∼10%). These metabolites can arise only from the enzymatic conversion of EPA to the 3-series PGH endoperoxide by cyclooxygenases, then PGI3 by prostacyclin synthase and, finally, nonenzymatic hydrolysis to 6-keto-PGF2α. The 6-keto-PGF derivatives are not formed by free radical mechanisms that generate isoprostanes, and thus, these metabolites provide an unbiased marker for utilization of EPA by cyclooxygenases. PMID:23644380

Concentrations of Phthalate Metabolites in Milk, Urine, Saliva, and Serum of Lactating North Carolina Women

PubMed Central

Hines, Erin P.; Calafat, Antonia M.; Silva, Manori J.; Mendola, Pauline; Fenton, Suzanne E.

2009-01-01

Background Phthalates are ubiquitous in the environment, but concentrations in multiple media from breast-feeding U.S. women have not been evaluated. Objectives The objective of this study was to accurately measure and compare the concentrations of oxidative monoester phthalate metabolites in milk and surrogate fluids (serum, saliva, and urine) of 33 lactating North Carolina women. Methods We analyzed serum, saliva, urine, and milk for the oxidative phthalate metabolites mono(3-carboxypropyl) phthalate, mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate using isotope-dilution high-performance liquid chromatography tandem mass spectroscopy. Because only urine lacks esterases, we analyzed it for the hydrolytic phthalate monoesters. Results We detected phthalate metabolites in few milk (< 10%) and saliva samples. MECPP was detected in > 80% of serum samples, but other metabolites were less common (3–22%). Seven of the 10 urinary metabolites were detectable in ≥ 85% of samples. Monoethyl phthalate had the highest mean concentration in urine. Metabolite concentrations differed by body fluid (urine > serum > milk and saliva). Questionnaire data suggest that frequent nail polish use, immunoglobulin A, and fasting serum glucose and triglyceride levels were increased among women with higher concentrations of urinary and/or serum phthalate metabolites; motor vehicle age was inversely correlated with certain urinary phthalate concentrations. Conclusions Our data suggest that phthalate metabolites are most frequently detected in urine of lactating women and are less often detected in serum, milk, or saliva. Urinary phthalate concentrations reflect maternal exposure and do not represent the concentrations of oxidative metabolites in other body fluids, especially milk. PMID:19165392

Personal care product use and urinary levels of phthalate metabolites in Mexican women.

PubMed

Romero-Franco, Michelle; Hernández-Ramírez, Raúl U; Calafat, Antonia M; Cebrián, Mariano E; Needham, Larry L; Teitelbaum, Susan; Wolff, Mary S; López-Carrillo, Lizbeth

2011-07-01

Sources of phthalates other than Polyvinyl chloride (PVC) related products are scarcely documented in Mexico. The objective of our study was to explore the association between urinary levels of nine phthalate metabolites and the use of personal care products. Subjects included 108 women who participated as controls in an ongoing population-based case-control study of environmental factors and genetic susceptibility to breast cancer in northern Mexico. Direct interviews were performed to inquire about sociodemographic characteristics, reproductive history, use of personal care products, and diet. Phthalate metabolites measured in urine by high performance liquid chromatography-isotope dilution tandem mass spectrometry were monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-3-carboxypropyl phthalate (MCPP) as well as mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP) that are metabolites of di-ethylhexyl phthalate (DEHP). Detectable urinary concentrations of phthalate metabolites varied from 75% (MEHP) to 100% (MEP, MBP, MEOHP, MEHHP and MECPP). Medians of urinary concentrations of some phthalate metabolites were significantly higher among users of the following personal care products compared to nonusers: body lotion (MEHHP, MECPP and sum of DEHP metabolites (ΣDEHP)), deodorant (MEHP and ΣDEHP), perfume (MiBP), anti-aging facial cream (MEP, MBP and MCPP) and bottled water (MCPP, MEHHP and MEOHP). Urinary concentrations of MEP showed a positive relationship with the number of personal care products used. Our results suggest that the use of some personal care products contributes to phthalate body burden that deserves attention due to its potential health impact. Copyright © 2011 Elsevier Ltd. All rights reserved.

Body Mass Changes Associated With Hyper-Gravity are Independent of Adrenal Derived Hormones

NASA Technical Reports Server (NTRS)

Wade, Charles E.; Moran, Megan M.; Wang, Tommy J.; Baer, Lisa A.; Yuan, Fang; Fung, Cyra K.; Stein, T. Peter; Dalton, Bonnie P. (Technical Monitor)

2001-01-01

Exposure to hyper-gravity results in a number of metabolic changes associated with increases in catecholamines and corticosterone. These changes result in a loss of body and fat mass. To assess the role of hormones derived from the adrenal gland in the changes we studied sham operated (SO) and adrenalectomized (ADX) male rats exposed to hyper-gravity of 2 G for 14 days. Control groups at 1 G were also studied. Urinary epinephrine (EPI) and corticosterone (CORT) were reduced in ADX animals. In response to 2 G there was an increase in urinary EPI and CORT in SO rats, while levels were unchanged in ADX animals. Both groups of animals had similar increases in urinary norepinephrine levels. The reductions of body mass gain in response to 2 G were the same in both groups. The decrease in relative fat mass was greater in ADX. Energy intake and expenditure were not different between groups. In response of returning to 1 G for 24 hours and reexposure to hyper-gravity there were no differences between SO and ADX in the changes of food and water intake, body mass or activity. The changes in metabolism with exposure to hyper-gravity do not appear to require hormones derived from the adrenal gland. The increase in lypolysis and alterations body and fat mass appear to be modulated by sympathetically derived norepinehrine.

Review of Pesticide Urinary Biomarker Measurements from Selected US EPA Children’s Observational Exposure Studies

PubMed Central

Egeghy, Peter P.; Cohen Hubal, Elaine A.; Tulve, Nicolle S.; Melnyk, Lisa J.; Morgan, Marsha K.; Fortmann, Roy C.; Sheldon, Linda S.

2011-01-01

Children are exposed to a wide variety of pesticides originating from both outdoor and indoor sources. Several studies were conducted or funded by the EPA over the past decade to investigate children’s exposure to organophosphate and pyrethroid pesticides and the factors that impact their exposures. Urinary metabolite concentration measurements from these studies are consolidated here to identify trends, spatial and temporal patterns, and areas where further research is required. Namely, concentrations of the metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol or TCPy), diazinon (2-isopropyl-6-methyl-4-pyrimidinol or IMP), and permethrin (3-phenoxybenzoic acid or 3-PBA) are presented. Information on the kinetic parameters describing absorption and elimination in humans is also presented to aid in interpretation. Metabolite concentrations varied more dramatically across studies for 3-PBA and IMP than for TCPy, with TCPy concentrations about an order of magnitude higher than the 3-PBA concentrations. Temporal variability was high for all metabolites with urinary 3-PBA concentrations slightly more consistent over time than the TCPy concentrations. Urinary biomarker levels provided only limited evidence of applications. The observed relationships between urinary metabolite levels and estimates of pesticide intake may be affected by differences in the contribution of each exposure route to total intake, which may vary with exposure intensity and across individuals. PMID:21655147

Urinary water-soluble vitamins and their metabolite contents as nutritional markers for evaluating vitamin intakes in young Japanese women.

PubMed

Fukuwatari, Tsutomu; Shibata, Katsumi

2008-06-01

Little information is available to estimate water-soluble vitamin intakes from urinary vitamins and their metabolite contents as possible nutritional markers. Determination of the relationships between the oral dose and urinary excretion of water-soluble vitamins in human subjects contributes to finding valid nutrition markers of water-soluble vitamin intakes. Six female Japanese college students were given a standard Japanese diet in the first week, the same diet with a synthesized water-soluble vitamin mixture as a diet with approximately onefold vitamin mixture based on Dietary Reference Intakes (DRIs) for Japanese in the second week, with a threefold vitamin mixture in the third week, and a sixfold mixture in the fourth week. Water-soluble vitamins and their metabolites were measured in the 24-h urine collected each week. All urinary vitamins and their metabolite levels except vitamin B(12) increased linearly in a dose-dependent manner, and highly correlated with vitamin intake (r=0.959 for vitamin B(1), r=0.927 for vitamin B(2), r=0.965 for vitamin B(6), r=0.957 for niacin, r=0.934 for pantothenic acid, r=0.907 for folic acid, r=0.962 for biotin, and r=0.952 for vitamin C). These results suggest that measuring urinary water-soluble vitamins and their metabolite levels can be used as good nutritional markers for assessing vitamin intakes.

Urinary Phthalate Metabolite Concentrations and Reproductive Outcomes among Women Undergoing in Vitro Fertilization: Results from the EARTH Study.

PubMed

Hauser, Russ; Gaskins, Audrey J; Souter, Irene; Smith, Kristen W; Dodge, Laura E; Ehrlich, Shelley; Meeker, John D; Calafat, Antonia M; Williams, Paige L

2016-06-01

Evidence from both animal and human studies suggests that exposure to phthalates may be associated with adverse female reproductive outcomes. We evaluated the associations between urinary concentrations of phthalate metabolites and outcomes of assisted reproductive technologies (ART). This analysis included 256 women enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2004-2012) who provided one to two urine samples per cycle before oocyte retrieval. We measured 11 urinary phthalate metabolites [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monoethyl phthalate (MEP), monocarboxyisooctyl phthalate (MCOP), monocarboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate (MCPP)]. We used generalized linear mixed models to evaluate the association of urinary phthalate metabolites with in vitro fertilization (IVF) outcomes, accounting for multiple IVF cycles per woman. In multivariate models, women in the highest as compared with lowest quartile of MEHP, MEHHP, MEOHP, MECPP, ΣDEHP (MEHP + MEHHP + MEOHP + MECPP), and MCNP had lower oocyte yield. Similarly, the number of mature (MII) oocytes retrieved was lower in the highest versus lowest quartile for these same phthalate metabolites. The adjusted differences (95% CI) in proportion of cycles resulting in clinical pregnancy and live birth between women in the fourth versus first quartile of ΣDEHP were -0.19 (-0.29, -0.08) and -0.19 (-0.28, -0.08), respectively, and there was also a lower proportion of cycles resulting in clinical pregnancy and live birth for individual DEHP metabolites. Urinary concentrations of DEHP metabolites were inversely associated with oocyte yield, clinical pregnancy, and live birth following ART. Hauser R, Gaskins AJ, Souter I, Smith KW, Dodge LE, Ehrlich S, Meeker JD, Calafat AM, Williams PL, for the EARTH Study Team. 2016. Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study. Environ Health Perspect 124:831-839; http://dx.doi.org/10.1289/ehp.1509760.

INFLUENCE OF DIETARY ARSENIC ON URINARY ARSENIC METABOLITE EXCRETION

EPA Science Inventory

Influence of Dietary Arsenic on Urinary Arsenic Metabolite Excretion

Cara L. Carty, M.S., Edward E. Hudgens, B.Sc., Rebecca L. Calderon, Ph.D., M.S.P.H., Richard Kwok, M.S.P.H., Epidemiology and Biomarkers Branch/HSD, NHEERL/US EPA; David J. Thomas, Ph.D., Pharmacokinetics...

RESIDENTIAL PESTICIDE USE AND URINARY ORGANOPHOSPHATE METABOLITES IN PRE-SCHOOL CHILDREN

EPA Science Inventory

Residential Pesticide Use and Urinary Organophosphate Metabolites in Pre-School Children
CL Carty1, P Mendola1, D Barr2, L Needham2, D Walsh1

1Epidemiology and Biomarkers Branch, Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S....

Urinary metabolites of organophosphate esters in children in South China: Concentrations, profiles and estimated daily intake.

PubMed

Chen, Yi; Fang, Jianzhang; Ren, Lu; Fan, Ruifang; Zhang, Jianqing; Liu, Guihua; Zhou, Li; Chen, Dingyan; Yu, Yingxin; Lu, Shaoyou

2018-04-01

Organophosphate esters (OPEs) are widely used in household products as flame retardants or plasticizers and have become ubiquitous pollutants in environmental media. However, little is known about OPE metabolites in humans, especially in children. In this study, eight OPE metabolites were measured in 411 urine samples collected from 6 to 14-year-old children in South China. Bis(2-chloroethyl) phosphate (BCEP), bis(1-chloro-2-propyl) phosphate (BCIPP) and diphenyl phosphate (DPHP) were the dominant OPE metabolites, and their median concentrations were 1.04, 0.15 and 0.28 μg/L, respectively. The levels of urinary OPE metabolites in the present study were much lower than those in participants from other countries, with the exception of BCEP, suggesting widespread exposure to tris(2-chlorethyl) phosphate (TCEP, the parent chemical of BCEP) in South China. No significant difference in the concentrations of any of the OPE metabolites was observed between males and females (p > .05). Significant negative correlations were observed between age and BCEP, BCIPP, bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-o-cresyl phosphate (DoCP) and di-p-cresyl phosphate (DpCP) (DCP), or DPHP (p < .05). Pearson correlation coefficients between urinary OPE metabolites indicated multiple sources and OPE exposure pathways in children. The estimated daily intake suggested that children in South China have a relatively high exposure level to TCEP. To the best of our knowledge, this is the first study to report the urinary levels of OPE metabolites in Chinese children. Copyright © 2018 Elsevier Ltd. All rights reserved.

Assessment of 1H NMR-based metabolomics analysis for normalization of urinary metals against creatinine.

PubMed

Cassiède, Marc; Nair, Sindhu; Dueck, Meghan; Mino, James; McKay, Ryan; Mercier, Pascal; Quémerais, Bernadette; Lacy, Paige

2017-01-01

Proton nuclear magnetic resonance ( 1 H NMR, or NMR) spectroscopy and inductively coupled plasma-mass spectrometry (ICP-MS) are commonly used for metabolomics and metal analysis in urine samples. However, creatinine quantification by NMR for the purpose of normalization of urinary metals has not been validated. We assessed the validity of using NMR analysis for creatinine quantification in human urine samples in order to allow normalization of urinary metal concentrations. NMR and ICP-MS techniques were used to measure metabolite and metal concentrations in urine samples from 10 healthy subjects. For metabolite analysis, two magnetic field strengths (600 and 700MHz) were utilized. In addition, creatinine concentrations were determined by using the Jaffe method. Creatinine levels were strongly correlated (R 2 =0.99) between NMR and Jaffe methods. The NMR spectra were deconvoluted with a target database containing 151 metabolites that are present in urine. A total of 50 metabolites showed good correlation (R 2 =0.7-1.0) at 600 and 700MHz. Metal concentrations determined after NMR-measured creatinine normalization were comparable to previous reports. NMR analysis provided robust urinary creatinine quantification, and was sufficient for normalization of urinary metal concentrations. We found that NMR-measured creatinine-normalized urinary metal concentrations in our control subjects were similar to general population levels in Canada and the United Kingdom. Copyright © 2016 Elsevier B.V. All rights reserved.

Human Urinary Composition Controls Antibacterial Activity of Siderocalin* ♦

PubMed Central

Shields-Cutler, Robin R.; Crowley, Jan R.; Hung, Chia S.; Stapleton, Ann E.; Aldrich, Courtney C.; Marschall, Jonas; Henderson, Jeffrey P.

2015-01-01

During Escherichia coli urinary tract infections, cells in the human urinary tract release the antimicrobial protein siderocalin (SCN; also known as lipocalin 2, neutrophil gelatinase-associated lipocalin/NGAL, or 24p3). SCN can interfere with E. coli iron acquisition by sequestering ferric iron complexes with enterobactin, the conserved E. coli siderophore. Here, we find that human urinary constituents can reverse this relationship, instead making enterobactin critical for overcoming SCN-mediated growth restriction. Urinary control of SCN activity exhibits wide ranging individual differences. We used these differences to identify elevated urinary pH and aryl metabolites as key biochemical host factors controlling urinary SCN activity. These aryl metabolites are well known products of intestinal microbial metabolism. Together, these results identify an innate antibacterial immune interaction that is critically dependent upon individualistic chemical features of human urine. PMID:25861985

Urinary Metabolites of Organophosphate and Pyrethroid Pesticides and Behavioral Problems in Canadian Children

PubMed Central

Oulhote, Youssef

2013-01-01

Background: Exposure to organophosphate pesticides has been associated with neurobehavioral deficits in children, although data on low levels of exposure experienced by the general population are sparse. Pyrethroids are insecticides rapidly gaining popularity, and epidemiological evidence on their potential effects is lacking. Objective: We examined the association between exposure to organophosphate and pyrethroid pesticides, indicated by urinary metabolites, and parentally reported behavioral problems in children. Methods: We used data on children 6–11 years of age from the Canadian Health Measures Survey (2007–2009). We used logistic regressions to estimate odds ratios (ORs) for high scores on the Strengths and Difficulties Questionnaire (SDQ), which may indicate behavioral problems, in association with concentrations of pyrethroid and organophosphate metabolites in the urine of 779 children, adjusting for covariates (sex, age, race/ethnicity, income, parental education, blood lead levels, maternal smoking during pregnancy, and others). Results: At least one urinary metabolite for organophosphates was detected in 91% of children, and for pyrethroids in 97% of children. Organophosphate metabolites were not significantly associated with high SDQ scores. The pyrethroid metabolite cis-DCCA [3-(2,2-dichlorovinyl)-2,2-dimethylycyclopropane carboxylic acid] was significantly associated with high scores for total difficulties on the SDQ (OR for a 10-fold increase = 2.0; 95% CI: 1.1, 3.6), and there was a nonsignificant association with trans-DCCA (OR = 1.6; 95% CI: 0.9, 3.0). Conclusion: In contrast with previous studies, we did not observe an association between exposure to organophosphate pesticides and behavioral scores in children. However, some pyrethroid urinary metabolites were associated with a high level of parent-reported behavioral problems. Longitudinal studies should be conducted on the potential risks of pyrethroids. Citation: Oulhote Y, Bouchard MF. 2013. Urinary metabolites of organophosphate and pyrethroid pesticides and behavioral problems in Canadian children. Environ Health Perspect 121:1378–1384; http://dx.doi.org/10.1289/ehp.1306667 PMID:24149046

A characteristic biosignature for discrimination of gastric cancer from healthy population by high throughput GC-MS analysis

PubMed Central

Guo, Lei; Liu, Lei; Wen, Jingran; Xu, Lu; Yan, Min; Li, Zuofeng; Zhang, Xiaoyan; Nan, Peng; Jiang, Jinling; Ji, Jun; Zhang, Jianian; Cai, Wei; Zhuang, Huisheng; Wang, Yan; Zhu, Zhenggang; Yu, Yingyan

2016-01-01

Early diagnosis of gastric cancer is crucial to improve patient′ outcome. A good biomarker will function in early diagnosis for gastric cancer. In order to find practical and cost-effective biomarkers, we used gas chromatography combined mass spectrometer (GC-MS) to profile urinary metabolites on 293 urine samples. Ninety-four samples are taken as training set, others for validating study. Orthogonal partial least squares discriminant analysis (OPLS-DA), significance analysis of microarray (SAM) and Mann-Whitney U test are used for data analysis. The diagnostic value of urinary metabolites was evaluated by ROC curve. As results, Seventeen metabolites are significantly different between patients and healthy controls in training set. Among them, 14 metabolites show diagnostic value better than classic blood biomarkers by quantitative assay on validation set. Ten of them are amino acids and four are organic metabolites. Importantly, proline, p-cresol and 4-hydroxybenzoic acid disclose outcome-prediction value by means of survival analysis. Therefore, the examination of urinary metabolites is a promising noninvasive strategy for gastric cancer screening. PMID:27589838

Identification of the urinary metabolites of 4-bromoaniline and 4-bromo-[carbonyl-13C]-acetanilide in rat.

PubMed

Scarfe, G B; Nicholson, J K; Lindon, J C; Wilson, I D; Taylor, S; Clayton, E; Wright, B

2002-04-01

1. The urinary excretion of 4-bromoaniline and its [carbonyl-(13)C]-labelled N-acetanilide, together with their corresponding metabolites, have been investigated in the rat following i.p. administration at 50 mg kg(-1). 2. Metabolite profiling was performed by reversed-phase HPLC with UV detection, whilst identification was performed using a combination of enzymic hydrolysis and directly coupled HPLC-NMR-MS analysis. The urinary metabolite profile was quantitatively and qualitatively similar for both compounds with little of either excreted unchanged. 3. The major metabolite present in urine was 2-amino-5-bromophenylsulphate, but, in addition, a number of metabolites with modification of the N-acetyl moiety were identified (from both the [(13)C]-acetanilide or produced following acetylation of the free bromoaniline). 4. For 4-bromoacetanilide, N-deacetylation was a major route of metabolism, but despite the detection of the acetanilide following the administration of the free aniline, there was no evidence of reacetylation (futile deacetylation). 5. Metabolites resulting from the oxidation of the acetyl group included a novel glucuronide of an N-glycolanilide, an unusual N-oxanilic acid and a novel N-acetyl cysteine conjugate.

Free and total urinary phthalate metabolite concentrations among pregnant women from the Healthy Baby Cohort (HBC), China.

PubMed

Zhu, Yingshuang; Wan, Yanjian; Li, Yuanyuan; Zhang, Bin; Zhou, Aifen; Cai, Zongwei; Qian, Zhengmin; Zhang, Chuncao; Huo, Wenqian; Huang, Kai; Hu, Jie; Cheng, Lu; Chang, Huailong; Huang, Zheng; Xu, Bing; Xia, Wei; Xu, Shunqing

2016-03-01

Total urinary phthalate metabolites (the free plus glucuronidated forms) have been frequently measured in the general population. However, data are limited on the free forms which may be more bioactive, especially for sensitive population such as pregnant women. Here the data gap was addressed by measuring concentrations of free and total forms of six phthalate metabolites in 293 urine samples from pregnant women at delivery, who were randomly selected from the prospective Healthy Baby Cohort (HBC), China. We observed detectable concentrations of the total amount of phthalate metabolites in all urine samples. The geometric mean (GM) urinary concentrations of free and total mono-butyl phthalate (MBP) (5.20, 54.49ng/mL) were the highest, followed by mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) (4.52, 7.27ng/mL). For most of phthalate metabolites, urinary concentrations were significantly higher in women who were nulliparous. Significantly higher concentrations of mono-ethyl phthalate (MEP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) were found in women who had higher educational level. To our knowledge, this is the first study to report the free and total forms of phthalate metabolites among pregnant women in China. The results suggest that exposure characteristics may be related to parity and education. Copyright © 2015 Elsevier Ltd. All rights reserved.

EVALUATION OF URINARY PAH METABOLITES AS BIOMARKERS OF EXPOSURE TO PM2.5 FROM COMBUSTION SOURCES

EPA Science Inventory

This study determined the relationship between daily personal exposure to airborne fine particles (PM2.5) and the excretion of urinary PAH metabolites over a 10-day period of repeated measurements. The samples (n=60) were selected from a large series of exposure and health pane...

Urinary concentrations of PAH and VOC metabolites in marijuana users.

PubMed

Wei, Binnian; Alwis, K Udeni; Li, Zheng; Wang, Lanqing; Valentin-Blasini, Liza; Sosnoff, Connie S; Xia, Yang; Conway, Kevin P; Blount, Benjamin C

2016-03-01

Marijuana is seeing increased therapeutic use, and is the world's third most-popular recreational drug following alcohol and tobacco. This widening use poses increased exposure to potentially toxic combustion by-products from marijuana smoke and the potential for public health concerns. To compare urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) among self-reported recent marijuana users and nonusers, while accounting for tobacco smoke exposure. Measurements of PAH and VOC metabolites in urine samples were combined with questionnaire data collected from participants in the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2012 in order to categorize participants (≥18years) into exclusive recent marijuana users and nonusers. Adjusted geometric means (GMs) of urinary concentrations were computed for these groups using multiple regression analyses to adjust for potential confounders. Adjusted GMs of many individual monohydroxy PAHs (OH-PAHs) were significantly higher in recent marijuana users than in nonusers (p<0.05). Urinary thiocyanate (p<0.001) and urinary concentrations of many VOC metabolites, including metabolites of acrylonitrile (p<0.001) and acrylamide (p<0.001), were significantly higher in recent marijuana users than in nonusers. We found elevated levels of biomarkers for potentially harmful chemicals among self-identified, recent marijuana users compared with nonusers. These findings suggest that further studies are needed to evaluate the potential health risks to humans from the exposure to these agents when smoking marijuana. Published by Elsevier Ltd.

Urinary concentrations of PAH and VOC metabolites in marijuana users

PubMed Central

Wei, Binnian; Alwis, K. Udeni; Li, Zheng; Wang, Lanqing; Valentin-Blasini, Liza; Sosnoff, Connie S.; Xia, Yang; Conway, Kevin P.; Blount, Benjamin C.

2016-01-01

Background Marijuana is seeing increased therapeutic use, and is the world’s third most-popular recreational drug following alcohol and tobacco. This widening use poses increased exposure to potentially toxic combustion by-products from marijuana smoke and the potential for public health concerns. Objectives To compare urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) among self-reported recent marijuana users and nonusers, while accounting for tobacco smoke exposure. Methods Measurements of PAH and VOC metabolites in urine samples were combined with questionnaire data collected from participants in the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2012 in order to categorize participants (≥18 years) into exclusive recent marijuana users and nonusers. Adjusted geometric means (GMs) of urinary concentrations were computed for these groups using multiple regression analyses to adjust for potential confounders. Results Adjusted GMs of many individual monohydroxy PAHs (OH-PAHs) were significantly higher in recent marijuana users than in nonusers (p < 0.05). Urinary thiocyanate (p < 0.001) and urinary concentrations of many VOC metabolites, including metabolites of acrylonitrile (p < 0.001) and acrylamide (p < 0.001), were significantly higher in recent marijuana users than in nonusers. Conclusions We found elevated levels of biomarkers for potentially harmful chemicals among self-identified, recent marijuana users compared with nonusers. These findings suggest that further studies are needed to evaluate the potential health risks to humans from the exposure to these agents when smoking marijuana. PMID:26690539

Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli.

PubMed

Bent, Stephen; Lawton, Brittany; Warren, Tracy; Widjaja, Felicia; Dang, Katherine; Fahey, Jed W; Cornblatt, Brian; Kinchen, Jason M; Delucchi, Kevin; Hendren, Robert L

2018-01-01

Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016.

Characterization of urinary metabolites of testosterone, methyltestosterone, mibolerone and boldebone in greyhound dogs.

PubMed

Williams, T M; Kind, A J; Hyde, W G; Hill, D W

2000-06-01

Androgenic steroids are used in female greyhound dogs to prevent the onset of estrus; moreover, these steroids also have potent anabolic activity. As anabolic steroids increase muscle mass and aggression in animals, the excessive use of these agents in racing greyhounds gives an unfair performance advantage to treated dogs. The biotransformation of most anabolic steroids has not been determined in greyhound dogs. The objective of the present study was to identify the urinary metabolites of testosterone, methyltestosterone, mibolerone, and boldenone in greyhound dogs. These steroids were administered orally (1 mg/kg) to either male or female greyhound dogs and urine samples were collected pre-administration and at 2, 4, 8, 12, 24, 72, and 96 h post-administration. Urine extracts were analyzed by high-performance liquid chromatography/mass spectrometry (HPLC/MS) to identify major metabolites and to determine their urinary excretion profiles. Major urinary metabolites, primarily glucuronide, conjugated and free, were detected for the selected steroids. Sulfate conjugation did not appear to be a major pathway for steroid metabolism and excretion in the greyhound dog. Phase I biotransformation was also evaluated using greyhound dog liver microsomes from untreated dogs. The identification of several in vivo steroid metabolites generated in this study will be useful in detecting these steroids in urine samples submitted for drug screening.

GSTO and AS3MT genetic polymorphisms and differences in urinary arsenic concentrations among residents in Bangladesh.

PubMed

Rodrigues, Ema G; Kile, Molly; Hoffman, Elaine; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Hsueh, Yumei; Christiani, David C

2012-05-01

We determined whether single nucleotide polymorphisms (SNPs) in the glutathione S-transferase omega (GSTO) and arsenic(III)methyltransferase (AS3MT) genes were associated with concentrations of urinary arsenic metabolites among 900 individuals without skin lesions in Bangladesh. Four SNPs were assessed in these genes. A pathway analysis evaluated the association between urinary arsenic metabolites and SNPs. GSTO1 rs4925 homozygous wild type was significantly associated with higher monomethylarsonic acid (MMA) and dimethylarsinic acid urinary concentrations, whereas wild-type AS3MT rs11191439 had significantly lower levels of As(III) and MMA. Genetic polymorphisms GSTO and As3MT modify arsenic metabolism as evidenced by altered urinary arsenic excretion.

Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors.

PubMed

James-Todd, Tamarra M; Meeker, John D; Huang, Tianyi; Hauser, Russ; Ferguson, Kelly K; Rich-Edwards, Janet W; McElrath, Thomas F; Seely, Ellen W

2016-11-01

Epidemiologic studies suggest phthalate metabolite concentrations are associated with type 2 diabetes. GDM is a strong risk factor for type 2 diabetes. Little is known about phthalates and GDM risk factors (i.e. 1st trimester body mass index (BMI), gestational weight gain (GWG), and 2nd trimester glucose levels). A total of 350 women participating in Lifecodes pregnancy cohort (Boston, MA), delivered at term and had pregnancy urinary phthalate metabolite concentrations. Nine specific gravity-adjusted urinary phthalate metabolites were evaluated. General linear regression was used to assess associations between quartiles of phthalate metabolites and continuous 1st trimester BMI and late 2nd trimester blood glucose. Linear mixed models were used for total GWG. Multivariable logistic regression was used for phthalate concentrations and categorized GWG and impaired glucose tolerance defined as glucose≥140mg/dL based on a 50-gram glucose load test. Models were adjusted for potential confounders. There were no associations between 1st trimester urinary phthalate metabolite concentrations and 1st trimester BMI. Mono-ethyl phthalate concentrations averaged across pregnancy were associated with a 2.17 increased odds of excessive GWG (95% CI: 0.98, 4.79). Second trimester mono-ethyl phthalate was associated with increased odds of impaired glucose tolerance (adj. OR: 7.18; 95% CI: 1.97, 26.15). A summary measure of di-2-ethylhexyl phthalate metabolite concentrations were inversely associated with impaired glucose tolerance (adj. OR: 0.25; adj. 95% CI: 0.08, 0.85). Higher exposure to mono-ethyl phthalate, a metabolite of the parent compound of di-ethyl phthalate, may be associated with excessive GWG and impaired glucose tolerance; higher di-2-ethylhexyl phthalate was associated with reduced odds of impaired glucose tolerance. Copyright © 2016 Elsevier Ltd. All rights reserved.

Detection of fenspiride and identification of in vivo metabolites in horse body fluids by capillary gas chromatography-mass spectrometry: administration, biotransformation and urinary excretion after a single oral dose.

PubMed

Dumasia, M C; Houghton, E; Hyde, W; Greulich, D; Nelson, T; Peterson, Jackie

2002-02-05

Studies related to the in vivo biotransforrmation and urinary excretion of fenspiride hydrochloride in the horse are described. After oral administration, the drug is metabolised by both phase I functionalisation and phase II conjugation pathways. Following enzymatic deconjugation, fenspiride and its phase I metabolites were isolated from post-administration biofluids using bonded co-polymeric mixed mode solid-phase extraction cartridges to isolate the basic compounds. Following trimethylsilylation (TMS), the parent drug and metabolites were identified by capillary gas chromatography-mass spectrometry (GC-MS). Fenspiride (A) and seven metabolites (B-->G) arising from oxidation on both the aromatic and heterocyclic substructures were detected in urine. The positive ion electron ionisation mass spectra of the TMS derivatives of fenspiride and its metabolites provided useful information on its metabolism. Positive ion methane chemical ionisation-GC-MS of the derivatives provided both derivatised molecular mass and structural information. Unchanged fenspiride can be detected in post-administration plasma and urine samples for up to 24 h. Maximum urinary levels of 100-200 ng ml(-1) were observed between 3 and 5 h after administration. After enzymatic deconjugation, the major phenolic metabolite (G) can be detected in urine for up to 72 h. This metabolite is the analyte of choice in the GC-MS screening of post-race equine urine samples for detection of fenspiride use. However, a distinct difference was observed in the urinary excretion of this metabolite between the thoroughbred horses used in UK study and the quarterbred and standardbred horses used for the USA administrations.

Urinary polycyclic aromatic hydrocarbons as a biomarker of exposure to PAHs in air: a pilot study among pregnant women.

PubMed

Nethery, Elizabeth; Wheeler, Amanda J; Fisher, Mandy; Sjödin, Andreas; Li, Zheng; Romanoff, Lovisa C; Foster, Warren; Arbuckle, Tye E

2012-01-01

Recent studies have linked increased polycyclic aromatic hydrocarbons (PAHs) in air and adverse fetal health outcomes. Urinary PAH metabolites are of interest for exposure assessment if they can predict PAHs in air. We investigated exposure to PAHs by collecting air and urine samples among pregnant women pre-selected as living in "high" (downtown and close to steel mills, n=9) and "low" (suburban, n=10) exposure areas. We analyzed first-morning urine voids from all 3 trimesters of pregnancy for urinary PAH metabolites and compared these to personal air PAH/PM(2.5)/NO(2)/NO(X) samples collected in the 3rd trimester. We also evaluated activities and home characteristics, geographic indicators and outdoor central site PM(2.5)/NO(2)/NO(X) (all trimesters). Personal air exposures to the lighter molecular weight (MW) PAHs were linked to indoor sources (candles and incense), whereas the heavier PAHs were related to outdoor sources. Geometric means of all personal air measurements were higher in the "high" exposure group. We suggest that centrally monitored heavier MW PAHs could be used to predict personal exposures for heavier PAHs only. Urine metabolites were only directly correlated with their parent air PAHs for phenanthrene (Pearson's r=0.31-0.45) and fluorene (r=0.37-0.58). Predictive models suggest that specific metabolites (3-hydroyxyfluorene and 3-hydroxyphenanthrene) may be related to their parent air PAH exposures. The metabolite 2-hydroxynaphthalene was linked to smoking and the metabolite 1-hydroxypyrene was linked to dietary exposures. For researchers interested in predicting exposure to airborne lighter MW PAHs using urinary PAH metabolites, we propose that hydroxyfluorene and hydroxyphenanthrene metabolites be considered.

Variability and Predictors of Urinary Concentrations of Phthalate Metabolites during Early Childhood

PubMed Central

2015-01-01

The variability and predictors of urinary concentrations of phthalate metabolites in preschool-aged children have not been thoroughly examined. Additionally, the impact of temporal changes in the use and restriction of phthalates in children’s products has not been assessed. Our objective was to identify demographic, behavioral, and temporal predictors of urinary phthalate metabolite concentrations in young children. Between 2004 and 2011, we collected up to five urine samples from each of 296 children participating in a prospective birth cohort during annual study visits at ages 1–5 years. We used linear mixed models to calculate intraclass correlation coefficients (ICCs), a measure of within-individual reproducibility, and identify demographic predictors of urinary phthalate metabolites. We used multivariable linear regression to examine cross-sectional relationships between food packaging or personal care product use and phthalate metabolites measured at age 5 years. Across annual measurements, monoethyl phthalate exhibited the least variation (ICC = 0.38), while di-2-ethylhexyl phthalate (ΣDEHP) metabolites exhibited the most variation (ICC = 0.09). Concentrations changed with age, suggesting age-related changes in phthalate exposure and perhaps metabolism. Our findings suggest that fast food consumption may be a source of butylbenzyl phthalate and di-isononyl phthalate (DiNP) exposure, and some personal care products may be sources of diethyl phthalate exposure. Concentrations of ΣDEHP metabolites decreased over the study period; however, concentrations of DiNP metabolites increased. This finding suggests that manufacturer practices and regulations, like the Consumer Product Safety Improvement Act of 2008, may decrease DEHP exposure, but additional work characterizing the nature and toxicity of replacements is critically needed. PMID:24977926

Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile.

PubMed

Muñoz-Quezada, María Teresa; Iglesias, Verónica; Lucero, Boris; Steenland, Kyle; Barr, Dana Boyd; Levy, Karen; Ryan, P Barry; Alvarado, Sergio; Concha, Carlos

2012-10-15

Few data exist in Latin America concerning the association between organophosphate (OP) urinary metabolites and the consumption of fruits and vegetables and other exposure risk variables in schoolchildren. We collected samples of urine from 190 Chilean children aged 6-12 years, fruits and vegetables, water and soil from schools and homes, and sociodemographic data through a questionnaire. We measured urinary dialkylphosphate (DAP) OP metabolites and OP pesticide residues in food consumed by these 190 children during two seasons: December 2010 (summer) and May 2011 (fall). We analyzed the relationship between urinary DAP concentrations and pesticide residues in food, home pesticide use, and residential location. Diethylalkylphosphates (DEAP) and dimethylalkylphosphates (DMAP) were detected in urine in 76% and 27% of the samples, respectively. Factors associated with urinary DEAP included chlorpyrifos in consumed fruits (p<0.0001), urinary creatinine (p<0.0001), rural residence (p=0.02) and age less than 9 years (p=0.004). Factors associated with urinary DMAP included the presence of phosmet residues in fruits (p<0.0001), close proximity to a farm (p=0.002), home fenitrothion use (p=0.009), and season (p<0.0001). Urinary DAP levels in Chilean school children were high compared to previously reported studies. The presence of chlorpyrifos and phosmet residues in fruits was the major factor predicting urinary DAP metabolite concentrations in children. Copyright © 2012 Elsevier Ltd. All rights reserved.

Brief Social Isolation in the Adolescent Wistar-Kyoto Rat Model of Endogenous Depression Alters Corticosterone and Regional Monoamine Concentrations.

PubMed

Shetty, Reshma A; Sadananda, Monika

2017-05-01

The Wistar-Kyoto rat (WKY) model has been suggested as a model of adult and adolescent depression though face, predictive and construct validities of the model to depression remain equivocal. The suitability of the WKY as a diathesis model that tests the double-hit hypothesis, particularly during critical periods of brain and behavioural development remains to be established. Here, effects of post-weaning social isolation were assessed during early adolescence (~30pnd) on behavioural despair and learned helplessness in the forced swim test (FST), plasma corticosterone levels and tissue monoamine concentrations in brain areas critically involved in depression, such as prefrontal cortex, nucleus accumbens, striatum and hippocampus. Significantly increased immobility in the FST was observed in socially-isolated, adolescent WKY with a concomitant increase in corticosterone levels over and above the FST-induced stress. WKY also demonstrated a significantly increased release and utilization of dopamine, as manifested by levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in nucleus accumbens, indicating that the large dopamine storage pool evident during adolescence induces greater dopamine release when stimulated. The serotonin metabolite 5-hydroxy-indoleacetic acid was also significantly increased in nucleus accumbens, indicating increased utilization of serotonin, along with norepinephrine levels which were also signficantly elevated in socially-isolated adolescent WKY. Differences in neurochemistry suggest that social or environmental stimuli during critical periods of brain and behavioural development can determine the developmental trajectories of implicated pathways.

Faecal corticosterone metabolite concentrations are not a good predictor of habitat suitability for common gartersnakes.

PubMed

Halliday, William D; Gilmour, Kathleen M; Blouin-Demers, Gabriel

2015-01-01

Measuring habitat suitability is important in conservation and in wildlife management. Measuring the abundance or presence-absence of a species in various habitats is not sufficient to measure habitat suitability because these metrics can be poor predictors of population success. Therefore, having some measure of population success is essential in assessing habitat suitability, but estimating population success is difficult. Identifying suitable proxies for population success could thus be beneficial. We examined whether faecal corticosterone metabolite (fCM) concentrations could be used as a proxy for habitat suitability in common gartersnakes (Thamnophis sirtalis). We conducted a validation study and confirmed that fCM concentrations indeed reflect circulating corticosterone concentrations. We estimated abundance, reproductive output and growth rate of gartersnakes in field and in forest habitat and we also measured fCM concentrations of gartersnakes from these same habitats. Common gartersnakes were more abundant and had higher reproductive outputs and higher growth rates in field habitat than in forest habitat, but fCM concentrations did not differ between the same two habitats. Our results suggest either that fCM concentrations are not a useful metric of habitat suitability in common gartersnakes or that the difference in suitability between the two habitats was too small to induce changes in fCM concentrations. Incorporating fitness metrics in estimates of habitat suitability is important, but these metrics of fitness have to be sensitive enough to vary between habitats.

Urinary Metabolite Profiles May be Predictive of Cognitive Performance Under Conditions of Acute Sleep Deprivation

DTIC Science & Technology

2016-01-01

temporal changes in urinary metabolite profiles mirrored cognitive performance during continuous wakefulness. Additionally , subjects identified by...profiles mirrored cognitive performance during continuous wakefulness. Additionally , subjects identified by cognitive assessments as having a high...field studies and would have little useful application in occupational or military operational environments. Addition - ally, their usefulness is

Urinary Phthalate Metabolite Concentrations and Reproductive Outcomes among Women Undergoing in Vitro Fertilization: Results from the EARTH Study

PubMed Central

Hauser, Russ; Gaskins, Audrey J.; Souter, Irene; Smith, Kristen W.; Dodge, Laura E.; Ehrlich, Shelley; Meeker, John D.; Calafat, Antonia M.; Williams, Paige L.

2015-01-01

Background: Evidence from both animal and human studies suggests that exposure to phthalates may be associated with adverse female reproductive outcomes. Objective: We evaluated the associations between urinary concentrations of phthalate metabolites and outcomes of assisted reproductive technologies (ART). Methods: This analysis included 256 women enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2004–2012) who provided one to two urine samples per cycle before oocyte retrieval. We measured 11 urinary phthalate metabolites [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monoethyl phthalate (MEP), monocarboxyisooctyl phthalate (MCOP), monocarboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate (MCPP)]. We used generalized linear mixed models to evaluate the association of urinary phthalate metabolites with in vitro fertilization (IVF) outcomes, accounting for multiple IVF cycles per woman. Results: In multivariate models, women in the highest as compared with lowest quartile of MEHP, MEHHP, MEOHP, MECPP, ΣDEHP (MEHP + MEHHP + MEOHP + MECPP), and MCNP had lower oocyte yield. Similarly, the number of mature (MII) oocytes retrieved was lower in the highest versus lowest quartile for these same phthalate metabolites. The adjusted differences (95% CI) in proportion of cycles resulting in clinical pregnancy and live birth between women in the fourth versus first quartile of ΣDEHP were –0.19 (–0.29, –0.08) and –0.19 (–0.28, –0.08), respectively, and there was also a lower proportion of cycles resulting in clinical pregnancy and live birth for individual DEHP metabolites. Conclusions: Urinary concentrations of DEHP metabolites were inversely associated with oocyte yield, clinical pregnancy, and live birth following ART. Citation: Hauser R, Gaskins AJ, Souter I, Smith KW, Dodge LE, Ehrlich S, Meeker JD, Calafat AM, Williams PL, for the EARTH Study Team. 2016. Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study. Environ Health Perspect 124:831–839; http://dx.doi.org/10.1289/ehp.1509760 PMID:26545148

Comparison of Urinary Biomarkers of Exposure in Humans Using Electronic Cigarettes, Combustible Cigarettes, and Smokeless Tobacco.

PubMed

Lorkiewicz, Pawel; Riggs, Daniel W; Keith, Rachel J; Conklin, Daniel J; Xie, Zhengzhi; Sutaria, Saurin; Lynch, Blake; Srivastava, Sanjay; Bhatnagar, Aruni

2018-06-02

Cigarette smoking is associated with an increase in cardiovascular disease risk, attributable in part to reactive volatile organic chemicals (VOCs). However, little is known about the extent of VOC exposure due to the use of other tobacco products. We recruited 48 healthy, tobacco users in four groups: cigarette, smokeless tobacco, occasional users of first generation e-cigarette and e-cigarette menthol and 12 healthy nontobacco users. After abstaining for 48 h, tobacco users used an assigned product. Urine was collected at baseline followed by five collections over a 3-h period to measure urinary metabolites of VOCs, nicotine, and tobacco alkaloids. Urinary levels of nicotine were ≃2-fold lower in occasional e-cigarette and smokeless tobacco users than in the cigarette smokers; cotinine and 3-hydroxycotinine levels were similar in all groups. Compared with nontobacco users, e-cigarette users had higher levels of urinary metabolites of xylene, cyanide, styrene, ethylbenzene, and benzene at baseline and elevated urinary levels of metabolites of xylene, N,N-dimethylformamide, and acrylonitrile after e-cigarette use. Metabolites of acrolein, crotonaldehyde, and 1,3-butadiene were significantly higher in smokers than in users of other products or nontobacco users. VOC metabolite levels in smokeless tobacco group were comparable to those found in nonusers with the exception of xylene metabolite-2-methylhippuric acid (2MHA), which was almost three fold higher than in nontobacco users. Smoking results in exposure to a range of VOCs at concentrations higher than those observed with other products, and first generation e-cigarette use is associated with elevated levels of N,N-dimethylformamide and xylene metabolites. This study shows that occasional users of first generation e-cigarettes have lower levels of nicotine exposure than the users of combustible cigarettes. Compared with combustible cigarettes, e-cigarettes, and smokeless tobacco products deliver lower levels of most VOCs, with the exception of xylene, N,N-dimethylformamide, and acrylonitrile, whose metabolite levels were higher in the urine of e-cigarette users than nontobacco users. Absence of anatabine in the urine of e-cigarette users suggests that measuring urinary levels of this alkaloid may be useful in distinguishing between users of e-cigarettes and combustible cigarettes. However, these results have to be validated in a larger cohortcomprised of users of e-cigarettes of multiple brands.

Effects of Neonatal Methamphetamine and Stress on Brain Monoamines and Corticosterone in Preweanling Rats

PubMed Central

Jablonski, Sarah A.; Graham, Devon L.; Vorhees, Charles V.; Williams, Michael T.

2017-01-01

Neonatal exposure to methamphetamine (MA) and developmental chronic stress significantly alter neurodevelopmental profiles that show a variety of long-term physiological and behavioral effects. In the current experiment, Sprague-Dawley rats were exposed to one of two housing conditions along with MA. Rats were given 0 (saline), 5, or 7.5 mg/kg MA, four times per day from postnatal day (P)11 to 15 or P11 to 20. Half of the litters were reared in cages with standard bedding and half with no bedding. Separate litters were assessed at P15 or P20 for organ weights (adrenals, spleen, thymus); corticosterone; and monoamine assessments (dopamine, serotonin, norepinephrine) and their metabolites within the neostriatum, hippocampus, and prefrontal cortex. Findings show neonatal MA altered mono-amines, corticosterone, and organ characteristics alone, and as a function of developmental age and stress compared with controls. These alterations may in part be responsible for MA and early life stress-induced long-term learning and memory deficits. PMID:27817108

Regional rat brain noradrenaline turnover in response to restraint stress.

PubMed

Glavin, G B; Tanaka, M; Tsuda, A; Kohno, Y; Hoaki, Y; Nagasaki, N

1983-08-01

Male Wistar rats were starved for 12 hr and then subjected to either 2 hr of wire mesh "envelope" restraint at room temperature; 2 hr of supine restraint in a specially constructed harness at room temperature or were not restrained. Eight brain regions were examined for NA level and the level of its major metabolite, MHPG-SO4. Plasma corticosterone and gastric ulcer incidence were also measured. All restrained rats displayed marked elevations in MHPG-SO4 levels in most brain regions. In addition, several brain regions in restrained animals showed a reduction in NA level. All restrained rats showed elevated plasma corticosterone levels and evidence of gastric lesions. In general, supine restraint produced greater alterations in regional brain NA turnover, greater evidence of ulcer disease, and higher plasma corticosterone levels than did wire mesh restraint. These data suggest that acute but intense stress in the form of restraint causes markedly altered brain NA activity--a possible neurochemical mechanism underlying the phenomenon of stress-induced disease.

Metabolomic Profiling of Extracellular Vesicles and Alternative Normalization Methods Reveal Enriched Metabolites and Strategies to Study Prostate Cancer-Related Changes

PubMed Central

Puhka, Maija; Takatalo, Maarit; Nordberg, Maria-Elisa; Valkonen, Sami; Nandania, Jatin; Aatonen, Maria; Yliperttula, Marjo; Laitinen, Saara; Velagapudi, Vidya; Mirtti, Tuomas; Kallioniemi, Olli; Rannikko, Antti; Siljander, Pia R-M; af Hällström, Taija Maria

2017-01-01

Body fluids are a rich source of extracellular vesicles (EVs), which carry cargo derived from the secreting cells. So far, biomarkers for pathological conditions have been mainly searched from their protein, (mi)RNA, DNA and lipid cargo. Here, we explored the small molecule metabolites from urinary and platelet EVs relative to their matched source samples. As a proof-of-concept study of intra-EV metabolites, we compared alternative normalization methods to profile urinary EVs from prostate cancer patients before and after prostatectomy and from healthy controls. Methods: We employed targeted ultra-performance liquid chromatography-tandem mass spectrometry to profile over 100 metabolites in the isolated EVs, original urine samples and platelets. We determined the enrichment of the metabolites in the EVs and analyzed their subcellular origin, pathways and relevant enzymes or transporters through data base searches. EV- and urine-derived factors and ratios between metabolites were tested for normalization of the metabolomics data. Results: Approximately 1 x 1010 EVs were sufficient for detection of metabolite profiles from EVs. The profiles of the urinary and platelet EVs overlapped with each other and with those of the source materials, but they also contained unique metabolites. The EVs enriched a selection of cytosolic metabolites including members from the nucleotide and spermidine pathways, which linked to a number of EV-resident enzymes or transporters. Analysis of the urinary EVs from the patients indicated that the levels of glucuronate, D-ribose 5-phosphate and isobutyryl-L-carnitine were 2-26-fold lower in all pre-prostatectomy samples compared to the healthy control and post-prostatectomy samples (p < 0.05). These changes were only detected from EVs by normalization to EV-derived factors or with metabolite ratios, and not from the original urine samples. Conclusions: Our results suggest that metabolite analysis of EVs from different samples is feasible using a high-throughput platform and relatively small amount of sample material. With the knowledge about the specific enrichment of metabolites and normalization methods, EV metabolomics could be used to gain novel biomarker data not revealed by the analysis of the original EV source materials. PMID:29109780

Reliability of concentrations of organophosphate pesticide metabolites in serial urine specimens from pregnancy in the Generation R Study.

PubMed

Spaan, Suzanne; Pronk, Anjoeka; Koch, Holger M; Jusko, Todd A; Jaddoe, Vincent W V; Shaw, Pamela A; Tiemeier, Henning M; Hofman, Albert; Pierik, Frank H; Longnecker, Matthew P

2015-05-01

The widespread use of organophosphate (OP) pesticides has resulted in ubiquitous exposure in humans, primarily through their diet. Exposure to OP pesticides may have adverse health effects, including neurobehavioral deficits in children. The optimal design of new studies requires data on the reliability of urinary measures of exposure. In the present study, urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined in 120 pregnant women participating in the Generation R Study in Rotterdam. Intra-class correlation coefficients (ICCs) across serial urine specimens taken at <18, 18-25, and >25 weeks of pregnancy were determined to assess reliability. Geometric mean total DAP metabolite concentrations were 229 (GSD 2.2), 240 (GSD 2.1), and 224 (GSD 2.2) nmol/g creatinine across the three periods of gestation. Metabolite concentrations from the serial urine specimens in general correlated moderately. The ICCs for the six DAP metabolites ranged from 0.14 to 0.38 (0.30 for total DAPs), indicating weak to moderate reliability. Although the DAP metabolite levels observed in this study are slightly higher and slightly more correlated than in previous studies, the low to moderate reliability indicates a high degree of within-person variability, which presents challenges for designing well-powered epidemiological studies.

Urinary pesticide metabolites in school students from northern Thailand.

PubMed

Panuwet, Parinya; Prapamontol, Tippawan; Chantara, Somporn; Barr, Dana B

2009-05-01

We evaluated exposure to pesticides among secondary school students aged 12-13 years old in Chiang Mai Province, Thailand. Pesticide-specific urinary metabolites were used as biomarkers of exposure for a variety of pesticides, including organophosphorus insecticides, synthetic pyrethroid insecticides and selected herbicides. We employed a simple solid-phase extraction with analysis using isotope dilution high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). A total of 207 urine samples from Thai students were analyzed for 18 specific pesticide metabolites. We found 14 metabolites in the urine samples tested; seven of them were detected with a frequency > or=17%. The most frequently detected metabolites were 2-[(dimethoxyphosphorothioyl) sulfanyl] succinic acid (malathion dicarboxylic acid), para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TPCY; metabolite of chlorpyrifos), 2,4-dichlorophenoxyacetic acid (2,4-D), cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acids (c-DCCA and t-DCCA; metabolite of permethrin) and 3-phenoxybenzoic acid (3-PBA; metabolite of pyrethroids). The students were classified into 4 groups according to their parental occupations: farmers (N=60), merchants and traders (N=39), government and company employees (N=52), and laborers (N=56). Children of farmers had significantly higher urinary concentrations of pyrethroid insecticide metabolites than did other children (p<0.05). Similarly, children of agricultural families had significantly higher pyrethroid metabolite concentrations. Males had significantly higher values of PNP (Mann-Whitney test, p=0.009); however, no other sex-related differences were observed. Because parental occupation and agricultural activities seemed to have little influence on pesticide levels, dietary sources were the likely contributors to the metabolite levels observed.

A less stressful alternative to oral gavage for pharmacological and toxicological studies in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Mary K., E-mail: mwalker@salud.unm.edu; Boberg, Jason R.; Walsh, Mary T.

Oral gavage dosing can induce stress and potentially confound experimental measurements, particularly when blood pressure and heart rate are endpoints of interest. Thus, we developed a pill formulation that mice would voluntarily consume and tested the hypothesis that pill dosing would be significantly less stressful than oral gavage. C57Bl/6 male mice were singly housed and on four consecutive days were exposed to an individual walking into the room (week 1, control), a pill being placed into the cage (week 2), and a dose of water via oral gavage (week 3). Blood pressure and heart rate were recorded by radiotelemetry continuouslymore » for 5 h after treatment, and feces collected 6–10 h after treatment for analysis of corticosterone metabolites. Both pill and gavage dosing significantly increased mean arterial pressure (MAP) during the first hour, compared to control. However, the increase in MAP was significantly greater after gavage and remained elevated up to 5 h, while MAP returned to normal within 2 h after a pill. Neither pill nor gavage dosing significantly increased heart rate during the first hour, compared to control; however, pill dosing significantly reduced heart rate while gavage significantly increased heart rate 2–5 h post dosing. MAP and heart rate did not differ 24 h after dosing. Lastly, only gavage dosing significantly increased fecal corticosterone metabolites, indicating a systemic stress response via activation of the hypothalamic–pituitary–adrenal axis. These data demonstrated that this pill dosing method of mice is significantly less stressful than oral gavage. -- Highlights: ► Developed a novel oral dosing method using a pill that mice will readily consume. ► Assessed stress by blood pressure, heart rate, and fecal corticosterone metabolites. ► Demonstrated that pill dosing is significantly less stressful than oral gavage.« less

Influence of fermentable carbohydrates or protein on large intestinal and urinary metabolomic profiles in piglets.

PubMed

Pieper, R; Neumann, K; Kröger, S; Richter, J F; Wang, J; Martin, L; Bindelle, J; Htoo, J K; Vahjen, V; Van Kessel, A G; Zentek, J

2012-12-01

It was recently shown that variations in the ratio of dietary fermentable carbohydrates (fCHO) and fermentable protein (fCP) differentially affect large intestinal microbial ecology and the mucosal response. Here we investigated the use of mass spectrometry to profile changes in metabolite composition in colon and urine associated with variation in dietary fCHO and fCP composition and mucosal physiology. Thirty-two weaned piglets were fed 4 diets in a 2 × 2 factorial design with low fCP and low fCHO, low fCP and high fCHO, high fCP and low fCHO, and high fCP and high fCHO. After 21 to 23 d, all pigs were euthanized and colon digesta and urine metabolite profiles were obtained by mass spectrometry. Analysis of mass spectra by partial least squares approach indicated a clustering of both colonic and urinary profiles for each pig by feeding group. Metabolite identification and annotation using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways revealed increased abundance of metabolites associated with arachidonic acid metabolism in colon of pigs fed a high concentration of fCP irrespective of dietary fCHO. Urinary metabolites did not show as clear patterns. Mass spectrometry can effectively differentiate metabolite profiles in colon contents and urine associated with changes in dietary composition. Whether metabolite profiling is an effective tool to identify specific metabolites (biomarkers) or metabolite profiles associated with gut function and integrity needs further elucidation.

Predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men.

PubMed

Wang, Yi-Xin; Liu, Chong; Chen, Ying-Jun; Chen, Heng-Gui; Yang, Pan; Wang, Peng; Huang, Li-Li; Ai, Song-Hua; Duan, Peng; Pan, An; Zeng, Qiang; Lu, Wen-Qing

2018-02-01

Certain phthalates are suspected to be endocrine disruptors that are adversely associated with male reproductive health. However, the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among reproductive-aged men have not been thoroughly studied. To investigate the predictors and correlations of phthalate metabolite concentrations in urine and seminal plasma among adult Chinese males. We measured mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-octyl phthalate (MOP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) concentrations in seminal plasma and repeated spot-urine samples from 687 men who visited a reproductive center. Mixed-effect models were used to examine the associations of sociodemographic, lifestyle and medical factors with urinary metabolite concentrations. Linear regression models were used to identify predictors of metabolite concentrations in seminal plasma and correlations between metabolite concentrations in spot urine samples and seminal plasma. Measurements taken from spot urine samples poorly predicted same-day seminal plasma concentrations (all R 2 <0.10). Inverse associations were observed between education level and urinary MBP and MEOHP and between household income and urinary MMP; receiving intravenous infusion therapy was associated with increased urinary MBP, MEHHP and MEOHP, use of facial cleanser/cream was associated with increased MEP, and smoking was associated with increased MEHP. The predictors of metabolite concentrations in seminal plasma differed from those in urine, except for the association of intravenous infusion therapy with MBP. BMI was associated with increased seminal plasma MBP, MEHP and MEOHP, smoking was associated with increased MEP, and contact with plastics was associated with increased MEOHP. Phthalate metabolite concentrations in adult men varied in accordance with sociodemographic variables, lifestyle factors and intravenous therapy. Measures of metabolite levels in urine may not directly reflect the exposure status of the male reproductive system. Copyright © 2017 Elsevier Inc. All rights reserved.

Catecholamine levels in the brain of rats exposed by inhalation to benzalkonium chloride.

PubMed

Swiercz, Radosław; Grzelińska, Zofia; Gralewicz, Sławomir; Wasowicz, Wojciech

2009-01-01

The aim of the study was to obtain quantitative data on the effect of inhalation exposure to benzalkonium chloride (BAC) on the concentration of catecholamines and their metabolites in selected brain structures. Additionally, concentration of corticosterone (CORT) in plasma was estimated. Wistar rats were subjected to a single (6-hour) or repeated (3 days, 6 h/day) exposure to BAC aerosol at ca. 30 mg/m3. The Waters integrated analytical system of HPLC was used to determine the plasma corticosterone. Qualitative and quantitative determinations of catecholamines and their metabolites: 3,4-dihydroxyphenylacetic (DOPAC) and homovanillic (HVA) acids were performed with the use of the Waters integrity HPLC. The determinations have shown that in the BAC-exposed rats the plasma CORT concentration was several times higher than in the control rats. A significant increase of the concentration of dopamine (DA) (striatum and diencephalon) and noradrenaline (NA) (hippocampus and cerebellum) and a significant reduction of adrenaline (A) level (cortex, hippocampus, striatum and mesencephaloon) was found to occur in the brain of rats exposed to BAC compared to control. In the animals exposed to BAC, the concentration of DOPAC, a DA metabolite, was significantly reduced, but the change occurred mainly in the striatum. This resulted in a significant decrease of the DOPAC/DA and HVA/DA metabolic ratio in this structure. It is assumed that the alterations in the concentration of catecholamines and their metabolites in the BAC-exposed rats were related to the unexpectedly strong and persistent activation of the hypothalamo-pituitary-adrenocortical (HPA) axis evidenced by the high plasma CORT concentration.

Corticosterone excretion patterns and affiliative behavior over development in ravens (Corvus corax)

PubMed Central

Stöwe, Mareike; Bugnyar, Thomas; Schloegl, Christian; Heinrich, Bernd; Kotrschal, Kurt; Möstl, Erich

2015-01-01

Averse effects of social stress may be buffered by the presence of social allies, which mainly has been demonstrated in mammals and recently also in birds. However, effects of socio-positive behavior prior to fledging in relation to corticosterone excretion in altricial birds have not been investigated yet. We here monitored corticosterone excretion patterns in three groups of hand raised juvenile ravens (n=5, 6 and 11) in the nest, post-fledging (May–July) and when ravens would be independent from their parents (September–November). We related these corticosterone excretion patterns to socio-positive behavior. Behavioral data were collected via focal sampling in each developmental period considered. We analyzed amounts of excreted immunoreactive corticosterone metabolites (CM) using enzyme immuno assays. We collected fecal samples in each developmental period considered and evaluated the most appropriate assay via an isolation stress experiment. Basal CM was significantly higher during the nestling period than post-fledging or when birds were independent. The time nestlings spent allopreening correlated negatively with mean CM. Post-fledging, individuals with higher CM levels sat close to (distance <50 cm) conspecifics more frequently and tended to preen them longer. When birds were independent and a stable rank hierarchy was established, dominant individuals were preened significantly longer than subordinates. These patterns observed in ravens parallel those described for primates, which could indicate that animal species living in a complex social environment may deal with social problems in a similar way that is not restricted to mammals or primates. PMID:18022623

Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors

PubMed Central

James-Todd, TM; Meeker, JD; Huang, T; Hauser, R; Ferguson, KK; Rich-Edwards, JW; McElrath, TF; Seely, EW

2016-01-01

Background Epidemiologic studies suggest phthalate metabolite concentrations are associated with type 2 diabetes. GDM is a strong risk factor for type 2 diabetes. Little is known about phthalates and GDM risk factors (i.e. 1st trimester body mass index (BMI), gestational weight gain (GWG), and 2nd trimester glucose levels). Methods A total of 350 women participating in Lifecodes pregnancy cohort (Boston, MA), delivered at term and had pregnancy urinary phthalate metabolite concentrations. Nine specific gravity-adjusted urinary phthalate metabolites were evaluated. General linear regression was used to assess associations between quartiles of phthalate metabolites and continuous 1st trimester BMI and late 2nd trimester blood glucose. Linear mixed models were used for total GWG. Multivariable logistic regression was used for phthalate concentrations and categorized GWG and impaired glucose tolerance defined as glucose ≥ 140mg/dL based on a 50-gram glucose load test. Models were adjusted for potential confounders. Results There were no associations between 1st trimester urinary phthalate metabolite concentrations and 1st trimester BMI. Mono-ethyl phthalate (MEP) concentrations averaged across pregnancy were associated with a 2.17 increased odds of excessive GWG (95% CI: 0.98, 4.79). Second trimester MEP was associated with an increased odds of impaired glucose tolerance (adj. OR: 7.18; 95% CI: 1.97, 26.15). Di-2-ethylhexyl phthalate metabolite concentrations were inversely associated with impaired glucose tolerance (adj. OR: 0.25; adj. 95% CI: 0.08, 0.85). Conclusions Higher exposure to di-ethyl phthalate, the parent compound of MEP, may be associated with excessive GWG and impaired glucose tolerance; higher di-2-ethylhexyl phthalate was associated with reduced odds of impaired glucose tolerance. PMID:27649471

Inter-individual variability in the production of flavan-3-ol colonic metabolites: preliminary elucidation of urinary metabotypes.

PubMed

Mena, Pedro; Ludwig, Iziar A; Tomatis, Virginia B; Acharjee, Animesh; Calani, Luca; Rosi, Alice; Brighenti, Furio; Ray, Sumantra; Griffin, Julian L; Bluck, Les J; Del Rio, Daniele

2018-04-03

There is much information on the bioavailability of (poly)phenolic compounds following acute intake of various foods. However, there are only limited data on the effects of repeated and combined exposure to specific (poly)phenol food sources and the inter-individual variability in their bioavailability. This study evaluated the combined urinary excretion of (poly)phenols from green tea and coffee following daily consumption by healthy subjects in free-living conditions. The inter-individual variability in the production of phenolic metabolites was also investigated. Eleven participants consumed both tablets of green tea and green coffee bean extracts daily for 8 weeks and 24-h urine was collected on five different occasions. The urinary profile of phenolic metabolites and a set of multivariate statistical tests were used to investigate the putative existence of characteristic metabotypes in the production of flavan-3-ol microbial metabolites. (Poly)phenolic compounds in the green tea and green coffee bean extracts were absorbed and excreted after simultaneous consumption, with green tea resulting in more inter-individual variability in urinary excretion of phenolic metabolites. Three metabotypes in the production of flavan-3-ol microbial metabolites were tentatively defined, characterized by the excretion of different amounts of trihydroxyphenyl-γ-valerolactones, dihydroxyphenyl-γ-valerolactones, and hydroxyphenylpropionic acids. The selective production of microbiota-derived metabolites from flavan-3-ols and the putative existence of characteristic metabotypes in their production represent an important development in the study of the bioavailability of plant bioactives. These observations will contribute to better understand the health effects and individual differences associated with consumption of flavan-3-ols, arguably the main class of flavonoids in the human diet.

Relationship between Urinary Pesticide Residue Levels and Neurotoxic Symptoms among Women on Farms in the Western Cape, South Africa

PubMed Central

Motsoeneng, Portia M.; Dalvie, Mohamed A.

2015-01-01

Background: This cross-sectional study aimed to investigate the relationship between urinary pesticide residue levels and neurotoxic symptoms amongst women working on Western Cape farms in South Africa. Method: A total of 211 women were recruited from farms (n = 121) and neighbouring towns (n = 90). Participant assessment was via a Q16 questionnaire, reporting on pesticide exposures and measurement of urinary OP metabolite concentrations of dialkyl phosphates (DAP) and chlorpyriphos, 3,5,6-trichloropyridinol (TCPY) and of pyrethroid (PYR) metabolite concentrations (3- phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), and the cis- and trans isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane-1-carboxylic acid. Results: Median urinary pesticide metabolites were slightly (6%–49%) elevated in the farm group compared to the town group, with 2 metabolites significantly higher and some lower in the farm group. The prevalence of all Q16 symptoms was higher amongst farm women compared to town women. Three Q16 symptoms (problems with buttoning, reading and notes) were significantly positively associated with three pyrethroid metabolites (cis- and trans-DCCA and DBCA), although associations may due to chance as multiple comparisons were made. The strongest association for a pyrethroid metabolite was between problems with buttoning and DBCA (odds ratio (OR) = 8.93, 95% confidence interval (CI):1.71–46.5. There was no association between Q16 symptoms and OP metabolites. Conclusions: Women farm residents and rural women from neighbouring towns in the Western Cape are exposed to OP and PYR pesticides. The study did not provide strong evidence that pesticides are associated with neurotoxic symptoms but associations found could be explored further. PMID:26042367

Longitudinal urinary metabolomic profiling reveals metabolites for asthma development in early childhood.

PubMed

Chiu, Chih-Yung; Lin, Gigin; Cheng, Mei-Ling; Chiang, Meng-Han; Tsai, Ming-Han; Su, Kuan-Wen; Hua, Man-Chin; Liao, Sui-Ling; Lai, Shen-Hao; Yao, Tsung-Chieh; Yeh, Kuo-Wei; Huang, Jing-Long

2018-04-21

Several metabolites and altered metabolic pathways have been reported to be associated with asthma. However, longitudinal analysis of the dynamics of metabolites contributing to the development of asthma has not yet been fully clarified. We sought to identify the metabolic mechanisms underlying asthma development in early childhood. Thirty children with asthma and paired healthy controls from a prospective birth cohort were enrolled. Time-series analysis of urinary metabolites collected at ages 1, 2, 3, and 4 years were assessed using 1 H-nuclear magnetic resonance (NMR) spectroscopy coupled with partial least-squares discriminant analysis (PLS-DA). Metabolites identified were studied in relation to changes over time in a linear mixed model for repeated measures. A total of 172 urine samples collected from the enrolled children were analyzed. Urinary metabolomics identified four metabolites significantly associated with childhood asthma development, with longitudinal analysis. Among them, dimethylamine, a metabolite produced by intestinal bacteria, appeared to shift from higher to lower level during asthma development. A persistent lower level of 1-methylnicotinamide and allantoin was found in children with asthma, with a peak difference at age 3 years (P = 0.032 and P = 0.021 respectively). Furthermore, a significant inverse correlation was found between allantoin and house dust mite sensitization (Spearman's r = -0.297 P = 0.035). Longitudinal urinary metabolomic profiling provides a link of microbe-environment interactions in the development of childhood asthma. 1-Methylnicotinamide and allantoin may participate in allergic reactions in response to allergen exposure, potentially serving as specific biomarkers for asthma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Urinary Urea, Uric Acid and Hippuric Acid as Potential Biomarkers in Multiple Sclerosis Patients.

PubMed

Atya, Hanaa B; Ali, Sahar A; Hegazy, Mohamed I; El Sharkawi, Fathia Z

2018-04-01

Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, noninvasive, inexpensive, and efficient diagnostic tool for various human diseases. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). The objective was to investigate the level of some urinary metabolites (urea, uric acid and hippuric acid) in patients with MS and correlate their levels to the severity of the disease, MS subtypes and MS treatment. The urine samples were collected from 73 MS patients-48 with RRMS and 25 with SPMS- and age matched 75 healthy controls. The values of urinary urea, uric acid and hippuric acid in MS patients were significantly decreased, and these metabolites in SPMS pattern showed significantly decrease than RRMS pattern. Also showed significant inverse correlation with expanded disability status scale and number of relapses. Accordingly, they may act as a potential urinary biomarkers for MS, and correlate to disease progression.

Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mínguez-Alarcón, Lidia, E-mail: lminguez@hsph.harv

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as an alternative to ortho-phthalate esters because of its favorable toxicological profile. However, the potential health effects from DINCH exposure remain largely unknown. We explored the associations between urinary concentrations of metabolites of DINCH on markers of ovarian response among women undergoing in vitro fertilization (IVF) treatments. Between 2011 and 2015, 113 women enrolled a prospective cohort study at the Massachusetts General Hospital Fertility Center and provided up to two urine samples prior to oocyte retrieval. The urinary concentrations of two DINCH metabolites, cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) andmore » cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), were quantified by isotope dilution tandem mass spectrometry. We used generalized linear mixed models to evaluate the association between urinary metabolite concentrations and markers of ovarian response, accounting for multiple IVF cycles per woman via random intercepts. On average, women with detectable urinary MHiNCH concentrations, as compared to those below LOD, had a lower estradiol levels (−325 pmol/l, p=0.09) and number of retrieved oocytes (−1.8, p=0.08), with a stronger association among older women. However, urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness. In conclusion, we found suggestive negative associations between urinary MHiNCH concentrations and peak estradiol levels and number of total oocyte yields. This is the first study evaluating the effect of DINCH exposure on human reproductive health and raises the need for further experimental and epidemiological studies to better understand the potential effects of this chemical on health. - Highlights: • Women with detectable urinary MHiNCH concentrations had a lower estradiol levels and number of retrieved oocytes. • The negative association between urinary MHiNCH concentrations and total oocyte yield was stronger in older women. • Urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness.« less

Organophosphate Urinary Metabolite Levels during Pregnancy, Delivery and Postpartum in Women Living in Agricultural Areas in Thailand

PubMed Central

Kongtip, Pornpimol; Nankongnab, Noppanun; Woskie, Susan; Phamonphon, Akkarat; Tharnpoophasiam, Prapin; Wilaiwan, Kitsiluck; Srasom, Punnee

2018-01-01

Organophosphate Urinary Metabolite Levels during Pregnancy, Delivery and Postpartum in Women Living in Agricultural Areas in Thailand: Pornpimol Kongtip, et al. Department of Occupational Health and Safety, Faculty of Public Health, Mahidol University, Thailand Objective Prenatal exposure to organophosphate pesticides can lead to developmental neurotoxicity. A longitudinal birth cohort was established to investigate pesticide exposures from different agricultural activities. Maternal urinary organophosphate metabolites were measured at 28 weeks of pregnancy (n=86), delivery (n=67) and 2 months postpartum (n=51). Method Subjects were interviewed with questionnaires about work, home and behavioral factors potentially associated with pesticide exposures, and spot urine samples were also collected. The urine samples were analyzed for dimethyl phosphate (DMP), diethyl phosphate (DEP), diethyl thiophosphate (DETP) and diethyl dithiophosphate (DEDTP), using gas chromatography-mass spectrometry. Results The urinary DMP and dialkyl phosphate (DAP) concentrations at 28 weeks of pregnancy and delivery were not significantly different, but the DMP and DAP concentrations at 28 weeks of pregnancy and DAP concentrations at delivery were significantly different (p<0.05) from those at 2 months postpartum. The factors influencing the urinary DAP concentrations at 28 weeks of pregnancy included insecticide used in the home, living close to agricultural farmland, frequency of agricultural field visits during the first and second trimesters of pregnancies, occupation of subjects, pesticide used and other agricultural activities. Conclusions The urinary organophosphate metabolites, DMP, DEP, DETP, DEDTP, total DEP and DAPs, at 28 weeks of pregnancy, delivery and 2 months postpartum fluctuated depending on their pesticide exposures both at home and in agricultural fields. PMID:23892639

Simultaneous quantification of four metabolites of sulfur mustard in urine samples by ultra-high performance liquid chromatography-tandem mass spectrometry after solid phase extraction.

PubMed

Liu, Chang-Cai; Liu, Shi-Lei; Xi, Hai-Ling; Yu, Hui-Lan; Zhou, Shi-Kun; Huang, Gui-Lan; Liang, Long-Hui; Liu, Jing-Quan

2017-04-07

Four HD urinary metabolites including hydrolysis metabolite thiodiglycol (TDG), glutathione-derived metabolite 1,1'-sulfonylbis[2-S-(N-acetylcysteinyl)ethane] (SBSNAE), as well as the β-lyase metabolites 1,1'-sulfonylbis[2-(methylsulfinyl)ethane] (SBMSE) and 1-methylsulfinyl-2-[2-(methylthio) ethylsulfonyl]ethane (MSMTESE) are considered as important biomarkers for short-term retrospective detection of HD exposure. In this study, a single method for simultaneous quantification of the four HD metabolites in urine samples was developed using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The four urinary metabolites were simultaneously extracted from urinary samples using a solid phase extraction (SPE) method with high extraction recoveries for all four metabolites varied in the range of 71.1-103% followed by UHPLC-MS/MS analysis. The SPE is simple and high effective only requiring 0.1mL of urinary samples and 0.5h time consuming. The problem of previous co-elution of TDG and SBSNAE in UHPLC was well solved, and complete separation of TDG, SBSNAE, SBMSE and MSMTESE from SPE-processed urine matrix was obtained to increase specificity and sensitivity. A full method validation was performed for each analyte in urine matrix. The linear range of calibration curves for the four analytes were respectively from 0.50-500ngmL -1 for TDG and SBSNAE, 0.05-500ngmL -1 for SBMSE and MSMTESE with coefficient of determination value (R 2 ) ≥0.990. The limit of detection was 0.25ngmL -1 for TDG and SBSNAE, 0.01ngmL -1 for SBMSE and MSMTESE spiked in normal urine. The intra/inter-day precision for each analyte at three QC levels had relative standard deviation (%RSD) of ≤10.3%, and the intra/inter-day accuracy ranged between 88.0-108%. This developed method allows for simultaneous and trace measurement of four HD urinary metabolites within one single determination with the lowest usage amount of urine samples over all previous methods This study provides a useful tool for early diagnosis and monitoring of HD poisoning for medical treatment with high confidence, avoiding the need for application of several analysis methods. Copyright © 2017 Elsevier B.V. All rights reserved.

[Gas chromatographic/mass spectrometric analysis of boldenone urinary metabolites in man].

PubMed

Zhang, J; Liu, C S; Zhou, T H

1991-01-01

The metabolism of boldenone (17 beta-hydroxy-1,4-androstem-3-one) in man has been investigated by gas chromatography/mass spectrometry. After oral administration of a 20 mg dose to man, six metabolites were detected in the conjugated fraction of the urinary samples. Boldenone, the major compound excreted in urine, was detected within 34 h after administration. In addition, several metabolites, resulting from the hydroxylation of boldenone and the reduction of the unsaturated carbon bonds of boldenone, were detected in the urine samples varying from 9 to 83 h. Extraction and fractionation of these metabolites were achieved by using XAD-2 column and gas chromatography. The recovery of the whole procedure was studied. Furthermore, the mass spectra of the metabolites are presented and major fragment pathways are discussed.

Urinary levels of estrone sulfate and 11-ketotetranor prostaglandin F metabolite in pregnant guinea pigs given Clophen A50 (polychlorinated biphenyls).

PubMed

Lundkvist, U; Kindahl, H; Madej, A

1987-02-01

The urinary levels of estrone sulfate and 11-ketotetranor prostaglandin F metabolite (11-ketotetranor PGF metabolite) during gestation in guinea pigs were measured by radioimmunoassays. Vehicle and Clophen A50 (polychlorinated biphenyls)-treated animals were compared. Gestation was arbitrarily divided into four periods, and the mean hormone levels during each period were compared between the two treatment groups. The Clophen A50 treatment (100 mg total, during Days 16-60), which causes fetal death, was correlated to significantly higher levels of estrone sulfate (p less than 0.05) and 11-ketotetranor PGF metabolite (p less than 0.01) during Days 47-60 (Period IV) of gestation.

COMPARATIVE TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC (IAS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV) AND ARSENITE (ASIII)

EPA Science Inventory

COMPARATIVE TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC (iAs) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (AsV) AND ARSENITE (AsIII). E M Kenyon, L M Del Razo and M F Hughes. U.S. EPA, ORD, NHEERL, ETD, PKB, RTP, NC, USA; ...

Reliability of concentrations of organophosphate pesticide metabolites in serial urine specimens from pregnancy in the Generation R study

PubMed Central

Spaan, Suzanne; Pronk, Anjoeka; Koch, Holger M.; Jusko, Todd A.; Jaddoe, Vincent W.V.; Shaw, Pamela A.; Tiemeier, Henning M.; Hofman, Albert; Pierik, Frank H.; Longnecker, Matthew P.

2014-01-01

The widespread use of organophosphate (OP) pesticides has resulted in ubiquitous exposure in humans, primarily through their diet. Exposure to OP pesticides may have adverse health effects, including neurobehavioral deficits in children. The optimal design of new studies requires data on the reliability of urinary measures of exposure. In the present study, urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined in 120 pregnant women participating in the Generation R Study in Rotterdam. Intra-class correlation coefficients (ICCs) across serial urine specimens taken at <18, 18–25, and >25 weeks of pregnancy were determined to assess reliability. Geometric mean total DAP metabolite concentrations were 229 (GSD 2.2), 240 (GSD 2.1), and 224 (GSD 2.2) nmol/g creatinine across the three periods of gestation. Metabolite concentrations from the serial urine specimens in general correlated moderately. The ICCs for the six DAP metabolites ranged from 0.14 to 0.38 (0.30 for total DAPs), indicating weak to moderate reliability. Although the DAP metabolite levels observed in this study are slightly higher and slightly more correlated than in previous studies, the low to moderate reliability indicates a high degree of within-person variability, which presents challenges for designing well-powered epidemiologic studies. PMID:25515376

Airborne arsenic and urinary excretion of arsenic metabolites during boiler cleaning operations in a Slovak coal-fired power plant.

PubMed Central

Yager, J W; Hicks, J B; Fabianova, E

1997-01-01

Little information is available on the relationship between occupational exposure to inorganic arsenic in coal fly ash and urinary excretion of arsenic metabolites. This study ws undertaken in a coal-fired power plant in Slovakia during a routine maintenance outage. Arsenic was measured in the breathing zone of workers during 5 consecutive workdays, and urine samples were obtained for analysis of arsenic metabolites--inorganic arsenic (Asi), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)--prior to the start of each shift. Results from a small number of cascade impactor air samples indicated that approximately 90% of total particle mass and arsenic was present in particle size fractions >/= 3.5 micron. The 8-hr time-weighted average (TWA) mean arsenic air concentration was 48.3 microg/m3 (range 0.17-375.2) and the mean sum of urinary arsenic (SigmaAs) metabolites was 16.9 microg As/g creatinine (range 2.6-50.8). For an 8-hr TWA of 10 microg/m3 arsenic from coal fly ash, the predicted mean concentration of the SigmaAs urinary metabolites was 13.2 microg As/G creatinine [95% confidence interval (CI), 10.1-16.3). Comparisons with previously published studies of exposure to arsenic trioxide vapors and dusts in copper smelters suggest that bioavailability of arsenic from airborne coal fly ash (as indicated by urinary excretion) is about one-third that seen in smelters and similar settings. Arsenic compound characteristics, matrix composition, and particle size distribution probably play major roles in determining actual uptake of airborne arsenic. Images Figure 1. A Figure 1. B Figure 2. PMID:9347899

Urinary Metabolomic Profiling to Identify Potential Biomarkers for the Diagnosis of Behcet's Disease by Gas Chromatography/Time-of-Flight-Mass Spectrometry.

PubMed

Ahn, Joong Kyong; Kim, Jungyeon; Hwang, Jiwon; Song, Juhwan; Kim, Kyoung Heon; Cha, Hoon-Suk

2017-11-02

Diagnosing Behcet's disease (BD) is challenging because of the lack of a diagnostic biomarker. The purposes of this study were to investigate distinctive metabolic changes in urine samples of BD patients and to identify urinary metabolic biomarkers for diagnosis of BD using gas chromatography/time-of-flight-mass spectrometry (GC/TOF-MS). Metabolomic profiling of urine samples from 44 BD patients and 41 healthy controls (HC) were assessed using GC/TOF-MS, in conjunction with multivariate statistical analysis. A total of 110 urinary metabolites were identified. The urine metabolite profiles obtained from GC/TOF-MS analysis could distinguish BD patients from the HC group in the discovery set. The parameter values of the orthogonal partial least squared-discrimination analysis (OPLS-DA) model were R ² X of 0.231, R ² Y of 0.804, and Q ² of 0.598. A biomarker panel composed of guanine, pyrrole-2-carboxylate, 3-hydroxypyridine, mannose, l-citrulline, galactonate, isothreonate, sedoheptuloses, hypoxanthine, and gluconic acid lactone were selected and adequately validated as putative biomarkers of BD (sensitivity 96.7%, specificity 93.3%, area under the curve 0.974). OPLS-DA showed clear discrimination of BD and HC groups by a biomarker panel of ten metabolites in the independent set (accuracy 88%). We demonstrated characteristic urinary metabolic profiles and potential urinary metabolite biomarkers that have clinical value in the diagnosis of BD using GC/TOF-MS.

Determination of N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine and its metabolites in human plasma and urine by column-switching high-performance liquid chromatography with ultraviolet detection.

PubMed

Ono, I; Matsuda, K; Kanno, S

1997-05-09

A simple, rapid and sensitive two column-switching high-performance liquid chromatographic (HPLC) method with ultraviolet detection at 210 nm has been developed for the determination of N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (AY4166, I) and its seven metabolites in human plasma and urine. Measurements of I and its metabolites were carried out by two column-switching HPLC, because metabolites were classified into two groups according to their retention times. After purification of plasma samples using solid-phase extraction and direct dilution of urinary samples, I and each metabolite were injected into HPLC. The calibration graphs for plasma and urinary samples were linear in the ranges 0.1 to 10 microg ml(-1) and 0.5 to 50 microg ml(-1), respectively. Recoveries of I and its seven metabolites were over 88% by the standard addition method and the relative standard deviations of I and its metabolites were 1-6%.

Women’s exposure to phthalates in relation to use of personal care products

PubMed Central

Parlett, Lauren E.; Calafat, Antonia M.; Swan, Shanna H.

2014-01-01

Background Several phthalates, particularly diethyl phthalate (DEP) and di-n-butyl phthalate (DnBP), can be used in personal care products (PCPs) to fix fragrance and hold color. We investigated associations between women’s reported use of personal care products within the 24 hours prior to urine collection and concentrations of several urinary phthalate metabolites. Methods Between 2002–2005, 337 women provided spot urine samples and answered questions regarding their use of thirteen PCPs at a follow-up visit 3–36 months after pregnancy. We examined associations between urinary concentrations of several phthalate metabolites and use of PCPs using linear regression. Results Use of individual PCPs ranged from 7% (nail polish) to 91% (deodorant). After adjusting for age, education, and urinary creatinine, women reporting use of perfume had 2.92 times higher (95% CI: 2.20–3.89) concentration of monoethyl phthalate (MEP, the primary metabolite of diethyl phthalate) than other women. Other PCPs that were significantly associated with MEP included: hair spray, nail polish, and deodorant. MEP concentrations increased with the number of PCPs used. Conclusion PCP use was widespread in this group of recently pregnant women. Women’s use of PCPs, particularly of perfumes and fragranced products, was positively associated with urinary concentration of multiple phthalate metabolites. PMID:23168567

Sex Differences in the Association of Urinary Concentrations of Phthalates Metabolites with Self-Reported Diabetes and Cardiovascular Diseases in Shanghai Adults.

PubMed

Dong, Ruihua; Zhao, Shanzhen; Zhang, Han; Chen, Jingsi; Zhang, Meiru; Wang, Min; Wu, Min; Li, Shuguang; Chen, Bo

2017-06-05

Phthalate exposure was reported to be associated with diabetes mellitus (DM) and cardiovascular disease (CVD). Yet, reported associations and the potential sex differences are inconsistent. We conducted a cross-sectional study involving 2330 participants in the Fall of 2012. Urinary metabolites of 10 phthalates were measured. The status of having DM and CVD-related outcomes were self-reported. In the overall study population, the logistic regression analyses showed that the urinary levels of mono-2-ethyl-5-oxohexyphthalate (MEOHP), mono-2-ethyl-5-hydroxyhexylphthalate(MEHHP) and mono-2-ethyl-5-carboxypentylphthalate (MECPP) were positively associated with DM. Higher urinary levels of monomethyl phthalate (MMP) and mono-2-carboxymethyl-hexyl phthalate (MCMHP) were associated with increased odds of hyperlipidemia, while mono-2-ethylhexylphthalate (MEHP) was significantly inverse-associated with hyperlipidemia. We did not observe significant associations for other CVD-related outcomes with phthalate metabolites. When stratifying by sex, MEHHP, MEOHP, MECPP, MCMHP and the micromolar sums of the oxidative metabolites of DEHP (ΣDEHP ox ) were all significantly related to DM in males, but not in females. No significant sex differences were found in CVD-related outcomes, except the sporadic associations between phthalates and hyperlipidemia. These findings highlight the importance of investigating the sex-specific relationship between phthalates exposure and DM.

Human urinary excretion profile after smoking and oral administration of ( sup 14 C)delta 1-tetrahydrocannabinol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johansson, E.; Gillespie, H.K.; Halldin, M.M.

The urinary excretion profiles of delta 1-tetrahydrocannabinol (delta 1-THC) metabolites have been evaluated in two chronic and two naive marijuana users after smoking and oral administration of ({sup 14}C)delta 1-THC. Urine was collected for five days after each administration route and analyzed for total delta 1-THC metabolites by radioactivity determination, for delta 1-THC-7-oic acid by high-performance liquid chromatography, and for cross-reacting cannabinoids by the EMIT d.a.u. cannabinoid assay. The average urinary excretion half-life of {sup 14}C-labeled delta 1-THC metabolites was calculated to be 18.2 +/- 4.9 h (+/- SD). The excretion profiles of delta 1-THC-7-oic acid and EMIT readings weremore » similar to the excretion profile of {sup 14}C-labeled metabolites in the naive users. However, in the chronic users the excretion profiles of delta 1-THC-7-oic acid and EMIT readings did not resemble the radioactive excretion due to the heavy influence from previous Cannabis use. Between 8-14% of the radioactive dose was recovered in the urine in both user groups after oral administration. Lower urinary recovery was obtained both in the chronic and naive users after smoking--5 and 2%, respectively.« less

Relation of dietary inorganic arsenic exposure and urinary inorganic arsenic metabolites excretion in Japanese subjects.

PubMed

Oguri, Tomoko; Yoshinaga, Jun; Suzuki, Yayoi; Tao, Hiroaki; Nakazato, Tetsuya

2017-06-03

Inorganic arsenic (InAs) is a ubiquitous metalloid that has been shown to exert multiple adverse health outcomes. Urinary InAs and its metabolite concentration has been used as a biomarker of arsenic (As) exposure in some epidemiological studies, however, quantitative relationship between daily InAs exposure and urinary InAs metabolites concentration has not been well characterized. We collected a set of 24-h duplicated diet and spot urine sample of the next morning of diet sampling from 20 male and 19 female subjects in Japan from August 2011 to October 2012. Concentrations of As species in duplicated diet and urine samples were determined by using liquid chromatography-ICP mass spectrometry with a hydride generation system. Sum of the concentrations of urinary InAs and methylarsonic acid (MMA) was used as a measure of InAs exposure. Daily dietary InAs exposure was estimated to be 0.087 µg kg -1 day -1 (Geometric mean, GM), and GM of urinary InAs+MMA concentrations was 3.5 ng mL -1 . Analysis of covariance did not find gender-difference in regression coefficients as significant (P > 0.05). Regression equation Log 10 [urinary InAs+MMA concentration] = 0.570× Log 10 [dietary InAs exposure level per body weight] + 1.15 was obtained for whole data set. This equation would be valuable in converting urinary InAs concentration to daily InAs exposure, which will be important information in risk assessment.

Evaluation of Temporal Changes in Urine-based Metabolomic and Kidney Injury Markers to Detect Compound Induced Acute Kidney Tubular Toxicity in Beagle Dogs.

PubMed

Wagoner, M P; Yang, Y; McDuffie, J E; Klapczynski, M; Buck, W; Cheatham, L; Eisinger, D; Sace, F; Lynch, K M; Sonee, M; Ma, J-Y; Chen, Y; Marshall, K; Damour, M; Stephen, L; Dragan, Y P; Fikes, J; Snook, S; Kinter, L B

2017-01-01

Urinary protein biomarkers and metabolomic markers have been leveraged to detect acute Drug Induced Kidney Injury (DIKI) in rats; however, the utility of these indicators to enable early detection of DIKI in canine models has not been well documented. Therefore, we evaluated temporal changes in biomarkers and metabolites in urine from male and female beagle dogs. Gentamicin- induced kidney lesions in male dogs were characterized by moderate to severe tubular epithelial cell degeneration/necrosis, epithelial cell regeneration and dilation; and a unique urinebased metabolomic fingerprint. These metabolite changes included time and treatment-dependent increases in lactate, taurine, glucose, lactate, alanine, and citrate as well as 9 other known metabolites. As early as 3 days post dose, gentamicin induced increases in urinary albumin, clusterin, neutrophil gelatinase associated protein (NGAL) and total protein concentrations. Urinary albumin, clusterin, and NGAL showed earlier and more robust elevations than traditional kidney safety biomarkers, blood urea nitrogen and serum creatinine. Elevations in urinary kidney injury molecule 1 (KIM-1) were less reliable for detection of gentamicin nephrotoxicity in dogs based on values generated utilizing multiple first-generation, canine-specific KIM-1 immunoassays. The metabolic fingerprint was further evaluated in male and female dogs that received Compound A which induced slightly reversible renal tubular alterations characterized as degeneration/necrosis and concurrent significant increases in urinary taurine amongst other markers. These data support further investigations to demonstrate the value of urinary metabolites, albumin, clusterin, NGAL and taurine as promising markers to enable early detection of DIKI in dogs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Clinical benefits of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease are not related to urinary eicosanoid release and are accompanied with decreased urine creatinine.

PubMed

Makowska, Joanna S; Olszewska-Ziąber, Agnieszka; Bieńkiewicz, Barbara; Lewandowska-Polak, Anna; Kurowski, Marcin; Woźniakowski, Bartłomiej; Rotkiewicz, Arkadiusz; Kowalski, Marek L

2016-05-01

Treatment with acetylsalicylic acid (ASA) after desensitization may be a therapeutic option in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD). The mechanisms that lead to improvement in rhinosinusitis and asthma symptoms remain unknown. To attribute the documented clinical effects of ASA treatment of chronic rhinosinusitis and/or asthma to the release of eicosanoid metabolites in urine. Fourteen patients with NERD were successfully desensitized, and, eventually, eight patients were treated with 650 mg of ASA daily for 3 months. In addition to clinical assessments, nuclear magnetic resonance imaging and smell test were performed before and after treatment with ASA. Venous blood and urine were collected before desensitization and after 1 and 3 months of treatment. The levels of urinary leukotrienes (LT) (cysteinyl LT and LTE4) and tetranor PGDM (metabolite of prostaglandin D2) were measured by enzyme-linked immunosorbent assay. Treatment with ASA after desensitization alleviated symptoms of rhinosinusitis, improved nasal patency (mean, 50% decrease in peak nasal inspiratory flow) and sense of smell (fourfold increase in smell test score) in as early as 4 weeks. Clinical improvements were not accompanied by any change in sinonasal mucosa thickness as assessed with nuclear magnetic resonance. Urinary cysteinyl LTs, LTE4, and prostaglandin D2 metabolite remained relatively stable during ASA treatment and did not correlate with clinical improvements. Desensitization was associated with a progressive decrease of urinary creatinine. Clinical improvement in rhinosinusitis and/or asthma after ASA desensitization was not related to concentrations of urinary eicosanoid metabolites. A decrease of urinary creatinine requires further study to determine the renal safety of long-term treatment with ASA after desensitization.

Phthalates and risk of endometriosis

PubMed Central

Upson, Kristen; Sathyanarayana, Sheela; De Roos, Anneclaire J.; Thompson, Mary Lou; Scholes, Delia; Dills, Russell; Holt, Victoria L.

2013-01-01

Background Phthalates are ubiquitous environmental chemicals with endocrine disruptive properties. The impact of these chemicals on endocrine-related disease in reproductive-age women is not well understood. Objective To investigate the relationship between urinary phthalate metabolite concentrations and the risk of a hormonally-driven disease, endometriosis, in reproductive-age women. Methods We used data from a population-based case-control study of endometriosis, conducted among female enrollees of a large healthcare system in the U.S. Pacific Northwest. We measured urinary phthalate metabolite concentrations on incident, surgically-confirmed cases (n=92) diagnosed between 1996 and 2001 and population-based controls (n=195). Odds ratios (OR), and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for urinary creatinine concentrations, age, and reference year. Results The majority of women in our study had detectable concentrations of phthalate metabolites. We observed a strong inverse association between urinary mono-(2-ethyl-5-hexyl) phthalate (MEHP) concentration and endometriosis risk, particularly when comparing the fourth and first MEHP quartiles (aOR 0.3, 95% CI: 0.1–0.7). Our data suggested an inverse association between endometriosis and urinary concentrations of other di-2-ethylhexyl phthalate (DEHP) metabolites (mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP)) and ΣDEHP, however, the confidence intervals include the null. Our data also suggested increased endometriosis risk with greater urinary concentrations of mono-benzyl phthalate (MBzP) and mono-ethyl phthalate (MEP), although the associations were not statistically significant. Conclusions Exposure to select phthalates is ubiquitous among female enrollees of a large healthcare system in the U.S. Pacific Northwest. The findings from our study suggest that phthalates may alter the risk of a hormonally-mediated disease among reproductive-age women. PMID:23890968

URINARY MUTAGENICITY: A BIOMARKER OF GENOTOXIC EXPOSURES VIA AIR, WATER, AND DIET

EPA Science Inventory

During the past 30 years, ~100 studies have evaluated human urine for mutagenic activity using the Salmonella (Ames) mutagenicity assay. Urinary mutagenicity has been shown to correlate well with other biomarkers, including DNA and hemoglobin adducts, urinary metabolites, and chr...

Assessment of exposure to organophosphate insecticides during spraying in Haiti: monitoring of urinary metabolites and blood cholinesterase levels*

PubMed Central

Warren, McWilson; Spencer, Harrison C.; Churchill, Frederick C.; Francois, Velly Jean; Hippolyte, Robert; Staiger, Michael A.

1985-01-01

Measurement of blood cholinesterase activity and of the urinary metabolites of fenitrothion (p-nitrocresol) and malathion (monocarboxylic acid) was used to assess the exposure to these insecticides of workers in the Haitian malaria control programme and of residents in the sprayed houses. Cholinesterase activity was significantly reduced at the end of the working week in 3 out of 28 fenitrothion workers. Urinary levels of p-nitrocresol (PNC) in the spraymen ranged from 2.2 to 25.2 mg/l. In fenitrothion workers who had no direct contact with spraying (weighers and supervisors), the cholinesterase activity remained ≥ 75% of the normal control value, and the urinary PNC levels were relatively low. Urinary malathion monocarboxylic acid (MCA) levels at the end of the working week ranged between 1.1 and 5.3 mg/l in workers using malathion and their blood cholinesterase activity remained essentially normal. In both groups of workers the cholinesterase levels improved and the urinary excretion of metabolites decreased after 2 days of rest from the spraying operations. In the residents of the sprayed houses, low concentrations of PNC and MCA were detected in the urine 1 day after spraying and measurable but reduced levels were still present after 7 days. In all these cases the cholinesterase activity remained ≥ 75% of the normal control value. PMID:3874716

Fecal glucocorticoid metabolites and assay validation: Stress response evaluation in captive brown howler monkeys (Alouatta clamitans).

PubMed

Eleonora Madeira Buti, Thais; Kugelmeier, Tatiana; Sobral, Gisela; Viau Furtado, Priscila; do Valle Dutra de Andrade Neves, Dafne; Alvarenga de Oliveira, Claudio

2018-04-25

The advent of non-invasive methods provides a powerful alternative to stress studies as the use of stressful handling techniques is no longer needed. However, many factors influence hormone metabolism such as sex, diet, and metabolic rate. Thus, validation should be species- and matrix-specific. To assess stress response in brown howler monkeys Alouatta clamitans, we adopted an ACTH challenge test and parallelism to provide physiological and laboratorial validation. Radioimmunoassay was used to measure fecal levels of corticosterone. All challenged animals presented a peak in fecal glucocorticoids levels the day after the treatment, while control animals did not. There were no significant sex differences, but females with infants had higher levels of corticosterone. Corticosterone levels showed parallelism to the standard curve of the diagnostics kit. Collectively, the data suggest that the method was validated and is useful for monitoring stress, thereby helping in conservation programs both in captivity and in the wild. Transit time information may be coupled with travel distance in seed dispersal studies. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Acclimatization of mice to different cage types and social groupings with respect to fecal secretion of IgA and corticosterone metabolites.

PubMed

Bundgaard, Cathrine Juel; Kalliokoski, Otto; Abelson, Klas S P; Hau, Jann

2012-01-01

Stress associated with transport and change of environment may have widespread effects on physiological parameters in laboratory animals. To investigate the time needed for mice to acclimatize to a new environment, based on fecal IgA and corticosterone excretion, eightweek-old BALB/c mice of both genders were housed either in groups of eight in different cage types in open conventional cages, in Individual Ventilated Cages (IVC), in open conventional cages inside a plastic isolator, or in different group sizes (8, 4, 8, 10 or 12 mice in each group) in open conventional cages. Feces were collected from each cage on routine cage changing. There was no significant difference in corticosterone excretion in feces between animals housed in the different cage types or between animals housed in different group sizes. IgA excretion for both males and females was found to be affected by transfer of mice into a novel cage, and it was found that it takes at least four weeks for the mice to acclimatize to a new environment with respect to this parameter.

TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC AND ITS METHYLATED METABOLITES IN C57BL/6 MICE FOLLOWING SUBCHRONIC EXPOSURE TO ARSENATE (ASV) IN DRINKING WATER

EPA Science Inventory

The relationship of exposure and tissue concentration of parent chemical and metabolites over prolonged exposure is a critical issue for chronic toxicities mediated by metabolite(s) rather than parent chemical alone. This is an issue for AsV because its trivalent metabolites hav...

Urinary Polycyclic Aromatic Hydrocarbon (OH-PAH) Metabolite Concentrations and the Effect of GST Polymorphisms Among US Air Force Personnel Exposed to Jet Fuel

PubMed Central

Rodrigues, Ema G.; Smith, Kristen; Maule, Alexis L.; Sjodin, Andreas; Li, Zheng; Romanoff, Lovisa; Kelsey, Karl; Proctor, Susan; McClean, Michael D.

2016-01-01

Objective To evaluate the association between inhalation exposure to jet propulsion fuel 8 (JP-8) and urinary metabolites among US Air Force (USAF) personnel, and investigate the role of glutathione S-transferase polymorphisms. Methods Personal air samples were collected from 37 full-time USAF personnel during 4 consecutive workdays and analyzed for JP-8 constituents and total hydrocarbons. Pre- and postshift urine samples were collected each day and analyzed for polycyclic aromatic hydrocarbon urinary metabolites. Results Work shift exposure to total hydrocarbons was significantly associated with postshift urinary 1-naphthol (β = 0.17; P = <0.0001), 2-naphthol (β = 0.09; P = 0.005), and 2-hydroxyfluorene concentrations (β = 0.08; P = 0.006), and a significant gene-environment interaction was observed with glutathione S-transferase mu-1. Conclusions USAF personnel experience inhalation exposure to JP-8, which is associated with absorption of JP-8 constituents while performing typical job-related tasks, and in our data the glutathione S-transferase mu-1 polymorphism was associated with differential metabolism of naphthalene. PMID:24806557

Urinary polycyclic aromatic hydrocarbon (OH-PAH) metabolite concentrations and the effect of GST polymorphisms among US Air Force personnel exposed to jet fuel.

PubMed

Rodrigues, Ema G; Smith, Kristen; Maule, Alexis L; Sjodin, Andreas; Li, Zheng; Romanoff, Lovisa; Kelsey, Karl; Proctor, Susan; McClean, Michael D

2014-05-01

To evaluate the association between inhalation exposure to jet propulsion fuel 8 (JP-8) and urinary metabolites among US Air Force (USAF) personnel, and investigate the role of glutathione S-transferase polymorphisms. Personal air samples were collected from 37 full-time USAF personnel during 4 consecutive workdays and analyzed for JP-8 constituents and total hydrocarbons. Pre- and postshift urine samples were collected each day and analyzed for polycyclic aromatic hydrocarbon urinary metabolites. Work shift exposure to total hydrocarbons was significantly associated with postshift urinary 1-naphthol (β = 0.17; P = <0.0001), 2-naphthol (β = 0.09; P = 0.005), and 2-hydroxyfluorene concentrations (β = 0.08; P = 0.006), and a significant gene-environment interaction was observed with glutathione S-transferase mu-1. USAF personnel experience inhalation exposure to JP-8, which is associated with absorption of JP-8 constituents while performing typical job-related tasks, and in our data the glutathione S-transferase mu-1 polymorphism was associated with differential metabolism of naphthalene.

Exposure of flight attendants to pyrethroid insecticides on commercial flights: urinary metabolite levels and implications

PubMed Central

Wei, Binnian; Mohan, Krishnan R.; Weisel, Clifford P.

2011-01-01

Pyrethroid insecticides have been used for disinsection of commercial aircrafts. However, little is known about the pyrethroids exposure of flight attendants. The objective of the study was to assess pyrethroids exposure of flight attendants working on commercial aircrafts through monitoring the urinary pyrethroids metabolite levels. Eighty four urine samples were collected from 28 flight attendants, 18 – 65 years of age, with seventeen working on planes that were non-disinsected, and eleven working on planes that had been disinsected. Five urinary metabolites of pyrethroids were measured using gas chromatographic–mass spectrometric method: 3-phenoxybenzoic acid (3-PBA), cis-/trans-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclo-propane carboxylic acid (cis-/trans-Cl2CA), cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclo-propane-1-carboxylic acid (cis-Br2CA) and 4-fluoro-3-phenoxybenzoic acid (4F-3-PBA). Flight attendants working on disinsected planes had significantly higher urinary levels of 3-PBA, cis- and trans-Cl2CA in pre, post- and 24hr-post flight samples than those on planes which did not report having been disinsected. Urinary levels of cis-Br2CA and 4F-3-PBA did not show significant differences between the two groups. Flight attendants working on international flights connected to Australia had higher urinary levels of 3-PBA, cis- and trans-Cl2CA than those on either domestic and other international flights flying among Asia, Europe and North America. Post-disinsection duration (number of days from disinsection date to flight date) was the most significant factor affecting the urinary pyrethroid metabolites levels of 3-PBA, cis- and trans-Cl2CA of the group flying on disinsected aircraft. It was concluded that working on commercial aircrafts disinsected by pyrethroids resulted in elevated body burden of 3-PBA, cis- and trans-Cl2CA. PMID:21937269

Biochemical diagnosis of phaeochromocytoma: two instructive case reports.

PubMed Central

Stewart, M F; Reed, P; Weinkove, C; Moriarty, K J; Ralston, A J

1993-01-01

The biochemical features of two patients with phaeochromocytomas illustrate the inadvisability of depending on a single group of analytes for the diagnosis. The first case presented as a surgical emergency with retroperitoneal haemorrhage. Biochemical diagnosis was difficult since total 24 hour urinary free catecholamine excretion was within normal limits in two out of three samples, and only marginally raised in the third with an atypical preponderance of adrenaline. Plasma catecholamine concentrations were also normal. But urinary excretion of the catecholamine metabolites, metadrenaline and 4-hydroxy-3-methoxy mandelic acid (HMMA), was consistently raised. In contrast, the second patient presenting with headache and labile hypertension showed normal metabolite excretion in the face of grossly increased free noradrenaline excretion and raised plasma noradrenaline concentrations. It is therefore recommend that, as well as urinary free catecholamines, one group of their main metabolites, the 3-methoxy amines (normetadrenaline and metadrenaline) or HMMA, should routinely be measured whenever a phaeochromocytoma is suspected. PMID:8463426

Job Demands & Pesticide Exposure among Immigrant Latino Farmworkers

PubMed Central

Grzywacz, Joseph G.; Quandt, Sara A.; Vallejos, Quirina M.; Whalley, Lara E.; Chen, Haiying; Isom, Scott; Barr, Dana B.; Arcury, Thomas A.

2010-01-01

The goal of this study was to understand the potential threat of job stressors to farmworker health. To accomplish this goal we studied pesticide exposure, an issue with immediate and long-term health consequences, and predictions from the demands-control model of occupational stress. Longitudinal, self-report data and urine samples were collected at monthly intervals from a cohort of Latino farmworkers (N=287) during the 2007 agricultural season. The primary hypothesis was that greater exposure to psychological demands, physical exertion, and hazardous work conditions are associated with greater odds of detecting DAP urinary pesticide metabolites, biomarkers indicating exposure to pesticides. Contrary to this hypothesis, results indicated that none of the elements of the Demands-Control model were independently associated with detection of DAP urinary pesticide metabolites. However, analyses produced several interaction effects, including evidence that high levels of control may buffer the effects of physical job demands on detection of DAP urinary pesticide metabolites. PMID:20604632

Predictors of Urinary 3-Phenoxybenzoic Acid Levels in 50 North Carolina Adults

EPA Science Inventory

Limited data are available on the non-chemical stressors that impact adult exposures to pyrethroid insecticides based on urinary biomonitoring. The urinary metabolite, 3-phenoxybenzoic acid (3-PBA), is commonly used to assess human exposure to a number of pyrethroids. In a furthe...

Determination of Urinary PAH Metabolites Using DLLME Hyphenated to Injector Port Silylation and GC-MS-MS.

PubMed

Gupta, Manoj Kumar; Jain, Rajeev; Singh, Pratibha; Ch, Ratnasekhar; Mudiam, Mohana Krishna Reddy

2015-06-01

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and well-known carcinogens. Hydroxy derivatives of PAH are considered as biomarkers of PAH exposure, and there is a need to measure these metabolites at low concentrations. So, a precise and eco-friendly analytical method has been developed for rapid determination of PAH metabolites. For the first time, a new analytical method based on coupling of dispersive liquid-liquid microextraction (DLLME) with auto-injector port silylation (auto-IPS) followed by gas chromatography-tandem mass spectrometry (GC-MS-MS) analysis is reported for the analysis of seven urinary PAH metabolites. Factors affecting DLLME and IPS, such as type and volume of extraction and disperser solvent, pH, ionic strength, injector port temperature, volume of N,O-bis(trimethylsilyl)trifluoroacetamide and type of solvent were investigated. Under optimized conditions, the limit of detection and limit of quantification were found to be in the range of 1-9 and 3-29 ng/mL, respectively. Satisfactory recoveries of metabolites in urine samples in the range of 87-95% were found. The developed method has been successfully applied for the determination of PAH metabolites in urine samples of exposed workers. DLLME-auto-IPS-GC-MS-MS method is time, labor, solvent and reagent saving, which can be routinely used for the analysis of urinary PAH metabolites. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Catecholamines profiles at diagnosis: Increased diagnostic sensitivity and correlation with biological and clinical features in neuroblastoma patients.

PubMed

Verly, Iedan R N; van Kuilenburg, André B P; Abeling, Nico G G M; Goorden, Susan M I; Fiocco, Marta; Vaz, Frédéric M; van Noesel, Max M; Zwaan, C Michel; Kaspers, GertJan L; Merks, Johannes H M; Caron, Huib N; Tytgat, Godelieve A M

2017-02-01

Neuroblastoma (NBL) accounts for 10% of the paediatric malignancies and is responsible for 15% of the paediatric cancer-related deaths. Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are most commonly analysed in urine of NBL patients. However, their diagnostic sensitivity is suboptimal (82%). Therefore, we performed in-depth analysis of the diagnostic sensitivity of a panel of urinary catecholamine metabolites. Retrospective study of a panel of 8 urinary catecholamine metabolites (VMA, HVA, 3-methoxytyramine [3MT], dopamine, epinephrine, metanephrine, norepinephrine and normetanephrine [NMN]) from 301 NBL patients at diagnosis. Special attention was given to subgroups, metaiodobenzylguanidine (MIBG) non-avid tumours and VMA/HVA negative patients. Elevated catecholamine metabolites, especially 3MT, correlated with nine out of 12 NBL characteristics such as stage, age, MYCN amplification, loss of heterozygosity for 1p and bone-marrow invasion. The combination of the classical markers VMA and HVA had a diagnostic sensitivity of 84%. NMN was the most sensitive single diagnostic metabolite with overall sensitivity of 89%. When all 8 metabolites were combined, a diagnostic sensitivity of 95% was achieved. Among the VMA and HVA negative patients, were also 29% with stage 4 disease, which usually had elevation of other catecholamine metabolites (93%). Diagnostic sensitivity for patients with MIBG non-avid tumour was improved from 33% (VMA and/or HVA) to 89% by measuring the panel. Our study demonstrates that analysis of a urinary catecholamine metabolite panel, comprising 8 metabolites, ensures the highest sensitivity to diagnose NBL patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparative neurobiological effects of ibogaine and MK-801 in rats.

PubMed

Baumann, M H; Rothman, R B; Ali, S F

2000-05-01

Ibogaine is a plant-derived alkaloid with putative 'anti-addictive' properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.

In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats.

PubMed

Baumann, M H; Rothman, R B; Pablo, J P; Mash, D C

2001-05-01

Ibogaine is a naturally occurring compound with purported antiaddictive properties. When administered to primates, ibogaine is rapidly o-demethylated to form the metabolite 12-hydroxyibogamine (noribogaine). Peak blood levels of noribogaine exceed those of ibogaine, and noribogaine persists in the bloodstream for at least 1 day. Very few studies have systematically evaluated the neurobiological effects of noribogaine in vivo. In the present series of experiments, we compared the effects of i.v. administration of ibogaine and noribogaine (1 and 10 mg/kg) on motor behaviors, stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. Ibogaine caused dose-related increases in tremors, whereas noribogaine did not. Both ibogaine and noribogaine produced significant elevations in plasma corticosterone and prolactin, but ibogaine was a more potent stimulator of corticosterone secretion. Neither drug altered extracellular DA levels in the nucleus accumbens. However, both drugs increased extracellular 5-HT levels, and noribogaine was more potent in this respect. Results from in vitro experiments indicated that ibogaine and noribogaine interact with 5-HT transporters to inhibit 5-HT uptake. The present findings demonstrate that noribogaine is biologically active and undoubtedly contributes to the in vivo pharmacological profile of ibogaine in rats. Noribogaine is approximately 10 times more potent than ibogaine as an indirect 5-HT agonist. More importantly, noribogaine appears less apt to produce the adverse effects associated with ibogaine, indicating the metabolite may be a safer alternative for medication development.

Semen quality and insulin-like factor 3: Associations with urinary and seminal levels of phthalate metabolites in adult males.

PubMed

Chang, Wei-Hsiang; Wu, Meng-Hsing; Pan, Hsien-An; Guo, Pao-Lin; Lee, Ching-Chang

2017-04-01

Certain phthalates have adverse effects on male reproductive functions in animals, and potentially affect human testicular function and spermatogenesis, but little is known about the active mechanisms. We measured the urinary and seminal phthalate metabolites and explored their associations on insulin-like factor 3 (INSL3) and semen quality. Urine, blood, and semen samples were collected from the male partners of subfertile (n = 253) and fertile (n = 37) couples in a reproductive center in southern Taiwan. INSL3, reproductive hormones, semen-quality, and 11 phthalate metabolites in urine and semen were measured. There were significant correlations in the distribution pattern of metabolites, such as the relative contribution of low or high molecular weight phthalate metabolites. The significantly monotonic trends in semen volume, sperm concentration and motility were associated with increasing quartiles of INSL3 (all p-trend < 0.001). In adjusted regression models, increases in urinary phthalate metabolites levels were adversely associated with sperm concentration (monobenzyl phthalate [MBzP], mono-2-ethylhexyl phthalate [MEHP] and MEHP%), motility (MBzP and MEHP) and INSL3 (MBzP, MEHP and MEHP%) (all p < 0.01). Higher seminal phthalate metabolite levels were associated with decreases in sperm concentration (MEHP and mono-2-ethyl-5-hydroxyhexyl phthalate), motility (mono-ethyl phthalate [MEP] and di-(2-ethylhexyl) phthalate [DEHP] metabolites), normal morphology (MEP), and INSL3 (monomethyl phthalate and MEP) (all p < 0.05). Our data suggest that INSL3 secretion, reproductive hormone balance, and sperm production and quality might be simultaneously adversely affected for individuals excreting increasing levels of phthalates metabolites (especially di-ethyl phthalate, butylbenzyl phthalate, and DEHP) in urine and semen samples. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of biological and behavioral factors on urinary arsenic ...

EPA Pesticide Factsheets

Abstract In older men and women who were long-term residents of Churchill County, Nevada, we examined the relation between arsenic exposure from home tap water and urinary levels of inorganic arsenic and its methylated metabolites. Over a wide exposure range (up to 1850 ug of arsenic per liter), urinary concentrations of inorganic, monomethylated, and dimethylated arsenicals strongly correlated with home tap water arsenic concentrations. However, percentages of summed urinary concentrations of inorganic, monomethylated, and dimethylated arsenicals accounted for by each arsenical species were unaffected by arsenic concentration in home tap water, suggesting thc1t capacity for formation and excretion of methylated metabolites was not exceeded. Biological factors (gender, age, body mass index, and genotype) and a behavioral factor (smoking) influenced absolute and relative levels of arsenicals in urine. A multivariate regression model showed that both biological and behavioral factors were significant predictors of absolute and relative concentrations of inorganic arsenic and its methylated metabolites in urine. These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for these biological and behavioral factors. Furthermore, evidence of significant effects of these factors on arsenic metabolism may support mode of action studies in appropriate experimental models. Running title- Methylated arsenicals as urinary b

Decreasing urinary organophosphate pesticide metabolites among pregnant women and their offspring in Jerusalem: Impact of regulatory restrictions on agricultural organophosphate pesticides use?

PubMed

Ein-Mor, Eliana; Ergaz-Shaltiel, Zivanit; Berman, Tamar; Göen, Thomas; Natsheh, Juma; Ben-Chetrit, Avraham; Haimov-Kochman, Ronit; Calderon-Margalit, Ronit

2018-06-01

Maternal urinary levels of dialkyl phosphate (DAP) metabolites of organophosphate pesticides (OP) during pregnancy are associated with adverse outcomes in the offspring. Between 2012 and 2014, eighteen active OP ingredients were restricted or banned in Israel for agricultural use. We aimed to study trends of urinary DAP metabolites among pregnant women and their offspring in the era of the new regulations. Pregnant women were recruited at 11-18 weeks of gestation and provided spot urine samples (n = 273). Soon after birth, neonatal urine samples were collected (n = 107). All urine specimens analyzed for DAP metabolites. Trends in DAP metabolites were tested using Mann-Kendall trend statistic (M-K S) and linear regression models were constructed to estimate the association between calendar period and DAP levels between September 2012 and March 2016. Over the study period, median maternal ∑DAP levels decreased from 248 nmol/L to 148 nmol/L. Time of recruitment was associated with a statistically significant decrease in DAP metabolites, which remained significant after multivariate adjustment. Overall, the results for the analysis of before and after June 2014 showed a significant decrease in ∑DAP of -0.198 log10 nmol/L (95%CI: -0.311,-0.084) which corresponds with a decrease of 36.6% in ∑DAP. A similar trend was found for DAP metabolites in neonatal urine. Compared to other studies, pregnant women in Jerusalem had higher ∑DAP levels, even at the end of the study period. We observed significant reductions in maternal and neonatal DAP urinary levels during the period of 2012-2016. Regulations restricting agricultural use of OP seem to be effective in reducing population exposure to OP, in an era when residential use of OP is banned. Copyright © 2018 Elsevier GmbH. All rights reserved.

Using urinary biomarkers to evaluate polycyclic hydrocarbon exposures in 126 preschool children in Ohio

EPA Science Inventory

Limited data exist on exposures of young children to polycyclic aromatic hydrocarbons (PAHs) in the United States (US). The urinary metabolite of pyrene, 1-hydroxypyrene (1-OHPyr), is widely used as a biomarker of total PAH exposure. Our objectives were to quantify urinary 1-OHPy...

Antiadhesive Activity and Metabolomics Analysis of Rat Urine after Cranberry (Vaccinium macrocarpon Aiton) Administration.

PubMed

Peron, Gregorio; Pellizzaro, Anna; Brun, Paola; Schievano, Elisabetta; Mammi, Stefano; Sut, Stefania; Castagliuolo, Ignazio; Dall'Acqua, Stefano

2017-07-19

Cranberry (Vaccinium macrocarpon Aiton) is used to treat noncomplicated urinary tract infections (UTIs). A-type procyanidins (PAC-A) are considered the active constituents able to inhibit bacterial adhesion to the urinary epithelium. However, the role of PAC-A in UTIs is debated, because of their poor bioavailability, extensive metabolism, limited knowledge about urinary excretion, and contradictory clinical trials. The effects of 35-day cranberry supplementation (11 mg/kg PAC-A, 4 mg/kg PAC-B) were studied in healthy rats using a ultra performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics approach. Microbial PAC metabolites, such as valeric acid and valerolactone derivatives, were related to cranberry consumption. An increased urinary excretion of glucuronidated metabolites was also observed. In a further experiment, urine samples were collected at 2, 4, 8, and 24 h after cranberry intake and their antiadhesive properties were tested against uropathogenic Escherichia coli. The 8 h samples showed the highest activity. Changes in urinary composition were studied by ultra performance liquid chromatography-time-of-flight (UPLC-QTOF), observing the presence of PAC metabolites. The PAC-A2 levels were measured in all collected samples, and the highest amounts, on the order of ng/mL, were found in the samples collected after 4 h. Results indicate that the antiadhesive activity against uropathogenic bacteria observed after cranberry consumption is ascribable to PAC-A metabolites rather than to a direct PAC-A effect, as the measured PAC-A levels in urine was lower than those reported as active in the literature.

TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ACUTE ORAL ADMINISTRATION OF ARSENATE

EPA Science Inventory

ABSTRACT The relationship of exposure dose and tissue concentration of parent chemical and metabolites is a critical issue in cases where toxicity may be mediated by a metabolite or parent chemical and metabolite acting together. This has emerged as an issue for inorganic ars...

Dose-response relationship between urinary polycyclic aromatic hydrocarbons metabolites and urinary 8-hydroxy-2'-deoxyguanosine in a Chinese general population.

PubMed

Sun, Huizhen; Hou, Jian; Zhou, Yun; Yang, Yuqing; Cheng, Juan; Xu, Tian; Xiao, Lili; Chen, Weihong; Yuan, Jing

2017-05-01

Association of exposure to polycyclic aromatic hydrocarbons (PAHs) with increased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation has been reported in occupational population and children. However, studies on the association between them in general population are limited. A total of 1864 eligible subjects from the baseline Wuhan participants of the Wuhan-Zhuhai Cohort Study (n = 3053) were included in this study, after excluding individuals with certain disease and missing data on urinary monohydroxy PAHs (OH-PAHs) and 8-OHdG levels. Urinary monohydroxy PAHs and 8-OHdG levels were measured by gas chromatography-mass spectrometry and high performance liquid chromatography-electrochemical detection, respectively. Association of urinary OH-PAHs with urinary 8-OHdG was analyzed by multiple linear regression analysis. We found a dose-dependent relationship between urinary PAHs metabolites and urinary 8-OHdG (p < 0.05 for all). Furthermore, more evidence for the association of total concentrations of urinary OH-PAHs with 8-OHdG levels were observed in individuals with normal body mass index or central obesity (p < 0.01 for all). There was a dose-dependent relationship between urinary OH-PAHs levels and urinary 8-OHdG levels among a general Chinese population. Exposure to background PAHs may have a greater influence on urinary 8-OHdG levels in individuals with central obesity. Copyright © 2017 Elsevier Ltd. All rights reserved.

A pilot study of the effect of human breast milk on urinary metabolome analysis in infants.

PubMed

Shoji, Hiromichi; Taka, Hikari; Kaga, Naoko; Ikeda, Naho; Kitamura, Tomohiro; Miura, Yoshiki; Shimizu, Toshiaki

2017-08-28

This study aimed to examine the nutritional effect of breast feeding on healthy term infants by using urinary metabolome analysis. Urine samples were collected from 19 and 14 infants at 1 and 6 months, respectively. Infants were separated into two groups: the breast-fed group receiving <540 mL/week of their intake from formula (n=13 at 1 month; n=9 at 6 months); and the formula-fed group receiving no breast milk (BM) (n=6 at 1 month; n=5 at 6 months). Urinary metabolome analysis was performed using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF/MS). A total of 29 metabolites were detected by CE-TOF/MS metabolome analysis in all samples. Urinary excretion of choline metabolites (choline base solution, N,N-dimethylglycine, sarcosine, and betaine) at 1 month were significantly (p<0.05) higher in breast-fed infants than in formula-fed infants. However, choline metabolites were not significantly different between the groups at 6 months. Urinary excretion of lactic acid in breast-fed infants at 1 and 6 months was significantly lower than that in formula-fed infants. Urinary l(-)-threonine and l-carnosine excretion at 1 month was significantly lower in breast-fed infants than in formula-fed infants, but it was not significantly different between the groups at 6 months. The type of feeding in early infancy affects choline metabolism, as well as lactate, threonine, and carnosine levels, in healthy term infants. Urinary metabolome analysis by the CE-TOF/MS method is useful for assessing nutritional metabolism in infants.

Parasites, stress and reindeer: infection with abomasal nematodes is not associated with elevated glucocorticoid levels in hair or faeces

PubMed Central

Carlsson, A. M.; Mastromonaco, G.; Vandervalk, E.; Kutz, S.

2016-01-01

Stress hormones (glucocorticoids), incorporated into hair/fur and faeces, have been proposed as biomarkers of overall health in wildlife. Although such biomarkers may be helpful for wildlife conservation and management, their use has rarely been validated. There is a paucity of studies examining the variation of stress hormones in mammals and how they relate to other health measures, such as parasitism. Parasites are ubiquitous in wildlife and can influence the fitness of individual animals and populations. Through a longitudinal experiment using captive reindeer (Rangifer tarandus tarandus), we tested whether animals infected with Ostertagia gruehneri, a gastrointestinal nematode with negative impacts on fitness of the host, had higher stress levels compared with those that had been treated to remove infection. Faecal samples were collected weekly for 12 weeks (June–September) and hair was collected at the start and end of the study; glucocorticoids were quantified using enzyme immunoassays. Contrary to what was expected, infected reindeer had similar levels of cortisol in hair and slightly lower glucocorticoid metabolites in faeces compared with uninfected reindeer. Faecal corticosterone levels were higher than faecal cortisol levels, and only corticosterone increased significantly after a handling event. These results suggest that reindeer may use a tolerance strategy to cope with gastrointestinal nematodes and raise the question as to whether moderate infection intensities with nematodes are beneficial to the host. By removing nematodes we may have altered the gut microbiota, leading to the observed elevated faecal glucocorticoid metabolite levels in the treated reindeer. These findings demonstrate the importance of considering both cortisol and corticosterone in physiological studies, as there is mounting evidence that they may have different functionalities. PMID:27957334

Comparative urinary androstanes in the great apes.

PubMed

Hagey, L R; Czekala, N M

2003-01-01

Urinary androstanes from seven species of male great apes (human, bonobo, chimpanzee, lowland gorilla, mountain gorilla, Bornean orangutan, and Sumatran orangutan) were separated by HPLC and detected by RIA using two testosterone antibodies. All animals examined showed the presence of testosterone and six additional immunoreactive peaks. Although testosterone was the dominant peak (85%) in human urine, its proportion in urine was much less in the other apes, ranging from a high of 59% in the bonobo and chimpanzee to a low of 24% in the mountain gorilla. Urinary androstanes were also directly visualized using nano-spray mass spectrometry (nanoESI-MS). Although the RIA can qualitatively produce a strong signal for testosterone in unchromatographed urine, it is quantitatively present only as a trace metabolite, as demonstrated by nanoESI-MS. The combination of the two techniques showed large differences in androstane metabolism between the seven species. A previously undescribed testosterone metabolite (tentatively identified as either delta1- or delta6-testosterone sulfate) was present in significant proportions in all of the non-human apes examined. We conclude that in the great apes, testosterone is only a trace metabolite in urine, and as a consequence, its measurement may not produce results that parallel the levels of serum testosterone. The RIA measurement of urinary testosterone in part records additional androstane metabolites, which vary even between closely related genera, making the results neither equivalent with nor comparable to different species.

Personal care product use and urinary phthalate metabolite and paraben concentrations during pregnancy among women from a fertility clinic

PubMed Central

Braun, Joe M.; Just, Allan C.; Williams, Paige L.; Smith, Kristen W.; Calafat, Antonia M.; Hauser, Russ

2014-01-01

Parabens and phthalates are potential endocrine disruptors frequently used in personal care/beauty products, and the developing fetus may be sensitive to these chemicals. We measured urinary butyl-paraben (BP), methyl-paraben (MP), propyl-paraben (PP), mono-n-butyl phthalate (MBP), and monoethyl phthalate (MEP) concentrations up to three times in 177 pregnant women from a fertility clinic in Boston MA. Using linear mixed models, we examined the relationship between self-reported personal care product use in the previous 24 hours and urinary paraben and phthalate metabolite concentrations. Lotion, cosmetic, and cologne/perfume use were associated with the greatest increases in the molar sum of phthalate metabolite and paraben concentrations, although the magnitude of individual biomarker increases varied by product used. For example, women who used lotion had BP concentrations 111% higher (95% confidence interval [CI]:41%, 216%) than non-users, while their MBP concentrations were only 28% higher (CI:2%, 62%). Women using/cologne/perfume had MEP concentrations 167% (CI:98%, 261%) higher than non-users, but BP concentrations were similar. We observed a monotonic dose-response relationship between the total number of products used and urinary paraben and phthalate metabolite concentrations. These results suggest that questionnaire data may be useful for assessing exposure to a mixture of chemicals from personal care products during pregnancy. PMID:24149971

Structural elucidation of new urinary tamoxifen metabolites by liquid chromatography quadrupole time-of-flight mass spectrometry.

PubMed

Lu, Jianghai; He, Chunji; He, Genye; Wang, Xiaobing; Xu, Youxuan; Wu, Yun; Dong, Ying; Ouyang, Gangfeng

2014-07-01

In this study, tamoxifen metabolic profiles were investigated carefully. Tamoxifen was administered to two healthy male volunteers and one female patient suffering from breast cancer. Urinary extracts were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry using full scan and targeted MS/MS techniques with accurate mass measurement. Chromatographic peaks for potential metabolites were selected by using the theoretical [M + H](+) as precursor ion in full-scan experiment and m/z 72, 58 or 44 as characteristic product ions for N,N-dimethyl, N-desmethyl and N,N-didesmethyl metabolites in targeted MS/MS experiment, respectively. Tamoxifen and 37 metabolites were detected in extraction study samples. Chemical structures of seven unreported metabolites were elucidated particularly on the basis of fragmentation patterns observed for these metabolites. Several metabolic pathways containing mono- and di-hydroxylation, methoxylation, N-desmethylation, N,N-didesmethylation, oxidation and combinations were suggested. All the metabolites were detected in the urine samples up to 1 week. Copyright © 2014 John Wiley & Sons, Ltd.

Urinary concentrations of organophosphate and carbamate pesticides in residents of a vegetarian community.

PubMed

Berman, T; Göen, T; Novack, L; Beacher, L; Grinshpan, L; Segev, D; Tordjman, K

2016-11-01

Few population studies have measured urinary levels of pesticides in individuals with vegan, vegetarian, or organic diets. The objectives of this study were to evaluate whether a vegan/vegetarian diet was associated with increased exposure to organophosphate and carbamate pesticides, and to evaluate the impact of organic consumption on pesticide exposure in vegans and vegetarians. In the current pilot study conducted in 2013-2014, we collected spot urine samples and detailed 24h recall dietary data in 42 adult residents of Amirim, a vegetarian community in Northern Israel. We measured urinary levels of non-specific organophosphate pesticide metabolites (dialkylphosphates, (DAPs)) and specific metabolites of the current-use pesticides chlorpyrifos (3,5,6-trichloro-2-pyridinol (TCPy)), propoxur (-isopropoxyphenol (IPPX)), and carbaryl (1-naphthol). Six DAP metabolites were detected in between 67 and 100% of urine samples, with highest geometric mean concentrations for dimethylphosphate (19.2μg/g). Creatinine-adjusted median concentrations of total DAPs and of TCPy were significantly higher in Amirim residents compared to the general Jewish population in Israel (0.29μmol/g compared to 0.16, p<0.05 for DAPs and 4.32μg/g compared to 2.34μg/g, p<0.05 for TCPy). Within Amirim residents, we observed a positive association between vegetable intake and urinary TCPy levels (rho=0.47, p<0.05) and lower median total dimethyl phosphate levels in individuals reporting that >25% of the produce they consume is organic (0.065μmol/L compared to 0.22, p<0.05). Results from this pilot study indicate relatively high levels of urinary organophosphate pesticide metabolite concentrations in residents of a vegetarian community, a positive association between vegetable intake and urinary levels of a chlorpyrifos specific metabolite, and lower levels of total dimethyl phosphate in individuals reporting higher intake of organic produce. Results suggest that consumption of organic produce may offer some protection from increased exposure to organophosphate pesticide residues in vegetarians. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fecal steroid hormones reveal reproductive state in female blue whales sampled in the Gulf of California, Mexico.

PubMed

Valenzuela-Molina, Marcia; Atkinson, Shannon; Mashburn, Kendall; Gendron, Diane; Brownell, Robert L

2018-05-15

Steroid hormone assessment using non-invasive sample collection techniques can reveal the reproductive status of aquatic mammals and the physiological mechanisms by which they respond to changes in their environment. A portion of the eastern North Pacific blue whale (Balaenoptera musculus) population that seasonally visits the Gulf of California, Mexico has been monitored using photo-identified individuals for over 30 years. The whales use the area in winter-early spring for nursing their calves and feeding and it therefore is well suited for fecal sample collection. Using radioimmunoassays in 25 fecal samples collected between 2009 and 2012 to determine reproductive state and stress, we validated three steroid hormones (progesterone, corticosterone and cortisol) in adult female blue whales. Females that were categorized as pregnant had higher mean fecal progesterone metabolite concentrations (1292.6 ± 415.6 ng·g -1 ) than resting and lactating females (14.0 ± 3.7 ng·g -1 ; 23.0 ± 5.4 ng·g -1 , respectively). Females classified as pregnant also had higher concentrations of corticosterone metabolites (37.5 ± 9.9 ng·g -1 ) than resting and lactating females (17.4 ± 2.0 ng·g -1 ; 16.8 ± 2.8 ng·g -1 , respectively). In contrast, cortisol metabolite concentrations showed high variability between groups and no significant relationship to reproductive state. We successfully determined preliminary baseline parameters of key steroid hormones by reproductive state in adult female blue whales. The presence of pregnant or with luteal activity and known lactating females confirms that the Gulf of California is an important winter-spring area for the reproductive phase of these blue whales. The baseline corticosterone levels we are developing will be useful for assessing the impact of the increasing coastal development and whale-watching activities on the whales in the Gulf of California. Copyright © 2018 Elsevier Inc. All rights reserved.

Variability of Urinary Phthalate Metabolite and Bisphenol A Concentrations before and during Pregnancy

PubMed Central

Braun, Joe M.; Smith, Kristen W.; Williams, Paige L.; Calafat, Antonia M.; Berry, Katharine; Ehrlich, Shelley

2012-01-01

Background: Gestational phthalate and bisphenol A (BPA) exposure may increase the risk of adverse maternal/child health outcomes, but there are few data on the variability of urinary biomarkers before and during pregnancy. Objective: We characterized the variability of urinary phthalate metabolite and BPA concentrations before and during pregnancy and the ability of a single spot urine sample to classify average gestational exposure. Methods: We collected 1,001 urine samples before and during pregnancy from 137 women who were partners in couples attending a Boston fertility clinic and who had a live birth. Women provided spot urine samples before (n ≥ 2) and during (n ≥ 2) pregnancy. We measured urinary concentrations of monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate, monobenzyl phthalate (MBzP), four metabolites of di-(2-ethylhexyl) phthalate (DEHP), and BPA. After adjusting for specific gravity, we characterized biomarker variability using intraclass correlation coefficients (ICCs) and conducted several surrogate category analyses to determine whether a single spot urine sample could adequately classify average gestational exposure. Results: Absolute concentrations of phthalate metabolites and BPA were similar before and during pregnancy. Variability was higher during pregnancy than before pregnancy for BPA and MBzP, but similar during and before pregnancy for MBP, MEP, and ΣDEHP. During pregnancy, MEP (ICC = 0.50) and MBP (ICC = 0.45) were less variable than BPA (ICC = 0.12), MBzP (ICC = 0.25), and ΣDEHP metabolites (ICC = 0.08). Surrogate analyses suggested that a single spot urine sample may reasonably classify MEP and MBP concentrations during pregnancy, but more than one sample may be necessary for MBzP, DEHP, and BPA. Conclusions: Urinary phthalate metabolites and BPA concentrations were variable before and during pregnancy, but the magnitude of variability was biomarker specific. A single spot urine sample adequately classified MBP and MEP concentrations during pregnancy. The present results may be related to unique features of the women studied, and replication in other pregnancy cohorts is recommended. PMID:22262702

Variability and predictors of urinary phthalate metabolites in Spanish pregnant women.

PubMed

Valvi, Damaskini; Monfort, Nuria; Ventura, Rosa; Casas, Maribel; Casas, Lidia; Sunyer, Jordi; Vrijheid, Martine

2015-03-01

Developmental exposure to phthalates may be associated with adverse health outcomes but information on the variability and predictors of urinary phthalate metabolite concentrations during pregnancy is limited. We evaluated in Spanish pregnant women (n=391) the reproducibility of urinary phthalate metabolite concentrations and predictors of exposure. We measured mono-(4-methyl-7-hydroxyoctyl) phthalate (7-OHMMeOP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-carboxyhexyl) phthalate (MCMHP), mono-benzyl phthalate (MBzP), mono-ethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) in two spot urine samples collected in the first and third pregnancy trimesters. Questionnaires on predictors and food-frequency questionnaires were administered in the first and/or third pregnancy trimesters. Using creatinine-adjusted phthalate metabolite concentrations (log10-trasformed) we calculated intraclass correlation coefficients (ICCs). Linear mixed and regression models assessed the associations between predictors and phthalate metabolites. The ICCs ranged from 0.24 to 0.07 and were higher for MBzP, MEP, MiBP, and lower for MEOHP and MEHHP. Overweight, lower education and social class, and less frequent consumption of organic food were associated with higher levels of some phthalate metabolites. The use of household cleaning products (bleach, ammonia, glass cleaners, oven cleaning sprays and degreasing products) at least once per week during pregnancy was associated with 10-44% higher urinary phthalate metabolites. Bottled-water consumption, consumption of food groups usually stored in plastic containers or cans, use of plastic containers for heating food and cosmetic use were not associated with increased concentrations of phthalate metabolites. This large study with repeated phthalate measurements suggests that, in this Spanish setting, sociodemographic and lifestyle factors and household cleaning product use are better predictors of phthalate exposure levels in pregnant women than average water and food consumption and use of plastic containers and cosmetics. Copyright © 2014 Elsevier GmbH. All rights reserved.

Age and isolation influence steroids release and chemical signaling in male mice.

PubMed

Mucignat-Caretta, Carla; Cavaggioni, Andrea; Redaelli, Marco; Da Dalt, Laura; Zagotto, Giuseppe; Gabai, Gianfranco

2014-05-01

Social interactions in mice involve olfactory signals, which convey information about the emitter. In turn, the mouse social and physiological status may modify the release of chemical cues. In this study, the influences of age and social isolation on the endocrine response and the release of chemical signals were investigated in male CD1 mice, allocated into four groups: Young Isolated (from weaning till 60days; N=6), Adult Isolated (till 180days; N=6), Young Grouped (6 mice/cage; till 60days; N=18), Adult Grouped (6 mice/cage; till 180days; N=18). Mice were transferred in a clean cage to observe the micturition pattern and then sacrificed. Body and organs weights, serum testosterone, dehydroepiandrosterone, corticosterone and the ratio Major Urinary Protein/creatinine were measured. Urinary volatile molecules potentially involved in pheromonal communication were identified. Androgen secretion was greater in isolated mice (P<0.05), suggesting a greater reactivity of the Hypothalamic-Pituitary-Gonadal axis. Grouped mice presented a higher degree of adrenal activity, and young mice showed a higher serum corticosterone (P<0.05) suggesting a greater stimulation of the Hypothalamic-Pituitary-Adrenal axis. The micturition pattern typical of dominant male, consisting in voiding numerous droplets, was observed in Young Isolated mice only, which showed a higher protein/creatinine ratio (P<0.05). Urinary 2-s-butyl-thiazoline was higher in both Young and Adult Isolated mice (P<0.005). Young Isolated mice showed the most prominent difference in both micturition pattern and potentially active substance emission, while long term isolation resulted in a less extreme phenotype; therefore social isolation had a higher impact on young mice hormone and pheromone release. Copyright © 2014 Elsevier Inc. All rights reserved.

Predictors and long-term reproducibility of urinary phthalate metabolites in middle-aged men and women living in urban Shanghai

PubMed Central

Starling, Anne P.; Engel, Lawrence S.; Calafat, Antonia M.; Koutros, Stella; Satagopan, Jaya M.; Yang, Gong; Matthews, Charles E.; Cai, Qiuyin; Buckley, Jessie P.; Ji, Bu-Tian; Cai, Hui; Chow, Wong-Ho; Zheng, Wei; Gao, Yu-Tang; Rothman, Nathaniel; Xiang, Yong-Bing; Shu, Xiao-Ou

2015-01-01

Phthalate esters are man-made chemicals commonly used as plasticizers and solvents, and humans may be exposed through ingestion, inhalation, and dermal absorption. Little is known about predictors of phthalate exposure, particularly in Asian countries. Because phthalates are rapidly metabolized and excreted from the body following exposure, it is important to evaluate whether phthalate metabolites measured at a single point in time can reliably rank exposures to phthalates over a period of time. We examined the concentrations and predictors of phthalate metabolite concentrations among 50 middle-aged women and 50 men from two Shanghai cohorts, enrolled in 1997-2000 and 2002-2006, respectively. We assessed the reproducibility of urinary concentrations of phthalate metabolites in three spot samples per participant taken several years apart (mean interval between first and third sample was 7.5 years [women] or 2.9 years [men]), using Spearman's rank correlation coefficients and intra-class correlation coefficients. We detected ten phthalate metabolites in at least 50% of individuals for two or more samples. Participant sex, age, menopausal status, education, income, body mass index, consumption of bottled water, recent intake of medication, and time of day of collection of the urine sample were associated with concentrations of certain phthalate metabolites. The reproducibility of an individual's urinary concentration of phthalate metabolites across several years was low, with all intra-class correlation coefficients and most Spearman rank correlation coefficients ≤ 0.3. Only mono(2-ethylhexyl) phthalate, a metabolite of di(2-ethylhexyl)phthalate, had a Spearman rank correlation coefficient ≥ 0.4 among men, suggesting moderate reproducibility. These findings suggest that a single spot urine sample is not sufficient to rank exposures to phthalates over several years in an adult urban Chinese population. PMID:26255822

Effect of Organic Diet Intervention on Pesticide Exposures in Young Children Living in Low-Income Urban and Agricultural Communities.

PubMed

Bradman, Asa; Quirós-Alcalá, Lesliam; Castorina, Rosemary; Aguilar Schall, Raul; Camacho, Jose; Holland, Nina T; Barr, Dana Boyd; Eskenazi, Brenda

2015-10-01

Recent organic diet intervention studies suggest that diet is a significant source of pesticide exposure in young children. These studies have focused on children living in suburban communities. We aimed to determine whether consuming an organic diet reduced urinary pesticide metabolite concentrations in 40 Mexican-American children, 3-6 years of age, living in California urban and agricultural communities. In 2006, we collected urine samples over 16 consecutive days from children who consumed conventionally grown food for 4 days, organic food for 7 days, and then conventionally grown food for 5 days. We measured 23 metabolites, reflecting potential exposure to organophosphorous (OP), pyrethroid, and other pesticides used in homes and agriculture. We used linear mixed-effects models to evaluate the effects of diet on urinary metabolite concentrations. For six metabolites with detection frequencies > 50%, adjusted geometric mean concentrations during the organic phase were generally lower for all children, and were significant for total dialkylphosphates (DAPs) and dimethyl DAPs (DMs; metabolites of OP insecticides) and 2,4-D (2,4-dichlorophenoxyacetic acid, a herbicide), with reductions of 40%, 49%, and 25%, respectively (p < 0.01). Chemical-specific metabolite concentrations for several OP pesticides, pyrethroids, and herbicides were either infrequently detected and/or not significantly affected by diet. Concentrations for most of the frequently detected metabolites were generally higher in Salinas compared with Oakland children, with DMs and metolachlor at or near significance (p = 0.06 and 0.03, respectively). An organic diet was significantly associated with reduced urinary concentrations of nonspecific dimethyl OP insecticide metabolites and the herbicide 2,4-D in children. Additional research is needed to clarify the relative importance of dietary and non-dietary sources of pesticide exposures to young children.

Tissue Distribution And Urinary Excretion Of Inorganic Arsenic And Its Methylated Metabolites In C57BL6 Mice Following Subchronic Exposure To Arsenate In Drinking Water

EPA Science Inventory

The relationship of exposure and tissue concentration of parent chemical and metabolites over prolonged exposure is a critical issue for chronic toxicities mediated by metabolite(s) rather than parent chemical alone. This is an issue for As^V because its trivalent meta...

Considering common sources of exposure in association studies - Urinary benzophenone-3 and DEHP metabolites are associated with altered thyroid hormone balance in the NHANES 2007-2008.

PubMed

Kim, Sujin; Kim, Sunmi; Won, Sungho; Choi, Kyungho

2017-10-01

Epidemiological studies have shown that thyroid hormone balances can be disrupted by chemical exposure. However, many association studies have often failed to consider multiple chemicals with possible common sources of exposure, rendering their conclusions less reliable. In the 2007-2008 National Health and Nutrition Examination Survey (NHANES) from the U.S.A., urinary levels of environmental phenols, parabens, and phthalate metabolites as well as serum thyroid hormones were measured in a general U.S. population (≥12years old, n=1829). Employing these data, first, the chemicals or their metabolites associated with thyroid hormone measures were identified. Then, the chemicals/metabolites with possible common exposure sources were included in the analytical model to test the sensitivities of their association with thyroid hormone levels. Benzophenone-3 (BP-3), bisphenol A (BPA), and a metabolite of di(2-ethylhexyl) phthalate (DEHP) were identified as significant determinants of decreased serum thyroid hormones. However, significant positive correlations were detected (p-value<0.05, r=0.23 to 0.45) between these chemicals/metabolites, which suggests that they might share similar exposure sources. In the subsequent sensitivity analysis, which included the chemicals/metabolite with potentially similar exposure sources in the model, we found that urinary BP-3 and DEHP exposure were associated with decreased thyroid hormones among the general population but BPA exposure was not. In association studies, the presence of possible common exposure sources should be considered to circumvent possible false-positive conclusions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Degraded protein adducts of cis-2-butene-1,4-dial are urinary and hepatocyte metabolites of furan.

PubMed

Lu, Ding; Sullivan, Mathilde M; Phillips, Martin B; Peterson, Lisa A

2009-06-01

Furan is a liver toxicant and carcinogen in rodents. On the basis of these observations and the large potential for human exposure, furan has been classified as a possible human carcinogen. The mechanism of tumor induction by furan is unknown. However, the toxicity requires cytochrome P450-catalyzed oxidation of furan. The product of this oxidation, cis-2-butene-1,4-dial (BDA), reacts readily with glutathione, amino acids, and DNA and is a bacterial mutagen in Ames assay strain TA104. Characterization of the urinary metabolites of furan is expected to provide information regarding the structure(s) of the reactive metabolite(s). Recently, several urinary metabolites have been identified. We reported the presence of a monoglutathione-BDA reaction product, N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-l-cysteinylglycine cyclic sulfide. Three additional urinary metabolites of furan were also characterized as follows: R-2-acetylamino-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid, N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine, and its sulfoxide. It was postulated that these three metabolites are derived from degraded protein adducts. However, the possibility that these metabolites result from the reaction of BDA with free lysine and/or cysteine was not ruled out. In this latter case, one might predict that the reaction of thiol-BDA with free lysine would not occur exclusively on the epsilon-amino group. Reaction of BDA with N-acetylcysteine or GSH in the presence of lysine indicated that both the alpha- and the epsilon-amino groups of lysine can be modified by thiol-BDA. The N-acetylcysteine-BDA-N-acetyllysine urinary metabolites were solely linked through the epsilon-amino group of lysine. A GSH-BDA-lysine cross-link was a significant hepatocyte metabolite of furan. In this case, the major product resulted from reaction with the epsilon-amino group of lysine; however, small amounts of the alpha-amino reaction product were also observed. Western analysis of liver and hepatocyte protein extracts using anti-GSH antibody indicated that GSH was covalently linked to proteins in tissues or cells exposed to furan. Our data support the hypothesis that GSH-BDA can react with either free lysine or protein lysine groups. These data suggest that there are multiple pathways by which furan can modify cellular nucleophiles. In one pathway, BDA reacts directly with proteins to form cysteine-lysine reaction products. In another, BDA reacts with GSH to form GSH-BDA conjugates, which then react with cellular nucleophiles like free lysine or lysine moieties in proteins. Both pathways will give rise to N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine. Given the abundance of these metabolites in urine of furan-treated rats, these pathways appear to be major pathways of furan biotransformation in vivo.

Degraded protein adducts of cis-2-butene-1,4-dial are urinary and hepatocyte metabolites of furan

PubMed Central

Lu, Ding; Sullivan, Mathilde M.; Phillips, Martin B.; Peterson, Lisa A.

2009-01-01

Furan is a liver toxicant and carcinogen in rodents. Based on these observations and the large potential for human exposure, furan has been classified as a possible human carcinogen. The mechanism of tumor induction by furan is unknown. However, the toxicity requires cytochrome P450 catalyzed oxidation of furan. The product of this oxidation, cis-2-butene-1,4-dial (BDA), reacts readily with glutathione, amino acids and DNA and is a bacterial mutagen in Ames assay strain TA104. Characterization of the urinary metabolites of furan is expected to provide information regarding the structure(s) of the reactive metabolite(s). Recently, several urinary metabolites have been identified. We reported the presence of a mono-glutathione-BDA reaction product, N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine cyclic sulfide. Three additional urinary metabolites of furan were also characterized: R-2-acetylamino-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid, N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine and its sulfoxide. It was postulated that these three metabolites are derived from degraded protein adducts. However, the possibility that these metabolites result from reaction of BDA with free lysine and/or cysteine was not ruled out. In this latter case, one might predict that the reaction of thiol-BDA with free lysine would not occur exclusively on the ε-amino group. Reaction of BDA with N-acetylcysteine or GSH in the presence of lysine indicated that both the α- and ε-amino groups of lysine can be modified by thiol-BDA. The N-acetylcysteine-BDA-N-acetyllysine urinary metabolites were solely linked through the ε-amino group of lysine. A GSH-BDA-lysine crosslink was a significant hepatocyte metabolite of furan. In this case, the major product resulted from reaction with the ε-amino group of lysine, however, small amounts of the α-amino reaction product were also observed. Western analysis of liver and hepatocyte protein extracts using anti-GSH antibody indicated that GSH was covalently linked to proteins in tissues or cells exposed to furan. Our data support the hypothesis that GSH-BDA can react with either free lysine or protein lysine groups. These data suggest that there are multiple pathways by which furan can modify cellular nucleophiles. In one pathway, BDA reacts directly with proteins to form cysteine-lysine reaction products. In another, BDA reacts with GSH to form GSH-BDA conjugates which then reacts with cellular nucleophiles like free lysine or lysine moieties in proteins. Both pathways will give rise to N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine. Given the abundance of these metabolites in urine of furan-treated rats, these pathways appear to be major pathways of furan biotransformation in vivo. PMID:19441776

Associations of urinary phthalate metabolites with residential characteristics, lifestyles, and dietary habits among young children in Shanghai, China.

PubMed

Liao, Chenxi; Liu, Wei; Zhang, Jialing; Shi, Wenming; Wang, Xueying; Cai, Jiao; Zou, Zhijun; Lu, Rongchun; Sun, Chanjuan; Wang, Heng; Huang, Chen; Zhao, Zhuohui

2018-03-01

Exposure to household phthalates has been reported to have adverse effects on children's health. In this paper, we used phthalate metabolites in the first morning urine as indicators of household phthalate exposures and examined their associations with residential characteristics, lifestyles and dietary habits among young children. During 2013-2014, we collected morning urines from children aged 5-10years in Shanghai, China and obtained the related information about analyzed factors in this study by questionnaires. Urinary phthalate metabolites were analyzed by isotope dilution-high performance liquid chromatography (HPLC)-heated electrospray ionization source (HESI) coupled with a triple quadrupole mass spectrometry. ANOVA, the Mann-Whitney or Kruskai-Wallis rank tests, and multivariate linear regression analyses were used to examine the target associations. Ten metabolites of seven phthalates in 434 urine samples were analyzed. The detection rates of eight metabolites (MiBP, MnBP, MEHP, MECPP, MEHHP, MEOHP, MEP, and MMP) were >90%, except for MBzP (51.2%), and MCHP with <10.0% of detection rate was not included in analyses. By multivariate linear regression analyses, factors significantly associated with higher concentrations of metabolites included non-usage household air cleaners (MEP and MEHP), changing the child's pillowcase less than one time a week (DEHP metabolites), dusting furniture in the child's bedroom less than three times a week (MMP and MnBP), using more plastic toys (DEHP metabolites and MEP), often having soft drinks (DEHP metabolites) and candies (MiBP). Our results indicated that phthalate exposures were common among Shanghai children and residential characteristics had less significant associations with urinary phthalate metabolites compared with lifestyles and dietary habits. Using less plastic toys, having less candies and soft drinks, using household air cleaner, as well as frequently changing the child's pillowcase and dusting furniture in the child's bedroom could reduce phthalate exposures among children. Copyright © 2017 Elsevier B.V. All rights reserved.

Determination of urinary 2- and 3-dechloroethylated metabolites of ifosfamide by high-performance liquid chromatography.

PubMed

Goren, M P

1991-10-04

In vivo oxidation of chloroethyl side-chains on ifosfamide produces the toxin chloroacetaldehyde. Production of this labile metabolite can be indirectly quantitated by monitoring the excretion of the residual 2- and 3-dechloroethylated ifosfamide. Urinary ifosfamide and the two dechloroethylated metabolites were extracted into chloroform from alkalinized salt-saturated urine, followed by high-performance liquid chromatographic separation using an acetonitrile gradient on a reversed-phase column and ultraviolet detection at 190 nm. In five patients given 1.6 g/m2 ifosfamide, 11-30% of the dose was excreted over 24 h as unchanged drug, 11-21% as 3-dechloroethylated and 3-10% as 2-dechloroethylated ifosfamide.

AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility.

PubMed

Antonelli, Ray; Shao, Kan; Thomas, David J; Sams, Reeder; Cowden, John

2014-07-01

Oral exposure to inorganic arsenic (iAs) is associated with adverse health effects. Epidemiological studies suggest differences in susceptibility to these health effects, possibly due to genotypic variation. Genetic polymorphisms in iAs metabolism could lead to increased susceptibility by altering urinary iAs metabolite concentrations. To examine the impact of genotypic polymorphisms on iAs metabolism. We screened 360 publications from PubMed and Web of Science for data on urinary mono- and dimethylated arsenic (MMA and DMA) percentages and polymorphic genes encoding proteins that are hypothesized to play roles in arsenic metabolism. The genes we examined were arsenic (+3) methyltransferase (AS3MT), glutathione-s-transferase omega (GSTO), and purine nucleoside phosphorylase (PNP). Relevant data were pooled to determine which polymorphisms are associated across studies with changes in urinary metabolite concentration. In our review, AS3MT polymorphisms rs3740390, rs11191439, and rs11191453 were associated with statistically significant changes in percent urinary MMA. Studies of GSTO polymorphisms did not indicate statistically significant associations with methylation, and there are insufficient data on PNP polymorphisms to evaluate their impact on metabolism. Collectively, these data support the hypothesis that AS3MT polymorphisms alter in vivo metabolite concentrations. Preliminary evidence suggests that AS3MT genetic polymorphisms may impact disease susceptibility. GSTO polymorphisms were not associated with iAs-associated health outcomes. Additional data are needed to evaluate the association between PNP polymorphisms and iAs-associated health outcomes. Delineation of these relationships may inform iAs mode(s) of action and the approach for evaluating low-dose health effects for iAs. Genotype impacts urinary iAs metabolite concentrations and may be a potential mechanism for iAs-related disease susceptibility. Published by Elsevier Inc.

Personal Care Product Use in Men and Urinary Concentrations of Select Phthalate Metabolites and Parabens: Results from the Environment And Reproductive Health (EARTH) Study.

PubMed

Nassan, Feiby L; Coull, Brent A; Gaskins, Audrey J; Williams, Michelle A; Skakkebaek, Niels E; Ford, Jennifer B; Ye, Xiaoyun; Calafat, Antonia M; Braun, Joseph M; Hauser, Russ

2017-08-18

Personal care products (PCPs) are exposure sources to phthalates and parabens; however, their contribution to men's exposure is understudied. We examined the association between PCP use and urinary concentrations of phthalate metabolites and parabens in men. In a prospective cohort, at multiple study visits, men self-reported their use of 14 PCPs and provided a urine sample (2004-2015, Boston, MA). We measured urinary concentrations of 9 phthalate metabolites and methylparaben, propylparaben, and butylparaben. We estimated the covariate-adjusted percent change in urinary concentrations associated with PCP use using linear mixed and Tobit mixed regressions. We also estimated weights for each PCP in a weighted binary score regression and modeled the resulting composite weighted PCP use. Four hundred men contributed 1,037 urine samples (mean of 3/man). The largest percent increase in monoethyl phthalate (MEP) was associated with use of cologne/perfume (83%, p -value<0.01) and deodorant (74%, p -value<0.01). In contrast, the largest percent increase for parabens was associated with the use of suntan/sunblock lotion (66-156%) and hand/body lotion (79-147%). Increases in MEP and parabens were generally greater with PCP use within 6 h of urine collection. A subset of 10 PCPs that were used within 6 h of urine collection contributed to at least 70% of the weighted score and predicted a 254-1,333% increase in MEP and parabens concentrations. Associations between PCP use and concentrations of the other phthalate metabolites were not statistically significant. We identified 10 PCPs of relevance and demonstrated that their use within 6 h of urine collection strongly predicted MEP and paraben urinary concentrations. https://doi.org/10.1289/EHP1374.

Urinary acrylamide metabolites as biomarkers for short-term dietary exposure to acrylamide.

PubMed

Bjellaas, Thomas; Stølen, Linn Helene; Haugen, Margaretha; Paulsen, Jan Erik; Alexander, Jan; Lundanes, Elsa; Becher, Georg

2007-06-01

It has previously been reported that heat-treated carbohydrate rich foods may contain high levels of acrylamide resulting in consumers being inadvertently exposed to acrylamide. Acrylamide is mainly excreted in the urine as mercapturic acid derivatives of acrylamide and glycidamide. In a clinical study comprising of 53 subjects, the urinary excretion of these metabolites was determined using solid-phase extraction and liquid chromatography with positive electrospray MS/MS detection. The median (range) total excretion of acrylamide in urine during 24 h was 16 (7-47) microg acrylamide for non-smokers and 74 (38-106) microg acrylamide for smokers, respectively. It was found that the median intake estimate in the study based on 24 h dietary recall was 21 (13-178) and 26 (12-67) for non-smokers and smokers, respectively. The median dietary exposure to acrylamide was estimated to be 0.47 (range 0.17-1.16) microg/kg body weight per day. In a multiple linear regression analysis, the urinary excretion of acrylamide metabolites correlated statistically significant with intake of aspartic acid, protein, starch and coffee. Consumption of citrus fruits correlated negatively with excretion of acrylamide metabolites.

Dietary administration of sodium arsenite to rats: Relations between dose and urinary concentrations of methylated and thio-metabolites and effects on the rat urinary bladder epithelium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suzuki, Shugo; Arnold, Lora L.; Pennington, Karen L.

2010-04-15

Based on epidemiological data, chronic exposure to high levels of inorganic arsenic in drinking water is carcinogenic to humans, inducing skin, urinary bladder and lung tumors. In vivo, inorganic arsenic is metabolized to organic methylated arsenicals including the highly toxic dimethylarsinous acid (DMA{sup III}) and monomethylarsonous acid (MMA{sup III}). Short-term treatment of rats with 100 mug/g trivalent arsenic (As{sup III}) as sodium arsenite in the diet or in drinking water induced cytotoxicity and necrosis of the urothelial superficial layer, with increased cell proliferation and hyperplasia. The objectives of this study were to determine if these arsenic-induced urothelial effects are dosemore » responsive, the dose of arsenic at which urothelial effects are not detected, and the urinary concentrations of the arsenical metabolites. We treated female F344 rats for 5 weeks with sodium arsenite at dietary doses of 0, 1, 10, 25, 50, and 100 ppm. Cytotoxicity, cell proliferation and hyperplasia of urothelial superficial cells were increased in a dose-responsive manner, with maximum effects found at 50 ppm As{sup III}. There were no effects at 1 ppm As{sup III}. The main urinary arsenical in As{sup III}-treated rats was the organic arsenical dimethylarsinic acid (DMA{sup V}). The thio-metabolites dimethylmonothioarsinic acid (DMMTA{sup V}) and monomethylmonothioarsinic acid (MMMTA{sup V}) were also found in the urine of As{sup III}-treated rats. The LC{sub 50} concentrations of DMMTA{sup V} for rat and human urothelial cells in vitro were similar to trivalent oxygen-containing arsenicals. These data suggest that dietary As{sup III}-induced urothelial cytotoxicity and proliferation are dose responsive, and the urothelial effects have a threshold corresponding to the urinary excretion of measurable reactive metabolites.« less

Within- and between-child variation in repeated urinary pesticide metabolite measurements over a 1-year period.

PubMed

Attfield, Kathleen R; Hughes, Michael D; Spengler, John D; Lu, Chensheng

2014-02-01

Children are exposed to pesticides from many sources and routes, including dietary and incidental ingestion, dermal absorption, and inhalation. Linking health outcomes to these exposures using urinary metabolites requires understanding temporal variability within subjects to avoid exposure misclassification. We characterized the within- and between-child variability of urinary organophosphorus and pyrethroid metabolites in 23 participants of the Children's Pesticide Exposure Study-Washington over 1 year and examined the ability of one to four spot urine samples to categorize mean exposures. Each child provided urine samples twice daily over 7- to 16-day sessions in four seasons in 2003 and 2004. Samples were analyzed for five pyrethroid and five organophosphorus (OP) metabolites. After adjusting for specific gravity, we used a customized maximum likelihood estimation linear mixed-effects model that accounted for values below the limit of detection to calculate intraclass correlation coefficients (ICC) and conducted surrogate category analyses. Within-child variability was 2-11 times greater than between-child variability. When restricted to samples collected during a single season, ICCs were higher in the fall, winter, and spring than in summer for OPs, and higher in summer and winter for pyrethroids, indicating an increase in between-person variability relative to within-person variability during these seasons. Surrogate category analyses demonstrated that a single spot urine sample did not categorize metabolite concentrations well, and that four or more samples would be needed to categorize children into quartiles consistently. Urinary biomarkers of these short half-life pesticides exhibited substantial within-person variability in children observed over four seasons. Researchers investigating pesticides and health outcomes in children may need repeated biomarker measurements to derive accurate estimates of exposure and relative risks.

Predictors of urinary flame retardant concentration among pregnant women

PubMed Central

Hoffman, Kate; Lorenzo, Amelia; Butt, Craig; Adair, Linda; Herring, Amy H.; Stapleton, Heather M.; Daniels, Julie

2016-01-01

Background Organophosphate compounds are commonly used in residential furniture, electronics, and baby products as flame retardants and are also used in other consumer products as plasticizers. Although the levels of exposure biomarkers are generally higher among children and decrease with age, relatively little is known about the individual characteristics associated with higher levels of exposure. Here, we investigate urinary metabolites of several organophosphate flame retardants (PFRs) in a cohort of pregnant women to evaluate patterns of exposure. Methods Pregnant North Carolina women (n=349) provided information on their individual characteristics (e.g. age and body mass index (BMI)) as a part of the Pregnancy Infection and Nutrition Study (2002–2005). Women also provided second trimester urine samples in which six PFR metabolites were measured using mass spectrometry methods. Results PFR metabolites were detected in every urine sample, with BDCIPP, DHPH, ip-PPP and BCIPHIPP detected in >80% of samples. Geometric mean concentrations were higher than what has been reported previously for similarly-timed cohorts. Women with higher pre-pregnancy BMI tended to have higher levels of urinary metabolites. For example, those classified as obese at the start of pregnancy had ip-PPP levels that were 1.52 times as high as normal weight range women (95% confidence interval: 1.23, 1.89). Women without previous children also tended to have higher urinary levels of DPHP, but lower levels of ip-PPP. In addition, we saw strong evidence of seasonal trends in metabolite concentrations (e.g. higher DPHP, BDCIPP, and BCIPHIPP in summer, and evidence of increasing ip-PPP between 2002 and 2005). Conclusions Our results indicate ubiquitous exposure to PFRs among NC women in the early 2000s. Additionally, our work suggests that individual characteristics are related to exposure and that temporal variation, both seasonal and annual, may exist. PMID:27745946

Life without plastic: A family experiment and biomonitoring study.

PubMed

Hutter, Hans-Peter; Kundi, Michael; Hohenblum, Philipp; Scharf, Sigrid; Shelton, Janie F; Piegler, Kathrin; Wallner, Peter

2016-10-01

Exposure to bisphenol-A (BPA) and phthalates has been associated with negative health outcomes in animal and human studies, and human bio-monitoring studies demonstrate widespread exposure in the US and Europe. Out of concern for the environment and health, individuals may attempt to modify their environment, diet, and consumer choices to avoid such exposures, but these natural experiments are rarely if ever quantitatively evaluated. The aim of the study was to evaluate the difference in urinary concentrations of BPA and phthalate metabolites following an exposure reduction intervention among an Austrian family of five. Urine samples were taken shortly after the family had removed all plastic kitchenware, toys, and bathroom products, and started a concerted effort to eat less food packaged in plastic. Two-months later, urine samples were collected at a follow-up visit, and concentrations of BPA and phthalate metabolites were compared. Shortly after removal of plastic urinary concentrations of BPA were below limit of quantification in all samples. Phthalate concentrations were low, however, 10 of 14 investigated metabolites could be found above limit of quantification. After the two-month intervention, phthalate urinary concentrations had declined in some but not all family members. In the mother most phthalate metabolites increased. The low levels might be partly due to the environmentally conscious lifestyle of the family and partly due to the fact that body levels had dropped already because of the delay of four days between finishing removal and first measurement. Further two months avoidance of dietary exposure and exposure to environmental plastics reduced urinary concentrations for all but one metabolite in the oldest son only, but decreased somewhat in all family members except the mother. Copyright © 2016 Elsevier Inc. All rights reserved.

Manual versus automated blood sampling: impact of repeated blood sampling on stress parameters and behavior in male NMRI mice

PubMed Central

Kalliokoski, Otto; Sørensen, Dorte B; Hau, Jann; Abelson, Klas S P

2014-01-01

Facial vein (cheek blood) and caudal vein (tail blood) phlebotomy are two commonly used techniques for obtaining blood samples from laboratory mice, while automated blood sampling through a permanent catheter is a relatively new technique in mice. The present study compared physiological parameters, glucocorticoid dynamics as well as the behavior of mice sampled repeatedly for 24 h by cheek blood, tail blood or automated blood sampling from the carotid artery. Mice subjected to cheek blood sampling lost significantly more body weight, had elevated levels of plasma corticosterone, excreted more fecal corticosterone metabolites, and expressed more anxious behavior than did the mice of the other groups. Plasma corticosterone levels of mice subjected to tail blood sampling were also elevated, although less significantly. Mice subjected to automated blood sampling were less affected with regard to the parameters measured, and expressed less anxious behavior. We conclude that repeated blood sampling by automated blood sampling and from the tail vein is less stressful than cheek blood sampling. The choice between automated blood sampling and tail blood sampling should be based on the study requirements, the resources of the laboratory and skills of the staff. PMID:24958546

Qualitative Profiling and Quantification of Neonicotinoid Metabolites in Human Urine by Liquid Chromatography Coupled with Mass Spectrometry

PubMed Central

Taira, Kumiko; Fujioka, Kazutoshi; Aoyama, Yoshiko

2013-01-01

Neonicotinoid pesticides have been widely applied for the production of fruits and vegetables, and occasionally detected in conventionally grown produce. Thus oral exposure to neonicotinoid pesticides may exist in the general population; however, neonicotinoid metabolites in human body fluids have not been investigated comprehensively. The purpose of this study is the qualitative profiling and quantitative analysis of neonicotinoid metabolites in the human spot urine by liquid chromatography coupled with mass spectrometry (LC/MS). Human urine samples were collected from three patients suspected of subacute exposure to neonicotinoid pesticides. A qualitative profiling of urinary metabolites was performed using liquid chromatography/time-of-flight mass spectrometry (LC/TOFMS) with a database of nominal molecular weights of 57 known metabolites of three neonicotinoid pesticides (acetamiprid, Imidacloprid, and clothianidin), as well as the parent compounds. Then a quantitative analysis of selected urinary metabolites was performed using liquid chromatography/tandem mass spectrometry (LC/MS/MS) with a standard pesticide and metabolite, which were detected by the qualitative profiling. The result of qualitative profiling showed that seven metabolites, i.e. an acetamiprid metabolite, N-desmethyl-acetamiprid; three Imidacloprid metabolites, 5-hydroxy-Imidacloprid, 4,5-dihydroxy-imidacloprid, 4,5-dehydro-Imidacloprid; a common metabolite of acetamiprid and Imidacloprid, N-(6-chloronicotinoyl)-glycine; and two clothianidin metabolites, N-desmethyl-clothianidin, N-(2-(methylsulfanyl)thiazole-5-carboxyl)-glycine, as well as acetamiprid, were detected in the urine of three cases. The result of the quantitative analysis showed N-desmethyl-acetamiprid was determined in the urine of one case, which had been collected on the first visit, at a concentration of 3.2 ng/mL. This is the first report on the qualitative and quantitative detection of N-desmethyl-acetamiprid in the human urine. The results suggest that the one case with detection of N-desmethyl-acetamiprid was exposed to acetamiprid through the consumption of contaminated foods. Urinary N-desmethyl-acetamiprid, as well as 5-hydroxy-Imidacloprid and N-desmethyl-clothianidin, may be a good biomarker for neonicotinoid exposure in humans and warrants further investigation. PMID:24265808

Urinary concentrations of bisphenol A and phthalate metabolites and weight change: a prospective investigation in US women

PubMed Central

Song, Y; Hauser, R; Hu, FB; Franke, AA; Liu, S; Sun, Q

2015-01-01

OBJECTIVE Both bisphenol A (BPA) and phthalates are known endocrine-disrupting chemicals for which there is widespread general population exposure. Human exposure occurs through dietary and non-dietary routes. Although animal studies have suggested a potential role of these chemicals in obesity, evidence from human studies is sparse and inconsistent, and prospective evidence is lacking. This study evaluated urinary concentrations of BPA and major phthalate metabolites in relation to prospective weight change. METHODS The study population was from the controls in a prospective case-control study of type 2 diabetes in the Nurses’ Health Study (NHS) and NHSII. A total of 977 participants provided first-morning-void urine samples in 1996–2002. Urinary concentrations of BPA and nine phthalate metabolites were measured using liquid chromatography–mass spectrometry. Body weights were self-reported at baseline and updated biennially thereafter for 10 years. RESULTS On average, the women gained 2.09 kg (95% confidence interval (CI), − 2.27 to 6.80 kg) during the 10-year follow-up. In multivariate analysis with adjustment of lifestyle and dietary factors, in comparison with women in the lowest quartile of BPA concentration, those in the highest quartile had 0.23 kg per year (95% CI, 0.07–0.38 kg per year) greater weight gain during the 10-year follow-up (P-trend = 0.02). Several phthalate metabolites, including phthalic acid, MBzP and monobutyl phthalate, were also associated with faster prospective weight gain in a dose-response fashion (P-trend < 0.01), whereas other phthalates metabolites, including MEP and monoethylhexyl phthalate, were not monotonically associated with body weight change. CONCLUSIONS These data suggest urinary concentrations of BPA and certain individual phthalate metabolites that were associated with modestly greater weight gain in a dose-response fashion. These data are consistent with a potential role of BPA and phthalates in obesity, although more prospective data are needed to corroborate these observations. PMID:24722546

Urinary concentrations of bisphenol A and phthalate metabolites and weight change: a prospective investigation in US women.

PubMed

Song, Y; Hauser, R; Hu, F B; Franke, A A; Liu, S; Sun, Q

2014-12-01

Both bisphenol A (BPA) and phthalates are known endocrine-disrupting chemicals for which there is widespread general population exposure. Human exposure occurs through dietary and non-dietary routes. Although animal studies have suggested a potential role of these chemicals in obesity, evidence from human studies is sparse and inconsistent, and prospective evidence is lacking. This study evaluated urinary concentrations of BPA and major phthalate metabolites in relation to prospective weight change. The study population was from the controls in a prospective case-control study of type 2 diabetes in the Nurses' Health Study (NHS) and NHSII. A total of 977 participants provided first-morning-void urine samples in 1996-2002. Urinary concentrations of BPA and nine phthalate metabolites were measured using liquid chromatography-mass spectrometry. Body weights were self-reported at baseline and updated biennially thereafter for 10 years. On average, the women gained 2.09 kg (95% confidence interval (CI), -2.27 to 6.80 kg) during the 10-year follow-up. In multivariate analysis with adjustment of lifestyle and dietary factors, in comparison with women in the lowest quartile of BPA concentration, those in the highest quartile had 0.23 kg per year (95% CI, 0.07-0.38 kg per year) greater weight gain during the 10-year follow-up (P-trend=0.02). Several phthalate metabolites, including phthalic acid, MBzP and monobutyl phthalate, were also associated with faster prospective weight gain in a dose-response fashion (P-trend<0.01), whereas other phthalates metabolites, including MEP and monoethylhexyl phthalate, were not monotonically associated with body weight change. These data suggest urinary concentrations of BPA and certain individual phthalate metabolites that were associated with modestly greater weight gain in a dose-response fashion. These data are consistent with a potential role of BPA and phthalates in obesity, although more prospective data are needed to corroborate these observations.

Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.

PubMed

Vikingsson, Svante; Gréen, Henrik; Brinkhagen, Linda; Mukhtar, Shahzabe; Josefsson, Martin

2016-09-01

Synthetic cannabinoids are a group of psychoactive drugs presently widespread among drug users in Europe. Analytical methods to measure these compounds in urine are in demand as urine is a preferred matrix for drug testing. For most synthetic cannabinoids, the parent compounds are rarely detected in urine. Therefore urinary metabolites are needed as markers of drug intake. AB-FUBINACA was one of the top three synthetic cannabinoids most frequently found in seizures and toxicological drug screening in Sweden (2013-2014). Drug abuse is also reported from several other countries such as the USA and Japan. In this study, 28 authentic case samples were used to identify urinary markers of AB-FUBINACA intake using liquid chromatography quadrupole tandem time of flight mass spectrometry and human liver microsomes. Three metabolites suitable as markers of drug intake were identified and at least two of them were detected in all but one case. In total, 15 urinary metabolites of AB-FUBINACA were reported, including hydrolxylations on the indazole ring and the amino-oxobutane moiety, dealkylations and hydrolysis of the primary amide. No modifications on the fluorobenzyl side-chain were observed. The parent compound was detected in 54% of the case samples. Also, after three hours of incubation with human liver microsomes, 77% of the signal from the parent compound remained. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Estimation of caffeine intake from analysis of caffeine metabolites in wastewater.

PubMed

Gracia-Lor, Emma; Rousis, Nikolaos I; Zuccato, Ettore; Bade, Richard; Baz-Lomba, Jose Antonio; Castrignanò, Erika; Causanilles, Ana; Hernández, Félix; Kasprzyk-Hordern, Barbara; Kinyua, Juliet; McCall, Ann-Kathrin; van Nuijs, Alexander L N; Plósz, Benedek G; Ramin, Pedram; Ryu, Yeonsuk; Santos, Miguel M; Thomas, Kevin; de Voogt, Pim; Yang, Zhugen; Castiglioni, Sara

2017-12-31

Caffeine metabolites in wastewater were investigated as potential biomarkers for assessing caffeine intake in a population. The main human urinary metabolites of caffeine were measured in the urban wastewater of ten European cities and the metabolic profiles in wastewater were compared with the human urinary excretion profile. A good match was found for 1,7-dimethyluric acid, an exclusive caffeine metabolite, suggesting that might be a suitable biomarker in wastewater for assessing population-level caffeine consumption. A correction factor was developed considering the percentage of excretion of this metabolite in humans, according to published pharmacokinetic studies. Daily caffeine intake estimated from wastewater analysis was compared with the average daily intake calculated from the average amount of coffee consumed by country per capita. Good agreement was found in some cities but further information is needed to standardize this approach. Wastewater analysis proved useful to providing additional local information on caffeine use. Copyright © 2017 Elsevier B.V. All rights reserved.

Follicular fluid and urinary concentrations of phthalate metabolites among infertile women and associations with in vitro fertilization parameters.

PubMed

Du, Yao-Yao; Fang, Yue-Li; Wang, Yi-Xin; Zeng, Qiang; Guo, Na; Zhao, Hua; Li, Yu-Feng

2016-06-01

Evidence from toxicological studies has demonstrated that phthalates can lead to reduced fertility through effects on folliculogenesis, oocyte maturation and embryonic development, but human data are limited. Concentrations of eight phthalate metabolites in 110 follicular fluid (FF) and urine samples collected from 112 women attending an infertility clinic in Wuhan, China were quantified, and correlations between paired matrices were explored. Associations between metabolite concentrations and in vitro fertilization (IVF) parameters were evaluated with multivariable models. Six metabolites were detected in >72.73% of the FF samples. MEHP and MBP were the dominant metabolites with a median level of 2.80 and 2.05ng/mL, respectively. Significant correlations between the two matrices, urine and FF, were found for MEP (rs=0.44), and MBP (rs=0.22). FF and urinary metabolite concentrations were not associated with any IVF parameters. However, given the prevalence of phthalates exposure, further work is needed to elucidate the potential hazard on female reproduction. Copyright © 2016 Elsevier Inc. All rights reserved.

Urinary Excretion of Niacin Metabolites in Humans After Coffee Consumption.

PubMed

Kremer, Jonathan Isaak; Gömpel, Katharina; Bakuradze, Tamara; Eisenbrand, Gerhard; Richling, Elke

2018-04-01

Coffee is a major natural source of niacin in the human diet, as it is formed during coffee roasting from the alkaloid trigonelline. The intention of our study was to monitor the urinary excretion of niacin metabolites after coffee consumption under controlled diet. We performed a 4-day human intervention study on the excretion of major niacin metabolites in the urine of volunteers after ingestion of 500 mL regular coffee containing 34.8 μmol nicotinic acid (NA) and 0.58 μmol nicotinamide (NAM). In addition to NA and NAM, the metabolites N 1 -methylnicotinamide (NMNAM), N 1 -methyl-2-pyridone-5-carboxamide (2-Py), and nicotinuric acid (NUA) were identified and quantified in the collected urine samples by stable isotope dilution analysis (SIVA) using HPLC-ESI-MS/MS. Rapid urinary excretion was observed for the main metabolites (NA, NAM, NMNAM, and 2-Py), with t max values within the first hour after ingestion. NUA appeared in traces even more rapidly. In sum, 972 nmol h -1 of NA, NAM, NMNAM, and 2-Py were excreted within 12 h after coffee consumption, corresponding to 6% of the ingested NA and NAM. The results indicate regular coffee consumption to be a source of niacin in human diet. © 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gas Chromatography-Mass Spectrometry for Metabolite Profiling of Japanese Black Cattle Naturally Contaminated with Zearalenone and Sterigmatocystin.

PubMed

Toda, Katsuki; Kokushi, Emiko; Uno, Seiichi; Shiiba, Ayaka; Hasunuma, Hiroshi; Fushimi, Yasuo; Wijayagunawardane, Missaka P B; Zhang, Chunhua; Yamato, Osamu; Taniguchi, Masayasu; Fink-Gremmels, Johanna; Takagi, Mitsuhiro

2017-09-21

The objective of this study was to evaluate the metabolic profile of cattle fed with or without zearalenone (ZEN) and sterigmatocystin (STC)-contaminated diets using a gas chromatography-mass spectrometry metabolomics approach. Urinary samples were collected from individual animals ( n = 6 per herd) from fattening female Japanese Black (JB) cattle herds (23 months old, 550-600 kg). Herd 1 had persistently high urinary ZEN and STC concentrations due to the presence of contaminated rice straw. Herd 2, the second female JB fattening herd (23 months old, 550-600 kg), received the same dietary feed as Herd 1, with non-contaminated rice straw. Urine samples were collected from Herd 1, two weeks after the contaminated rice straw was replaced with uncontaminated rice straw (Herd 1N). Identified metabolites were subjected to principal component analysis (PCA) and ANOVA. The PCA revealed that the effects on cattle metabolites depended on ZEN and STC concentrations. The contamination of cattle feed with multiple mycotoxins may alter systemic metabolic processes, including metabolites associated with ATP generation, amino acids, glycine-conjugates, organic acids, and purine bases. The results obtained from Herd 1N indicate that a two-week remedy period was not sufficient to improve the levels of urinary metabolites, suggesting that chronic contamination with mycotoxins may have long-term harmful effects on the systemic metabolism of cattle.

Gas Chromatography-Mass Spectrometry for Metabolite Profiling of Japanese Black Cattle Naturally Contaminated with Zearalenone and Sterigmatocystin

PubMed Central

Toda, Katsuki; Kokushi, Emiko; Uno, Seiichi; Shiiba, Ayaka; Hasunuma, Hiroshi; Fushimi, Yasuo; Wijayagunawardane, Missaka P. B.; Zhang, Chunhua; Yamato, Osamu; Taniguchi, Masayasu; Fink-Gremmels, Johanna; Takagi, Mitsuhiro

2017-01-01

The objective of this study was to evaluate the metabolic profile of cattle fed with or without zearalenone (ZEN) and sterigmatocystin (STC)-contaminated diets using a gas chromatography-mass spectrometry metabolomics approach. Urinary samples were collected from individual animals (n = 6 per herd) from fattening female Japanese Black (JB) cattle herds (23 months old, 550–600 kg). Herd 1 had persistently high urinary ZEN and STC concentrations due to the presence of contaminated rice straw. Herd 2, the second female JB fattening herd (23 months old, 550–600 kg), received the same dietary feed as Herd 1, with non-contaminated rice straw. Urine samples were collected from Herd 1, two weeks after the contaminated rice straw was replaced with uncontaminated rice straw (Herd 1N). Identified metabolites were subjected to principal component analysis (PCA) and ANOVA. The PCA revealed that the effects on cattle metabolites depended on ZEN and STC concentrations. The contamination of cattle feed with multiple mycotoxins may alter systemic metabolic processes, including metabolites associated with ATP generation, amino acids, glycine-conjugates, organic acids, and purine bases. The results obtained from Herd 1N indicate that a two-week remedy period was not sufficient to improve the levels of urinary metabolites, suggesting that chronic contamination with mycotoxins may have long-term harmful effects on the systemic metabolism of cattle. PMID:28934162

Dose-response relationships of polycyclic aromatic hydrocarbons exposure and oxidative damage to DNA and lipid in coke oven workers.

PubMed

Kuang, Dan; Zhang, Wangzhen; Deng, Qifei; Zhang, Xiao; Huang, Kun; Guan, Lei; Hu, Die; Wu, Tangchun; Guo, Huan

2013-07-02

Polycyclic aromatic hydrocarbons (PAHs) are known to induce reactive oxygen species and oxidative stress, but the dose-response relationships between exposure to PAHs and oxidative stress levels have not been established. In this study, we recruited 1333 male coke oven workers, monitored the levels of environmental PAHs, and measured internal PAH exposure biomarkers including 12 urinary PAH metabolites and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, as well as the two oxidative biomarkers urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α). We found that the total concentration of urinary PAH metabolites and plasma BPDE-Alb adducts were both significantly associated with increased 8-OHdG and 8-iso-PGF2α in both smokers and nonsmokers (all p < 0.05). This exposure-response effect was also observed for most PAH metabolites (all p(trend) < 0.01), except for 4-hydroxyphenanthrene and 8-OHdG (p(trend) = 0.108). Furthermore, it was shown that only urinary 1-hydroxypyrene has a significant positive association with both 8-OHdG and 8-iso-PGF2α after a Bonferroni correction (p < 0.005). Our results indicated that urinary ΣOH-PAHs and plasma BPDE-Alb adducts can result in significant dose-related increases in oxidative damage to DNA and lipids. Furthermore, when a multianalyte method is unavailable, our findings demonstrate that urinary 1-hydroxypyrene is a useful biomarker for evaluating total PAHs exposure and assessing oxidative damage in coke oven workers.

Comparative Pharmacokinetics of Chlorpyrifos versus its Major Metabolites Following Oral Administration in the Rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Busby-Hjerpe, Andrea L.; Campbell, James A.; Smith, Jordan N.

Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of in vivo metabolism and environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. Hence, urinary biomonitoring of TCPy, DEP and DETP may be reflective of an individual’s contact with both the parent pesticide and exposure to these metabolites. In the current study, simultaneous dosing of 13C- or 2H- isotopically labeled CPF (13Clabeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to directly compare themore » pharmacokinetics and metabolism of CPF with TCPy, and DETP. Individual metabolites were co-administered (oral gavage) with the parent compound at equal molar doses (14 μmol/kg; ~5mg/kg CPF). The key objective in the current study was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Major differences in the pharmacokinetics between CPF and metabolites doses were observed within the first 3 h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (≥ 3 h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or 2H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to 3 CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact the pharmacokinetics of either.« less

Influence of body mass index status on urinary creatinine and specific gravity for epidemiological study of children.

PubMed

Wang, Bin; Tang, Chuanxi; Wang, Hexing; Zhou, Wei; Chen, Yue; Zhou, Ying; Jiang, Qingwu

2015-11-01

In epidemiological studies, urinary biomonitoring is a valid approach to assess the association between environmental chemical exposure and children's health. Many clinical biomarkers (e.g., endogenous metabolites) are also based on analysis of urine. Considering the variability in urinary output, urinary concentrations of chemicals are commonly adjusted by creatinine and specific gravity (SG). However, there is a lack of systematic evaluation of their appropriateness for children. Furthermore, urinary SG and creatinine excretion could be influenced by body mass index (BMI), but the effect of BMI status on the two correction factors is unknown. We measured SG and creatinine concentrations of repeated first morning urine samples collected from 243 primary school children (8-11 years) over 5 consecutive weekdays. Urinary SG presented a higher temporal consistency compared with creatinine. Urinary SG was associated with sex (p < 0.001), whereas sex (p =0.034) and BMI (p = 00.008) were associated with urinary creatinine levels. Inter-day collection time was not associated with SG or creatinine after excluding the effect of Monday as a confounder. When stratified by BMI status, none of the factors were associated with creatinine among the overweight and obese children. Generally, SG is preferable for correcting the variability in urinary output for children although creatinine correction may also perform well in overweight and obese children. SG correction is recommended for epidemiological exposure analysis in children based on urinary levels of exogenous or endogenous metabolites.

PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Willemin, Marie-Emilie; Sorbonne University, Université de Technologie de Compiègne, CNRS, UMR 7338 Biomechanics and Bioengineering, Centre de recherche Royallieu CS 60319,60203 Compiègnee Cedex; Desmots, Sophie

2016-03-01

Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acidmore » (3-PBA) and 4′OH-phenoxybenzoic acid (4′-OH-PBA). In vivo experiments performed in Sprague–Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4′-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine. - Highlights: • A PBPK model of isomers of permethrin and its urinary metabolites was developed. • A quantitative link was established for permethrin and its biomarkers of exposure. • The bayesian framework allows getting confidence interval on the estimated parameters. • The PBPK model can be extrapolated to human and used in a reverse dosimetry context.« less

Urinary concentrations of phthalates and phenols in a population of Spanish pregnant women and children.

PubMed

Casas, Lidia; Fernández, Mariana F; Llop, Sabrina; Guxens, Mònica; Ballester, Ferran; Olea, Nicolás; Irurzun, Mikel Basterrechea; Rodríguez, Loreto Santa Marina; Riaño, Isolina; Tardón, Adonina; Vrijheid, Martine; Calafat, Antonia M; Sunyer, Jordi

2011-07-01

Phthalate and phenol exposure is prevalent among the general population and of potential concern for pregnant women and children because of their suspected susceptibility to endocrine effects. To evaluate the extent of exposure to several phthalates and phenols in a sample of Spanish pregnant women - according to their individual characteristics (age, social class, education, and body mass index) - and children who participated in the INMA - Infancia y Medio Ambiente (Environment and Childhood) project. One spot urine sample was taken during the third trimester of pregnancy from 120 pregnant women and from 30 4-year old children belonging to 5 Spanish birth cohorts, and analyzed for 11 phthalate metabolites and 9 phenols. Three metabolites of di(2-ethylhexyl) phthalate, mono-2-ethyl-5-carboxypentyl phthalate, mono-2-ethyl-5-hydroxyhexyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate; two metabolites of dibutyl phthalates, mono-isobutyl phthalate and mono-n-butyl phthalate; monoethyl phthalate (MEP), the main metabolite of diethyl phthalate; and two phenols, methyl paraben (M-PB) and 2,5-dichlorophenol were detected in the urine samples of all women. The highest urinary concentrations were for MEP and M-PB. Urinary concentrations of all phthalate metabolites and of 2,4-dichlorophenol, 2,5-dichlorophenol, and bisphenol A were lower in the pregnant women than in the children. Among women, a positive relationship with social class and education was shown for most of the phthalate metabolites and phenols. Almost all phthalate metabolites varied by region even after adjusting for social class and education. Phthalate and phenol exposures are prevalent in a group of pregnant women and young children, two susceptible populations, and these exposures might be positively related to social class. Copyright © 2011 Elsevier Ltd. All rights reserved.

Exposure to polycyclic aromatic hydrocarbons and volatile organic compounds among recently pregnant rural Guatemalan women cooking and heating with solid fuels.

PubMed

Weinstein, John R; Asteria-Peñaloza, Renée; Diaz-Artiga, Anaité; Davila, Gilberto; Hammond, S Katharine; Ryde, Ian T; Meyer, Joel N; Benowitz, Neal; Thompson, Lisa M

2017-06-01

Household air pollution is a major contributor to death and disability worldwide. Over 95% of rural Guatemalan households use woodstoves for cooking or heating. Woodsmoke contains carcinogenic or fetotoxic polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs). Increased PAHs and VOCs have been shown to increase levels of oxidative stress. We examined PAH and VOC exposures among recently pregnant rural Guatemalan women exposed to woodsmoke and compared exposures to levels seen occupationally or among smokers. Urine was collected from 23 women who were 3 months post-partum three times over 72h: morning (fasting), after lunch, and following dinner or use of wood-fired traditional sauna baths (samples=68). Creatinine-adjusted urinary concentrations of metabolites of four PAHs and eight VOCs were analyzed by liquid chromatography-mass spectrometry. Creatinine-adjusted urinary biomarkers of oxidative stress, 8-isoprostane and 8-OHdG, were analyzed using enzyme-linked immunosorbent assays (ELISA). Long-term (pregnancy through 3 months prenatal) exposure to particulate matter and airborne PAHs were measured. Women using wood-fueled chimney stoves are exposed to high levels of particulate matter (median 48h PM 2.5 105.7μg/m 3 ; inter-quartile range (IQR): 77.6-130.4). Urinary PAH and VOC metabolites were significantly associated with woodsmoke exposures: 2-naphthol (median (IQR) in ng/mg creatinine: 295.9 (74.4-430.9) after sauna versus 23.9 (17.1-49.5) fasting; and acrolein: 571.7 (429.3-1040.7) after sauna versus 268.0 (178.3-398.6) fasting. Urinary PAH (total PAH: ρ=0.89, p<0.001) and VOC metabolites of benzene (ρ=0.80, p<0.001) and acrylonitrile (ρ=0.59, p<0.05) were strongly correlated with long-term exposure to particulate matter. However urinary biomarkers of oxidative stress were not correlated with particulate matter (ρ=0.01 to 0.05, p>0.85) or PAH and VOC biomarkers (ρ=-0.20 to 0.38, p>0.07). Urinary metabolite concentrations were significantly greater than those of heavy smokers (mean cigarettes/day=18) across all PAHs. In 15 (65%) women, maximum 1-hydroxypyrene concentrations exceeded the occupational exposure limit of coke-oven workers. The high concentrations of urinary PAH and VOC metabolites among recently pregnant women is alarming given the detrimental fetal and neonatal effects of prenatal PAH exposure. As most women used chimney woodstoves, cleaner fuels are critically needed to reduce smoke exposure. Copyright © 2017 Elsevier GmbH. All rights reserved.

H-1 Nuclear Magnetic Resonance Metabolomics Analysis Identifies Novel Urinary Biomarkers for Lung Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

MCClay, Joseph L.; Adkins, Daniel E.; Isern, Nancy G.

2010-06-04

Chronic obstructive pulmonary disease (COPD), characterized by chronic airflow limitation, is a serious and growing public health concern. The major environmental risk factor for COPD is tobacco smoking, but the biological mechanisms underlying COPD are not well understood. In this study, we used proton nuclear magnetic resonance (1H-NMR) spectroscopy to identify and quantify metabolites associated with lung function in COPD. Plasma and urine were collected from 197 adults with COPD and from 195 adults without COPD. Samples were assayed using a 600 MHz NMR spectrometer, and the resulting spectra were analyzed against quantitative spirometric measures of lung function. After correctingmore » for false discoveries and adjusting for covariates (sex, age, smoking) several spectral regions in urine were found to be significantly associated with baseline lung function. These regions correspond to the metabolites trigonelline, hippurate and formate. Concentrations of each metabolite, standardized to urinary creatinine, were associated with baseline lung function (minimum p-value = 0.0002 for trigonelline). No significant associations were found with plasma metabolites. Two of the three urinary metabolites positively associated with baseline lung function, i.e. hippurate and formate, are often related to gut microflora. This suggests that the microbiome composition is variable between individuals with different lung function. Alternatively, the nature and origins of all three associated metabolites may reflect lifestyle differences affecting overall health. Our results will require replication and validation, but demonstrate the utility of NMR metabolomics as a screening tool for identifying novel biomarkers of lung disease or disease risk.« less

Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet

PubMed Central

Cheng, Yuan; Song, Haiying; Pan, Xiaoqing; Xue, Hong; Wan, Yifei; Wang, Tao; Tian, Zhongmin; Hou, Entai; Lanza, Ian R.; Liu, Pengyuan; Liu, Yong; Laud, Purushottam W.; Usa, Kristie; He, Yongcheng; Liang, Mingyu

2018-01-01

Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood, and it is difficult to assess blood pressure salt-sensitivity clinically. Methods: We examined urinary levels of metabolites in 103 participants of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial after nearly 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol per day). Targeted chromatography/mass spectrometry analysis was performed in 24 h urine samples for 47 amino metabolites and 10 metabolites related to the tricarboxylic acid cycle. The effect of an identified metabolite on blood pressure was examined in Dahl salt-sensitive rats. Results: Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations of 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine with systolic blood pressure and cystine with diastolic blood pressure. The differences in homocysteine levels between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. Conclusion: These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries, which could be developed as markers or therapeutic targets for salt-sensitive hypertension. PMID:29556335

Monitoring population exposure to pesticides based on liquid chromatography-tandem mass spectrometry measurement of their urinary metabolites in urban wastewater: A novel biomonitoring approach.

PubMed

Rousis, Nikolaos I; Zuccato, Ettore; Castiglioni, Sara

2016-11-15

Biomonitoring studies have documented the high exposure of the population to pesticides which are widely used for crop protection, industrial and household purposes. This is the first study which has measured human urinary metabolites of pesticides in urban wastewater as biomarkers of population exposure. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to measure fifteen urinary metabolites selected from the major classes of pesticides. Raw wastewater samples were processed by solid phase extraction (SPE) or direct injection into the LC-MS/MS system. Recoveries ranged from 75 to 115% and the limits of quantification were 1-15ng/L for the SPE method and 40-800ng/L for direct injection. The method was employed for the analysis of 44 composite 24-h wastewater samples collected in seven Italian cities. Most of the target substances were detected at concentrations ranging from 1.1ng/L to 1.6μg/L. The highest concentrations were for some common metabolites of alkyl phosphates and pyrethroids and the specific metabolite of chlorpyrifos and chlorpyrifos-methyl (3,5,6-trichloro-2-pyridinol). The frequency of detection and abundance of most of the measured metabolites were in line with the profiles reported in urine biomonitoring studies. This method is therefore proposed as a novel "biomonitoring approach" for obtaining objective, direct information on the levels of exposure of a specific population to pesticides, and current research is addressed to validate the method identifying the most reliable biomarkers. Copyright © 2016 Elsevier B.V. All rights reserved.

Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet.

PubMed

Cheng, Yuan; Song, Haiying; Pan, Xiaoqing; Xue, Hong; Wan, Yifei; Wang, Tao; Tian, Zhongmin; Hou, Entai; Lanza, Ian R; Liu, Pengyuan; Liu, Yong; Laud, Purushottam W; Usa, Kristie; He, Yongcheng; Liang, Mingyu

2018-01-01

Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood, and it is difficult to assess blood pressure salt-sensitivity clinically. Methods: We examined urinary levels of metabolites in 103 participants of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial after nearly 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol per day). Targeted chromatography/mass spectrometry analysis was performed in 24 h urine samples for 47 amino metabolites and 10 metabolites related to the tricarboxylic acid cycle. The effect of an identified metabolite on blood pressure was examined in Dahl salt-sensitive rats. Results: Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations of 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine with systolic blood pressure and cystine with diastolic blood pressure. The differences in homocysteine levels between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. Conclusion: These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries, which could be developed as markers or therapeutic targets for salt-sensitive hypertension.

Orange juice (poly)phenols are highly bioavailable in humans.

PubMed

Pereira-Caro, Gema; Borges, Gina; van der Hooft, Justin; Clifford, Michael N; Del Rio, Daniele; Lean, Michael E J; Roberts, Susan A; Kellerhals, Michele B; Crozier, Alan

2014-11-01

We assessed the bioavailability of orange juice (poly)phenols by monitoring urinary flavanone metabolites and ring fission catabolites produced by the action of the colonic microbiota. Our objective was to identify and quantify metabolites and catabolites excreted in urine 0-24 h after the acute ingestion of a (poly)phenol-rich orange juice by 12 volunteers. Twelve volunteers [6 men and 6 women; body mass index (in kg/m(2)): 23.9-37.2] consumed a low (poly)phenol diet for 2 d before first drinking 250 mL pulp-enriched orange juice, which contained 584 μmol (poly)phenols of which 537 μmol were flavanones, and after a 2-wk washout, the procedure was repeated, and a placebo drink was consumed. Urine collected for a 24-h period was analyzed qualitatively and quantitatively by using high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography-mass spectrometry (GC-MS). A total of 14 metabolites were identified and quantified in urine by using HPLC-MS after orange juice intake. Hesperetin-O-glucuronides, naringenin-O-glucuronides, and hesperetin-3'-O-sulfate were the main metabolites. The overall urinary excretion of flavanone metabolites corresponded to 16% of the intake of 584 μmol (poly)phenols. The GC-MS analysis revealed that 8 urinary catabolites were also excreted in significantly higher quantities after orange juice consumption. These catabolites were 3-(3'-methoxy-4'-hydroxyphenyl)propionic acid, 3-(3'-hydroxy-4'-methoxyphenyl)propionic acid, 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic acid, 3-(3'-hydroxyphenyl)hydracrylic acid, 3'-methoxy-4'-hydroxyphenylacetic acid, hippuric acid, 3'-hydroxyhippuric acid, and 4'-hydroxyhippuric acid. These aromatic acids originated from the colonic microbiota-mediated breakdown of orange juice (poly)phenols and were excreted in amounts equivalent to 88% of (poly)phenol intake. When combined with the 16% excretion of metabolites, this percentage raised the overall urinary excretion to ∼ 100% of intake. When colon-derived phenolic catabolites are included with flavanone glucuronide and sulfate metabolites, orange juice (poly)phenols are much-more bioavailable than previously envisaged. In vitro and ex vivo studies on mechanisms underlying the potential protective effects of orange juice consumption should use in vivo metabolites and catabolites detected in this investigation at physiologic concentrations. The trial was registered at BioMed Central Ltd (www.controlledtrials.com) as ISRCTN04271658. © 2014 American Society for Nutrition.

Consumer product exposures associated with urinary phthalate levels in pregnant women

PubMed Central

Buckley, Jessie P.; Palmieri, Rachel T.; Matuszewski, Jeanine M.; Herring, Amy H.; Baird, Donna D.; Hartmann, Katherine E.; Hoppin, Jane A.

2012-01-01

Human phthalate exposure is ubiquitous, but little is known regarding predictors of urinary phthalate levels. To explore this, 50 pregnant women aged 18–38 years completed two questionnaires on potential phthalate exposures and provided a first morning void. Urine samples were analyzed for 12 phthalate metabolites. Associations with questionnaire items were evaluated via Wilcoxon tests and t-tests, and r-squared values were calculated in multiple linear regression models. Few measured factors were statistically significantly associated with phthalate levels. Individuals who used nail polish had higher levels of mono-butyl phthalate (p=0.048) than non-users. Mono-benzyl phthalate levels were higher among women who used eye makeup (p=0.034) or used makeup on a regular basis (p=0.004). Women who used cologne or perfume had higher levels of di-(2-ethylhexyl) phthalate metabolites. Household products, home flooring or paneling, and other personal care products were also associated with urinary phthalates. The proportion of variance in metabolite concentrations explained by questionnaire items ranged between 0.31 for mono-ethyl phthalate and 0.42 for mono-n-methyl phthalate. Although personal care product use may be an important predictor of urinary phthalate levels, most of the variability in phthalate exposure was not captured by our relatively comprehensive set of questionnaire items. PMID:22760436

High wavenumber Raman spectroscopy in the characterization of urinary metabolites of normal subjects, oral premalignant and malignant patients

NASA Astrophysics Data System (ADS)

Brindha, Elumalai; Rajasekaran, Ramu; Aruna, Prakasarao; Koteeswaran, Dornadula; Ganesan, Singaravelu

2017-01-01

Urine has emerged as one of the diagnostically potential bio fluids, as it has many metabolites. As the concentration and the physiochemical properties of the urinary metabolites may vary under pathological transformation, Raman spectroscopic characterization of urine has been exploited as a significant tool in identifying several diseased conditions, including cancers. In the present study, an attempt was made to study the high wavenumber (HWVN) Raman spectroscopic characterization of urine samples of normal subjects, oral premalignant and malignant patients. It is concluded that the urinary metabolites flavoproteins, tryptophan and phenylalanine are responsible for the observed spectral variations between the normal and abnormal groups. Principal component analysis-based linear discriminant analysis was carried out to verify the diagnostic potentiality of the present technique. The discriminant analysis performed across normal and oral premalignant subjects classifies 95.6% of the original and 94.9% of the cross-validated grouped cases correctly. In the second analysis performed across normal and oral malignant groups, the accuracy of the original and cross-validated grouped cases was 96.4% and 92.1% respectively. Similarly, the third analysis performed across three groups, normal, oral premalignant and malignant groups, classifies 93.3% and 91.2% of the original and cross-validated grouped cases correctly.

Differential urinary metabolites related with the severity of major depressive disorder.

PubMed

Chen, Jian-Jun; Zhou, Chan-Juan; Zheng, Peng; Cheng, Ke; Wang, Hai-Yang; Li, Juan; Zeng, Li; Xie, Peng

2017-08-14

Major depressive disorder (MDD) is a common mental disorder that affects a person's general health. However, there is still no objective laboratory test for diagnosing MDD. Here, an integrated analysis of data from our previous studies was performed to identify the differential metabolites in the urine of moderate and severe MDD patients. A dual platform approach (NMR spectroscopy and GC-MS) was used. Consequently, 14 and 22 differential metabolites responsible for separating moderate and severe MDD patients, respectively, from their respective healthy controls (HCs) were identified. Meanwhile, the moderate MDD-specific panel (N-Methylnicotinamide, Acetone, Choline, Citrate, vanillic acid and azelaic acid) and severe MDD-specific panel (indoxyl sulphate, Taurine, Citrate, 3-hydroxyphenylacetic acid, palmitic acid and Lactate) could discriminate moderate and severe MDD patients, respectively, from their respective HCs with high accuracy. Moreover, the differential metabolites in severe MDD were significantly involved in three metabolic pathways and some biofunctions. These results showed that there were divergent urinary metabolic phenotypes in moderate and severe MDD patients, and the identified potential urinary biomarkers might be useful for future developing objective diagnostic tests for MDD diagnosis. Our results could also be helpful for researchers to study the pathogenesis of MDD. Copyright © 2017 Elsevier B.V. All rights reserved.

Non-invasive endocrine monitoring of ovarian and adrenal activity in chinchilla (Chinchilla lanigera) females during pregnancy, parturition and early post-partum period.

PubMed

Mastromonaco, Gabriela F; Cantarelli, Verónica I; Galeano, María G; Bourguignon, Nadia S; Gilman, Christine; Ponzio, Marina F

2015-03-01

The chinchilla is a rodent that bears one of the finest and most valuable pelts in the world. The wild counterpart is, however, almost extinct because of a drastic past and ongoing population decline. The present work was developed to increase our knowledge of the reproductive physiology of pregnancy and post-partum estrus in the chinchilla, characterizing the endocrine patterns of urinary progesterone, estradiol, LH and cortisol metabolites throughout gestation and post-partum estrus and estimating the ovulation timing at post-partum estrus. Longitudinal urine samples were collected once per week throughout pregnancy and analyzed for creatinine, cortisol, LH, estrogen and progesterone metabolite concentrations. To indirectly determine the ovulation timing at post-partum estrus, a second experiment was performed using pregnant females subjected to a post-partum in vivo fertilization scheme. Urinary progestagen metabolites increased above baseline levels in early pregnancy between weeks-8 and -11 respectively to parturition, and slightly declined at parturition time. Urinary estrogens showed rising levels throughout mid- and late pregnancy (weeks-9 to -6 and a further increase at week-5 to parturition) and decreased in a stepwise manner after parturition, returning to baseline levels two weeks thereafter. Cortisol metabolite levels were relatively constant throughout pregnancy with a tendency for higher levels in the last third of gestation and after the pups' birth. Parturition was associated with dramatic reductions in urinary concentrations of sex steroids (especially progestagens). Observations in breeding farms indicated that the females that resulted in a second pregnancy after mating, did so on the second day after parturition. These data were in agreement with an LH peak detected 24h after parturition. Urinary steroid hormone patterns of estrogen and progestagen metabolites provided valuable information on endocrine events during pregnancy and after parturition in the chinchilla. Results presented in this study enhance our understanding of natural reproductive dynamics in the chinchilla and support empirical observations of breeders that post-partum ovulation occurs ∼ 48 h after parturition. Copyright © 2015 Elsevier Inc. All rights reserved.

Kidney injury biomarkers and urinary creatinine variability in nominally healthy adults

EPA Science Inventory

Environmental exposure diagnostics use creatinine concentrations in urine aliquots as the internal standard for dilution normalization of all other excreted metabolites when urinary excretion rate data are not available. This is a reasonable approach for healthy adults as creati...

RELIABILITY OF BIOMARKERS OF PESTICIDE EXPOSURE AMONG CHILDREN AND ADULTS IN CTEPP OHIO

EPA Science Inventory

Urinary biomarkers offer the potential for providing an efficient tool for exposure classification by reflecting the aggregate of all exposure routes. Substantial variability observed in urinary pesticide metabolite concentrations over short periods of time, however, has cast so...

Multiple metal exposures and their correlation with monoamine neurotransmitter metabolism in Chinese electroplating workers.

PubMed

Wu, Lin-Lin; Gong, Wei; Shen, Si-Peng; Wang, Zhong-He; Yao, Jia-Xi; Wang, Jun; Yu, Jing; Gao, Rong; Wu, Gang

2017-09-01

Excessive metal exposure has been recognized as one of the detrimental factors for brain damage. However, the potential adverse effects induced by heavy metals on monoamine neurotransmitter pathways remains poorly understood. Our study aimed to investigate the possible association between metal exposure and neurotransmitter metabolism. By a cross-sectional investigation, 224 electroplating workers and 213 non-electroplating exposure workers were recruited in the exposure and control groups. Metal exposure levels were analyzed using inductively-coupled plasma mass spectrometry and monoamine neurotransmitter pathway metabolites were measured by ultra-performance liquid chromatography tandem mass spectrometry in human urine samples. Multivariate linear regression model was used to assess the dose-response relationships of urinary metals and neurotransmitter pathway metabolites. Significant dose-dependent trends of urinary vanadium quartiles with all metabolites were observed, and the trends demonstrated significance after multiple testing correction. It also showed that urinary chromium levels were significantly associated with decreased serotonin level and cadmium was positively associated with norepinephrine and epinephrine. In addition, arsenic was positively associated with tryptophan, serotonin, dopamine and norepinephrine. Iron was positively associated with increased homovanillic acid (HVA) and epinephrine while nickel was negatively associated with increased epinephrine levels. Zinc was positively related to tryptophan, kynurenin (KYN), 5-hydroxyindole acetic acid (5-HIAA), dopamine, HVA and norepinephrine. There was no significant association between urinary copper with any other metabolites after adjusting of multiple metal models. Metal exposure may be associated with neurotransmitter metabolism disturbances. The present work is expected to provide some support in the prevention and management of metal-associated neurological diseases. Copyright © 2017. Published by Elsevier Ltd.

Analysis of 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (DTMBA) as a new potential biomarker of exposure to vinclozolin in urine.

PubMed

Cruz-Hurtado, Marycarmen; López-González, Ma de Lourdes; Escobar-Wilches, Derly Constanza; Sierra-Santoyo, Adolfo

2018-05-01

Vinclozolin (V) is a fungicide with anti-androgenic properties whose metabolism is not fully understood, and data on urinary elimination of either V or its metabolites are limited. Therefore the kinetics of urinary elimination of V and its metabolites, after an oral dose in adult male rats were investigated. A single oral dose of V (100 mg/kg) suspended in corn oil was administered to male adult Wistar rats, and urine was collected at different times after dosing. V and its metabolites were extracted from urine, then enzymatically hydrolyzed using β-glucuronidase/sulfatase of H. pomatia, and analyzed by HPLC/DAD. Urinary pharmacokinetic parameters were calculated using the analyte concentrations adjusted by creatinine levels. V and its metabolites 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (DTMBA, formerly denoted as M5), 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), 3,5-dichloroaniline (M3), and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2) were efficiently detected. The mean urine concentrations of V and M1 metabolite were fitted to a two-compartmental model for pharmacokinetic analysis. DTMBA approximately represented 88% of the total excreted metabolites, it was easily detected up to 168 h after dosing and its half-lives were 21.5 and 74.1 h, respectively. M1 was the second most abundant metabolite and was detected up to 144 h after being void. V and M3 were detected before 48 h, and M2 exhibited the lowest levels during the first 8 h after dosing. DTMBA, the most abundant V metabolite is quickly eliminated by urine, it is chemically stable, specific and could represent a useful alternative to be used as a biomarker of exposure to V. Copyright © 2018 Elsevier Inc. All rights reserved.

Steroid hormone release as well as renal water and electrolyte excretion of mice expressing PKB/SGK-resistant GSK3.

PubMed

Boini, Krishna M; Bhandaru, Madhuri; Mack, Andreas; Lang, Florian

2008-09-01

Insulin and insulin-like growth factor (IGF1) participate in the regulation of renal electrolyte excretion. Insulin- and IGF1-dependent signaling includes phosphatidylinositide-3 (PI3)-kinase, phosphoinositide-dependent kinase PDK1 as well as protein kinase B (PKB) and serum and glucocorticoid inducible kinase (SGK) isoforms, which in turn phosphorylate and thus inhibit glycogen synthase kinase GSK3alpha,beta. Replacement of the serines in the PKB/SGK consensus sequences by alanine (gsk3 ( KI )) confers resistance of GSK3 to PKB/SGK. To explore the role of PKB/SGK-dependent inhibition of GSK3 in the regulation of water/electrolyte metabolism, mice carrying the PKB/SGK resistant mutant (gsk3 ( KI )) were compared to their wild-type littermates (gsk3 ( WT ) ). Body weight was similar in gsk3 ( KI ) and gsk3 ( WT ) mice. Plasma aldosterone at 10 A.M: . and corticosterone concentrations at 5 P.M: . were significantly lower, but 24-h urinary aldosterone was significantly higher, and corticosterone excretion tended to be higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. Food and water intake, fecal excretion, glomerular filtration rate, urinary flow rate, urine osmolarity, as well as urinary Na+, K+, urea excretion were significantly larger, and plasma Na+, urea, but not K+ concentration, were significantly lower in gsk3 ( KI ) than in gsk3 ( WT ) mice. Body temperature was significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. When allowed to choose between tap water and saline, gsk3 ( WT ) mice drank more saline, whereas gsk3 ( KI ) mice drank similar large volumes of tap water and saline. During high-salt diet, urinary vasopressin excretion increased to significantly higher levels in gsk3 ( KI ) than in gsk3 ( WT ) mice. After water deprivation, body weight decreased faster in gsk3 ( KI ) than in gsk3 ( WT ) mice. Blood pressure, however, was significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. The observations disclose a role of PKB/SGK-dependent GSK3 activity in the regulation of steroid hormone release, renal water and electrolyte excretion and blood pressure control.

Urinary metabolomic profiling in rats exposed to dietary di(2-ethylhexyl) phthalate (DEHP) using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS).

PubMed

Dong, Xinwen; Zhang, Yunbo; Dong, Jin; Zhao, Yue; Guo, Jipeng; Wang, Zhanju; Liu, Mingqi; Na, Xiaolin; Wang, Cheng

2017-07-01

Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental chemical with widespread nonoccupational human exposure through multiple ways. Although considerable efforts have been invested to investigate mechanisms of DEHP toxicity, the key metabolic biomarkers of DEHP toxicity remain to be identified. The aim of this study was to assess the urinary metabonomics of dietary DEHP in rats using the technique of ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS). Fourteen female Wistar rats were divided into two groups and given increasing dietary doses of DEHP for 30 consecutive days. The urinary metabolite profile was studied using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) enabled clusters to be clearly separated. Eleven principal urinary metabolites were identified as contributing to the clusters. The clusters in the positive electrospray ionization (ESI) mode were xanthurenic acid, kynurenic acid, nonate, N6-methyladenosine, and L-isoleucyl-L-proline. The clusters in the negative ESI mode were hippuric acid, tetrahydrocortisol, citric acid, phenylpropionylglycine, cPA(18:2(9Z, 12Z)/0:0), and LysoPC(14:1(9Z)). The urinary metabonomic changes indicated that exposure to dietary DEHP can affect energy-related metabolism, liver and renal function, fatty acid metabolism, and cause DNA damage in rats. The findings of this study on the urinary metabolites and metabolic pathways of DEHP may form the basis for future studies on the mechanisms of toxicity of this commonly found environmental chemical.

Does exposure to phthalates influence thyroid function and growth hormone homeostasis? The Taiwan Environmental Survey for Toxicants (TEST) 2013.

PubMed

Huang, Han-Bin; Pan, Wen-Harn; Chang, Jung-Wei; Chiang, Hung-Che; Guo, Yue Leon; Jaakkola, Jouni J K; Huang, Po-Chin

2017-02-01

Previous epidemiologic and toxicological studies provide some inconsistent evidence that exposure to phthalates may affect thyroid function and growth hormone homeostasis. To assess the relations between exposure to phthalates and indicators of thyroid function and growth hormone homeostasis disturbances both among adults and minors. We conducted a population-based cross-sectional study of 279 Taiwanese adults (≥18 years old) and 79 minors (<18 years old) in 2013. Exposure assessment was based on urinary biomarkers, 11 phthalate metabolites measured by using online liquid chromatography/tandem mass spectrometry. Indicators of thyroid function included serum levels of thyroxine (T 4 ), free T 4 , triiodothyronine, thyroid-stimulating hormone, and thyroxine-binding globulin (TBG). Growth hormone homeostasis was measured as the serum levels of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3). We applied multivariate linear regression models to examine these associations after adjusting for covariates. Among adults, serum T 4 levels were negatively associated with urinary mono-(2-ethyl-5-hydroxyhexyl) phthalate (β=-0.028, P=0.043) and the sum of urinary di-(2-ethylhexyl) phthalate (DEHP) metabolite (β=-0.045, P=0.017) levels. Free T 4 levels were negatively associated with urinary mono-ethylhexyl phthalate (MEHP) (β=-0.013, P=0.042) and mono-(2-ethyl-5-oxohexyl) phthalate (β=-0.030, P=0.003) levels, but positively associated with urinary monoethyl phthalate (β=0.014, P=0.037) after adjustment for age, BMI, gender, urinary creatinine levels, and TBG levels. Postive associations between urinary MEHP levels and IGF-1 levels (β=0.033, P=0.006) were observed. Among minors, free T 4 was positively associated with urinary mono benzyl phthalate levels (β=0.044, P=0.001), and IGF-1 levels were negatively associated with the sum of urinary DEHP metabolite levels (β=-0.166, P=0.041) after adjustment for significant covariance and IGFBP3. Our results are consistent with the hypothesis that exposure to phthalates influences thyroid function and growth hormone homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Biologically driven neural platform invoking parallel electrophoretic separation and urinary metabolite screening.

PubMed

Page, Tessa; Nguyen, Huong Thi Huynh; Hilts, Lindsey; Ramos, Lorena; Hanrahan, Grady

2012-06-01

This work reveals a computational framework for parallel electrophoretic separation of complex biological macromolecules and model urinary metabolites. More specifically, the implementation of a particle swarm optimization (PSO) algorithm on a neural network platform for multiparameter optimization of multiplexed 24-capillary electrophoresis technology with UV detection is highlighted. Two experimental systems were examined: (1) separation of purified rabbit metallothioneins and (2) separation of model toluene urinary metabolites and selected organic acids. Results proved superior to the use of neural networks employing standard back propagation when examining training error, fitting response, and predictive abilities. Simulation runs were obtained as a result of metaheuristic examination of the global search space with experimental responses in good agreement with predicted values. Full separation of selected analytes was realized after employing optimal model conditions. This framework provides guidance for the application of metaheuristic computational tools to aid in future studies involving parallel chemical separation and screening. Adaptable pseudo-code is provided to enable users of varied software packages and modeling framework to implement the PSO algorithm for their desired use.

Recommendations and Standardization of Biomarker Quantification Using NMR-Based Metabolomics with Particular Focus on Urinary Analysis.

PubMed

Emwas, Abdul-Hamid; Roy, Raja; McKay, Ryan T; Ryan, Danielle; Brennan, Lorraine; Tenori, Leonardo; Luchinat, Claudio; Gao, Xin; Zeri, Ana Carolina; Gowda, G A Nagana; Raftery, Daniel; Steinbeck, Christoph; Salek, Reza M; Wishart, David S

2016-02-05

NMR-based metabolomics has shown considerable promise in disease diagnosis and biomarker discovery because it allows one to nondestructively identify and quantify large numbers of novel metabolite biomarkers in both biofluids and tissues. Precise metabolite quantification is a prerequisite to move any chemical biomarker or biomarker panel from the lab to the clinic. Among the biofluids commonly used for disease diagnosis and prognosis, urine has several advantages. It is abundant, sterile, and easily obtained, needs little sample preparation, and does not require invasive medical procedures for collection. Furthermore, urine captures and concentrates many "unwanted" or "undesirable" compounds throughout the body, providing a rich source of potentially useful disease biomarkers; however, incredible variation in urine chemical concentrations makes analysis of urine and identification of useful urinary biomarkers by NMR challenging. We discuss a number of the most significant issues regarding NMR-based urinary metabolomics with specific emphasis on metabolite quantification for disease biomarker applications and propose data collection and instrumental recommendations regarding NMR pulse sequences, acceptable acquisition parameter ranges, relaxation effects on quantitation, proper handling of instrumental differences, sample preparation, and biomarker assessment.

Urinary excretion of mutagens in coke oven workers.

PubMed

Clonfero, E; Granella, M; Marchioro, M; Barra, E L; Nardini, B; Ferri, G; Foà, V

1995-03-01

The influence of occupational exposure to polycyclic aromatic hydrocarbons (PAHs) on urinary mutagenic activity was assessed in 75 coke oven workers, using a highly sensitive bacterial mutagen technique (extraction with C18 resin and liquid micro-preincubation test on strain TA98 of Salmonella typhimurium in the presence of metabolizing and deconjugating enzymes). Exposure to PAHs was assessed according to the urinary excretion of 1-pyrenol; the main confounding factors were checked by the number of cigarettes smoked per day and the levels of nicotine and its metabolites in urine, or by ascertaining whether recommended dietary restrictions had been followed. Of the 20 urine samples which turned out to be positive (producing at least double the number of spontaneous revertants), 19 (95%) belonged to smokers. Only one non-smoker had obvious urinary mutagenic activity, and was highly exposed occupationally to PAHs (urinary 1-pyrenol of 3.930 mumol/mol of creatinine). Of the five urine samples from subjects who had not followed the recommended diet, two (40%) were clearly mutagenic. Multiple regression analysis (n = 67) showed that the presence of samples positive for urinary mutagenic activity depended only on smoking habits, if this confounding factor was assessed according to the number of cigarettes smoked per day, while the significant influence of exposure to PAH could be shown when the confounding factor was objectively estimated according to the urinary levels of nicotine and its metabolites. Assessment of the mutagenic potency of urinary extracts (net revertants/mmol creatinine) confirmed the strong influence of smoking habits on urinary mutagenic activity (all smokers 2156 +/- 2691 versus non-smokers 939 +/- 947 net revertants/mmol creatinine; Mann-Whitney test: P < 0.01). In smokers highly exposed to PAHs, greater excretion of mutagens with respect to low-exposure smokers was revealed (3548 +/- 4009 versus 1552 +/- 1227 net revertants/mmol creatinine; Mann-Whitney test: P < 0.01). Multiple regression analysis showed that the mutagenic potency of urinary extracts of coke oven workers depended on exposure to PAHs, tobacco smoking habits, and consumption of fried, grilled or barbecued meat. Increased urinary mutagenic activity strengthens epidemiological evidence of the increased risk of renal and urinary tract tumours in these workers. The presence of mutagenic metabolites in urine as a result of occupational exposure to PAH may be demonstrated only by using highly sensitive techniques for assessing urinary mutagenic activity in studies which include careful checking of the main confounding factors.

Urinary excretion of the metabolites of n-hexane and its isomers during occupational exposure.

PubMed Central

Perbellini, L; Brugnone, F; Faggionato, G

1981-01-01

Environmental exposure to commercial hexane (n-hexane, 2-methylpentane, and 3-methylpentane) was tested in several work places in five shoe factories by taking three grap-air samples during the afternoon shift. Individual exposure ranges were 32-500 mg/m3 for n-hexane, 11-250 mg/m3 for 2-methylpentane, and 10-204 mg/m3 for 3-methylpentane. The metabolites of commercial hexane in the urine of 41 workers were measured at the end of the work shift. 2-Hexanol, 2,5-hexanedione, 2,5-dimethylfuran, and gamma-valerolactone were found as n-hexane metabolites and 2-methyl-2-pentanol and 3-methyl-2-pentanol as 2-methylpentane and 3-methylpentane metabolites. The presence of metabolites in the urine was correlated with occupational exposure to solvents. n-Hexane exposure was correlated more positively with 2-hexanol and 2,5-hexanedione than with 2,5-dimethylfuran and gamma-valerolactone. A good correlation was also found between total n-hexane metabolites and n-hexane exposure. 2-Methyl-2-pentanol and 3-methyl-2-pentanol were highly correlated with 2-methylpentane and 3-methylpentane exposure. The results suggest that the urinary excretion of hexane metabolites may be used for monitoring occupational exposure to n-hexane and its isomers. PMID:7470400

Measurements of the levels of organic solvent vapours by personal air samplers and the levels of urinary metabolites of workers. Part 2. Toluene vapour in a shipbuilding yard (author's transl).

PubMed

Kira, S

1977-05-01

Personal air samplers were applied to shipyard's painters putting on gas masks during the spraying work, and the levels of toluene vapour surrounding the workers were measured. On the other hand, levels of urinary hippuric acid (metabolites of toluene) of the workers were measured, and the levels of toluene vapour inhaled were calculated from the levels of urinary hippuric acid. Then the actual removing-efficiencies of toluene vapours by the use of gas masks were estimated from these two levels (i.e., toluene vapours exposed and inhaled). The values of removing-efficiencies were found to be 65.9-98.1%. The concentrations of hippuric and methylhippuric acids in the urine of workers exposed to toluene and xylene for 3 hours, collected just after the exposure, are valuable indices of these organic solvent vapours inhaled. A minute amount of urinary methylhippuric acid can be determined by means of gas chromatography.

Acute sleep deprivation preconditions the heart against ischemia/ reperfusion injury: the role of central GABA-A receptors

PubMed Central

Parsa, Hoda; Imani, Alireza; Faghihi, Mahdieh; Riahi, Esmail; Badavi, Mohammad; Shakoori, Abbas; Rastegar, Tayebeh; Aghajani, Marjan; Rajani, Sulail Fatima

2017-01-01

Objective(s): Central γ-aminobutyric acid (GABA) neurotransmission modulates cardiovascular functions and sleep. Acute sleep deprivation (ASD) affects functions of various body organs via different mechanisms. Here, we evaluated the effect of ASD on cardiac ischemia/reperfusion injury (IRI), and studied the role of GABA-A receptor inhibition in central nucleus of amygdala (CeA) by assessing nitric oxide (NO) and oxidative stress. Materials and Methods: The CeA in sixty male Wistar rats was cannulated for saline or bicuculline (GABA-A receptor antagonist) administration. All animals underwent 30 min of coronary occlusion (ischemia), followed by 2 hr reperfusion (IR). The five experimental groups (n=12) included are as follows: IR: received saline; BIC+IR: received Bicuculline; MLP+IR: received saline, followed by the placement of animals in an aquarium with multiple large platforms; ASD+IR: underwent ASD in an aquarium with multiple small platforms; and BIC+ASD+IR: received bicuculline prior to ASD. Results: Bicuculline administration increased the malondialdehyde levels and infarct size, and decreased the NO metabolites levels and endothelial nitric oxide synthase (eNOS) gene expression in infarcted and non-infarcted areas in comparison to IR group. ASD reduced malondialdehyde levels and infarct size and increased NO metabolites, corticosterone levels and eNOS expression in infarcted and non-infarcted areas as compared to the IR group. Levels of malondialdehyde were increased while levels of NO metabolites, corticosterone and eNOS expression in infarcted and non-infarcted areas were reduced in the BIC+ASD+IR as compared to the ASD+IR group. Conclusion: Blockade of GABA-A receptors in the CeA abolishes ASD-induced cardioprotection by suppressing oxidative stress and NO production. PMID:29299201

Acute sleep deprivation preconditions the heart against ischemia/ reperfusion injury: the role of central GABA-A receptors.

PubMed

Parsa, Hoda; Imani, Alireza; Faghihi, Mahdieh; Riahi, Esmail; Badavi, Mohammad; Shakoori, Abbas; Rastegar, Tayebeh; Aghajani, Marjan; Rajani, Sulail Fatima

2017-11-01

Central γ-aminobutyric acid (GABA) neurotransmission modulates cardiovascular functions and sleep. Acute sleep deprivation (ASD) affects functions of various body organs via different mechanisms. Here, we evaluated the effect of ASD on cardiac ischemia/reperfusion injury (IRI), and studied the role of GABA-A receptor inhibition in central nucleus of amygdala (CeA) by assessing nitric oxide (NO) and oxidative stress. The CeA in sixty male Wistar rats was cannulated for saline or bicuculline (GABA-A receptor antagonist) administration. All animals underwent 30 min of coronary occlusion (ischemia), followed by 2 hr reperfusion (IR). The five experimental groups (n=12) included are as follows: IR: received saline; BIC+IR: received Bicuculline; MLP+IR: received saline, followed by the placement of animals in an aquarium with multiple large platforms; ASD+IR: underwent ASD in an aquarium with multiple small platforms; and BIC+ASD+IR: received bicuculline prior to ASD. Bicuculline administration increased the malondialdehyde levels and infarct size, and decreased the NO metabolites levels and endothelial nitric oxide synthase (eNOS) gene expression in infarcted and non-infarcted areas in comparison to IR group. ASD reduced malondialdehyde levels and infarct size and increased NO metabolites, corticosterone levels and eNOS expression in infarcted and non-infarcted areas as compared to the IR group. Levels of malondialdehyde were increased while levels of NO metabolites, corticosterone and eNOS expression in infarcted and non-infarcted areas were reduced in the BIC+ASD+IR as compared to the ASD+IR group. Blockade of GABA-A receptors in the CeA abolishes ASD-induced cardioprotection by suppressing oxidative stress and NO production.

Urinary phthalate excretion in 555 healthy Danish boys with and without pubertal gynaecomastia.

PubMed

Mieritz, Mikkel G; Frederiksen, Hanne; Sørensen, Kaspar; Aksglaede, Lise; Mouritsen, Annette; Hagen, Casper P; Skakkebaek, Niels E; Andersson, Anna-Maria; Juul, Anders

2012-06-01

Pubertal gynaecomastia is a clinical sign of an oestrogen-androgen imbalance, which occurs in 40-60% of adolescent Caucasian boys. In most cases no underlying endocrinopathy can be identified. A recent study reports higher plasma phthalate levels in Turkish boys with pubertal gynaecomastia. Therefore, we asked whether there was an association between concurrent measures of urinary phthalate metabolites and pubertal timing as well as the presence of gynaecomastia in otherwise healthy boys. We studied a total of 555 healthy boys (age 6.07-19.83 years) as part of the COPENHAGEN Puberty Study. Anthropometry and pubertal stages (PH1-6 and G1-5) were evaluated, and the presence of gynaecomastia was assessed. Non-fasting blood samples were analysed for serum testosterone and morning urine samples were analysed for the total content of 12 phthalate metabolites (MEP, MnBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MiNP, MHiNP, MiONP and MCiOP) by LC-MS/MS. A statistically significant negative correlation was observed between chronological age and the urinary concentration of the sum of measured metabolites DEHP (∑DEHPm) (r = -0.164) and DiNP (∑DiNPm) (r = -0.224), respectively, and the sum of monobutyl phthalate (MBP) isomers (∑MBP((i+n))) (r = -0.139) (all with p < 0.01). In contrast urinary monoethyl phthalate concentration was positively correlated to age (r = 0.187, p < 0.01). The urinary levels of phthalate metabolites were not associated with age at pubertal onset, serum testosterone levels or presence of gynaecomastia. In conclusion, we did not find evidence of anti-androgenic effects of phthalates in our healthy boys. Thus, current phthalate exposure was not associated with pubertal timing, testosterone levels or with the presence of pubertal gynaecomastia in this cross-sectional study. However, longitudinal studies are needed to evaluate possible perinatal or long-term postnatal effects of phthalates on healthy boys. © 2012 The Authors. International Journal of Andrology © 2012 European Academy of Andrology.

Personal Care Product Use in Men and Urinary Concentrations of Select Phthalate Metabolites and Parabens: Results from the Environment And Reproductive Health (EARTH) Study

PubMed Central

Coull, Brent A.; Gaskins, Audrey J.; Williams, Michelle A.; Skakkebaek, Niels E.; Ford, Jennifer B.; Ye, Xiaoyun; Calafat, Antonia M.; Braun, Joseph M.; Hauser, Russ

2017-01-01

Background: Personal care products (PCPs) are exposure sources to phthalates and parabens; however, their contribution to men’s exposure is understudied. Objectives: We examined the association between PCP use and urinary concentrations of phthalate metabolites and parabens in men. Methods: In a prospective cohort, at multiple study visits, men self-reported their use of 14 PCPs and provided a urine sample (2004–2015, Boston, MA). We measured urinary concentrations of 9 phthalate metabolites and methylparaben, propylparaben, and butylparaben. We estimated the covariate-adjusted percent change in urinary concentrations associated with PCP use using linear mixed and Tobit mixed regressions. We also estimated weights for each PCP in a weighted binary score regression and modeled the resulting composite weighted PCP use. Results: Four hundred men contributed 1,037 urine samples (mean of 3/man). The largest percent increase in monoethyl phthalate (MEP) was associated with use of cologne/perfume (83%, p-value<0.01) and deodorant (74%, p-value<0.01). In contrast, the largest percent increase for parabens was associated with the use of suntan/sunblock lotion (66–156%) and hand/body lotion (79–147%). Increases in MEP and parabens were generally greater with PCP use within 6 h of urine collection. A subset of 10 PCPs that were used within 6 h of urine collection contributed to at least 70% of the weighted score and predicted a 254–1,333% increase in MEP and parabens concentrations. Associations between PCP use and concentrations of the other phthalate metabolites were not statistically significant. Conclusions: We identified 10 PCPs of relevance and demonstrated that their use within 6 h of urine collection strongly predicted MEP and paraben urinary concentrations. https://doi.org/10.1289/EHP1374 PMID:28886595

Characterization of Urinary Phthalate Metabolites Among Custodians

PubMed Central

Cavallari, Jennifer M.; Simcox, Nancy J.; Wakai, Sara; Lu, Chensheng; Garza, Jennifer L.; Cherniack, Martin

2015-01-01

Phthalates, a ubiquitous class of chemicals found in consumer, personal care, and cleaning products, have been linked to adverse health effects. Our goal was to characterize urinary phthalate metabolite concentrations and to identify work and nonwork sources among custodians using traditional cleaning chemicals and ‘green’ or environmentally preferable products (EPP). Sixty-eight custodians provided four urine samples on a workday (first void, before shift, end of shift, and before bedtime) and trained observers recorded cleaning tasks and types of products used (traditional, EPP, or disinfectant) hourly over the work shifts. Questionnaires were used to assess personal care product use. Four different phthalate metabolites [monoethyl phthalate (MEP), monomethyl phthalate (MMP), mono (2-ethylhexyl) phthalate (MEHP), and monobenzyl phthalate (MBzP)] were quantified using liquid chromatography mass spectrometry. Geometric means (GM) and 95% confidence intervals (95% CI) were calculated for creatinine-adjusted urinary phthalate concentrations. Mixed effects univariate and multivariate modeling, using a random intercept for each individual, was performed to identify predictors of phthalate metabolites including demographics, workplace factors, and personal care product use. Creatinine-adjusted urinary concentrations [GM (95% CI)] of MEP, MMP, MEHP, and MBzP were 107 (91.0–126), 2.69 (2.18–3.30), 6.93 (6.00–7.99), 8.79 (7.84–9.86) µg g−1, respectively. An increasing trend in phthalate concentrations from before to after shift was not observed. Creatinine-adjusted urinary MEP was significantly associated with frequency of traditional cleaning chemical intensity in the multivariate model after adjusting for potential confounding by demographics, workplace factors, and personal care product use. While numerous demographics, workplace factors, and personal care products were statistically significant univariate predictors of MMP, MEHP, and MBzP, few associations persisted in multivariate models. In summary, among this population of custodians, we identified both occupational and nonoccupational predictors of phthalate exposures. Identification of phthalates as ingredients in cleaning chemicals and consumer products would allow workers and consumers to avoid phthalate exposure. PMID:26240196

Concentration determination of urinary metabolites of N,N-dimethylacetamide by high-performance liquid chromatography-tandem mass spectrometry.

PubMed

Yamamoto, Shinobu; Matsumoto, Akiko; Yui, Yuko; Miyazaki, Shota; Kumagai, Shinji; Hori, Hajime; Ichiba, Masayoshi

2018-03-27

N,N-Dimethylacetamide (DMAC) is widely used in industry as a solvent. It can be absorbed through human skin. Therefore, it is necessary to determine exposure to DMAC via biological monitoring. However, the precision of traditional gas chromatography (GC) is low due to the thermal decomposition of metabolites in the high-temperature GC injection port. To overcome this problem, we have developed a new method for the simultaneous separation and quantification of urinary DMAC metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Urine samples were diluted 10-fold in formic acid, and 1-μl aliquots were injected into the LC-MS/MS equipment. A C18 reverse-phase Octa Decyl Silyl (ODS) column was used as the analytical column, and the mobile phase consisted of a mixture of methanol and aqueous formic acid solution. Urinary concentrations of DMAC and its known metabolites (N-hydroxymethyl-N-methylacetamide (DMAC-OH), N-methylacetamide (NMAC), and S- (acetamidomethyl) mercapturic acid (AMMA) ) were determined in a single run. The dynamic ranges of the calibration curves were 0.05-5 mg/l (r≥0.999) for all four compounds. The limits of detection for DMAC, DMAC-OH, NMAC, and AMMA in urine were 0.04, 0.02, 0.05, and 0.02 mg/l, respectively. Within-run accuracies were 96.5%-109.6% with relative standard deviations of precision being 3.43%-10.31%. The results demonstrated that the proposed method could successfully quantify low concentrations of DMAC and its metabolites with high precision. Hence, this method is useful for evaluating DMAC exposure. In addition, this method can be used to examine metabolite behaviors in human bodies after exposure and to select appropriate biomarkers.

Concentration determination of urinary metabolites of N,N-dimethylacetamide by high-performance liquid chromatography-tandem mass spectrometry

PubMed Central

Yamamoto, Shinobu; Matsumoto, Akiko; Yui, Yuko; Miyazaki, Shota; Kumagai, Shinji; Hori, Hajime; Ichiba, Masayoshi

2017-01-01

Objectives: N,N-Dimethylacetamide (DMAC) is widely used in industry as a solvent. It can be absorbed through human skin. Therefore, it is necessary to determine exposure to DMAC via biological monitoring. However, the precision of traditional gas chromatography (GC) is low due to the thermal decomposition of metabolites in the high-temperature GC injection port. To overcome this problem, we have developed a new method for the simultaneous separation and quantification of urinary DMAC metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Methods: Urine samples were diluted 10-fold in formic acid, and 1-μl aliquots were injected into the LC-MS/MS equipment. A C18 reverse-phase Octa Decyl Silyl (ODS) column was used as the analytical column, and the mobile phase consisted of a mixture of methanol and aqueous formic acid solution. Results: Urinary concentrations of DMAC and its known metabolites (N-hydroxymethyl-N-methylacetamide (DMAC-OH), N-methylacetamide (NMAC), and S- (acetamidomethyl) mercapturic acid (AMMA) ) were determined in a single run. The dynamic ranges of the calibration curves were 0.05-5 mg/l (r≥0.999) for all four compounds. The limits of detection for DMAC, DMAC-OH, NMAC, and AMMA in urine were 0.04, 0.02, 0.05, and 0.02 mg/l, respectively. Within-run accuracies were 96.5%-109.6% with relative standard deviations of precision being 3.43%-10.31%. Conclusions: The results demonstrated that the proposed method could successfully quantify low concentrations of DMAC and its metabolites with high precision. Hence, this method is useful for evaluating DMAC exposure. In addition, this method can be used to examine metabolite behaviors in human bodies after exposure and to select appropriate biomarkers. PMID:29213009

Polycyclic aromatic hydrocarbons exposure decreased sperm mitochondrial DNA copy number: A cross-sectional study (MARHCS) in Chongqing, China.

PubMed

Ling, Xi; Zhang, Guowei; Sun, Lei; Wang, Zhi; Zou, Peng; Gao, Jianfang; Peng, Kaige; Chen, Qing; Yang, Huan; Zhou, Niya; Cui, Zhihong; Zhou, Ziyuan; Liu, Jinyi; Cao, Jia; Ao, Lin

2017-01-01

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants that have adverse effects on the male reproductive function. Many studies have confirmed that PAHs preferentially accumulate in mitochondria DNA relative to nuclear DNA and disrupt mitochondrial functions. However, it is rare whether exposure to PAHs is associated with mitochondrial damage and dysfunction in sperm. To evaluate the effects of PAHs on sperm mitochondria, we measured mitochondrial membrane potential (MMP), mitochondrial DNA copy number (mtDNAcn) and mtDNA integrity in 666 individuals from the Male Reproductive Health in Chongqing College Students (MARHCS) study. PAHs exposure was estimated by measuring eight urinary PAH metabolites (1-OHNap, 2-OHNap, 1-OHPhe, 2-OHPhe, 3-OHPhe, 4-OHPhe, 2-OHFlu and 1-OHPyr). The subjects were divided into low, median and high exposure groups using the tertile levels of urinary PAH metabolites. In univariate analyses, the results showed that increased levels of 2-OHPhe, 3-OHPhe, ∑Phe metabolites and 2-OHFlu were found to be associated with decreased sperm mtDNAcn. After adjusting for potential confounders, significantly negative associations of these metabolites remained (p = 0.039, 0.012, 0.01, 0.035, respectively). Each 1 μg/g creatinine increase in 2-OHPhe, 3-OHPhe, ∑Phe metabolites and 2-OHFlu was associated with a decrease in sperm mtDNAcn of 9.427%, 11.488%, 9.635% and 11.692%, respectively. There were no significant associations between urinary PAH metabolites and sperm MMP or mtDNA integrity. The results indicated that the low exposure levels of PAHs can cause abnormities in sperm mitochondria. Copyright © 2016 Elsevier Ltd. All rights reserved.

Agmatine induces Nrf2 and protects against corticosterone effects in hippocampal neuronal cell line.

PubMed

Freitas, Andiara E; Egea, Javier; Buendía, Izaskun; Navarro, Elisa; Rada, Patricia; Cuadrado, Antonio; Rodrigues, Ana Lúcia S; López, Manuela G

2015-01-01

Hyperactivation of the hypothalamic-pituitary-adrenal axis is a common finding in major depression; this may lead to increased levels of cortisol, which are known to cause oxidative stress imbalance and apoptotic neuronal cell death, particularly in the hippocampus, a key region implicated in mood regulation. Agmatine, an endogenous metabolite of L-arginine, has been proposed for the treatment of major depression. Corticosterone induced apoptotic cell death and increased ROS production in cultured hippocampal neuronal cells, effects that were abolished in a concentration- and time-dependent manner by agmatine. Interestingly, the combination of sub-effective concentrations of agmatine with fluoxetine or imipramine afforded synergic protection. The neuroprotective effect of agmatine was abolished by yohimbine (α2-adrenoceptor antagonist), ketanserin (5-HT2A receptor antagonist), LY294002 (PI3K inhibitor), PD98059 (MEK1/2 inhibitor), SnPP (HO-1 inhibitor), and cycloheximide (protein synthesis inhibitor). Agmatine increased Akt and ERK phosphorylation and induced the transcription factor Nrf2 and the proteins HO-1 and GCLc; induction of these proteins was prevented by yohimbine, ketanserin, LY294002, and PD98059. In conclusion, agmatine affords neuroprotection against corticosterone effects by a mechanism that implicates Nrf2 induction via α2-adrenergic and 5-HT2A receptors, Akt and ERK pathways, and HO-1 and GCLc expression.

Associations of Urinary Caffeine and Caffeine Metabolites With Arterial Stiffness in a Large Population-Based Study.

PubMed

Ponte, Belen; Pruijm, Menno; Ackermann, Daniel; Ehret, Georg; Ansermot, Nicolas; Staessen, Jan A; Vogt, Bruno; Pechère-Bertschi, Antoinette; Burnier, Michel; Martin, Pierre-Yves; Eap, Chin B; Bochud, Murielle; Guessous, Idris

2018-05-01

To assess the influence of caffeine on arterial stiffness by exploring the association of urinary excretion of caffeine and its related metabolites with pulse pressure (PP) and pulse wave velocity (PWV). Families were randomly selected from the general population of 3 Swiss cities from November 25, 2009, through April 4, 2013. Pulse pressure was defined as the difference between the systolic and diastolic blood pressures obtained by 24-hour ambulatory monitoring. Carotid-femoral PWV was determined by applanation tonometry. Urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured in 24-hour urine collections. Multivariate linear and logistic mixed models were used to explore the associations of quartiles of urinary caffeine and metabolite excretions with PP, high PP, and PWV. We included 863 participants with a mean ± SD age of 47.1±17.6 years, 24-hour PP of 41.9±9.2 mm Hg, and PWV of 8.0±2.3 m/s. Mean (SE) brachial PP decreased from 43.5 (0.5) to 40.5 (0.6) mm Hg from the lowest to the highest quartiles of 24-hour urinary caffeine excretion (P<.001). The odds ratio (95% CI) of high PP decreased linearly from 1.0 to 0.52 (0.31-0.89), 0.38 (0.22-0.65), and 0.31 (0.18-0.55) from the lowest to the highest quartile of 24-hour urinary caffeine excretion (P<.001). Mean (SE) PWV in the highest caffeine excretion quartile was significantly lower than in the lowest quartile (7.8 [0.1] vs 8.1 [0.1] m/s; P=.03). Similar associations were found for paraxanthine and theophylline, whereas no associations were found with theobromine. Urinary caffeine, paraxanthine, and theophylline excretions were associated with decreased parameters of arterial stiffness, suggesting a protective effect of caffeine intake beyond its blood pressure-lowering effect. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Urinary and dietary analysis of 18,470 bangladeshis reveal a correlation of rice consumption with arsenic exposure and toxicity.

PubMed

Melkonian, Stephanie; Argos, Maria; Hall, Megan N; Chen, Yu; Parvez, Faruque; Pierce, Brandon; Cao, Hongyuan; Aschebrook-Kilfoy, Briseis; Ahmed, Alauddin; Islam, Tariqul; Slavcovich, Vesna; Gamble, Mary; Haris, Parvez I; Graziano, Joseph H; Ahsan, Habibul

2013-01-01

We utilized data from the Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh, to evaluate the association of steamed rice consumption with urinary total arsenic concentration and arsenical skin lesions in the overall study cohort (N=18,470) and in a subset with available urinary arsenic metabolite data (N=4,517). General linear models with standardized beta coefficients were used to estimate associations between steamed rice consumption and urinary total arsenic concentration and urinary arsenic metabolites. Logistic regression models were used to estimate prevalence odds ratios (ORs) and their 95% confidence intervals (CIs) for the associations between rice intake and prevalent skin lesions at baseline. Discrete time hazard models were used to estimate discrete time (HRs) ratios and their 95% CIs for the associations between rice intake and incident skin lesions. Steamed rice consumption was positively associated with creatinine-adjusted urinary total arsenic (β=0.041, 95% CI: 0.032-0.051) and urinary total arsenic with statistical adjustment for creatinine in the model (β=0.043, 95% CI: 0.032-0.053). Additionally, we observed a significant trend in skin lesion prevalence (P-trend=0.007) and a moderate trend in skin lesion incidence (P-trend=0.07) associated with increased intake of steamed rice. This study suggests that rice intake may be a source of arsenic exposure beyond drinking water.

Urinary hydroxy-metabolites of naphthalene, phenanthrene and pyrene as markers of exposure to diesel exhaust.

PubMed

Kuusimäki, Leea; Peltonen, Yrjö; Mutanen, Pertti; Peltonen, Kimmo; Savela, Kirsti

2004-01-01

The objective of this study was to assess the exposure of bus-garage and waste-collection workers to polycyclic aromatic hydrocarbons (PAHs) derived from diesel exhaust by the measurement of levels of seven urinary PAH metabolites: 2-naphthol, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, 3-hydroxyphenanthrene, 1+9-hydroxyphenanthrene, 4-hydroxyphenanthrene and 1-hydroxypyrene. One urine sample from each of 46 control persons, and one pre-shift and two post-shift spot urine samples from 32 exposed workers were obtained in winter and in summer. The metabolites were analysed after enzymatic hydrolysis by high performance liquid chromatography (HPLC) with fluorescence detection. The sum of seven PAH metabolites (mean 3.94 +/- 3.40 and 5.60 +/- 6.37 micromol/mol creatinine in winter and summer, respectively) was higher [P=0.01, degrees of freedom (df) =61.2 and P=0.01, df=67.6 in winter and summer, respectively] in the exposed group than in the control group (mean 3.18 +/- 3.99 and 3.03 +/- 2.01 micromol/mol creatinine in winter and summer, respectively). The mean concentrations of 2-naphthol among exposed and controls ranged between 3.34 and 4.85 micromol/mol creatinine and 2.51 and 2.58 micromol/mol creatinine, respectively (P<0.01 in winter, P<0.03 in summer). The mean level of the hydroxyphenanthrenes in the samples of exposed workers was between 0.40 and 0.70 micromol/mol creatinine and in the control samples 0.40-0.60 micromol/mol creatinine. The concentration of 1-hydroxypyrene was higher among exposed workers in both pre-shift and post-shift samples (mean 0.10-0.15 micromol/mol creatinine) than in control group (mean 0.05-0.06 micromol/mol creatinine) in winter (P=0.002, df=78) and in summer (P<0.001, df=68). The urinary hydroxy-metabolites of naphthalene, phenanthrene and pyrene showed low exposure to diesel-derived PAHs; however, it was higher in exposed workers than in control group. Urinary PAH monohydroxy-metabolites measured in this study did not correlate with the PAHs in the air samples, reported earlier, in 2002 and 2003.

Predictors of urinary flame retardant concentration among pregnant women.

PubMed

Hoffman, Kate; Lorenzo, Amelia; Butt, Craig M; Adair, Linda; Herring, Amy H; Stapleton, Heather M; Daniels, Julie L

2017-01-01

Organophosphate compounds are commonly used in residential furniture, electronics, and baby products as flame retardants and are also used in other consumer products as plasticizers. Although the levels of exposure biomarkers are generally higher among children and decrease with age, relatively little is known about the individual characteristics associated with higher levels of exposure. Here, we investigate urinary metabolites of several organophosphate flame retardants (PFRs) in a cohort of pregnant women to evaluate patterns of exposure. Pregnant North Carolina women (n=349) provided information on their individual characteristics (e.g. age and body mass index (BMI)) as a part of the Pregnancy Infection and Nutrition Study (2002-2005). Women also provided second trimester urine samples in which six PFR metabolites were measured using mass spectrometry methods. PFR metabolites were detected in every urine sample, with BDCIPP, DHPH, ip-PPP and BCIPHIPP detected in >80% of samples. Geometric mean concentrations were higher than what has been reported previously for similarly-timed cohorts. Women with higher pre-pregnancy BMI tended to have higher levels of urinary metabolites. For example, those classified as obese at the start of pregnancy had ip-PPP levels that were 1.52 times as high as normal weight range women (95% confidence interval: 1.23, 1.89). Women without previous children also tended to have higher urinary levels of DPHP, but lower levels of ip-PPP. In addition, we saw strong evidence of seasonal trends in metabolite concentrations (e.g. higher DPHP, BDCIPP, and BCIPHIPP in summer, and evidence of increasing ip-PPP between 2002 and 2005). Our results indicate ubiquitous exposure to PFRs among NC women in the early 2000s. Additionally, our work suggests that individual characteristics are related to exposure and that temporal variation, both seasonal and annual, may exist. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Dietary Treatment with Dimethylarsinous Acid (DMAIII) on the Urinary Bladder Epithelium of Arsenic (+3 Oxidation State) Methyltransferase (As3mt) Knockout and C57BL/6 Wild Type Female Mice

EPA Science Inventory

Abstract Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAv, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the...

Using fecal glucocorticoids for stress assessment in Mourning Doves

USGS Publications Warehouse

Washburn, Brian E.; Millspaugh, Joshua J.; Schulz, John H.; Jones, Susan B.; Mong, T.

2003-01-01

Fecal glucocorticoid assays provide a potentially useful, noninvasive means to study physiological responses of wildlife to various stressors. The objective of our study was to validate a method for measuring glucocorticoid metabolites in Mourning Dove (Zenaida macroura) feces. We validated the assay using standard procedures (e.g., parallelism, recovery of exogenous corticosterone) to demonstrate that the assay accurately and precisely measured glucocorticoid metabolites in Mourning Dove fecal extracts. We conducted adrenocorticotropin (ACTH) challenge experiments to validate the assay's ability to determine biologically important changes in fecal glucocorticoids. Fecal glucocorticoid levels increased significantly approximately 2-3 hr after administration of ACTH at 50 IU per kg body mass to wild Mourning Doves held in captivity. In contrast, fecal glucocorticoid metabolites did not increase in control birds, birds that received saline injections, or a lower dose of ACTH (1 IU per kg body mass). Variation in overall fecal glucocorticoid metabolite levels may have been influenced by season and the length of time birds were held in captivity. Non-invasive fecal glucocorticoid metabolite analyses, in combination with demographic information, may have considerable utility for monitoring the effects of natural and anthropogenic disturbances on Mourning Dove populations.

Within-person reproducibility of urinary bisphenol A and phthalate metabolites over a 1 to 3 year period among women in the Nurses’ Health Studies: a prospective cohort study

PubMed Central

2013-01-01

Background Associations of bisphenol A and phthalates with chronic disease health outcomes are increasingly being investigated in epidemiologic studies. The majority of previous studies of within-person variability in urinary bisphenol A and phthalate metabolite concentrations have focused on reproducibility over short time periods. Long-term reproducibility data are needed to assess the potential usefulness of these biomarkers for prospective studies, particularly those examining risk of diseases with long latency periods. Low within-person reproducibility may attenuate relative risk estimates and reduce statistical power to detect associations with disease. Therefore, we assessed within-person reproducibility of bisphenol A, eight phthalate metabolites, and phthalic acid in spot urine samples over 1 to 3 years among women enrolled in two large cohort studies. Methods Women in the Nurses’ Health Study and Nurses’ Health Study II provided two spot urine samples, 1 to 3 years apart (n = 80 women for analyses of bisphenol A; n = 40 women for analyses of phthalate metabolites; n = 34 women for analyses of phthalic acid). To measure within-person reproducibility, we calculated Spearman rank correlation coefficients and intraclass correlation coefficients for creatinine-adjusted concentrations of bisphenol A, phthalate metabolites, and phthalic acid. Results Over 1 to 3 years, within-person variability of bisphenol A was high relative to total variability (intraclass correlation coefficient = 0.14) and rankings of bisphenol A levels between time-points were weakly correlated (Spearman correlation = 0.19). Seven of the eight phthalate metabolites and phthalic acid demonstrated moderate within-person stability over time (Spearman correlation or intraclass correlation coefficient = 0.39-0.55). Restricting analyses to first-morning urine samples did not alter results. Conclusions Single measurements of bisphenol A in spot urine samples were highly variable within women over 1 to 3 years, indicating that investigation of associations between a single urinary bisphenol A measurement and disease risk may be challenging in epidemiologic studies. The majority of urinary phthalate metabolites and phthalic acid appeared moderately reproducible within women over time, suggesting single measurements may be useful in epidemiologic studies, although observed relative risks can be substantially attenuated. PMID:24034517

Within-person reproducibility of urinary bisphenol A and phthalate metabolites over a 1 to 3 year period among women in the Nurses' Health Studies: a prospective cohort study.

PubMed

Townsend, Mary K; Franke, Adrian A; Li, Xingnan; Hu, Frank B; Eliassen, A Heather

2013-09-13

Associations of bisphenol A and phthalates with chronic disease health outcomes are increasingly being investigated in epidemiologic studies. The majority of previous studies of within-person variability in urinary bisphenol A and phthalate metabolite concentrations have focused on reproducibility over short time periods. Long-term reproducibility data are needed to assess the potential usefulness of these biomarkers for prospective studies, particularly those examining risk of diseases with long latency periods. Low within-person reproducibility may attenuate relative risk estimates and reduce statistical power to detect associations with disease. Therefore, we assessed within-person reproducibility of bisphenol A, eight phthalate metabolites, and phthalic acid in spot urine samples over 1 to 3 years among women enrolled in two large cohort studies. Women in the Nurses' Health Study and Nurses' Health Study II provided two spot urine samples, 1 to 3 years apart (n = 80 women for analyses of bisphenol A; n = 40 women for analyses of phthalate metabolites; n = 34 women for analyses of phthalic acid). To measure within-person reproducibility, we calculated Spearman rank correlation coefficients and intraclass correlation coefficients for creatinine-adjusted concentrations of bisphenol A, phthalate metabolites, and phthalic acid. Over 1 to 3 years, within-person variability of bisphenol A was high relative to total variability (intraclass correlation coefficient = 0.14) and rankings of bisphenol A levels between time-points were weakly correlated (Spearman correlation = 0.19). Seven of the eight phthalate metabolites and phthalic acid demonstrated moderate within-person stability over time (Spearman correlation or intraclass correlation coefficient = 0.39-0.55). Restricting analyses to first-morning urine samples did not alter results. Single measurements of bisphenol A in spot urine samples were highly variable within women over 1 to 3 years, indicating that investigation of associations between a single urinary bisphenol A measurement and disease risk may be challenging in epidemiologic studies. The majority of urinary phthalate metabolites and phthalic acid appeared moderately reproducible within women over time, suggesting single measurements may be useful in epidemiologic studies, although observed relative risks can be substantially attenuated.

Effect of fasting on the urinary excretion of water-soluble vitamins in humans and rats.

PubMed

Fukuwatari, Tsutomu; Yoshida, Erina; Takahashi, Kei; Shibata, Katsumi

2010-01-01

Recent studies showed that the urinary excretion of the water-soluble vitamins can be useful as a nutritional index. To determine how fasting affects urinary excretion of water-soluble vitamins, a human study and an animal experiment were conducted. In the human study, the 24-h urinary excretion of water-soluble vitamins in 12 healthy Japanese adults fasting for a day was measured. One-day fasting drastically decreased urinary thiamin content to 30%, and increased urinary riboflavin content by 3-fold. Other water-soluble vitamin contents did not show significant change by fasting. To further investigate the alterations of water-soluble vitamin status by starvation, rats were starved for 3 d, and water-soluble vitamin contents in the liver, blood and urine were measured during starvation. Urinary excretion of thiamin, riboflavin, vitamin B(6) metabolite 4-pyridoxic acid, nicotinamide metabolites and folate decreased during starvation, but that of vitamin B(12), pantothenic acid and biotin did not. As for blood vitamin levels, only blood vitamin B(1), plasma PLP and plasma folate levels decreased with starvation. All water-soluble vitamin contents in the liver decreased during starvation, whereas vitamin concentrations in the liver did not decrease. Starvation decreased only concentrations of vitamin B(12) and folate in the skeletal muscle. These results suggest that water-soluble vitamins were released from the liver, and supplied to the peripheral tissues to maintain vitamin nutrition. Our human study also suggested that the effect of fasting should be taken into consideration for subjects showing low urinary thiamin and high urinary riboflavin.

A statistical analysis of the effects of urease pre-treatment on the measurement of the urinary metabolome by gas chromatography–mass spectrometry

DOE PAGES

Webb-Robertson, Bobbie-Jo; Kim, Young -Mo; Zink, Erika M.; ...

2014-02-27

Urease pre-treatment of urine has been utilized since the early 1960s to remove high levels of urea from samples prior to further processing and analysis by gas chromatography-mass spectrometry (GC-MS). Aside from the obvious depletion or elimination of urea, the effect, if any, of urease pre-treatment on the urinary metabolome has not been studied in detail. Here, we report the results of three separate but related experiments that were designed to assess possible indirect effects of urease pre-treatment on the urinary metabolome as measured by GC-MS. In total, 235 GC-MS analyses were performed and over 106 identified and 200 unidentifiedmore » metabolites were quantified across the three experiments. The results showed that data from urease pre-treated samples 1) had the same or lower coefficients of variance among reproducibly detected metabolites, 2) more accurately reflected quantitative differences and the expected ratios among different urine volumes, and 3) increased the number of metabolite identifications. Altogether, we observed no negative consequences of urease pre-treatment. In contrast, urease pretreatment enhanced the ability to distinguish between volume-based and biological sample types compared to no treatment. Taken together, these results show that urease pretreatment of urine offers multiple beneficial effects that outweigh any artifacts that may be introduced to the data in urinary metabolomics analyses.« less

A Statistical Analysis of the Effects of Urease Pre-treatment on the Measurement of the Urinary Metabolome by Gas Chromatography-Mass Spectrometry

PubMed Central

Webb-Robertson, Bobbie-Jo; Kim, Young-Mo; Zink, Erika M.; Hallaian, Katherine A.; Zhang, Qibin; Madupu, Ramana; Waters, Katrina M.; Metz, Thomas O.

2014-01-01

Urease pre-treatment of urine has been utilized since the early 1960s to remove high levels of urea from samples prior to further processing and analysis by gas chromatography-mass spectrometry (GC-MS). Aside from the obvious depletion or elimination of urea, the effect, if any, of urease pre-treatment on the urinary metabolome has not been studied in detail. Here, we report the results of three separate but related experiments that were designed to assess possible indirect effects of urease pre-treatment on the urinary metabolome as measured by GC-MS. In total, 235 GC-MS analyses were performed and over 106 identified and 200 unidentified metabolites were quantified across the three experiments. The results showed that data from urease pre-treated samples 1) had the same or lower coefficients of variance among reproducibly detected metabolites, 2) more accurately reflected quantitative differences and the expected ratios among different urine volumes, and 3) increased the number of metabolite identifications. Overall, we observed no negative consequences of urease pre-treatment. In contrast, urease pretreatment enhanced the ability to distinguish between volume-based and biological sample types compared to no treatment. Taken together, these results show that urease pretreatment of urine offers multiple beneficial effects that outweigh any artifacts that may be introduced to the data in urinary metabolomics analyses. PMID:25254001

Differences in Urinary Arsenic Metabolites between Diabetic and Non-Diabetic Subjects in Bangladesh

PubMed Central

Nizam, Saika; Kato, Masashi; Yatsuya, Hiroshi; Khalequzzaman, Md.; Ohnuma, Shoko; Naito, Hisao; Nakajima, Tamie

2013-01-01

Ingestion of inorganic arsenic (iAs) is considered to be related to the development of diabetes mellitus. In order to clarify the possible differences in the metabolism in diabetics, we measured urinary iAs metabolites in diabetic cases and non-diabetic control subjects in Faridpur, an arsenic-contaminated area in Bangladesh. Physician-diagnosed type 2 diabetic cases (140 persons) and non-diabetic controls (180 persons) were recruited. Drinking water and spot urine samples were collected. Mean concentrations of total arsenic in drinking water did not differ between cases (85.1 μg/L) and controls (85.8 μg/L). The percentage of urinary iAs (iAs%) was significantly lower in cases (8.6%) than in controls (10.4%), while that of dimethylarsinic acid (DMA%) was higher in cases (82.6%) than in controls (79.9%). This may have been due to the higher secondary methylation index (SMI) in the former (11.6) rather than the latter (10.0). Adjusting for matching factors (sex and unions), and the additional other covariates (age and water arsenic) significantly attenuated the differences in iAs%, SMI, and DMA%, respectively, though the difference in monomethylarsonic acid% was newly significant in the latter adjustment. Our study did not suggest any significant differences in urinary arsenic metabolites between diabetic and non-diabetic subjects. PMID:23481591

Associations between urinary phthalate metabolites and bisphenol A levels, and serum thyroid hormones among the Korean adult population - Korean National Environmental Health Survey (KoNEHS) 2012-2014.

PubMed

Park, Choonghee; Choi, Wookhee; Hwang, Moonyoung; Lee, Youngmee; Kim, Suejin; Yu, Seungdo; Lee, Inae; Paek, Domyung; Choi, Kyungho

2017-04-15

Phthalates and bisphenol A (BPA) have been used extensively in many consumer products, resulting in widespread exposure in the general population. Studies have suggested associations between exposure to phthalates and BPA, and serum thyroid hormone levels, but confirmation on larger human populations is warranted. Data obtained from nationally representative Korean adults (n=6003) recruited for the second round of the Korean National Environmental Health Survey (KoNEHS), 2012-2014, were employed. Three di-(2-ethylhexyl) phthalate (DEHP) metabolites, along with benzyl-butyl phthalate (BBzP) and di-butyl phthalate (DBP) metabolites, and BPA were measured in subjects' urine. Thyroxine (T4), total triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured in serum. The associations between urinary phthalates or BPA and thyroid hormone levels were determined. Urinary phthalate metabolites were generally associated with lowered total T4 or T3, or increased TSH levels in serum. Interquartile range (IQR) increases of mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were associated with a 3.7% increase of TSH, and a 1.7% decrease of total T4 levels, respectively. When grouped by sex, urinary MEHHP levels were inversely associated with T4 only among males. Among females, mono-benzyl phthalate (MBzP) and mono-n-butyl phthalate (MnBP) levels were inversely associated with TSH and T3, respectively. In addition, negative association between BPA and TSH was observed. Several phthalates and BPA exposures were associated with altered circulatory thyroid hormone levels among general Korean adult population. Considering the importance of thyroid hormones, public health implications of such alteration warrant further studies. Copyright © 2017 Elsevier B.V. All rights reserved.

[Association between urinary polycyclic aromatic hydrocarbon metabolites and elevated serum uric acid levels in coke oven workers].

PubMed

Deng, Siyun; Deng, Qifei; Hu, Die; Li, Jun; Zhu, Xiaoyan; Guo, Huan; Wu, Tangchun

2014-06-01

To analyze the relationship between metabolites of polycyclic aromatic hydrocarbons (PAHs) and serum uric acid levels in coke oven workers and to provide new clues to the pathogenic mechanism of PAHs. A total of 1302 coke oven workers were divided into four groups, namely control group and low-, intermediate-, and high-dose exposure groups. The concentrations of ambient PAHs at each workplace were determined by high-performance liquid chromatography. The detailed information on the occupational history and health of workers was collected by questionnaire survey and physical examination, and so were their blood and urine samples. Serum uric acid and creatinine levels were measured using a Hitachi 7020 automatic biochemical analyzer. Ten urinary PAH metabolites were detected by gas chromatography-mass spectrometry. Serum uric acid levels were the highest in the high-dose exposure group, followed by the intermediate- and low-dose exposure groups, and were the lowest in the control group. There were significant correlations between serum uric acid levels and the quartiles of 1-hydroxynaphthalene and 1-hydroxyphenanthrene (P < 0.05). After adjustment for PAH metabolite-related relationship, only urinary 1-hydroxyphenanthrene was significantly correlated with serum uric acid levels (P = 0.001). After adjustment for confounding factors and using the 1st quartile of 1-hydroxyphenanthrene as a reference, the odds ratio for hyperuricemia in subjects with the 2nd, 3rd, and 4th quartiles of 1-hydroxyphenanthrene were 1.55, 1.57, and 2.35, respectively. Urinary 1-hydroxyphenanthrene is associated with a dose-response increase in serum uric acid levels in coke oven workers, and exposure to phenanthrene in PAHs may be a risk factor for hyperuricemia.

Speciation of arsenic in exfoliated urinary bladder epithelial cells from individuals exposed to arsenic in drinking water.

PubMed

Hernández-Zavala, Araceli; Valenzuela, Olga L; Matousek, Tomás; Drobná, Zuzana; Dĕdina, Jirí; García-Vargas, Gonzalo G; Thomas, David J; Del Razo, Luz M; Stýblo, Miroslav

2008-12-01

The concentration of arsenic in urine has been used as a marker of exposure to inorganic As (iAs). Relative proportions of urinary metabolites of iAs have been identified as potential biomarkers of susceptibility to iAs toxicity. However, the adverse effects of iAs exposure are ultimately determined by the concentrations of iAs metabolites in target tissues. In this study we examined the feasibility of analyzing As species in cells that originate in the urinary bladder, a target organ for As-induced cancer in humans. Exfoliated bladder epithelial cells (BECs) were collected from urine of 21 residents of Zimapan, Mexico, who were exposed to iAs in drinking water. We determined concentrations of iAs, methyl-As (MAs), and dimethyl-As (DMAs) in urine using conventional hydride generation-cryotrapping-atomic absorption spectrometry (HG-CT-AAS). We used an optimized HG-CT-AAS technique with detection limits of 12-17 pg As for analysis of As species in BECs. All urine samples and 20 of 21 BEC samples contained detectable concentrations of iAs, MAs, and DMAs. Sums of concentrations of these As species in BECs ranged from 0.18 to 11.4 ng As/mg protein and in urine from 4.8 to 1,947 ng As/mL. We found no correlations between the concentrations or ratios of As species in BECs and in urine. These results suggest that urinary levels of iAs metabolites do not necessarily reflect levels of these metabolites in the bladder epithelium. Thus, analysis of As species in BECs may provide a more effective tool for risk assessment of bladder cancer and other urothelial diseases associated with exposures to iAs.

Influence of storage vial material on measurement of organophosphate flame retardant metabolites in urine.

PubMed

Carignan, Courtney C; Butt, Craig M; Stapleton, Heather M; Meeker, John D; Minguez-Alarcón, Lidia; Williams, Paige L; Hauser, Russ

2017-08-01

Use of organophosphate flame retardants (PFRs) has increased over the past decade with the phase out of polybrominated diphenyl ethers. Urinary metabolites of PFRs are used as biomarkers of exposure in epidemiologic research, which typically uses samples collected and stored in polypropylene plastic cryovials. However, a small study suggested that the storage vial material may influence reported concentrations. Therefore, we aimed to examine the influence of the storage vial material on analytical measurement of PFR urinary metabolites. Using urine samples collected from participants in the Environment and Reproductive Health (EARTH) Study, we analyzed the PFR metabolites in duplicate aliquots that were stored in glass and plastic vials (n = 31 pairs). Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP) and isopropyl-phenyl phenyl phosphate (ip-PPP) were detected in 98%, 97% and 87% of duplicates. We observed high correlations between glass-plastic duplicates for BDCIPP (r s  = 0.95), DPHP (r s  = 0.79) and ip-PPP (r s  = 0.82) (p < 0.0001). Urinary ip-PPP was an average of 0.04 ng/ml (p = 0.04) higher among samples stored in glass, with a mean relative difference of 14%. While this difference is statistically significant, it is small in magnitude. No differences were observed for BDCIPP or DPHP, however future research should seek to reduce the potential for type II error (false negatives). We conclude that storing urine samples in polypropylene plastic cryovials may result in slightly reduced concentrations of urinary ip-PPP relative to storage in glass vials and future research should seek to increase the sample size, reduce background variability and consider the material of the urine collection cup. Copyright © 2017 Elsevier Ltd. All rights reserved.

Secondary metabolites produced by marine streptomyces as antibiofilm and quorum-sensing inhibitor of uropathogen Proteus mirabilis.

PubMed

Younis, Khansa Mohammed; Usup, Gires; Ahmad, Asmat

2016-03-01

Quorum-sensing regulates bacterial biofilm formation and virulence factors, thereby making it an interesting target for attenuating pathogens. In this study, we investigated anti-biofilm and anti-quorum-sensing compounds from secondary metabolites of halophiles marine streptomyces against urinary catheter biofilm forming Proteus mirabilis without effect on growth viability. A total of 40 actinomycetes were isolated from samples collected from different places in Iraq including marine sediments and soil samples. Fifteen isolates identified as streptomyces and their supernatant screened as anti-quorum-sensing by inhibiting quorum-sensing regulated prodigiosin biosynthesis of Serratia marcescens strain Smj-11 as a reporter strain. Isolate Sediment Lake Iraq (sdLi) showed potential anti-quorum-sensing activity. Out of 35 clinical isolates obtained from Urinary catheter used by patient at the Universiti Kebangsaan Malaysia Medical Center, 22 isolates were characterized and identified as Proteus mirabilis. Isolate Urinary Catheter B4 (UCB4) showed the highest biofilm formation with highest resistance to used antibiotic and was chosen for further studies. Ethyl acetate secondary metabolites extract was produced from sdLi isolate. First, we determined the Minimum Inhibitory Concentration (MIC) of sdLi crude extract against UCB4 isolate, and all further experiments used concentrations below the MIC. Tests of subinhibitory concentrations of sdLi crude extract showed good inhibition against UCB4 isolate biofilm formation on urinary catheter and cover glass using Scanning electron microscopy and light microscopy respectively. The influence of sub-MIC of sdLi crude extract was also found to attenuate the quorum sensing (QS)-dependent factors such as hemolysin activity, urease activity, pH value, and motility of UCB4 isolate. Evidence is presented that these nontoxic secondary metabolites may act as antagonists of bacterial quorum sensing by competing with quorum-sensing signals for receptor binding.

Moderate alcohol consumption and 24-hour urinary levels of melatonin in postmenopausal women

USDA-ARS?s Scientific Manuscript database

Low overnight urinary melatonin metabolite concentrations have been associated with increased risk for breast cancer among postmenopausal women. The Postmenopausal Women's Alcohol Study was a controlled feeding study to test the effects of low to moderate alcohol intake on potential risk factors for...

Identification of urinary metabolites of imperatorin with a single run on an LC/Triple TOF system based on multiple mass defect filter data acquisition and multiple data mining techniques.

PubMed

Qiao, Shi; Shi, Xiaowei; Shi, Rui; Liu, Man; Liu, Ting; Zhang, Kerong; Wang, Qiao; Yao, Meicun; Zhang, Lantong

2013-08-01

The detection of drug metabolites, especially for minor metabolites, continues to be a challenge because of the complexity of biological samples. Imperatorin (IMP) is an active natural furocoumarin component originating from many traditional Chinese herbal medicines and is expected to be pursued as a new vasorelaxant agent. In the present study, a generic and efficient approach was developed for the in vivo screening and identification of IMP metabolites using liquid chromatography-Triple TOF mass spectrometry. In this approach, a novel on-line data acquisition method mutiple mass defect filter (MMDF) combined with dynamic background subtraction was developed to trace all probable urinary metabolites of IMP. Comparing with the traditionally intensity-dependent data acquisition method, MMDF method could give the information of low-level metabolites masked by background noise and endogenous components. Thus, the minor metabolites in complex biological matrices could be detected. Then, the sensitive and specific multiple data-mining techniques extracted ion chromatography, mass defect filter, product ion filter, and neutral loss filter were used for the discovery of IMP metabolites. Based on the proposed strategy, 44 phase I and 7 phase II metabolites were identified in rat urine after oral administration of IMP. The results indicated that oxidization was the main metabolic pathway and that different oxidized substituent positions had a significant influence on the fragmentation of the metabolites. Two types of characteristic ions at m/z 203 and 219 can be observed in the MS/MS spectra. This is the first study of IMP metabolism in vivo. The interpretation of the MS/MS spectra of these metabolites and the proposed metabolite pathway provide essential data for further pharmacological studies of other linear-type furocoumarins.

[The dose response decrease of lung function associated with the urinary polycyclic aromatic hydrocarbons metabolites in coke oven workers].

PubMed

Hu, Die; Deng, Qi-fei; Huang, Su-li; He, Yun-feng; Guo, Huan; Wu, Tang-chun

2012-12-01

To analyze the relationship between metabolites of polycyclic aromatic hydrocarbons (PAHs) and lung function in coke oven workers, and to provide scientific basis for further exploring the potential mechanism and developing the preventing strategies of the workers' early lung damage. We measured carbon monoxide, sulfur dioxide, benzene soluble matter, particulate matters, and PAHs at different workplaces of a coke oven plant. Detailed information on demography and occupational health condition of 912 workers were collected. We divided these workers into control group and coke oven group according to their workplaces and the different concentrations of COEs in the environment. We detected 10 urinary PAH metabolites and lung function using gas chromatography-mass spectrometry and spirometric tests, respectively. FEV(1.0) (91.12 ± 13.31) and FEV(1.0)/FVC (108.61 ± 20.37) of the coke oven group is significantly lower than the control group (94.16 ± 15.57, 113.45 ± 19.70). In the coke oven group, the hydroxyphenanthrene and 1-hydroxypyrene are negatively correlated with FEV(1.0)/FVC (β = -0.136, β = -0.100), Ptrend < 0.05 for all. The dose response decrease of lung function is associated with the urinary PAH metabolites in coke oven workers. Indicated that the long exposure to PAHs may cause the early lung damage in coke oven workers, phenanthrene and pyrene may be the main factors.

Measuring Personal Exposure to Organophosphate Flame Retardants using Silicone Wristbands and Hand Wipes

PubMed Central

Hammel, Stephanie C.; Hoffman, Kate; Webster, Thomas F.; Anderson, Kim A.; Stapleton, Heather M.

2016-01-01

Organophosphate flame retardants (PFRs) are widely used as replacements for polybrominated diphenyl ethers in consumer products. With high detection in indoor environments and increasing toxicological evidence suggesting a potential for adverse health effects, there is a growing need for reliable exposure metrics to examine individual exposures to PFRs. Silicone wristbands have been used as passive air samplers for quantifying exposure in the general population and occupational exposure to polycyclic aromatic hydrocarbons. Here we investigated the utility of silicone wristbands in measuring exposure and internal dose of PFRs through measurement of urinary metabolite concentrations. Wristbands were also compared to hand wipes as metrics of exposure. Participants wore wristbands for five consecutive days and collected first morning void urine samples on three alternating days. Urine samples were pooled across the three days and analyzed for metabolites of the following PFRs: tris(1,3-dichloroisopropyl) phosphate (TDCIPP), tris(1-chloro-2-isopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), and mono-substituted isopropylated triaryl phosphate (mono-ITP). All four PFRs and their urinary metabolites were ubiquitously detected. Correlations between TDCIPP and TCIPP and their corresponding urinary metabolites were highly significant on the wristbands (rs= 0.5-0.65, p<0.001), which suggest that wristbands can serve as strong predictors of cumulative, five-day exposure and may be an improved metric compared to hand wipes. PMID:26975559

Organophosphorous pesticide exposure increases the frequency of sperm sex null aneuploidy.

PubMed Central

Recio, R; Robbins, W A; Borja-Aburto, V; Morán-Martínez, J; Froines, J R; Hernández, R M; Cebrián, M E

2001-01-01

It has been estimated that 4 of 1,000 live births and 35% of spontaneous abortions are aneuploid and that an important proportion of embryo and newborn aneuploidy is of paternal origin. Exposure to organophosphorous pesticides (OP) has been associated with sperm hyperploidy/polyploidy. Therefore, we aimed to assess the frequency of sperm aneuploidy (X, Y, and 18) and its relationship with urinary OP metabolites in agricultural workers. We performed multicolor fluorescence in situ hybridization on samples from nine men obtained before and during the pesticide spraying season to assess sperm aneuploidy. We measured urinary OP metabolite levels by gas-liquid chromatography. Aneuploidies were found in 0.67% of total sperm nuclei. The most frequent aneuploidy was the lack of a sexual chromosome or sex null (0.19%), followed by XY18 (0.15%) and XY18-18 (0.06%). OP metabolites detected at higher concentrations were dimethylthiophosphate, dimethyldithiophosphate, and diethylphosphate (DEP). There were no differences in average aneuploidy frequency or urinary metabolite levels between samples collected before and after exposure. However, Poisson regression analysis adjusted for age, alcohol intake, and sperm concentration showed significant associations between OP metabolite concentrations and increased frequency of sperm aneuploidies. The association was more evident between DEP and sex null, and the risk increased further during the spraying season. Thus, OP exposure could interfere with sperm chromosome segregation and increase the risk for genetic syndromes, such as Turner's. Further studies are required to assess the prevalence of spontaneous abortions, birth defects, and genetic syndromes in agricultural communities. PMID:11748030

Effects of profession on urinary PAH metabolite levels in the US population.

PubMed

Liu, Bian; Jia, Chunrong

2016-01-01

Although exposure to polycyclic aromatic hydrocarbons (PAHs) is common in both environmental and occupational settings, few studies have compared PAH exposure among people with different professions. The purpose of this study was to investigate the variations in recent PAH exposure among different occupational groups over time using national representative samples. The study population consisted of 4162 participants from the 2001 to 2008 National Health and Nutrition Examination Survey, who had both urinary PAH metabolites and occupational information. Four corresponding monohydroxy-PAH urine metabolites: naphthalene (NAP), fluorene (FLUO), phenanthrene (PHEN), and pyrene (PYR) among seven broad occupational groups were analyzed using weighted linear regression models, adjusting for creatinine levels, sociodemographic factors, smoking status, and sampling season. The overall geometric mean concentrations of NAP, FLUO, PHEN, and PYR were 6927, 477, 335, and 87 ng/L, respectively. All four PAH metabolites were elevated in the "extractive, construction, and repair (ECR)" group, with 21-42 % higher concentrations than those in the reference group of "management." Similar trends were seen in the "operators, fabricators, and laborers (OFL)" group for FLUO, PHEN, and PYR. In addition, both "service" and "support" groups had elevated FLUO. Significant (p < 0.001) upward temporal trends were seen in NAP and PYR, with an approximately 6-17 % annual increase, and FLUO and PHEN remained relatively stable. Race and socioeconomic status show independent effects on PAH exposure. Heterogeneous distributions of urinary PAH metabolites among people with different job categories exist at the population level. The upward temporal trends in NAP and PYR warrant reduction in PAH exposure, especially among those with OFL and ECR occupations.

Metabolites of the endophytic fungus Penicillium sp. FJ-1 of Acanthus ilicifolius.

PubMed

Liu, Jian-Fang; Chen, Wei-Jie; Xin, Ben-Ru; Lu, Jie

2014-06-01

Two new compounds, named as (2R,3S)-pinobanksin-3-cinnamate (1), and 15alpha-hydroxy-(22E,24R)-ergosta-3,5,8(14),22-tetraen-7-one (2), were isolated from the endophytic fungus Penicillium sp. FJ-1 of Acanthus ilicifolius Linn. Their structures were elucidated on the basis of spectroscopic analysis. Additionally, compound 1 exhibited potent neuroprotective effects on corticosterone-damaged PC12 cells, and compound 2 showed potent cytotoxicity on glioma cell lines.

Detection, quantification, metabolism, and behavioral effects of selegiline in horses.

PubMed

Dirikolu, Levent; Lehner, Andreas F; Karpiesiuk, Wojciech; Hughes, Charlie; Woods, William E; Boyles, Jeff; Harkins, John D; Troppmann, Amy; Tobin, Thomas

2003-01-01

Selegiline ([R]-[-]N,alpha-dimethyl-N-2- propynylphenethylamine or l-deprenyl), an irreversible inhibitor of monoamine oxidase, is a classic antidyskinetic and antiparkinsonian agent widely used in human medicine both as monotherapy and as an adjunct to levodopa therapy. Selegiline is classified by the Association of Racing Commissioners International (ARCI) as a class 2 agent, and is considered to have high abuse potential in racing horses. A highly sensitive LC/MS/MS quantitative analytical method has been developed for selegiline and its potential metabolites amphetamine and methamphetamine using commercially available deuterated analogs of these compounds as internal standards. After administering 40 mg of selegiline orally to two horses, relatively low (<60 ng/ml) concentrations of parent selegiline, amphetamine, and methamphetamine were recovered in urine samples. However, relatively high urinary concentrations of another selegiline metabolite were found, tentatively identified as N- desmethylselegiline. This metabolite was synthesized and found to be indistinguishable from the new metabolite recovered from horse urine, thereby confirming the chemical identity of the equine metabolite. Additionally, analysis of urine samples from four horses dosed with 50 mg of selegiline confirmed that N-desmethylselegiline is the major urinary metabolite of selegiline in horses. In related behavior studies, p.o. and i.v. administration of 30 mg of selegiline produced no significant changes in either locomotor activities or heart rates.

Phthalate exposure and reproductive parameters in young men from the general Swedish population.

PubMed

Axelsson, Jonatan; Rylander, Lars; Rignell-Hydbom, Anna; Jönsson, Bo A G; Lindh, Christian H; Giwercman, Aleksander

2015-12-01

In animals, exposure to certain phthalates negatively affects the male reproductive function. Human results are conflicting and mostly based on subfertile males, in whom the association between exposure and reproductive function may differ from the general population. To study if levels of phthalate metabolites were associated with semen quality and reproductive hormones in general Swedish men. We recruited 314 young men delivering semen, urine and blood samples at the same visit. We analyzed reproductive hormones and several semen parameters including progressive motility and high DNA stainability (HDS)-a marker for sperm immaturity. In urine, we analyzed metabolites of phthalates, including diethylhexyl phthalate (DEHP). We studied associations between urinary levels of the metabolites and seminal as well as serum reproductive parameters, accounting for potential confounders. DEHP metabolite levels, particularly urinary mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), were negatively associated with progressive sperm motility, which was 11 (95% CI: 5.0-17) percentage points lower in the highest quartile of MECPP than in the lowest. Further, men in the highest quartile of the DEHP metabolite monoethylhexyl phthalate had 27% (95% CI: 5.5%-53%) higher HDS than men in the lowest quartile. DEHP metabolite levels seemed negatively associated with sperm motility and maturation. Copyright © 2015 Elsevier Ltd. All rights reserved.

A pilot study on association between phthalate exposure and missed miscarriage.

PubMed

Yi, H; Gu, H; Zhou, T; Chen, Y; Wang, G; Jin, Y; Yuan, W; Zhao, H; Zhang, L

2016-05-01

The incidence of missed miscarriage has been increasing during the past decade in China and the etiology of about half of the cases remains unclear. Exposure to phthalates has been considered as a risk factor. The aim of this paper is to assess the association between exposure to phthalates and missed miscarriage. A case-control study was performed including 150 cases of missed miscarriage and 150 matched controls with normal pregnancies. The levels of phthalate exposure were compared between the two groups by measuring 13 phthalate metabolites in urine samples. Blood samples were collected for serum hormone measurement to assess the relationship between serum hormone level and phthalate exposure. The urinary levels of metabolites of di-(2-ethylhexyl) phthalate (DEHP) and dimethyl phthalate (DMP) were significantly higher in the cases than in the controls. A strong dose-response relationship was observed between urinary metabolite levels and the odds of missed miscarriage. Monomethyl phthalate (MMP), a metabolite of DMP, and mono-2-ethylhexyl phthalate (MEHP), a metabolite of DEHP, each had significant negative correlation with maternal serum hormone levels. In the current study, exposure to DEHP and DMP was found to be associated with missed miscarriage. Interruption of hormone synthesis by DMP and DEHP metabolites represents a plausible mechanism of phthalate reproductive toxicity.

Metabolism of norethisterone in the greyhound.

PubMed

Biddle, S T B; O'Donnell, A; Houghton, E; Creaser, C S

2013-10-30

Norethisterone has been used as a successful oral contraceptive in humans for many years. It was recently permitted for use as an oestrus suppressant in racing greyhounds. To monitor the use of norethisterone as part of a routine drug surveillance programme, knowledge of its metabolism was required to enable detection. Gas chromatography/mass spectrometry and selective derivatisation techniques have been used to identify urinary metabolites of norethisterone following oral administration to the greyhound. Metabolites were extracted using solid-phase and liquid-liquid extraction techniques. Several metabolites were identified, including reduced, mono-, di- and trihydroxylated steroids. The major metabolites observed were 17α-ethynyl-5β-estrane-3α,17β-diol, 17α-ethynyl-5α-estrane-3β,17β-diol, three 17α-ethynylestranetriol stereoisomers and two 17α-ethynylestranetetrol stereoisomers. The major metabolites were predominantly excreted as glucuronic acid conjugates and detection of the administration of norethisterone was possible for up to 8 days post-dose using the methods described. The nandrolone metabolites, 19-norepiandrosterone, estranediol and 19-noretiocholanolone, were also identified in the post-administration samples collected up to 8 h after dosing the treated animals. The urinary metabolites identified in this study have further increased the knowledge of steroid metabolism in the greyhound, providing information to support routine drug testing programmes for greyhound racing. Copyright © 2013 John Wiley & Sons, Ltd.

Prenatal phthalate metabolite concentrations and infant fat mass across the first year of life: A pilot study

USDA-ARS?s Scientific Manuscript database

Phthalates are endocrine-disrupting chemicals associated with childhood obesity. While studies have found positive associations for certain prenatal and postnatal urinary phthalate metabolites and weight/length or BMI as indicators of adiposity levels, little is known about the direct associations b...

NMR ANALYSIS OF MALE FATHEAD MINNOW URINARY METABOLITES: A POTENTIAL APPROACH FOR STUDYING IMPACTS OF CHEMICAL EXPOSURES

EPA Science Inventory

The potential for profiling endogenous metabolites in urine from male fathead minnows (Pimephales promelas) to assess chemical exposures was explored using nuclear magnetic resonance (NMR) spectroscopy. Both one dimensional (1D) and two dimensional (2D) NMR spectroscopy w...

Conversion in vitro of urinary (+)-penicillamine to its major metabolites, PSSP and PSSC.

PubMed Central

Carruthers, G; Weir, D; Freeman, D; Harth, M

1983-01-01

To investigate the discrepancy between the apparent pharmacokinetic disposition of (+)-penicillamine in plasma and urine, the spontaneous degradation of (+)-penicillamine was studied in acidified and non-acidified urine. Degradation was prevented by acidification. The oxidized metabolites were converted to reduced (+)-penicillamine by electrolysis. PMID:6871074

Racial and ethnic variations in phthalate metabolite concentration changes across full-term pregnancies.

PubMed

James-Todd, Tamarra M; Meeker, John D; Huang, Tianyi; Hauser, Russ; Seely, Ellen W; Ferguson, Kelly K; Rich-Edwards, Janet W; McElrath, Thomas F

2017-03-01

Higher concentrations of certain phthalate metabolites are associated with adverse reproductive and pregnancy outcomes, as well as poor infant/child health outcomes. In non-pregnant populations, phthalate metabolite concentrations vary by race/ethnicity. Few studies have documented racial/ethnic differences between phthalate metabolite concentrations at multiple time points across the full-course of pregnancy. The objective of the study was to characterize the change in phthalate metabolite concentrations by race/ethnicity across multiple pregnancy time points. Women were participants in a prospectively collected pregnancy cohort who delivered at term (≥37 weeks) and had available urinary phthalate metabolite concentrations for ≥3 time points across full-term pregnancies (n=350 women). We assessed urinary concentrations of eight phthalate metabolites that were log-transformed and specific gravity-adjusted. We evaluated the potential racial/ethnic differences in phthalate metabolite concentrations at baseline (median 10 weeks gestation) using ANOVA and across pregnancy using linear mixed models to calculate the percent change and 95% confidence intervals adjusted for sociodemographic and lifestyle factors. Almost 30% of the population were non-Hispanic black or Hispanic. With the exception of mono-(3-carboxypropyl) (MCPP) and di-ethylhexyl phthalate (DEHP) metabolites, baseline levels of phthalate metabolites were significantly higher in non-whites (P<0.05). When evaluating patterns by race/ethnicity, mono-ethyl phthalate (MEP) and MCPP had significant percent changes across pregnancy. MEP was higher in Hispanics at baseline and decreased in mid-pregnancy but increased in late pregnancy for non-Hispanic blacks. MCPP was substantially higher in non-Hispanic blacks at baseline but decreased later in pregnancy. Across pregnancy, non-Hispanic black and Hispanic women had higher concentrations of certain phthalate metabolites. These differences may have implications for racial/ethnic differences in adverse pregnancy and child health outcomes.

Hydroxy-fipronil is a new urinary biomarker of exposure to fipronil

PubMed Central

Vasylieva, Natalia; Barnych, Bogdan; Wan, Debin; El-Sheikh, El-Sayed A.; Nguyen, Hai M.; Wulff, Heike; McMahen, Rebecca; Strynar, Mark; Gee, Shirley J.; Hammock, Bruce D.

2017-01-01

Occupational medical surveillance is highly desirable in manufacturing facilities where exposure to chemicals is significant. The insecticide fipronil is generally considered safe for humans but with increasing use, exposure to fipronil is of concern. Identification of urinary metabolites of fipronil may allow development of affordable, cheap and rapid procedures for human exposure evaluation. In this study we developed a fast and easy approach for synthesis of hydroxy-fipronil, a potential urinary metabolite of fipronil. This standard was used to develop a sensitive analytical LC-MS/MS method with a limit of quantification (LOQ) of 0.4 ng/mL. Fipronil sulfone, a known metabolite, and hydroxy-fipronil were quantified in urine samples from rats treated with a fipronil containing diet. Fipronil sulfone concentration centered around 20 ng/mL, while the concentration of hydroxy-fipronil was dose-dependent ranging in 10–10 000 ng/mL and thus being a more sensitive marker of fipronil exposure. A fipronil immunoassay with cross-reactivity to hydroxy-fipronil showed a good correlation in signal intensity with LC-MS data. It was also used to demonstrate the applicability of the method for sample screening in the evaluation of exposure levels. PMID:28343720

Measurement of Urinary Biomarkers of Parabens, Benzophenone-3, and Phthalates in a Belgian Population

PubMed Central

Dewalque, Lucas; Pirard, Catherine; Charlier, Corinne

2014-01-01

Parabens, benzophenone-3 (BP3), and phthalates are commonly used as antimicrobial conservator, UV-filter, and plasticizer, respectively, and are thought to exhibit endocrine disrupting properties. These endocrine disrupting activities have been recently assumed to lead to cutaneous malignant melanoma. Humans are exposed to these chemicals through different sources such as food, personal care products, or cosmetics. In this study, we measured urinary levels of 4 parabens, BP3, and 7 metabolites of phthalates in samples collected from 261 participants living in and around Liege (Belgium). The analyses were carried out by liquid chromatography tandem mass spectrometry (LC-MS/MS) using isotopic dilution. To the best of our knowledge, this is the first time that the urinary levels of these 3 classes of chemicals are reported for the same general population in Belgium. Most of the parabens, the BP3, and all the phthalate metabolites were detected in 82.8 to 100.0% of the samples. For most of these chemicals, the exposure patterns significantly differ not only between children and adults, but also between males and females, especially with higher concentrations of parabens and phthalate metabolites in female and children subjects, respectively. PMID:24719881

L-DOPA therapy interferes with urine catecholamine analysis in children with suspected neuroblastoma: a case series.

PubMed

Kelly, Alison U; Srivastava, Rajeev; Dow, Ellie; Davidson, D Fraser

2017-09-01

Neuroblastoma is the most common solid extracranial malignancy diagnosed in childhood. Clinical presentation is variable, and metastatic disease is common at diagnosis. Analyses of urinary catecholamines and their metabolites are commonly requested as a first-line investigation when clinical suspicion exists. Levodopa (L-Dopa) therapy is utilized as a treatment for a number of disorders in childhood, including Dopa-responsive dystonia. Neuroblastoma may mimic some of the clinical features of this disorder. L-Dopa can interfere with analysis of urinary catecholamines and their metabolites and complicate the interpretation of results. We present the cases of three children who were prescribed L-dopa at the time of analysis of urinary catecholamines and metabolites as a screen for neuroblastoma, but who did not have the disease. Comparison of their results with those from cases with true neuroblastoma reveal that it is impossible to reliably distinguish true neuroblastoma from L-Dopa therapy using these tests. We recommend that patients should be off L-dopa therapy, if possible when these tests are performed. These cases illustrate the importance of providing clinical details and drug history to the laboratory in order to avoid diagnostic confusion.

Urinary metabolic insights into host-gut microbial interactions in healthy and IBD children

PubMed Central

Martin, Francois-Pierre; Su, Ming-Ming; Xie, Guo-Xiang; Guiraud, Seu Ping; Kussmann, Martin; Godin, Jean-Philippe; Jia, Wei; Nydegger, Andreas

2017-01-01

AIM To identify metabolic signatures in urine samples from healthy and inflammatory bowel disease (IBD) children. METHODS We applied liquid chromatography and gas chromatography coupled to targeted mass spectrometry (MS)-based metabolite profiling to identify and quantify bile acids and host-gut microbial metabolites in urine samples collected from 21 pediatric IBD patients monitored three times over one year (baseline, 6 and 12 mo), and 27 age- and gender-matched healthy children. RESULTS urinary metabolic profiles of IBD children differ significantly from healthy controls. Such metabolic differences encompass central energy metabolism, amino acids, bile acids and gut microbial metabolites. In particular, levels of pyroglutamic acid, glutamic acid, glycine and cysteine, were significantly higher in IBD children in the course of the study. This suggests that glutathione cannot be optimally synthesized and replenished. Whilst alterations of the enterohepatic circulation of bile acids in pediatric IBD patients is known, we show here that non-invasive urinary bile acid profiling can assess those altered hepatic and intestinal barrier dysfunctions. CONCLUSION The present study shows how non-invasive sampling of urine followed by targeted MS-based metabonomic analysis can elucidate and monitor the metabolic status of children with different GI health/disease status. PMID:28611517

Recommendations and Standardization of Biomarker Quantification Using NMR-Based Metabolomics with Particular Focus on Urinary Analysis

PubMed Central

2016-01-01

NMR-based metabolomics has shown considerable promise in disease diagnosis and biomarker discovery because it allows one to nondestructively identify and quantify large numbers of novel metabolite biomarkers in both biofluids and tissues. Precise metabolite quantification is a prerequisite to move any chemical biomarker or biomarker panel from the lab to the clinic. Among the biofluids commonly used for disease diagnosis and prognosis, urine has several advantages. It is abundant, sterile, and easily obtained, needs little sample preparation, and does not require invasive medical procedures for collection. Furthermore, urine captures and concentrates many “unwanted” or “undesirable” compounds throughout the body, providing a rich source of potentially useful disease biomarkers; however, incredible variation in urine chemical concentrations makes analysis of urine and identification of useful urinary biomarkers by NMR challenging. We discuss a number of the most significant issues regarding NMR-based urinary metabolomics with specific emphasis on metabolite quantification for disease biomarker applications and propose data collection and instrumental recommendations regarding NMR pulse sequences, acceptable acquisition parameter ranges, relaxation effects on quantitation, proper handling of instrumental differences, sample preparation, and biomarker assessment. PMID:26745651

Maternal urinary phthalate metabolites during pregnancy and thyroid hormone concentrations in maternal and cord sera: The HOME Study.

PubMed

Romano, Megan E; Eliot, Melissa N; Zoeller, R Thomas; Hoofnagle, Andrew N; Calafat, Antonia M; Karagas, Margaret R; Yolton, Kimberly; Chen, Aimin; Lanphear, Bruce P; Braun, Joseph M

2018-05-01

Phthalates, endocrine-disrupting chemicals that are commonly found in consumer products, may adversely affect thyroid hormones, but findings from prior epidemiologic studies are inconsistent. In a prospective cohort study, we investigated whether maternal urinary phthalate metabolite concentrations and phthalate mixtures measured during pregnancy were associated with thyroid hormones among pregnant women and newborns. We measured nine phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate, mono-isobutyl phthalate, monobenzyl phthalate (MBzP), and four monoesthers of di(2-ethylhexyl) phthalate] in urine collected at approximately 16 and 26 weeks' gestation among women in the Health Outcomes and Measures of the Environment Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine and triiodothyronine were measured in maternal serum at 16 weeks' gestation (n = 202) and cord serum at delivery (n = 276). We used multivariable linear regression to assess associations between individual urinary phthalate metabolites and concentrations of maternal or cord serum thyroid hormones. We used weighted quantile sum regression (WQS) to create a phthalate index describing combined concentrations of phthalate metabolites and to investigate associations of the phthalate index with individual thyroid hormones. With each 10-fold increase in 16-week maternal urinary MEP, maternal serum total thyroxine (TT 4 ) decreased by 0.52 μg/dL (95% CI: -1.01, -0.03). For each 10-fold increase in average (16- and 26-week) maternal urinary MBzP, cord serum TSH decreased by 19% (95% CI: -33.1, -1.9). Among mothers, the phthalate index was inversely associated with maternal serum TT 4 (WQS beta = -0.60; 95% CI: -1.01, -0.18). Among newborns, the phthalate index was inversely associated with both cord serum TSH (WQS beta = -0.11; 95% CI: -0.20, -0.03) and TT 4 (WQS beta = -0.53; 95% CI: -0.90, -0.16). Our results suggest that co-exposure to multiple phthalates was inversely associated with certain thyroid hormones (TT 4 in pregnant women and newborns, and TSH in newborns) in this birth cohort. These findings highlight the need to study chemical mixtures in environmental epidemiology. Copyright © 2018 Elsevier GmbH. All rights reserved.

Porphyrinuria in childhood autistic disorder is not associated with urinary creatinine deficiency.

PubMed

Nataf, Robert; Skorupka, Corinne; Lam, Alain; Springbett, Anthea; Lathe, Richard

2008-08-01

Urinary metabolite measurements are often normalized to levels of the ubiquitous metabolite creatinine (CRT) to take account of variations in fluid export. Following CRT normalization, excesses of porphyrins and isoprostanes have been reported in the urines of children with neurodevelopmental disorders. It was suggested (Whiteley et al., 2006, Pediatr. Int. 2006; 48: 292-297) that urinary CRT levels may be depressed in children with autism spectrum disorders. This prompted re-evaluation of CRT levels in such children. First matinal urinary CRT levels were compared between subjects in different diagnostic categories including autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS) and hyperactivity, before and after correction for age and gender. A larger reference group, consisting of subjects with unrelated disorders and Asperger disorder, with no reported porphyrin excess, was also compared to the group with autistic disorder, both for CRT and for porphyrin (coproporphyrin, COPRO) excess. No significant difference in CRT was observed between any of the categories analyzed, also when corrected for age and gender. In contrast, urinary COPRO levels were significantly higher in autistic disorder versus reference groups, either when expressed as absolute values (independent of CRT levels) or when normalized to CRT. These data do not support a systematic reduction in urinary CRT levels in subjects with autism spectrum disorders including autistic disorder and PDD-NOS. Urinary COPRO excess in autistic disorder was not associated with or consequent upon urinary CRT deficiency. Differences between affected and control subjects in age and sampling time, as reported by Whiteley et al., may underlie the apparent CRT reduction.

Urinary and Dietary Analysis of 18,470 Bangladeshis Reveal a Correlation of Rice Consumption with Arsenic Exposure and Toxicity

PubMed Central

Melkonian, Stephanie; Argos, Maria; Hall, Megan N.; Chen, Yu; Parvez, Faruque; Pierce, Brandon; Cao, Hongyuan; Aschebrook-Kilfoy, Briseis; Ahmed, Alauddin; Islam, Tariqul; Slavcovich, Vesna; Gamble, Mary; Haris, Parvez I.; Graziano, Joseph H.; Ahsan, Habibul

2013-01-01

Background We utilized data from the Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh, to evaluate the association of steamed rice consumption with urinary total arsenic concentration and arsenical skin lesions in the overall study cohort (N=18,470) and in a subset with available urinary arsenic metabolite data (N=4,517). Methods General linear models with standardized beta coefficients were used to estimate associations between steamed rice consumption and urinary total arsenic concentration and urinary arsenic metabolites. Logistic regression models were used to estimate prevalence odds ratios (ORs) and their 95% confidence intervals (CIs) for the associations between rice intake and prevalent skin lesions at baseline. Discrete time hazard models were used to estimate discrete time (HRs) ratios and their 95% CIs for the associations between rice intake and incident skin lesions. Results Steamed rice consumption was positively associated with creatinine-adjusted urinary total arsenic (β=0.041, 95% CI: 0.032-0.051) and urinary total arsenic with statistical adjustment for creatinine in the model (β=0.043, 95% CI: 0.032-0.053). Additionally, we observed a significant trend in skin lesion prevalence (P-trend=0.007) and a moderate trend in skin lesion incidence (P-trend=0.07) associated with increased intake of steamed rice. Conclusions This study suggests that rice intake may be a source of arsenic exposure beyond drinking water. PMID:24260455

COMPARISON OF GENE EXPRESSION IN KIDNEY AND URINARY BLADDER FROM RATS TREATED WITH DIMETHYLARSINIC ACID

EPA Science Inventory

Arsenic is widespread in the environment and a human carcinogen. A major metabolite of inorganic arsenic (iAs) in most species, including humans, is dimethylarsinic acid (DMA), which is also used as a pesticide. Unlike iAs, DMA induces urinary bladder tumors in rats. DMA is belie...

Effects of biological and behavioral factors on urinary arsenic metabolic profiles in a U.S. population

EPA Science Inventory

Abstract In older men and women who were long-term residents of Churchill County, Nevada, we examined the relation between arsenic exposure from home tap water and urinary levels of inorganic arsenic and its methylated metabolites. Over a wide exposure range (up to 1850 ug of a...

Associations between paternal urinary phthalate metabolite concentrations and reproductive outcomes among couples seeking fertility treatment

PubMed Central

Dodge, LE; Williams, PL; Williams, MA; Missmer, SA; Souter, I; Calafat, AM; Hauser, R

2015-01-01

INTRODUCTION Limited evidence suggests that male exposure to ubiquitous environmental phthalates may result in poor reproductive outcomes among female partners. METHODS This analysis included male-female couples undergoing in vitro fertilization (IVF) and/or intrauterine insemination (IUI). We evaluated associations between the geometric mean of paternal specific gravity-adjusted urinary phthalate concentrations prior to the female partners’ cycle and fertilization, embryo quality, implantation, and live birth using generalized linear mixed models. RESULTS Two-hundred eighteen couples underwent 211 IVF and 195 IUI cycles. Trends were observed between paternal urinary mono-3-carboxypropyl phthalate (MCPP; P=0.01) and mono(carboxyoctyl) phthalate (MCOP; P=0.01) and decreased odds of implantation. MCPP and MCOP were also associated with decreased odds of live birth following IVF (P=0.01 and P=0.04, respectively), and monobutyl phthalate above the first quartile was significantly associated with decreased odds of live birth following IUI (P=0.04). However, most urinary phthalate metabolites were not associated with these reproductive outcomes. CONCLUSION Selected phthalates were associated with decreased odds of implantation and live birth. PMID:26456810

Differences of urinary arsenic metabolites and methylation capacity between individuals with and without skin lesions in Inner Mongolia, Northern China.

PubMed

Zhang, Qiang; Li, Yongfang; Liu, Juan; Wang, Da; Zheng, Quanmei; Sun, Guifan

2014-07-18

Incomplete arsenic (As) methylation has been considered a risk factor of As-related diseases. This study aimed to examine the difference of urinary As metabolites and the methylation capacity between subjects with and without skin lesions. Urinary inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were analyzed. The percentage of each As species (iAs%, MMA%, and DMA%), the primary methylation index (PMI) and secondary methylation index (SMI) were calculated. The results showed that subjects with skin lesions have higher levels of urinary iAs (99.08 vs. 70.63 μg/g Cr, p = 0.006) and MMA (69.34 vs. 42.85 μg/g Cr, p = 0.016) than subjects without skin lesions after adjustment for several confounders. Significant differences of urianry MMA% (15.49 vs. 12.11, p = 0.036) and SMI (0.74 vs. 0.81, p = 0.025) were found between the two groups. The findings of the present study suggest that subjects with skin lesions may have a lower As methylation capacity than subjects without skin lesions.

Valerenic Acid Protects Against Physical and Psychological Stress by Reducing the Turnover of Serotonin and Norepinephrine in Mouse Hippocampus-Amygdala Region

PubMed Central

Jung, Hyo Young; Yoo, Dae Young; Nam, Sung Min; Kim, Jong Whi; Choi, Jung Hoon; Yoo, Miyoung; Lee, Sanghee; Yoon, Yeo Sung

2015-01-01

Abstract In a previous study, we demonstrated that a Valeriana officinalis extract could attenuate increases in serum corticosterone levels in a mouse model of physical and psychological stress. In addition, our results showed that the extract could modulate serotonin (5-HT) and norepinephrine (NE) turnover in the hippocampus and amygdala region. In this study, we intended to investigate the effects of valerenic acid (VA), the main component of V. officinalis extract, on corticosterone levels in serum in normal mice and monoamine turnover in hippocampus-amygdala homogenates in a mouse model of physical and psychological stress. To determine the minimum dose of VA for antianxiety effect, eight-week-old ICR mice were orally administered VA (0.2, 0.5, and 1.0 mg/kg/0.3 mL) once daily for 3 weeks to probe for immobility time and serum corticosterone levels. At a VA dose of 0.5 and 1.0 mg/kg, animals showed a decrease in the duration of immobility time and serum corticosterone levels. To confirm the antianxiety effect of VA, eight-week-old ICR mice received VA at a dose of 0.5 mg/kg, orally, once daily for 3 weeks, before being subjected to physical or psychological stress for 3 days, in a specially designed communication box, followed by estimation of levels of monoamines and their metabolites in the hippocampus-amygdala region. In conclusion, VA administration at 0.5 mg/kg can mitigate the physical and psychological stress response by decreasing the turnover of 5-HT to 5-hydroxyindoleacetic acid and NE to 3-methoxy-4-hydroxyphenylethyleneglycol sulfate in the hippocampus and amygdala. PMID:26177123

Welfare indicators in laying hens in relation to nest exclusion.

PubMed

Alm, M; Tauson, R; Holm, L; Wichman, A; Kalliokoski, O; Wall, H

2016-06-01

Consumer concerns about the welfare of laying hens are increasing, leading to increased interest in identifying reliable ways to assess welfare. The present study evaluated invasive and non-invasive welfare indicators in relation to a stressful challenge. The study included 126 Lohmann Selected Leghorn hens housed in furnished cages. Welfare indicators were measured between 61 and 70 wk of age in birds excluded from their nests for 5 consecutive d and control birds that had continuous access to nests. Baseline recordings were carried out in both groups prior to and post exclusion period. The assessed indicators were: corticosterone metabolites in droppings (FCM), corticosterone concentration in yolk, corticosterone concentration in plasma, irregularities of eggshells, heterophil to lymphocyte (H:L) ratio, tonic immobility duration, and feather cover. Behavioral observations showed that the birds had a clear preference for using the secluded nest sites, confirming that they were likely to perceive nest exclusion as an undesirable experience. Further, elevated levels of FCM in droppings, yolk corticosterone concentrations, H:L ratios and irregular eggshells were detected in both nest deprived and control birds during the exclusion. This suggests that these indicators were able to detect an increased stress response arising from nest deprivation, and it is hypothesized that the stress spread to birds in adjacent cages with access to nests. There was a positive and consistent correlation between FCM in droppings and eggshell irregularities, also supporting the use of eggshell irregularities as a potential non-invasive welfare indicator. However, the pattern of the stress response varied between indicators and correlations were generally few and inconsistent, highlighting the complexity of the relationship among welfare indicators. © 2016 Poultry Science Association Inc.

Effect of acute swim stress on plasma corticosterone and brain monoamine levels in bidirectionally selected DxH recombinant inbred mouse strains differing in fear recall and extinction.

PubMed

Browne, Caroline A; Hanke, Joachim; Rose, Claudia; Walsh, Irene; Foley, Tara; Clarke, Gerard; Schwegler, Herbert; Cryan, John F; Yilmazer-Hanke, Deniz

2014-12-01

Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites 3,4-dihydroxyphenyacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 min after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or post-traumatic stress disorder.

Effect of Acute Swim Stress on Plasma Corticosterone and Brain Monoamine Levels in Bidirectionally Selected DxH Recombinant Inbred Mouse Strains Differing in Fear Recall and Extinction

PubMed Central

Browne, Caroline A.; Hanke, Joachim; Rose, Claudia; Walsh, Irene; Foley, Tara; Clarke, Gerard; Schwegler, Herbert; Cryan, John F.; Yilmazer-Hanke, Deniz

2015-01-01

Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus, and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 minutes after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or posttraumatic stress disorder. PMID:25117886

Urinary androgens and cortisol metabolites in field-sampled bonobos (Pan paniscus).

PubMed

Dittami, John; Katina, Stanislav; Möstl, Erich; Eriksson, Jonas; Machatschke, Ivo H; Hohmann, Gottfried

2008-02-01

Urinary metabolites of androgens and cortisol were measured in free-living male and female bonobos. Sex differences and correlations between adrenal and gonadal steroid excretion were investigated. The immunoreactive concentrations of androgens were measured with two different androgen assays. One assay used a testosterone (T) antibody raised with a 17beta-hydroxy group, and the other employed an antibody raised against a reduced form, 5alpha-androstane-17alpha-ol-3-one-CM (17alpha) with cross reactivity for epitestosterone and 5alpha-androstanedione. Both assays have been used in bonobo and chimpanzee studies where non-invasive techniques were employed. The levels of 17alpha-androgen metabolites were 1.7- and 3-fold higher than those of T-metabolites in males and females. The two androgen assay results correlated in males but not females. There was a sex difference in the T-metabolites measured. Male levels were significantly higher. Levels of 17alpha in the two sexes were similar. Cortisol metabolite levels (CORT) were similar between the sexes. The T-metabolites were significantly correlated with CORT in males but not in females. In females, the 17alpha-androgen metabolites correlated with CORT. This suggests that either androgen secretion or metabolism differs between the sexes. A parsimonious interpretation of the androgen assay cortisol/androgen correlation differences would be that larger components of dehydroepiandrosterone (DHEA), androstenedione or epitestosterone from the adrenal androgens were being excreted and measured in the females. The CORT/T metabolite interactions in males may reflect male-specific social or metabolic endocrine conditions.

Semen quality in Peruvian pesticide applicators: association between urinary organophosphate metabolites and semen parameters

PubMed Central

Yucra, Sandra; Gasco, Manuel; Rubio, Julio; Gonzales, Gustavo F

2008-01-01

Background Organophosphates are broad class of chemicals widely used as pesticides throughout the world. We performed a cross-sectional study of associations between dialkylphosphate metabolites of organophosphates and semen quality among pesticide applicators in Majes (Arequipa), Peru. Methods Thirty-one men exposed to organophosphate (OP) pesticides and 31 non-exposed were recruited (age, 20–60 years). In exposed subjects, semen and a blood sample were obtained one day after the last pesticide application. Subjects were grouped according to levels of OP metabolites in urine. Semen samples were analyzed for sperm concentration, percentage of sperm motility, percentage of normal morphology, semen leucocytes and concentrations of fructose and zinc. Exposure to OP was assessed by measuring six urinary OP metabolites (dimethyl and diethyl phosphates and thiophosphates) by gas chromatography using a single flame photometric detector. Results Diethyldithiophosphate (p = 0.04) and diethylthiophosphate (p = 0.02) better reflected occupational pesticide exposure than other OP metabolites. Semen analysis revealed a significant reduction of semen volume and an increase in semen pH in men with OP metabolites. Multiple regression analysis showed that both occupational exposure to pesticides and the time of exposure to pesticides were more closely related to alterations in semen quality parameters than the single measurement of OP metabolites in urine. Conclusion The study demonstrated that occupational exposure to OP pesticides was more closely related to alterations in semen quality than a single measurement of urine OP metabolites. Current measurement of OP metabolites in urine may not reflect the full risk. PMID:19014632

Concentrations of the urinary pyrethroid metabolite 3-phenoxybenzoic acid in farm worker families in the MICASA study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trunnelle, Kelly J., E-mail: kjtrunnelle@ucdavis.edu; Bennett, Deborah H.; Ahn, Ki Chang

Indoor pesticide exposure is a growing concern, particularly from pyrethroids, a commonly used class of pesticides. Pyrethroid concentrations may be especially high in homes of immigrant farm worker families who often live in close proximity to agricultural fields, and are faced with poor housing conditions, causing higher pest infestation and more pesticide use. We investigate exposure of farm worker families to pyrethroids in a study of mothers and children living in Mendota, CA within the population-based Mexican Immigration to California: Agricultural Safety and Acculturation (MICASA) Study. We present pyrethroid exposure based on an ELISA analysis of urinary metabolite 3-phenoxybenzoic acidmore » (3PBA) levels among 105 women and 103 children. The median urinary 3PBA levels (children=2.56 ug/g creatinine, mothers=1.46 ug/g creatinine) were higher than those reported in population based studies for the United States general population, but similar to or lower than studies with known high levels of pyrethroid exposure. A positive association was evident between poor housing conditions and the urinary metabolite levels, showing that poor housing conditions are a contributing factor to the higher levels of 3PBA seen in the urine of these farm worker families. Further research is warranted to fully investigate sources of exposure. - Highlights: • We investigate exposure of farm worker families to pyrethroids. • We present pyrethroid exposure based on an ELISA analysis of urinary 3PBA levels. • 3PBA levels were higher than those reported for the U.S. general population. • Poor housing conditions may be associated with pyrethroid exposure.« less

Urinary Trivalent Methylated Arsenic Species in a Population Chronically Exposed to Inorganic Arsenic

PubMed Central

Valenzuela, Olga L.; Borja-Aburto, Victor H.; Garcia-Vargas, Gonzalo G.; Cruz-Gonzalez, Martha B.; Garcia-Montalvo, Eliud A.; Calderon-Aranda, Emma S.; Del Razo, Luz M.

2005-01-01

Chronic exposure to inorganic arsenic (iAs) has been associated with increased risk of various forms of cancer and of noncancerous diseases. Metabolic conversions of iAs that yield highly toxic and genotoxic methylarsonite (MAsIII) and dimethylarsinite (DMAsIII) may play a significant role in determining the extent and character of toxic and cancer-promoting effects of iAs exposure. In this study we examined the relationship between urinary profiles of MAsIII and DMAsIII and skin lesion markers of iAs toxicity in individuals exposed to iAs in drinking water. The study subjects were recruited among the residents of an endemic region of central Mexico. Drinking-water reservoirs in this region are heavily contaminated with iAs. Previous studies carried out in the local populations have found an increased incidence of pathologies, primarily skin lesions, that are characteristic of arseniasis. The goal of this study was to investigate the urinary profiles for the trivalent and pentavalent As metabolites in both high- and low-iAs–exposed subjects. Notably, methylated trivalent arsenicals were detected in 98% of analyzed urine samples. On average, the major metabolite, DMAsIII, represented 49% of total urinary As, followed by DMAsV (23.7%), iAsV (8.6%), iAsIII (8.5%), MAsIII (7.4%), and MAsV (2.8%). More important, the average MAsIII concentration was significantly higher in the urine of exposed individuals with skin lesions compared with those who drank iAs-contaminated water but had no skin lesions. These data suggest that urinary levels of MAsIII, the most toxic species among identified metabolites of iAs, may serve as an indicator to identify individuals with increased susceptibility to toxic and cancer-promoting effects of arseniasis. PMID:15743710

The urinary metabolites of DINCH® have an impact on the activities of the human nuclear receptors ERα, ERβ, AR, PPARα and PPARγ.

PubMed

Engel, Anika; Buhrke, Thorsten; Kasper, Stefanie; Behr, Anne-Cathrin; Braeuning, Albert; Jessel, Sönke; Seidel, Albrecht; Völkel, Wolfgang; Lampen, Alfonso

2018-05-01

DINCH ® (di-isononyl cyclohexane-1,2-dicarboxylate) is a non-phthalate plasticizer that has been developed to replace phthalate plasticizers such as DEHP (di-2-ethylhexyl phthalate) or DINP (di-isononyl phthalate). DINCH ® is metabolized to its corresponding monoester and subsequently to oxidized monoester derivatives. These are conjugated to glucuronic acid and subject to urinary excretion. In contrast to DINCH ® , there are almost no toxicological data available regarding its primary and secondary metabolites. The present study aimed at the characterization of potential endocrine properties of DINCH ® and five DINCH ® metabolites by using reporter gene assays to monitor the activity of the human nuclear receptors ERα, ERβ, AR, PPARα and PPARγ in vitro. DINCH ® itself did not have any effect on the activity of these receptors whereas DINCH ® metabolites were shown to activate all these receptors. In the case of AR, DINCH ® metabolites predominantly enhanced dihydrotestosterone-stimulated AR activity. In the H295R steroidogenesis assay, neither DINCH ® nor any of its metabolites affected estradiol or testosterone synthesis. In conclusion, primary and secondary DINCH ® metabolites exert different effects at the molecular level compared to DINCH ® itself. All these in vitro effects of DINCH ® metabolites, however, were only observed at high concentrations such as 10 μM or above which is about three orders of magnitude above reported DINCH ® metabolite concentrations in human urine. Thus, the in vitro data do not support the notion that DINCH ® or any of the investigated metabolites may exert considerable endocrine effects in vivo at relevant human exposure levels. Copyright © 2018 Elsevier B.V. All rights reserved.

Phthalate exposure and childrens neurodevelopment: A systematic review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ejaredar, Maede, E-mail: mejareda@ucalgary.ca; Nyanza, Elias C.; Ten Eycke, Kayla

Background: Emerging evidence from observational studies suggests that prenatal exposure to phthalates affects neurodevelopment in children. Objective: To conduct a systematic review of the existing literature on the association between urinary phthalate concentrations and children's neurodevelopment. Methods: We searched electronic bibliographic databases (MEDLINE, PubMed, EMBASE, PsycINFO, CINAHL, Global Health, CAB abstracts, and ERIC) (1910 to February 21st, 2014); reference lists of included articles, and conference abstracts (American Psychiatric Association, American Academy of Neurology, and Pediatric Academic Societies). Two independent reviewers screened abstracts and extracted data. We included original studies reporting on the association between prenatal or childhood urinary phthalate metabolites,more » and cognitive and behavioral outcomes (e.g., IQ scores, BASC-2 scores or equivalent) in children 0–12 years of age. Results: Of 2804 abstracts screened, 11 original articles met our criteria for inclusion. Conclusions: A systematic review of the literature supports the contention that prenatal exposure phthalates is associated with adverse cognitive and behavioral outcomes in children, including lower IQ, and problems with attention, hyperactivity, and poorer social communication. Further research characterizing the associations between specific phthalate metabolites and children's neurodevelopmental outcomes is needed to support the development of mitigation strategies and enhance the development of appropriate health policy. - Highlights: • Prenatal maternal urinary concentrations of phthalate metabolites appear to be associated with adverse cognitive and behavioral outcomes in children. • Both low molecular weight (e.g., monobutyl phthalate, MBP) and high molecular weight (e.g., di(2-ethylhexyl) phthalate, DEHP) phthalate metabolites are associated with adverse cognitive and behavioral outcomes. • Sex-specific effects from phthalate exposure were noted between low (e.g., mono-n-butyl phthalate, MnBP) and high (e.g., DEHP) molecular weight phthalate metabolites, and cognitive and behavioral outcomes.« less

Urinary Estrogen Metabolites in 2 Soy Trials with Premenopausal Women

PubMed Central

Maskarinec, Gertraud; Morimoto, Yukiko; Heak, Sreang; Isaki, Marissa; Steinbrecher, Astrid; Custer, Laurie; Franke, Adrian A.

2012-01-01

Background Soy consumption may protect against breast cancer through modification of estrogen metabolism. Objective We examined the effect of soy foods on urinary estrogens and the 2-hydroxy (OH)/16α-OH estrone (E1) ratio in 2 dietary interventions with premenopausal women. Methods BEAN1 was a 2-year randomized trial and BEAN2 a 13-month randomized crossover study. In both interventions, study participants consumed a high-soy diet with 2 soy food servings/day and a low-soy diet with <3 servings of soy/week. Urine samples were collected at baseline and at the end of the diet periods, analyzed for 9 estrogen metabolites by liquid chromatography mass spectrometry, and adjusted for creatinine levels. For BEAN1, 2 samples for 188 participants and for BEAN2, 3 samples for 79 women were analyzed. We applied mixed-effects regression models with log-transformed values of estrogen metabolites and soy intake as the exposure variable. Results In BEAN1, no effect of the high-soy diet on individual estrogen metabolites or hydroxylation pathways was observed. The median 2-OH/16α-OH E1 ratio decreased non-significantly in the intervention group from 6.2 to 5.2 as compared to 6.8 and 7.2 in the control group (p=0.63). In BEAN2, only 4-OHE1 was significantly lower after the high-soy diet. Interaction terms of the high-soy diet with equol producer status, ethnicity, and weight status revealed no significant effect modification. Conclusions Contrary to our hypothesis and some previous reports, the results from 2 well controlled dietary interventions do not support an effect of a high-soy diet on a panel of urinary estrogen metabolites and the 2-OH/16α-OHE1 ratio. PMID:22713773

Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy

PubMed Central

Johns, Lauren E.; Ferguson, Kelly K.; McElrath, Thomas F.; Mukherjee, Bhramar; Meeker, John D.

2016-01-01

Background: Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women. Objectives: We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection. Methods: Data were obtained from pregnant women (n = 439) participating in a nested case–control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy. Results: Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation. Conclusions: These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women. Citation: Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808–1815; http://dx.doi.org/10.1289/EHP170 PMID:27152641

Identification of sex-specific urinary biomarkers for major depressive disorder by combined application of NMR- and GC-MS-based metabonomics.

PubMed

Zheng, P; Chen, J-J; Zhou, C-J; Zeng, L; Li, K-W; Sun, L; Liu, M-L; Zhu, D; Liang, Z-H; Xie, P

2016-11-15

Women are more vulnerable to major depressive disorder (MDD) than men. However, molecular biomarkers of sex differences are limited. Here we combined gas chromatography-mass spectrometry (GC-MS)- and nuclear magnetic resonance (NMR)-based metabonomics to investigate sex differences of urinary metabolite markers in MDD, and further explore their potential of diagnosing MDD. Consequently, the metabolite signatures of women and men MDD subjects were significantly different from of that in their respective healthy controls (HCs). Twenty seven women and 36 men related differentially expressed metabolites were identified in MDD. Fourteen metabolites were changed in both women and men MDD subjects. Significantly, the women-specific (m-Hydroxyphenylacetate, malonate, glycolate, hypoxanthine, isobutyrate and azelaic acid) and men-specific (tyrosine, N-acetyl-d-glucosamine, N-methylnicotinamide, indoxyl sulfate, citrate and succinate) marker panels were further identified, which could differentiate men and women MDD patients from their respective HCs with higher accuracy than previously reported sex-nonspecific marker panels. Our findings demonstrate that men and women MDD patients have distinct metabonomic signatures and sex-specific biomarkers have promising values in diagnosing MDD.

Raised urinary glucocorticoid and adrenal androgen precursors in the urine of young hypertensive patients: possible evidence for partial glucocorticoid resistance

PubMed Central

Shamim, W; Yousufuddin, M; Francis, D; Gualdiero, P; Honour, J; Anker, S; Coats, A

2001-01-01

OBJECTIVE—To evaluate urinary glucocorticoid excretion profiles in a cohort of recently diagnosed young hypertensive patients.
METHODS—After excluding patients with secondary causes, 60 individuals with premature hypertension were recruited (diagnosed by ambulatory blood pressure monitoring before the age of 36 years). In addition, 30 older hypertensive controls (age of onset > 36 years, "middle aged hypertensive controls"), and 30 normal controls (age matched to the young hypertensive group) were studied. All provided 24 hour urine collections for mass spectrometry for total cortisol metabolites and total androgen metabolites by gas chromatography.
RESULTS—Among male patients, those with premature hypertension had higher total urinary excretion of cortisol metabolites (mean (SD), 13 332 (6472) µg/day) than age matched normal controls (7270 (1788) µg/day; p = 0.00001) or middle aged hypertensive controls (8315 (3565) µg/day; p = 0.002). A similar increase was seen among the female patients, although the absolute concentrations were lower. There was no significant difference between middle aged hypertensive patients and normal controls. Urinary total androgen excretion profiles in female patients also showed an unusual increase in the premature hypertension group (2958 (1672) µg/day) compared with the other groups (middle aged hypertensive controls, 1373 (748) µg/day, p = 0.0003; normal controls, 1687 (636) µg/day, p = 0.002). In all subjects, serum sodium and creatinine concentrations were within the normal range; serum potassium concentrations were found to be low before the start of treatment.
CONCLUSIONS—Individuals presenting with premature hypertension have an abnormally high excretion of glucocorticoid metabolites in the urine. While the mechanism remains uncertain, these findings are compatible with partial resistance of the glucocorticoid receptors, with a compensatory increase in cortisol and androgen metabolites. The mineralocorticoid effects of the latter (sodium and water retention) may contribute to an abnormally high blood pressure and may have implications for targeted selection of first line treatment in young hypertensive patients.


Keywords: premature hypertension; glucocorticoid resistance; cortisol metabolites; glucocorticoid receptor resistance PMID:11454825

Environmental exposure to human carcinogens in teenagers and the association with DNA damage.

PubMed

Franken, Carmen; Koppen, Gudrun; Lambrechts, Nathalie; Govarts, Eva; Bruckers, Liesbeth; Den Hond, Elly; Loots, Ilse; Nelen, Vera; Sioen, Isabelle; Nawrot, Tim S; Baeyens, Willy; Van Larebeke, Nicolas; Boonen, Francis; Ooms, Daniëlla; Wevers, Mai; Jacobs, Griet; Covaci, Adrian; Schettgen, Thomas; Schoeters, Greet

2017-01-01

We investigated whether human environmental exposure to chemicals that are labeled as (potential) carcinogens leads to increased (oxidative) damage to DNA in adolescents. Six hundred 14-15-year-old youngsters were recruited all over Flanders (Belgium) and in two areas with important industrial activities. DNA damage was assessed by alkaline and formamidopyrimidine DNA glycosylase (Fpg) modified comet assays in peripheral blood cells and analysis of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Personal exposure to potentially carcinogenic compounds was measured in urine, namely: chromium, cadmium, nickel, 1-hydroxypyrene as a proxy for exposure to other carcinogenic polycyclic aromatic hydrocarbons (PAHs), t,t-muconic acid as a metabolite of benzene, 2,5-dichlorophenol (2,5-DCP), organophosphate pesticide metabolites, and di(2-ethylhexyl) phthalate (DEHP) metabolites. In blood, arsenic, polychlorinated biphenyl (PCB) congeners 118 and 156, hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and perfluorooctanoic acid (PFOA) were analyzed. Levels of methylmercury (MeHg) were measured in hair. Multiple linear regression models were used to establish exposure-response relationships. Biomarkers of exposure to PAHs and urinary chromium were associated with higher levels of both 8-OHdG in urine and DNA damage detected by the alkaline comet assay. Concentrations of 8-OHdG in urine increased in relation with increasing concentrations of urinary t,t-muconic acid, cadmium, nickel, 2,5-DCP, and DEHP metabolites. Increased concentrations of PFOA in blood were associated with higher levels of DNA damage measured by the alkaline comet assay, whereas DDT was associated in the same direction with the Fpg-modified comet assay. Inverse associations were observed between blood arsenic, hair MeHg, PCB 156 and HCB, and urinary 8-OHdG. The latter exposure biomarkers were also associated with higher fish intake. Urinary nickel and t,t-muconic acid were inversely associated with the alkaline comet assay. This cross-sectional study found associations between current environmental exposure to (potential) human carcinogens in 14-15-year-old Flemish adolescents and short-term (oxidative) damage to DNA. Prospective follow-up will be required to investigate whether long-term effects may occur due to complex environmental exposures. Copyright © 2016 Elsevier Inc. All rights reserved.

Urinary cotinine in narguila or chicha tobacco smokers.

PubMed

Macaron, C; Macaron, Z; Maalouf, M T; Macaron, N; Moore, A

1997-01-01

Urinary levels of nicotine metabolites were measured in nonsmokers and smokers of tobacco either as cigarettes or as the Middle-Eastern water pipes (narguila). Levels of urinary cotinine were similar for the smokers of cigarettes (median 30 cigarettes per day) and narguila (median 2 pipes per day, or around 40 grams of tobacco). Use of water pipes may remove a small amount of nicotine, but smokers appear to titrate dose to effect. It is unlikely that narguila smoking confers any less risk.

Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

EPA Science Inventory

Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions which convert inorganic arsenic to methylated metabolites. This study determined whether the As3mt null genotype in the mouse modifies cytotoxic and proliferative effects seen in urinary bladders of wild t...

Urinary paracetamol and time-to-pregnancy

PubMed Central

Smarr, Melissa M.; Grantz, Katherine L.; Sundaram, Rajeshwari; Maisog, José M.; Honda, Masato; Kannan, Kurunthachalam; Buck Louis, Germaine M.

2016-01-01

STUDY QUESTION Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)? SUMMARY ANSWER Higher urinary paracetamol concentrations among male partners were associated with a longer TTP. WHAT IS KNOWN ALREADY Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking. STUDY DESIGN, SIZE, DURATION This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005–2009 and residing in Michigan or Texas, USA. PARTICIPANTS/MATERIALS, SETTING, METHODS Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other. MAIN RESULTS AND THE ROLE OF CHANCE Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously. LIMITATIONS, REASONS FOR CAUTION Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders. WIDER IMPLICATIONS OF THE FINDINGS If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare. PMID:27412248

Urinary paracetamol and time-to-pregnancy.

PubMed

Smarr, Melissa M; Grantz, Katherine L; Sundaram, Rajeshwari; Maisog, José M; Honda, Masato; Kannan, Kurunthachalam; Buck Louis, Germaine M

2016-09-01

Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)? Higher urinary paracetamol concentrations among male partners were associated with a longer TTP. Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking. This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas, USA. Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other. Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously. Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders. If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment. This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Documenting the kinetic time course of lambda-cyhalothrin metabolites in orally exposed volunteers for the interpretation of biomonitoring data.

PubMed

Khemiri, Rania; Côté, Jonathan; Fetoui, Hamadi; Bouchard, Michèle

2017-07-05

Lambda-cyhalothrin is a pyrethroid pesticide largely used in agriculture. Exposure assessment can be performed by measuring key urinary metabolites. For a proper use of biomonitoring data, it is however important to gain information on the toxicokinetics of these key biomarkers of exposure. A human volunteer study was performed to document the plasma and urinary time courses of major lambda-cyhalothrin metabolites. Seven volunteers ingested 0.025mgkg -1 body weight of lambda-cyhalothrin. Blood samples were withdrawn prior to dosing and at fixed time periods over the 72 h-period following ingestion and complete urine voids were collected pre-exposure and at pre-established intervals over 84h post-dosing. The cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) metabolites were quantified in these samples. Plasma concentrations of CFMP and 3-PBA increased rapidly after ingestion, with average peak values at 3.1 and 4.0h post-dosing, respectively; subsequent elimination phase showed a rapid decay with a mean half-life (t ½ ) of ≈5.3 and 6.4h for CFMP and 3-PBA, respectively. Urinary rate time courses displayed a profile similar to the plasma concentration-time curves with corresponding mean t ½ of ≈4.2 and 5.9h. In the 84-h period post-treatment, on average 21% of lambda-cyhalothrin dose were excreted in urine as CFMP as compared to 30% as 3-PBA. Overall, CFMP and 3-PBA metabolites were confirmed to be major metabolites of lambda-cyhalothrin and exhibited similar kinetics with short half-lives; they thus both appear as useful biomarkers of exposure to lambda-cyhalothrin in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

The modulation of corticosteroid metabolism by hydrocortisone therapy in patients with hypopituitarism increases tissue glucocorticoid exposure.

PubMed

Sherlock, Mark; Behan, Lucy Ann; Hannon, Mark J; Alonso, Aurora Aragon; Thompson, Christopher J; Murray, Robert D; Crabtree, Nicola; Hughes, Beverly A; Arlt, Wiebke; Agha, Amar; Toogood, Andrew A; Stewart, Paul M

2015-11-01

Patients with hypopituitarism have increased morbidity and mortality. There is ongoing debate about the optimum glucocorticoid (GC) replacement therapy. To assess the effect of GC replacement in hypopituitarism on corticosteroid metabolism and its impact on body composition. We assessed the urinary corticosteroid metabolite profile (using gas chromatography/mass spectrometry) and body composition (clinical parameters and full body DXA) of 53 patients (19 female, median age 46 years) with hypopituitarism (33 ACTH-deficient/20 ACTH-replete) (study A). The corticosteroid metabolite profile of ten patients with ACTH deficiency was then assessed prospectively in a cross over study using three hydrocortisone (HC) dosing regimens (20/10 mg, 10/10 mg and 10/5 mg) (study B) each for 6 weeks. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity was assessed by urinary THF+5α-THF/THE. Endocrine Centres within University Teaching Hospitals in the UK and Ireland. Urinary corticosteroid metabolite profile and body composition assessment. In study A, when patients were divided into three groups - patients not receiving HC and patients receiving HC≤20 mg/day or HC>20 mg/day - patients in the group receiving the highest daily dose of HC had significantly higher waist-to-hip ratio (WHR) than the ACTH replete group. They also had significantly elevated THF+5α-THF/THE (P=0.0002) and total cortisol metabolites (P=0.015). In study B, patients on the highest HC dose had significantly elevated total cortisol metabolites and all patients on HC had elevated THF+5α-THF/THE ratios when compared to controls. In ACTH-deficient patients daily HC doses of >20 mg/day have increased WHR, THF+5α-THF/THE ratios and total cortisol metabolites. GC metabolism and induction of 11β-HSD1 may play a pivitol role in the development of the metabolically adverse hypopituitary phenotype. © 2015 European Society of Endocrinology.

Metabolomic Analysis of Overactive Bladder in Male Patients: Identification of Potential Metabolite Biomarkers.

PubMed

Shimura, Hiroshi; Mitsui, Takahiko; Kira, Satoru; Ihara, Tatsuya; Sawada, Norifumi; Nakagomi, Hiroshi; Miyamoto, Tatsuya; Tsuchiya, Sachiko; Kanda, Mie; Takeda, Masayuki

2018-05-09

To identify metabolites that are associated with an overactive bladder (OAB) using metabolomics. A total of 58 male patients without apparent neurologic disease completed 24-hour bladder diaries of their micturition behavior and International Prostate Symptom Score (IPSS) for the assessment of micturition behavior and lower urinary tract symptoms. Urgency was defined as an IPSS urgency score of ≥2 (OAB group), and patients with IPSS urgency scores of ≤1 belonged to the control group. A comprehensive study of plasma metabolites was also conducted using capillary electrophoresis time-of-flight mass spectrometry. Metabolite levels were compared between the control and OAB groups using the Mann-Whitney U test. Potential metabolite biomarkers were selected using multivariate logistic regression analysis. Of the 58 subjects, the control and OAB groups consisted of 32 and 26 male patients, respectively. Nocturnal urinary volume, 24-hour micturition frequency, nocturnal micturition frequency, and the nocturia index were significantly higher in the OAB group. Metabolomic analysis revealed 60 metabolites in the subjects' plasma. The levels of 11 metabolites differed between the control and OAB groups. Multivariate analysis showed that an increased glutamate level and reduced arginine, glutamine, and inosine monophosphate levels are significantly associated with OAB in male patients. Reduced levels of asparagine and hydroxyproline could also be associated with OAB. Urgency is associated with abnormal metabolism. Analyses of amino acid profiles might aid the search for new treatment targets for OAB. Copyright © 2018 Elsevier Inc. All rights reserved.

Feasibility of Biomonitoring of Exposure to Permethrin Through Analysis of Long-Lived (Metabolite) Adducts to Proteins

DTIC Science & Technology

2006-09-01

lowering agents (gemfibrozil, clofibric acid ), diuretic agents (furosemide)and the antiepileptic drug valproic acid (Benet et al, 1993; see Bailey and...exposure to the insecticide permethrin is usually performed by analysis of its urinary metabolite 3-phenoxybenzoic acid (3- PBA). However, chronic low...permethrin metabolites 3-PBA and cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cis/trans-Cl2CA) will form persistent

Urinary phthalate metabolite concentrations in relation to history of infertility and use of assisted reproductive technology.

PubMed

Alur, Snigdha; Wang, Hongyue; Hoeger, Kathy; Swan, Shanna H; Sathyanarayana, Sheela; Redmon, Bruce J; Nguyen, Ruby; Barrett, Emily S

2015-11-01

To examine urinary phthalate metabolite concentrations in pregnant women with planned pregnancies in relation to history of infertility and use of assisted reproductive technology (ART). Phthalate metabolite concentrations were measured in first-trimester urine samples collected from women participating in a prospective pregnancy cohort study. Prenatal clinics. A total of 750 women, of whom 86 had a history of infertility. Forty-one women used ART to conceive. None. Primary outcomes were concentrations of four metabolites of diethylhexyl phthalate (DEHP) and their molar sum (∑DEHP). Multivariable analyses compared phthalate metabolite levels in [1] women reporting a history of infertility vs. those who did not (comparison group); and [2] those who used ART to conceive the index pregnancy vs. women with a history of infertility who did not use ART. Among women with a history of infertility, ∑DEHP was significantly lower in women who conceived after ART compared with those who did not (geometric mean ratio: 0.83; 95% confidence interval 0.71-0.98). Similar significant associations were observed for all of the individual DEHP metabolites. There were no differences in DEHP metabolite concentrations between women with a history of infertility and the comparison group. Women who used ART to conceive had lower first-trimester phthalate metabolite concentrations than women with a history of infertility who did not use ART. Further research is needed to explore whether those pursuing fertility treatments take precautions to avoid exposure to environmental toxins, to improve treatment outcomes. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Immunoreactive cortisone in droppings reflect stress levels, diet and growth rate of gull-billed tern chicks.

PubMed

Albano, Noelia; Santiago-Quesada, Francisco; Masero, José A; Sánchez-Guzmán, Juan M; Möstl, Erich

2015-03-01

Blood levels of corticosterone have been traditionally analyzed to assess stress levels in birds; however, measuring steroid hormone metabolites in feces and droppings has gained much interest as a noninvasive technique successfully used for such purposed in vertebrates. Diet may affect these fecal metabolite levels (e.g., due to nutritional stress), however, this variable has not been taken into account in studies with chicks despite the great dietary flexibility of many avian species. In this study, we addressed for the first time this key issue and validated the technique in wild gull-billed tern chicks (Gelochelidon nilotica). Several enzyme immunoassays were used to determine the most appropriate test to measure the stress response. Subsequently, we performed an experiment in captivity to assess adrenocortical activity in gull-billed tern chicks fed with two diets: piscivorous vs. insectivorous. Finally, the relation between the chicks' growth rate and excreted immunoreactive glucocorticoid metabolites (EGMs) was also evaluated. We found the immunoreactive cortisone metabolites to be a good index of stress (as being an index of adrenocortical reactivity) in chicks of this species. Fish-fed chicks had higher levels of cortisone metabolites when comparing both concentration and total daily excreted metabolites. Within each treatment diet, cortisone metabolite levels and growth rates were negatively correlated. These findings suggest that the diet should be considered when using this technique for comparative purposes and highlight the trade-off between stress levels and chicks growth rates. Copyright © 2015 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Jun; Wanibuchi, Hideki; Waalkes, Michael P.

Epidemiological studies indicated that human arsenic exposure can induce urinary bladder cancer. Methylation of inorganic arsenic can generate more reactive and toxic organic arsenical species. In this regard, it was recently reported that the methylated arsenical metabolite, dimethylarsinic acid [DMA(V)], induced urinary bladder tumors in rats. However, other methylated metabolites, like monomethylarsonic acid [MMA(V)] and trimethylarsine oxide (TMAO) were not carcinogenic to the urinary bladder. In order to compare the early effects of DMA(V), MMA(V), and TMAO on the urinary bladder transitional cell epithelium at the scanning electron microscope (SEM) level, we investigated the sub-chronic (13 weeks) toxicological effects ofmore » MMA(V) (187 ppm), DMA(V) (184 ppm), TMAO (182 ppm) given in the drinking water to male and female F344 rats with a focus on the urinary bladder in this study. Obvious pathological changes, including ropy microridges, pitting, increased separation of epithelial cells, exfoliation, and necrosis, were found in the urinary bladders of both sexes, but particularly in females receiving carcinogenic doses of DMA(V). Urine arsenical metabolic differences were found between males and females, with levels of MMA(III), a potential genotoxic form, higher in females treated with DMA(V) than in males. Thus, this study provides clear evidence that DMA(V) is more toxic to the female urinary bladder, in accord with sensitivity to carcinogenesis. Important gender-related metabolic differences including enhanced presentation of MMA(III) to the urothelial cells might possibly account for heightened sensitivity in females. However, the potential carcinogenic effects of MMA(III) need to be further elucidated.« less

Intra- and inter-individual variations of blood and urinary water-soluble vitamins in Japanese young adults consuming a semi-purified diet for 7 days.

PubMed

Shibata, Katsumi; Fukuwatari, Tsutomu; Watanabe, Toshiaki; Nishimuta, Mamoru

2009-12-01

We have previously reported the levels of water-soluble vitamins in the blood and urine of Japanese young adults. In the present paper, to assess the variations in these water-soluble vitamin markers during the above experiment, we comprehensively determined the intra- and inter-individual variations of blood and urinary water-soluble vitamins to exactly the same amount of water-soluble vitamin intakes in the same experiment. The blood samples before breakfast and the 24-h urine samples were periodically collected from Japanese college male (n=10) and female (n=10) students consuming a semi-purified diet with water-soluble vitamins based on Japanese Dietary Reference Intakes for 7 d, and the intra- and inter-individual variations of blood and urinary water-soluble vitamins or their metabolites in blood and urine samples after adaptation were calculated. Although urinary excretion of vitamin B(12) and vitamin C showed high intra-individual variations in both males and females, other urinary vitamins and all blood vitamins showed less than 20% of within-subject coefficients of variance in either male or female. Those showing more than 20% of between-subject coefficients of variances in both male and female were blood vitamin B(6), vitamin B(12) and folate levels, and urinary vitamin B(1), vitamin B(2), vitamin B(12), nicotinamide metabolites, pantothenic acid, biotin and vitamin C. These results showed that oral administration of constant of water-soluble vitamins generally decreased intra-individual variation, while individual differences in urinary vitamin excretion were observed.

Urinary concentrations of acrylamide (AA) and N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and associations with demographic factors in the South Korean population.

PubMed

Lee, Jin Heon; Lee, Kee Jae; Ahn, Ryoungme; Kang, Hee Sook

2014-09-01

Acrylamide (AA) and N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) are important urinary biomarkers of acrylamide exposure in human biomonitoring, because AA is classified as a probable carcinogen in humans. In this study, urinary AA and AAMA were assessed in the South Korean adult population aged 18-69, based on the Korean National Human Biomonitoring Survey conducted in 2009. Urinary metabolites in samples were analyzed with LC-MS/MS system. Relying on data from 1873 representative South Korean adults, the population-weighted geometric means of urinary AA and AAMA concentrations were 6.8 ng/ml (95% CI: 6.4-7.3), and 30.0 ng/ml (95% confidence interval (CI): 28.2-31.8), respectively. The creatinine-adjusted geometric means of AA and AAMA were 6.2 μg/g creatinine (95% CI: 5.8-6.7) and 26.4μg/g creatinine (95% CI: 24.9-28.0), respectively. When covariates for predictors of urinary metabolites were adjusted simultaneously in a log-linear multiple regressions, the strongest predictors of urinary AA were education (OR=1.08-1.28; 95% CI: 1.11-1.48; p=0.0024) and age (OR=0.66-0.84; 95% CI: 0.54-0.97; p=0.0003), and those of urinary AAMA were smoking status (OR=1.16-2.63; 95% CI: 0.98-3.08; p=0.001) and education (OR=1.12-1.19; 95% CI: 1.02-1.38; p=0.0425). The ratio of current/never smokers for urinary AA was 1.3, whereas the same ratio for urinary AAMA was 3.0. These findings suggested that most South Koreans had detectable levels of AA and AAMA (98.7% and 99.4%, respectively) in their urine and that the body burden of AA and AAMA varied according to demographic, geographic, and lifestyle (smoking) factors. Copyright © 2014 Elsevier GmbH. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Webb-Robertson, Bobbie-Jo; Kim, Young -Mo; Zink, Erika M.

Urease pre-treatment of urine has been utilized since the early 1960s to remove high levels of urea from samples prior to further processing and analysis by gas chromatography-mass spectrometry (GC-MS). Aside from the obvious depletion or elimination of urea, the effect, if any, of urease pre-treatment on the urinary metabolome has not been studied in detail. Here, we report the results of three separate but related experiments that were designed to assess possible indirect effects of urease pre-treatment on the urinary metabolome as measured by GC-MS. In total, 235 GC-MS analyses were performed and over 106 identified and 200 unidentifiedmore » metabolites were quantified across the three experiments. The results showed that data from urease pre-treated samples 1) had the same or lower coefficients of variance among reproducibly detected metabolites, 2) more accurately reflected quantitative differences and the expected ratios among different urine volumes, and 3) increased the number of metabolite identifications. Altogether, we observed no negative consequences of urease pre-treatment. In contrast, urease pretreatment enhanced the ability to distinguish between volume-based and biological sample types compared to no treatment. Taken together, these results show that urease pretreatment of urine offers multiple beneficial effects that outweigh any artifacts that may be introduced to the data in urinary metabolomics analyses.« less

Formation and disposition of the minor metabolites of acetaminophen in the hamster.

PubMed

Gemborys, M W; Mudge, G H

1981-01-01

The urinary metabolites of acetaminophen and N-hydroxyacetaminophen were studied in the hamster over a wide dose range and with pretreatments designed to modify drug metabolism. Attention was focused on the origin and disposition of the minor metabolites. The sum of the 3-thio adducts, rather than just the 3-mercapturic adduct, is considered the better index of the formation of the reactive immediate precursor, presumably N-acetyl-p-benzoquinoneimine. At low dosage this amounts to 33% of the administered dose in this species. There is a major contribution from the 3-methylthio adduct, the magnitude of which has not been previously recognized. The 3-methylthio and the 3-methylsulfoxide derivates of acetaminophen are secondarily derived from the 3-glutathione adduct within the enterohepatic circulation, as indicated by their late appearance in the urine, the effect of common bile duct ligation and the metabolism of the minor metabolites when they themselves are administered. Following the administration of N-hydroxyacetaminophen this was excreted in the urine along with its phenolic conjugates, but no urinary N-hydroxyacetaminophen was detectable after the administration of acetaminophen itself. Of particular interest to the pathogenesis of analgesic nephropathy was the detection in the urine of small amounts of p-aminophenol, a known nephrotoxic agent, following dosage with acetaminophen. This metabolite has not been previously detected.

Individual variability in the human metabolism of an arsenic-containing carbohydrate, 2',3'-dihydroxypropyl 5-deoxy-5-dimethylarsinoyl-beta-D-riboside, a naturally occurring arsenical in seafood.

PubMed

Raml, Reingard; Raber, Georg; Rumpler, Alice; Bauernhofer, Thomas; Goessler, Walter; Francesconi, Kevin A

2009-09-01

We report studies on the variability in human metabolism of an oxo-arsenosugar involving the ingestion of a chemically synthesized arsenosugar and quantitative determination of the arsenic metabolites in urine and serum by HPLC coupled with arsenic-selective mass spectrometric detection (ICPMS, inductively coupled plasma mass spectrometry). The total, four-day, urinary excretion of arsenic for six volunteers ranged widely from ca. 4-95%. The arsenic metabolites present in the urine also showed great variability: high arsenic excretion was accompanied by almost complete biotransformation of the ingested oxo-arsenosugar into a multitude of metabolites (>10), whereas the subjects that excreted low amounts of arsenic produced low quantities of metabolites relative to unchanged oxo-arsenosugar and its thio-analogue. Major arsenic urinary metabolites were dimethylarsinate (DMA) and possible intermediates in the degradation of arsenosugar to DMA, namely, dimethylarsinoylethanol (DMAE) and dimethylarsinoylacetate (DMAA) present both as their oxo- and thio-analogues. Thio-DMAE and thio-DMAA were also found in blood serum indicating that these species were formed in the liver rather than on storage of the urine in the bladder. The large variability in the way individuals metabolize arsenosugars has implications for risk assessment of arsenic intake from seafood.

A STUDY OF THE INTERCONVERSION OF METHYLATED ARSENIC OXIDES TO METHYLATED ARSENIC SULFIDES IN SOLUTIONS CONTAINING FREE SULFIDE

EPA Science Inventory

Evidence suggests that thiolated arsenicals are urinary metabolites in both humans and rats. These thiolated species may be formed in the digestive system or as metabolites within the body. The role they may play in the overall toxicity of arsenic is an active area of research....

URINARY AND AMNIOTIC FLUID LEVELS OF PHTHALATE MONOESTERS IN RATS AFTER THE ORAL ADMINISTRATION OF DI(2-ETHYLHEXYL) PHTHALATE AND DI-N-BUTYL PHTHALATE

EPA Science Inventory

Two studies were designed to examine amniotic fluid and maternal urine concentrations of the di(2-ethylhexyl) phthalate (DEHP) metabolite mono(2-ethylhexyl) phthalate (MEHP) and the di-n-butyl phthalate (DBP) metabolite monobutyl phthalate (MBP) after administration of DEHP and D...

Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness.

PubMed

Leaf, David E; Jacob, Kirolos A; Srivastava, Anand; Chen, Margaret E; Christov, Marta; Jüppner, Harald; Sabbisetti, Venkata S; Martin, Aline; Wolf, Myles; Waikar, Sushrut S

2017-06-01

Elevated plasma levels of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful biomarker of cardiovascular disease and death in patients with CKD. Whether elevated urinary or plasma FGF23 levels are prospectively associated with AKI and death in critically ill patients is unknown. We therefore conducted a prospective cohort study of 350 critically ill patients admitted to intensive care units at an academic medical center to investigate whether higher urinary FGF23 levels associate with the composite end point of AKI or in-hospital mortality (AKI/death). We measured urinary FGF23 levels within 24 hours of admission to the intensive care unit. In a subcohort ( n =131) we also measured plasma levels of FGF23, calcium, phosphate, parathyroid hormone, and vitamin D metabolites. Urinary and plasma FGF23 levels, but not other mineral metabolites, significantly associated with AKI/death. In multivariate analyses, patients in the highest compared with the lowest quartile of urinary FGF23 had a 3.9 greater odds (95% confidence interval, 1.6 to 9.5) of AKI/death. Higher urinary FGF23 levels also independently associated with greater hospital, 90-day, and 1-year mortality; longer length of stay; and several other important adverse outcomes. In conclusion, elevated FGF23 levels measured in the urine or plasma may be a promising novel biomarker of AKI, death, and other adverse outcomes in critically ill patients. Copyright © 2017 by the American Society of Nephrology.

Human metabolism and excretion kinetics of aniline after a single oral dose.

PubMed

Modick, Hendrik; Weiss, Tobias; Dierkes, Georg; Koslitz, Stephan; Käfferlein, Heiko Udo; Brüning, Thomas; Koch, Holger Martin

2016-06-01

Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half-times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen.

Effects of anesthesia and blood sampling techniques on plasma metabolites and corticosterone in the rat.

PubMed

Arnold, Myrtha; Langhans, Wolfgang

2010-04-19

Blood is routinely sampled from laboratory animals in biomedical research, and many of the commonly applied sampling techniques require anesthesia. Acute effects of many sampling and anesthesia procedures may confound the results, but those effects are incompletely characterized. We here compare the effects of four common anesthesia procedures (inhalation anesthesia with ether (EA) or isoflurane (IA) and intraperitoneal injection anesthesia with xylazin/ketamine (XKA) or medetomidine/midazolam/fentanyl (MMFA)) on plasma concentrations of glucose, lactate, non-esterified fatty acids (NEFAs), and corticosterone in blood obtained from a previously implanted jugular vein (JV) catheter with the effect of JV blood sampling from non-anesthetized, freely-moving rats (JV-NA). Also, we included in the comparison two other blood sampling procedures usually performed without anesthesia (NA), i.e., puncture of the saphenic vein (SV) and tail incision (TI). Whereas the control procedure (JV-NA) did not significantly affect any of the target parameters, plasma glucose increased from 14 (JV-IA) to 44 (JV-MMFA) % (all Ps=0.05 when compared with the control procedure) in all blood samples collected in anesthesia and was 12 and 14% lower (both Ps<0.05) in SV-NA and TI-NA samples, respectively. Plasma lactate increased from 74 (JV-IA) to 226% (SV-NA) (all Ps<0.05) with all sampling and anesthesia procedures except for JV-XKA and JV-MMF. Plasma NEFAs increased to 52% (P<0.05) with the TI-NA procedure and appeared to decrease with the JV-IA and JV-MMFA procedures (both Ps>0.05). Finally, only the JV-EA and the JV-MMFA procedures increased plasma corticosterone (+525 and +353%, respectively, both Ps< 0.05). The JV-IA and JV-XKA procedures appeared to increase it as well, but these differences did not reach statistical significance. Thus, anesthesia and blood sampling procedures can have profound acute effects on plasma metabolite and hormone concentrations. This must be considered for the design and interpretation of blood sampling experiments in laboratory animals. (c) 2010. Published by Elsevier Inc.

Total dietary fat and omega-3 fatty acids have modest effects on urinary sex hormones in postmenopausal women

USDA-ARS?s Scientific Manuscript database

Total fat and omega-3 fatty acids in the diet may affect breast cancer risk by altering estrogen metabolism. The purpose of this study was to elucidate the effects of differing total fat and omega-3 fatty acid content of diets on a panel of urinary estrogens and metabolites. A controlled, cross-ove...

DEVELOPMENT OF URINARY METABOLITE BIOMARKERS TO ASSESS POPULATION EXPOSURE TO PM2.5 FROM VARIOUS COMBUSTION SOURCES

EPA Science Inventory

A primary goal of our research is to validate the use of urinary biomarkers to apportion the sources of human exposure to PM2.5. Organic source tracers have been used in source apportionment studies of ambient PM2.5 to distinguish a range of combustion sources. Both gas and par...

Determination of urinary 2,5-hexanedione concentration by an improved analytical method as an index of exposure to n-hexane.

PubMed Central

Saito, I; Shibata, E; Huang, J; Hisanaga, N; Ono, Y; Takeuchi, Y

1991-01-01

2,5-Hexanedione is a main metabolite of n-hexane and is considered as the cause of n-hexane polyneuropathy. Therefore, it is useful to measure 2,5-hexanedione for biological monitoring of exposure to n-hexane. The analytical methods existing for n-hexane metabolites, however, were controversial and not established enough. Hence, a simple and precise method for determination of urinary 2,5-hexanedione has been developed. Five ml of urine was acidified to pH 0.5 with concentrated hydrochloric acid and heated for 30 minutes at 90-100 degrees C. After cooling in water, sodium chloride and dichloromethane containing internal standard were added. The sample was shaken and centrifuged. 2,5-Hexanedione concentration in an aliquot of dichloromethane extract was quantified by gas chromatography using a widebore column (DB-1701). Urinary concentration of 2,5-hexanedione showed a good correlation with exposure to n-hexane (n = 50, r = 0.973, p less than 0.001). This method is simple and precise for analysis of urinary 2,5-hexanedione as an index of exposure to n-hexane. PMID:1878315

Mutagenic activity and metabolites in the urine of workers exposed to trinitrotoluene (TNT).

PubMed Central

Ahlborg, G; Einistö, P; Sorsa, M

1988-01-01

Urine samples taken after work and after a free weekend from 50 workers employed in various activities in a chemical plant manufacturing explosives were analysed. On the basis of hygienic surveys, the subjects were divided into three categories of exposure to trinitrotoluene (TNT). The urine analyses consisted of gas chromatographic identification of TNT and its two metabolites, 4-ADNT and 2-ADNT, and a determination of the mutagenic activity. Two frame shift detector strains of Salmonella typhimurium were used, TA 98 and TA 98 NR, the latter being deficient in endogenous nitroreductase activity. On the basis of previous results on TNT mutagenicity, no exogeneous metabolic system was used to test the urine concentrates. Both tester strains showed that the mean urinary mutagenic activity was higher in the after work samples than in post weekend samples from the same subjects, showing that bacterial nitroreductase activity was not significantly responsible for the mutagenicity, although the response was higher with strain TA 98 than with TA 98 NR. The interindividual variation in urine mutagenicity was high, however, and the difference between the two sampling times was statistically significant (p less than 0.05) only for the high exposed group (workers in trotyl foundry and sieve house). Correlation between urinary mutagenicity and concentration of TNT in urine was poor; correlation was significant only with the urinary concentration of 4-ADNT. The correlation between urinary TNT and both metabolites was good (p less than 0.001). These results suggest that analysis of 4-ADNT in urine would be a sufficient biological measure for controlling exposure to TNT. PMID:3378017

Simulation of urinary excretion of 1-hydroxypyrene in various scenarios of exposure to polycyclic aromatic hydrocarbons with a generic, cross-chemical predictive PBTK-model.

PubMed

Jongeneelen, Frans; ten Berge, Wil

2012-08-01

A physiologically based toxicokinetic (PBTK) model can predict blood and urine concentrations, given a certain exposure scenario of inhalation, dermal and/or oral exposure. The recently developed PBTK-model IndusChemFate is a unified model that mimics the uptake, distribution, metabolism and elimination of a chemical in a reference human of 70 kg. Prediction of the uptake by inhalation is governed by pulmonary exchange to blood. Oral uptake is simulated as a bolus dose that is taken up at a first-order rate. Dermal uptake is estimated by the use of a novel dermal physiologically based module that considers dermal deposition rate and duration of deposition. Moreover, evaporation during skin contact is fully accounted for and related to the volatility of the substance. Partitioning of the chemical and metabolite(s) over blood and tissues is estimated by a Quantitative Structure-Property Relationship (QSPR) algorithm. The aim of this study was to test the generic PBTK-model by comparing measured urinary levels of 1-hydroxypyrene in various inhalation and dermal exposure scenarios with the result of model simulations. In the last three decades, numerous biomonitoring studies of PAH-exposed humans were published that used the bioindicator 1-hydroxypyrene (1-OH-pyrene) in urine. Longitudinal studies that encompass both dosimetry and biomonitoring with repeated sampling in time were selected to test the accuracy of the PBTK-model by comparing the reported concentrations of 1-OHP in urine with the model-predicted values. Two controlled human volunteer studies and three field studies of workers exposed to polycyclic aromatic hydrocarbons (PAH) were included. The urinary pyrene-metabolite levels of a controlled human inhalation study, a transdermal uptake study of bitumen fume, efficacy of respirator use in electrode paste workers, cokery workers in shale oil industry and a longitudinal study of five coke liquefaction workers were compared to the PBTK-predicted values. The simulations showed that the model-predicted concentrations of urinary pyrene and metabolites over time, as well as peak-concentrations and total excreted amount in different exposure scenarios of inhalation and transdermal exposure were in all comparisons within an order of magnitude. The model predicts that only a very small fraction is excreted in urine as parent pyrene and as free 1-OH-pyrene. The predominant urinary metabolite is 1-OH-pyrene-glucuronide. Enterohepatic circulation of 1-OH-pyrene-glucuronide seems the reason of the delayed release from the body. It appeared that urinary excretion of pyrene and pyrene-metabolites in humans is predictable with the PBTK-model. The model outcomes have a satisfying accuracy for early testing, in so-called 1st tier simulations and in range finding. This newly developed generic PBTK-model IndusChemFate is a tool that can be used to do early explorations of the significance of uptake of pyrene in the human body following industrial or environmental exposure scenarios. And it can be used to optimize the sampling time and urine sampling frequency of a biomonitoring program.

Metabolism of boldenone in man: gas chromatographic/mass spectrometric identification of urinary excreted metabolites and determination of excretion rates.

PubMed

Schänzer, W; Donike, M

1992-01-01

Urinary metabolites of boldenone (androsta-1,4-dien-17 beta-ol-3-one) following oral administration of boldenone (doses from 11 to 80 mg) to man were isolated from urine via XAD-2 adsorption and enzymatic hydrolysis with beta-glucuronidase from Escherichia coli. The isolated metabolites were derivatized with N-methyl-N-trimethylsilyltri- fluoroacetamide/trimethyliodosilane and analysed by gas chromatography/mass spectrometry with electron impact (EI) ionization at 70 eV. Boldenone (I) and four metabolites were identified after hydrolysis of the urine with beta-glucuronidase: 5 beta-androst-1-en-17 beta-ol-3-one (II), 5 beta-androst-1-ene-3 alpha, 17 beta-diol (III), 5 beta-androst-1-en-3 alpha-ol-17-one (IV) and 5 beta-androst-1-en-6 beta-ol-3,17-dione (V). Five further metabolites in low concentration were identified without enzymatic hydrolysis after treatment of the urine with potassium carbonate: 5 beta-androst-1-ene-3,17-dione (VI), 5 alpha-androst-1-ene-3,17-dione (VII), androsta-1,4-diene-3,17-dione (VIII), androsta-1,4-diene-6 beta,17 beta-diol-3-one (IX) and androsta-1,4-dien-6 beta-ol-3,17-dione (X). The identification of the metabolites is based on the gas chromatography retention index, high-performance liquid chromatography retention, EI mass spectrum, chemical reactions of the isolated metabolites, and synthesis of metabolites II, III, IV, VI and VII. The EI mass spectra of the bis-trimethylsilyl derivatives of boldenone and its metabolites display all intense molecular ions, M-15 ions and fragment ions originating from cleavage of the B-ring. The excreted metabolites can be separated in basic extractable labile conjugates and in stable conjugates. More than 95% of metabolites are excreted as stable conjugates.

Nonylphenol Toxicity Evaluation and Discovery of Biomarkers in Rat Urine by a Metabolomics Strategy through HPLC-QTOF-MS.

PubMed

Zhang, Yan-Xin; Yang, Xin; Zou, Pan; Du, Peng-Fei; Wang, Jing; Jin, Fen; Jin, Mao-Jun; She, Yong-Xin

2016-05-14

Nonylphenol (NP) was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) in the urine and plasma of rats treated with 0, 50, and 250 mg/kg/day of NP for four consecutive days. A urinary metabolomic strategy was originally implemented by high performance liquid chromatography time of flight mass spectrometry (HPLC-QTOF-MS) to explore the toxicological effects of NP and determine the overall alterations in the metabolite profiles so as to find potential biomarkers. It is essential to point out that from the observation, the metabolic data were clearly clustered and separated for the three groups. To further identify differentiated metabolites, multivariate analysis, including principal component analysis (PCA), orthogonal partial least-squares discriminant analysis (OPLS-DA), high-resolution MS/MS analysis, as well as searches of Metlin and Massbank databases, were conducted on a series of metabolites between the control and dose groups. Finally, five metabolites, including glycine, glycerophosphocholine, 5-hydroxytryptamine, malonaldehyde (showing an upward trend), and tryptophan (showing a downward trend), were identified as the potential urinary biomarkers of NP-induced toxicity. In order to validate the reliability of these potential biomarkers, an independent validation was performed by using the multiple reaction monitoring (MRM)-based targeted approach. The oxidative stress reflected by urinary 8-oxo-deoxyguanosine (8-oxodG) levels was elevated in individuals highly exposed to NP, supporting the hypothesis that mitochondrial dysfunction was a result of xenoestrogen accumulation. This study reveals a promising approach to find biomarkers to assist researchers in monitoring NP.

Nonylphenol Toxicity Evaluation and Discovery of Biomarkers in Rat Urine by a Metabolomics Strategy through HPLC-QTOF-MS

PubMed Central

Zhang, Yan-Xin; Yang, Xin; Zou, Pan; Du, Peng-Fei; Wang, Jing; Jin, Fen; Jin, Mao-Jun; She, Yong-Xin

2016-01-01

Nonylphenol (NP) was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) in the urine and plasma of rats treated with 0, 50, and 250 mg/kg/day of NP for four consecutive days. A urinary metabolomic strategy was originally implemented by high performance liquid chromatography time of flight mass spectrometry (HPLC-QTOF-MS) to explore the toxicological effects of NP and determine the overall alterations in the metabolite profiles so as to find potential biomarkers. It is essential to point out that from the observation, the metabolic data were clearly clustered and separated for the three groups. To further identify differentiated metabolites, multivariate analysis, including principal component analysis (PCA), orthogonal partial least-squares discriminant analysis (OPLS-DA), high-resolution MS/MS analysis, as well as searches of Metlin and Massbank databases, were conducted on a series of metabolites between the control and dose groups. Finally, five metabolites, including glycine, glycerophosphocholine, 5-hydroxytryptamine, malonaldehyde (showing an upward trend), and tryptophan (showing a downward trend), were identified as the potential urinary biomarkers of NP-induced toxicity. In order to validate the reliability of these potential biomarkers, an independent validation was performed by using the multiple reaction monitoring (MRM)-based targeted approach. The oxidative stress reflected by urinary 8-oxo-deoxyguanosine (8-oxodG) levels was elevated in individuals highly exposed to NP, supporting the hypothesis that mitochondrial dysfunction was a result of xenoestrogen accumulation. This study reveals a promising approach to find biomarkers to assist researchers in monitoring NP. PMID:27187439

In vivo involvement of cytochrome P450 4A family in the oxidative metabolism of the lipid peroxidation product trans-4-hydroxy-2-nonenal, using PPARalpha-deficient mice.

PubMed

Guéraud, F; Alary, J; Costet, P; Debrauwer, L; Dolo, L; Pineau, T; Paris, A

1999-01-01

Trans-4-hydroxy-2-nonenal (HNE) is a potent cytotoxic and genotoxic compound originating from the peroxidation of n-6 polyunsaturated fatty acids. Its metabolism has been previously studied in the rat (Alary et al. 1995. Chem. Res. Toxicol., 8: 35-39). In addition to major urinary mercapturic derivatives, some polar urinary metabolites were isolated and could correspond to hydroxylated compounds. 4-Hydroxynonenoic acid (HNA), resulting from the oxidation of the HNE carbonyl group, is a medium chain fatty acid and its omega-hydroxylation might be hypothesized. Therefore, the involvement of the CYP 4A family isoenzymes in the metabolism of [3H]HNE has been investigated in vivo using inducer treatments (fibrates) in wild-type or in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice. In wild-type mice, but not in PPARalpha (-/-) mice, fibrate treatments resulted in an increase of two urinary metabolites characterized, after HPLC purifications and mass spectrometry analyses, as the omega-hydroxylated metabolite of HNA, i.e., 4,9-dihydroxy-2-nonenoic acid, and its oxidized form, 4-hydroxy-2-nonene-1,9-dicarboxylic acid. The formation of the latter is correlated accurately to laurate hydroxylase activity studied concurrently in microsomes prepared from the liver of these animals. Basal levels of these two metabolites were measured in urine of normal and PPARalpha-deficient mice. These results are in accord with an implication of the P450 4A family in the extended oxidative metabolism of 4-HNE.

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study.

PubMed

Diaz, Sílvia O; Pinto, Joana; Barros, António S; Morais, Elisabete; Duarte, Daniela; Negrão, Fátima; Pita, Cristina; Almeida, Maria do Céu; Carreira, Isabel M; Spraul, Manfred; Gil, Ana M

2016-01-04

This work assesses the urinary metabolite signature of prematurity in newborns by nuclear magnetic resonance (NMR) spectroscopy, while establishing the role of possible confounders and signature specificity, through comparison to other disorders. Gender and delivery mode are shown to impact importantly on newborn urine composition, their analysis pointing out at specific metabolite variations requiring consideration in unmatched subject groups. Premature newborns are, however, characterized by a stronger signature of varying metabolites, suggestive of disturbances in nucleotide metabolism, lung surfactants biosynthesis and renal function, along with enhancement of tricarboxylic acid (TCA) cycle activity, fatty acids oxidation, and oxidative stress. Comparison with other abnormal conditions (respiratory depression episode, large for gestational age, malformations, jaundice and premature rupture of membranes) reveals that such signature seems to be largely specific of preterm newborns, showing that NMR metabolomics can retrieve particular disorder effects, as well as general stress effects. These results provide valuable novel information on the metabolic impact of prematurity, contributing to the better understanding of its effects on the newborn's state of health.

Validation of a LC-MS/MS Method for Quantifying Urinary Nicotine, Six Nicotine Metabolites and the Minor Tobacco Alkaloids—Anatabine and Anabasine—in Smokers' Urine

PubMed Central

McGuffey, James E.; Wei, Binnian; Bernert, John T.; Morrow, John C.; Xia, Baoyun; Wang, Lanqing; Blount, Benjamin C.

2014-01-01

Tobacco use is a major contributor to premature morbidity and mortality. The measurement of nicotine and its metabolites in urine is a valuable tool for evaluating nicotine exposure and for nicotine metabolic profiling—i.e., metabolite ratios. In addition, the minor tobacco alkaloids—anabasine and anatabine—can be useful for monitoring compliance in smoking cessation programs that use nicotine replacement therapy. Because of an increasing demand for the measurement of urinary nicotine metabolites, we developed a rapid, low-cost method that uses isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously quantifying nicotine, six nicotine metabolites, and two minor tobacco alkaloids in smokers' urine. This method enzymatically hydrolyzes conjugated nicotine (primarily glucuronides) and its metabolites. We then use acetone pretreatment to precipitate matrix components (endogenous proteins, salts, phospholipids, and exogenous enzyme) that may interfere with LC-MS/MS analysis. Subsequently, analytes (nicotine, cotinine, hydroxycotinine, norcotinine, nornicotine, cotinine N-oxide, nicotine 1′-N-oxide, anatabine, and anabasine) are chromatographically resolved within a cycle time of 13.5 minutes. The optimized assay produces linear responses across the analyte concentrations typically found in urine collected from daily smokers. Because matrix ion suppression may influence accuracy, we include a discussion of conventions employed in this procedure to minimize matrix interferences. Simplicity, low cost, low maintenance combined with high mean metabolite recovery (76–99%), specificity, accuracy (0–10% bias) and reproducibility (2–9% C.V.) make this method ideal for large high through-put studies. PMID:25013964

Altered metabolism of orally administered loxoprofen in human subjects after an oral administration of loxoprofen for three consecutive days followed by a seven-day washout.

PubMed

Kim, In-Wha; Chung, Suk-Jae; Shim, Chang-Koo

2002-04-01

The effect of pretreatment (i.e., oral administration of loxoprofen for 3 consecutive days followed by a 7-day washout) on the pharmacokinetics and metabolism of the drug was studied in humans. In a control study, a Loxonin tablet (60 mg as loxoprofen anhydrous) was administered orally to 6 healthy male Korean subjects. In a pretreatment study, a Loxonin tablet was administered orally to the subjects once daily for 3 consecutive days. On the 10(th) day, a Loxonin tablet was administered orally to the subjects, and the concentrations of loxoprofen and the trans- and cis-alcohol metabolites in the plasma and urine were measured as a function of time. Using this pretreatment, the area under the curve (AUC) of the trans-alcohol metabolite of loxoprofen in the plasma, but not those of loxoprofen and the cis-alcohol metabolite, was increased (1.5-fold, p < 0.05), leading to increased contribution of the trans-alcohol metabolite to the total urinary recovery of loxoprofen (1.3-fold, p < 0.05). The urinary recovery of total metabolites, which was largely (> 90%) comprised of conjugate metabolites, was also increased as a result of the pretreatment (1.5-fold, p < 0.05). These results indicate that stereoselective reduction to trans-alcohol metabolites as well as the phase II metabolism of loxoprofen may be increased by such a pretreatment in human subjects. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:973-979, 2002

Association of urinary metals levels with type 2 diabetes risk in coke oven workers.

PubMed

Liu, Bing; Feng, Wei; Wang, Jing; Li, Yaru; Han, Xu; Hu, Hua; Guo, Huan; Zhang, Xiaomin; He, Meian

2016-03-01

Studies indicated that occupationally exposed to metals could result in oxidative damage and inflammation and increase cardiovascular diseases risk. However, epidemiological studies about the associations of metals exposure with diabetes risk among coke oven workers were limited. This study aims to investigate the potential associations of 23 metals levels with the risk of diabetes among coke oven workers. The analysis was conducted in a cross-sectional study including 1493 participants. Urinary metals and urinary polycyclic aromatic hydrocarbons (PAHs) metabolites levels were determined by inductively coupled plasma mass spectrometer and gas chromatograph-mass spectrometer respectively. Multivariate logistic regression was used to investigate the associations of urinary metal levels with diabetes risk with adjustment for potential confounding factors including gender, age, BMI, education, smoking, drinking, physical activity, hypertension, hyperlipidemia and urinary PAHs metabolites levels. Compared with the normoglycemia group, the levels of urinary copper, zinc, arsenic, selenium, molybdenum, and cadmium were significantly higher in the diabetes group (all p < 0.05). Participants with the highest tertile of urinary copper and zinc had 2.12 (95%CI: 1.12-4.01) and 5.43 (95%CI: 2.61-11.30) fold risk of diabetes. Similar results were found for hyperglycemia risk. Besides, participants with the highest tertile of manganese, barium, and lead had 1.65(1.22-2.23), 1.60(1.19-2.16) and 1.45(1.05-1.99) fold risk of hyperglycemia when compared with the lowest tertlie. The results indicated that the urinary copper and zinc levels were positively associated with the risk of diabetes and hyperglycemia among coke oven workers. Urinary manganese, barium and lead levels were also associated with increased risk of hyperglycemia independently of other traditional risk factors. These findings need further validation in prospective study with larger sample size. Copyright © 2015 Elsevier Ltd. All rights reserved.

Association of plasma IL-6 and Hsp70 with HRV at different levels of PAHs metabolites.

PubMed

Ye, Jian; Zhu, Rui; He, Xiaosheng; Feng, Yingying; Yang, Liangle; Zhu, Xiaoyan; Deng, Qifei; Wu, Tangchun; Zhang, Xiaomin

2014-01-01

Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with reduced heart rate variability (HRV), a strong predictor of cardiovascular diseases, but the mechanism is not well understood. We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function. HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6) and heat shock protein 70 (Hsp70) were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs) were measured by gas chromatography-mass spectrometry. We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all Ptrend<0.05); and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP) and low frequency (LF) (Ptrend = 0.014 and 0.006, respectively). In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all Ptrend<0.05), but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN), TP and LF in the low-PAHs metabolites groups (all Ptrend<0.05). We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV. In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups.

Association of Plasma IL-6 and Hsp70 with HRV at Different Levels of PAHs Metabolites

PubMed Central

He, Xiaosheng; Feng, Yingying; Yang, Liangle; Zhu, Xiaoyan; Deng, Qifei; Wu, Tangchun; Zhang, Xiaomin

2014-01-01

Background Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with reduced heart rate variability (HRV), a strong predictor of cardiovascular diseases, but the mechanism is not well understood. Objectives We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function. Methods HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6) and heat shock protein 70 (Hsp70) were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs) were measured by gas chromatography-mass spectrometry. Results We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all P trend<0.05); and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP) and low frequency (LF) (P trend = 0.014 and 0.006, respectively). In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all P trend<0.05), but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN), TP and LF in the low-PAHs metabolites groups (all P trend<0.05). We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV. Conclusions In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups. PMID:24722336

Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.

PubMed

Li, Yong; Sekula, Peggy; Wuttke, Matthias; Wahrheit, Judith; Hausknecht, Birgit; Schultheiss, Ulla T; Gronwald, Wolfram; Schlosser, Pascal; Tucci, Sara; Ekici, Arif B; Spiekerkoetter, Ute; Kronenberg, Florian; Eckardt, Kai-Uwe; Oefner, Peter J; Köttgen, Anna

2018-05-01

Background The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions. Methods We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD. Results After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines ( AOC1 , P -min=2.4×10 -12 ), a relatively high carrier frequency (2%) for rare deleterious missense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines ( P -burden=6.6×10 -16 ), and associations of a common variant in SLC7A9 with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio ( P =2.2×10 -23 ). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with SLC7A9 functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells. Conclusions Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology. Copyright © 2018 by the American Society of Nephrology.

Environmental exposure to human carcinogens in teenagers and the association with DNA damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Franken, Carmen, E-mail: carmen.franken@vito.be

Background: We investigated whether human environmental exposure to chemicals that are labeled as (potential) carcinogens leads to increased (oxidative) damage to DNA in adolescents. Material and methods: Six hundred 14–15-year-old youngsters were recruited all over Flanders (Belgium) and in two areas with important industrial activities. DNA damage was assessed by alkaline and formamidopyrimidine DNA glycosylase (Fpg) modified comet assays in peripheral blood cells and analysis of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Personal exposure to potentially carcinogenic compounds was measured in urine, namely: chromium, cadmium, nickel, 1-hydroxypyrene as a proxy for exposure to other carcinogenic polycyclic aromatic hydrocarbons (PAHs), t,t-muconic acid asmore » a metabolite of benzene, 2,5-dichlorophenol (2,5-DCP), organophosphate pesticide metabolites, and di(2-ethylhexyl) phthalate (DEHP) metabolites. In blood, arsenic, polychlorinated biphenyl (PCB) congeners 118 and 156, hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and perfluorooctanoic acid (PFOA) were analyzed. Levels of methylmercury (MeHg) were measured in hair. Multiple linear regression models were used to establish exposure-response relationships. Results: Biomarkers of exposure to PAHs and urinary chromium were associated with higher levels of both 8-OHdG in urine and DNA damage detected by the alkaline comet assay. Concentrations of 8-OHdG in urine increased in relation with increasing concentrations of urinary t,t-muconic acid, cadmium, nickel, 2,5-DCP, and DEHP metabolites. Increased concentrations of PFOA in blood were associated with higher levels of DNA damage measured by the alkaline comet assay, whereas DDT was associated in the same direction with the Fpg-modified comet assay. Inverse associations were observed between blood arsenic, hair MeHg, PCB 156 and HCB, and urinary 8-OHdG. The latter exposure biomarkers were also associated with higher fish intake. Urinary nickel and t,t-muconic acid were inversely associated with the alkaline comet assay. Conclusion: This cross-sectional study found associations between current environmental exposure to (potential) human carcinogens in 14–15-year-old Flemish adolescents and short-term (oxidative) damage to DNA. Prospective follow-up will be required to investigate whether long-term effects may occur due to complex environmental exposures. - Highlights: • Exposure to (potential) carcinogens is associated with (oxidative) damage to DNA. • Most associations of exposures are with urinary 8-OHdG. • 1-Hydroxypyrene and chromium are associated with the comet assay and 8-OHdG. • PFOA is associated with higher levels of DNA damage in the alkaline comet assay.« less

Urinary metabolites of histamine and leukotrienes before and after placebo-controlled challenge with ASA and food additives in chronic urticaria patients.

PubMed

Di Lorenzo, G; Pacor, M L; Vignola, A M; Profita, M; Esposito-Pellitteri, M; Biasi, D; Corrocher, R; Caruso, C

2002-12-01

The recovery of mediator metabolites from urine has the potential to provide a rapid, safe, and easily available index of release of mediators. We aimed to determine urinary metabolites of both histamine and leukotrienes (LTs) in patients affected by chronic urticaria (CU). Twenty patients with CU were studied. They were selected on the basis of double-blind placebo-controlled challenge (DBPC) with acetyl salicylic acid (ASA) and food additives. Ten patients (group B) were negative to both challenges. Ten patients (group C) presented urticaria and/or the appearance of angioedema during or 24 h after challenge, with reactions to ASA (five patients) or food additives (five patients). We recruited 15 healthy volunteers as controls (group A). During a second challenge, groups B and C were challenged double-blind with a single dose of ASA, or a specific food additive, or placebo. The healthy group was challenged only with a placebo (talc capsule). Patients in groups B and C were challenged twice: with placebo (as groups B1 and C1) and with ASA (groups B2 and C2) or food additives (C2). Four samples of urine were collected; one during the night before the specific or sham challenge (baseline), and three at 2, 6 and 24 h after the challenge. Urinary methylhistamine (N-MH) and LTE4 were analyzed and normalized for urinary creatinine. For urinary N-MH at baseline, there was a significant difference only between group A and groups B1, B2, C1 and C2 (A vs. B1, P < 0.0001; A vs. B2, P < 0.0001; A vs. C1, P < 0.0001; A vs. C2, P < 0.0001). We detected a significant variation in urinary methylhistamine excretion only in group C2 after 2 h, 6 h and 24 h (P < 0.0001). However, no variations were observed in N-MH excretion rate in the other groups (A, B1, C1) after challenge with placebo, and in B2 after challenge with ASA 20 mg. For urinary LTE4 at baseline no differences were found between the mean values for the different groups. After specific challenge, only C2 patients showed significantly increased excretion rates of urinary LTE4 compared with the other groups challenged with placebo (A, B1, C1), or ASA (B2) (P < 0.0001). No significant correlation was seen between urinary LTE4 and methylhistamine excretion rate in any patients. Our results show that urinary excretion of N-MH and LTE4 is different for CU patients without ASA or food hypersensitivity, compared to those with CU with ASA or food additive hypersensitivity after specific challenge.

Assessment of carprofen and buprenorphine on recovery of mice after surgical removal of the mammary fat pad.

PubMed

Adamson, Trinka W; Kendall, Lon V; Goss, Sherri; Grayson, Kevin; Touma, Chadi; Palme, Rupert; Chen, Jane Q; Borowsky, Alexander D

2010-09-01

The purpose of this study was to determine the level of pain elicited by mammary fat pad removal surgery and the effects of postoperative analgesics on recovery. Female FVB mice were anesthetized, and mammary fat pad removal was performed. After surgery, mice received carprofen, buprenorphine, a combination of carprofen and buprenorphine, or saline treatment. Additional mice received anesthesia but no surgery or treatment. Food and water intake, body weight, wheel running activity, and a visual assessment score were recorded daily for 4 d after surgery and compared with presurgical findings. Corticosterone metabolites in fecal samples were analyzed at 12 and 24 h postsurgically and compared with baseline values. All surgical groups had significantly decreased food intake at 24 h, with a return to baseline by 48 h. The combination treatment resulted in a significantly decreased water intake and body weight at 24 h. All surgical groups had significantly decreased wheel running activity at 24 h only. The visual assessment scores indicated mild pain for all surgical groups, with the buprenorphine treated mice showing the highest pain index scores, as compared with nonsurgical controls. Fecal corticosterone metabolite levels did not differ significantly between any of the groups or across time. The parameters used in this study did not indicate that administration of these analgesic regimens improved recovery as compared with that of saline-treated mice. Care should be taken when using visual assessment scores to evaluate pain in mice, given that analgesics may have side effects that inadvertently elevate the score.

Assessment of Carprofen and Buprenorphine on Recovery of Mice after Surgical Removal of the Mammary Fat Pad

PubMed Central

Adamson, Trinka W; Kendall, Lon V; Goss, Sherri; Grayson, Kevin; Touma, Chadi; Palme, Rupert; Chen, Jane Q; Borowsky, Alexander D

2010-01-01

The purpose of this study was to determine the level of pain elicited by mammary fat pad removal surgery and the effects of postoperative analgesics on recovery. Female FVB mice were anesthetized, and mammary fat pad removal was performed. After surgery, mice received carprofen, buprenorphine, a combination of carprofen and buprenorphine, or saline treatment. Additional mice received anesthesia but no surgery or treatment. Food and water intake, body weight, wheel running activity, and a visual assessment score were recorded daily for 4 d after surgery and compared with presurgical findings. Corticosterone metabolites in fecal samples were analyzed at 12 and 24 h postsurgically and compared with baseline values. All surgical groups had significantly decreased food intake at 24 h, with a return to baseline by 48 h. The combination treatment resulted in a significantly decreased water intake and body weight at 24 h. All surgical groups had significantly decreased wheel running activity at 24 h only. The visual assessment scores indicated mild pain for all surgical groups, with the buprenorphine treated mice showing the highest pain index scores, as compared with nonsurgical controls. Fecal corticosterone metabolite levels did not differ significantly between any of the groups or across time. The parameters used in this study did not indicate that administration of these analgesic regimens improved recovery as compared with that of saline-treated mice. Care should be taken when using visual assessment scores to evaluate pain in mice, given that analgesics may have side effects that inadvertently elevate the score. PMID:20858363

Valeriana officinalis root extract suppresses physical stress by electric shock and psychological stress by nociceptive stimulation-evoked responses by decreasing the ratio of monoamine neurotransmitters to their metabolites.

PubMed

Jung, Hyo Young; Yoo, Dae Young; Kim, Woosuk; Nam, Sung Min; Kim, Jong Whi; Choi, Jung Hoon; Kwak, Youn-Gil; Yoon, Yeo Sung; Hwang, In Koo

2014-12-11

In this study, we investigate the effects of valerian root extracts (VE) on physical and psychological stress responses by utilizing a communication box. Eight-week-old ICR mice received oral administration of VE (100 mg/kg/0.5 ml) or equal volume of distilled water in every day for 3 weeks prior to being subjected to physical or psychological stress for 3 days, which are induced by communication box developed for physical electric shock and psychological stress by nociceptive stimulation-evoked responses. The stress condition was assessed by forced swimming test and serum corticosterone levels. In addition, norepinephrine (NE), serotonin (5-HT), and their metabolites such as 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and amygdala at 1 h after final stress condition, respectively. Immobility time and corticosterone levels were significantly increased in both the physical and psychological stress groups compared to the control group. The administration of VE significantly reduced these parameters in both the physical and psychological stress groups. In addition, compared to the control group, physical and psychological stress groups showed significantly increased levels of MHPG-SO4 and 5-HIAA in the hippocampus and amygdala, respectively. The administration of VE significantly suppressed the increase of MHPG-SO4 and 5-HIAA in the two stress groups. These results suggest that VE can suppress physical and psychological stress responses by modulating the changes in 5-HT and NE turnover in the hippocampus and amygdala.

Biomarkers of exposure to polycyclic aromatic hydrocarbons (PAHs) and DNA damage: a cross-sectional pilot study among roofers in South Florida

PubMed Central

Lee, David; Dou, Zihong

2012-01-01

Objective The main goal of this pilot study was to assess the technical and logistic feasibility of a future study. The research hypothesis is that occupational exposures to polycyclic aromatic hydrocarbons (PAHs) are associated with increased risk of DNA damage among roofers who work with hot asphalt. Design This is a cross-sectional pilot study. Setting The study included roofers from four different construction sites in Miami-Dade County, Florida. Participants 19 roofers were recruited (six Hispanics and 13 African–Americans, all male), all of whom were eligible (no history of cancer and no history of chronic diseases of kidneys or liver). All participants provided pre-shift samples and 18 provided post-shift samples. Samples of one participant were excluded from the final analyses as they were considered unreliable. Results Levels of urinary PAH metabolites increased during 6 h of work. Linear regression models of post-shift metabolites included their pre-shift levels, post-shift urinary creatinine levels (for models of 1-OHPyr and 9-OHPhe), and skin burn due to contact with hot asphalt (for models of 1-OHPyr and 1-OHNap). Pre-shift levels of urinary 8-OHdG were not associated with any of the variables considered. For post-shift levels of 8-OHdG, however, post-shift 1-OHPyr (95% CI 0.091 to 0.788) and use of protective gloves (95% CI −1.57 to −0.61) during work explained 86.8% of its variation. Overall, highest levels of urinary PAH metabolites and of 8-OHdG were observed among workers who reported having skin burn and who did not use gloves during work. Conclusions Urinary 1-OHPyr is a promising predictor of oxidative DNA damage among roofers. Work-related skin burn and use of protective gloves appear to influence PAH exposure and DNA damage levels in this group, suggesting the importance of dermal absorption. PMID:22815468

Urinary nandrolone metabolite detection after ingestion of a nandrolone precursor.

PubMed

Watson, Phillip; Judkins, Catherine; Houghton, Ed; Russell, Caroline; Maughan, Ronald J

2009-04-01

Quantities of various anabolic/androgenic steroids have been found in dietary supplements without their presence being disclosed on the label. The aim of this study was to quantify the excretion patterns of the diagnostic metabolites, 19-norandrosterone (19-NA), and 19-noretiocholanolone (19-NE) after ingestion of small doses of 19-nor-4-androstene-3,17-dione (19-norandrostenedione). Eleven males and nine females entered the laboratory in the morning after an overnight fast. An initial urine sample was collected, and volunteers then ingested 500 mL of water containing 5 g of creatine monohydrate and 1.0, 2.5, or 5.0 microg of 19-norandrostenedione. The volume of each urine void was measured, and an aliquot was taken. Samples were analyzed for the metabolites 19-NA and 19-NE by GCMS. Baseline urinary 19-NA concentrations were 0.19 +/- 0.14 ng x mL. Ingestion of the supplement resulted in peak mean urinary 19-NA concentrations of 0.68 +/- 0.36, 1.56 +/- 0.86, and 3.89 +/- 3.11 ng.mL in the 1.0-, 2.5-, or 5.0-microg trials, respectively. Under current WADA regulations, ingestion of the 1.0-microg dose produced 0 positive doping tests, 5 subjects (20%) tested positive in the 2.5-microg trial, and 15 subjects (75%) had urinary 19-NA concentrations exceeding 2 ng x mL after ingesting creatine containing 5.0 microg of the steroid. The recovery of the ingested dose was highly variable between individuals, with values ranging from 11% to 84% (mean +/- SD = 47% +/- 18%). Ingestion of trace amounts of 19-norandrostenedione can result in transient elevations of urinary 19-NA and 19-NE concentrations. The addition of as little as 2.5 microg of 19-norandrostenedione to a supplement (0.00005% contamination) appears sufficient to result in a doping violation in some individuals.

Metabolism of 1-Fluro-1,1,2-trichloroethane, 1,2-dichloro-1,1-difluoroethane, and 1,1,1-trifluoro-2-chloroethane

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, H.; Jones, J.P.; Anders, M.W.

1995-03-01

1-Fluoro-1,1,2-trichloroethane (HCFC-131a), 1,2-dichloro-1,1-difluoroethane (HCFC-132b), and 1,1,1-trifluoro-2-chloroethane (HCFC-133a) were chosen as models for comparative metabolism studies on 1,1,1,2-tetrahaloethanes, which are under consideration as replacements for ozone-depleting chlorofluorocarbons (CFCs). Male Fischer 344 rats were given 10 mmol/kg ip HCFC-131a or HCFC-132b or exposed by inhalation to 1% HCFC-133a for 2 h. Urine collected in the first 24 h after exposure was analyzed by {sup 19}F NMR and GC/MS and with a fluoride-selective ion electrode for the formation of fluorine-containing metabolites. Metabolites of HCFC-131a included 2,2-dichloro-2-fluoroethyl glucuronide, 2,2-dichloro-2-fluorethyl sulfate, dichlorofluoroacetic acid, and inorganic fluoride. Metabolites of HCFC-132b were characterized as 2-chloro-2,2-difluoroethyl glucuronide, 2-chloro-2,2-difluoroethylmore » sulfate, chlorodifluoroacetic acid, chlorodifluoroacetaldehyde hydrate, chlorodifluoroacetaldehyde-urea adduct, inorganic fluoride, and a minor, unidentified metabolite. With HCFC-131a and HCFC-132b, glucuronide conjugates of 2,2,2-trihaloethanols were the major urinary metabolites, whereas with HCFC-133a, a trifluroacetaldehyde-urea adduct was the major urinary metabolite. Analysis of metabolite distribution in vivo indicated that aldehydic metabolites increased as fluorine substitution increased in the order HCFC-131a < HCFC-132b < HCFC-133a. With NADPH-fortified rat liver microsomes, HCFC-133a and HCFC-133a and HCFC-132b were biotransformed to trifluoroacetaldehyde and chlorodifluoroacetaldehyde, respectively, whereas HCFC-131a was converted to dichlorofluoroacetic acid. No covalently bound metabolites of HCFC-131a and HCFC-133a metabolites were detected by {sup 19}F NMR spectroscopy. 18 refs., 2 figs., 3 tabs.« less

Stress associated with group living in a long-lived bird.

PubMed

Selva, Nuria; Cortés-Avizanda, Ainara; Lemus, Jesús A; Blanco, Guillermo; Mueller, Thomas; Heinrich, Bernd; Donázar, José A

2011-08-23

Many long-lived avian species adopt life strategies that involve a gregarious way of life at juvenile and sub-adult stages and territoriality during adulthood. However, the potential associated costs of these life styles, such as stress, are poorly understood. We examined the effects of group living, sex and parasite load on the baseline concentration of faecal stress hormone (corticosterone) metabolites in a wild population of common ravens (Corvus corax). Corticosterone concentrations were significantly higher in non-breeding gregarious ravens than in territorial adults. Among territorial birds, males showed higher stress levels than their mates. Parasite burdens did not affect hormone levels. Our results suggest a key role of the social context in the stress profiles of the two population fractions, and that group living may be more energetically demanding than maintaining a territory. These findings have implications for understanding hormonal mechanisms under different life styles and may inspire further research on the link between hormone levels and selective pressures modulating gregarious and territorial strategies in long-lived birds. This journal is © 2011 The Royal Society

Plasma and Urinary Phenolic Profiles after Acute and Repetitive Intake of Wild Blueberry.

PubMed

Feliciano, Rodrigo P; Istas, Geoffrey; Heiss, Christian; Rodriguez-Mateos, Ana

2016-08-25

Recent studies have shown that blueberries may have cardiovascular and cognitive health benefits. In this work, we investigated the profile of plasma and urine (poly)phenol metabolites after acute and daily consumption of wild blueberries for 30 days in 18 healthy men. The inter-individual variability in plasma and urinary polyphenol levels was also investigated. Blood samples were collected at baseline and 2 h post-consumption on day 1 and day 30. Twenty-four-hour urine was also collected on both days. A total of 61 phenolic metabolites were quantified in plasma at baseline, of which 43 increased after acute or chronic consumption of blueberries over one month. Benzoic and catechol derivatives represented more than 80% of the changes in phenolic profile after 2 h consumption on day 1, whereas hippuric and benzoic derivatives were the major compounds that increased at 0 and 2 h on day 30, respectively. The total (poly)phenol urinary excretion remained unchanged after 30 days of wild blueberry intake. The inter-individual variability ranged between 40%-48% in plasma and 47%-54% in urine. Taken together, our results illustrate that blueberry (poly)phenols are absorbed and extensively metabolized by phase II enzymes and by the gut microbiota, leading to a whole array of metabolites that may be responsible for the beneficial effects observed after blueberry consumption.

Hydroxy-fipronil is a new urinary biomarker of exposure to ...

EPA Pesticide Factsheets

Occupational medical surveillance is highly desirable in manufacturing facilities where exposure to chemicals is significant. The insecticide fipronil is generally considered safe for humans but with increasing use, exposure to fipronil is of concern. Identification of urinary metabolites of fipronil may allow development of affordable, cheap and rapid procedures for human exposure evaluation. In this study we developed a fast and easy approach for synthesis of hydroxy-fipronil, a potential urinary metabolite of fipronil. This standard was used to develop a sensitive analytical LC-MS/MS method with a limit of quantification (LOQ) of 0.4 ng/mL. Fipronil sulfone, a known metabolite, and hydroxy-fipronil were quantified in urine samples from rats treated with a fipronil containing diet. Fipronil sulfone concentration centered around 20 ng/mL, while the concentration of hydroxy-fipronil was dose-dependent ranging in 10–10,000 ng/mL and thus being a more sensitive marker of fipronil exposure. A fipronil immunoassay with cross-reactivity to hydroxy-fipronil showed a good correlation in signal intensity with LC-MS data. It was also used to demonstrate the applicability of the method for sample screening in the evaluation of exposure levels. Fipronil is a broad spectrum insecticide from the phenylpyrazole family. It is often used in four major domains: pest control in a wide variety of field crops, urban pest management, veterinary applications (especially in topical

Urinary concentrations of pyrethroid metabolites in the convenience sample of an urban population of Northern Poland.

PubMed

Wielgomas, Bartosz; Nahorski, Wacław; Czarnowski, Wojciech

2013-06-01

Urinary concentrations of pyrethroid metabolites were measured in the first void urine samples collected from 132 healthy people living in the Gdańsk region of Northern Poland in 2010 and 2011. Four metabolites of synthetic pyrethroids: cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acids (cis-, trans-Cl2CA), cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Br2CA) and 3-phenoxybenzoic acid (3-PBA) were simultaneously liquid-liquid extracted, derivatized with hexafluoroisopropanol and analyzed by a gas chromatography ion-trap mass spectrometry. All the analytes were detected and quantified in the samples with various frequency, 3-phenoxybenzoic being the most often (80%) and the others less frequently (7-11%). Distribution of 3-PBA concentrations followed log-normal model, the mean concentration of 3-phenoxybenzoic acid: 0.393 μg/L (0.327 μg/g creatinine) is similar to those of the other general populations in various regions of the world. Neither sex nor age were predictors of urinary 3-PBA. Our findings suggest wide exposure to pyrethroid insecticides in the Polish general population. There is a continuous need to further study the exposure to synthetic pyrethroids among the general population since there is a strong, increasing trend in their usage. Copyright © 2012 Elsevier GmbH. All rights reserved.

Urinary profiling of tryptophan and its related metabolites in patients with metabolic syndrome by liquid chromatography-electrospray ionization/mass spectrometry.

PubMed

Oh, Ji Sun; Seo, Hong Seong; Kim, Kyoung Heon; Pyo, Heesoo; Chung, Bong Chul; Lee, Jeongae

2017-09-01

Tryptophan (Trp) is an essential amino acid that plays an important role in protein synthesis and is a precursor of various substances related to diverse biological functions. An imbalance in Trp metabolites is associated with inflammatory diseases. The accurate and precise measurement of these compounds in biological specimens would provide meaningful information for understanding the biochemical states of various metabolic syndrome-related diseases, such as hyperlipidemia, hypertension, diabetes, and obesity. In this study, we developed a rapid, accurate, and sensitive liquid chromatography-tandem mass spectrometry-based method for the simultaneous targeted analysis of Trp and its related metabolites of the kynurenine (Kyn), serotonin, and tryptamine pathways in urine. The application of the developed method was tested using urine samples after protein precipitation. The detection limits of Trp and its metabolites were in the range of 0.01 to 0.1 μg/mL. The method was successfully validated and applied to urine samples from controls and patients with metabolic syndrome. Our results revealed high concentrations of Kyn, kynurenic acid, xanthurenic acid, and quinolinic acid as well as a high Kyn-to-Trp ratio (KTR) in patients with metabolic syndromes. The levels of urine Kyn and KTR were significantly increased in patients under 60 years old. The profiling of urinary Trp metabolites could be a useful indicator for age-related diseases including metabolic syndrome. ᅟ.

Testing for nandrolone metabolites in urine samples of professional athletes and sedentary subjects by GC/MS/MS analysis.

PubMed

Gambelunghe, Cristiana; Sommavilla, Marco; Rossi, Ruggero

2002-12-01

The concentrations of nandrolone metabolites, 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE) were analysed in urine samples of professional athletes doing intense physical activity and sedentary subjects to verify if there was endogenous production of nandrolone and if there was any link between physical effort and the urinary metabolites of the steroid. We collected 18 urine samples from professional footballers age range 20-30 years, all from the same team, and 18 urine samples from males not doing any physical activity, age range 20-30 years. Neither group used nandrolone. Qualitative and quantitative analyses of urinary nandrolone metabolites were carried out by GC/MS followed by GC/MS/MS to confirm positive samples. This technique has been demonstrated to be an excellent analytical approach for the determination of anabolic steroids at very low detection limits in complex matrices such as urine. In five urine samples from professional footballers traces of 19-NA were detected. No trace of 19-NA was found in the group of sedentary subjects and no trace of 19-NE was found in any urine sample. The absence of nandrolone metabolites in sedentary subjects supports the hypothesis that the presence of 19-NA and 19-NE could be linked to physical effort even though the origin is not yet clear. Copyright 2002 John Wiley & Sons, Ltd.

Urinary metabolites of phosphate flame retardants in workers occupied with e-waste recycling and incineration.

PubMed

Yan, Xiao; Zheng, Xiaobo; Wang, Meihuan; Zheng, Jing; Xu, Rongfa; Zhuang, Xi; Lin, Ying; Ren, Mingzhong

2018-06-01

Urinary metabolites of phosphate flame retardants (PFRs) were determined in workers from an electronic waste (e-waste) recycling site and an incineration plant, in order to assess the PFR exposure risks of workers occupied with e-waste recycling and incineration. Bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP) were the most frequently detected chemicals (82-93%). The median concentrations of BCEP, BDCIPP, and DPHP were 1.77, 0.23, and 0.70 ng/mL, and 1.44, 0.22, and 0.11 ng/mL in samples from the e-waste site and the incineration plant, respectively. Dibutyl phosphate (DBP) was detected in all samples from the incineration plant, with a median level of 0.30 ng/mL. The concentrations of BDCIPP (r = -0.31, p < 0.05) were significantly correlated with the occupational exposure time rather than age in workers from the e-waste site. Negative and significant correlations were also observed between the concentrations of BCEP (r = -0.42, p < 0.05), BDCIPP (r = -0.37, p < 0.05), and DPHP (r = -0.37, p < 0.05) and occupational exposure time rather than age in workers from the incineration plant. No gender differences were observed in levels of PFR metabolites in urine samples (p > 0.05). Concentrations of BDCIPP in female were significantly correlated with occupational exposure time (r = -0.507, p < 0.01). Concentrations of PFR metabolites in male were not significantly correlated with age or occupational exposure time (p > 0.05). Overall, the workers with occupational exposure to PFRs had different profiles of urinary PFR metabolites. The age, occupational exposure time, and gender seemed not to be main factors mediating the exposure to PFRs for workers occupied with e-waste recycling and incineration. Copyright © 2018 Elsevier Ltd. All rights reserved.

Urinary Metabolites of the Dietary Carcinogen PhIP are Predictive of Colon DNA Adducts After a Low Dose Exposure in Humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malfatti, M; Dingley, K; Nowell, S

2006-04-28

Epidemiologic evidence indicates that exposure to heterocyclic amines (HAs) in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of HAs which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of HA bioactivation in humans, the most mass abundant HA, 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers were administered a dietary relevant dose of [{sup 14}C]PhIP 48-72 h prior to surgery to remove colon tumors. Urine was collected for 24 h after dosingmore » for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All ten subjects were phenotyped for CYP1A2, NAT2, and SULT1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N{sup 2}-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N{sup 2}-glucuronide, had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-PhIP-N{sup 2}-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group.« less

Parental contributions to early embryo development: influences of urinary phthalate and phthalate alternatives among couples undergoing IVF treatment.

PubMed

Wu, Haotian; Ashcraft, Lisa; Whitcomb, Brian W; Rahil, Tayyab; Tougias, Ellen; Sites, Cynthia K; Pilsner, J Richard

2017-01-01

Are preconception urinary concentrations of phthalates and phthalate alternatives associated with diminished early stage embryo quality in couples undergoing IVF? Male, but not female, urinary concentrations of select metabolites of phthalates and phthalate alternatives are associated with diminished blastocyst quality. Although phthalates are endocrine disrupting compounds associated with adverse reproductive health, they are in widespread use across the world. Male and female preconception exposures to select phthalates have been previously associated with adverse reproductive outcomes in both the general population and in those undergoing IVF. This prospective cohort included 50 subfertile couples undergoing IVF in western Massachusetts. This study includes the first 50 couples recruited from the Baystate Medical Center's Fertility Center in Springfield, MA, as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Relevant data from both partners, including embryo quality at the cleavage (Day 3) and blastocyst (Day 5) stages, were collected by clinic personnel during the normal course of an IVF cycle. A spot urine sample was collected from both male and female partners on the same day as semen sample procurement and oocyte retrieval. Concentrations of 17 urinary metabolite were quantified by liquid chromatography mass spectrometry and normalized via specific gravity. Generalized estimating equations were used to estimate odds ratios (OR) and 95% CI, with urinary phthalates and phthalate alternatives fitted as continuous variables and embryo quality as a binary variable. The 50 couples contributed 761 oocytes, of which 423 progressed to the cleavage stage, 261 were high-quality cleavage stage embryos, 137 were transferrable quality blastocysts and 47 were high-quality blastocysts. At the cleavage stage, male urinary monoethyl phthalate concentrations were positively associated with high-quality cleavage stage embryos (OR = 1.20, 95% CI 1.01-1.43, P = 0.04); no other significant associations were observed at this stage. At the blastocyst stage, male urinary concentrations of monobenzyl phthalate (OR = 0.55, 95% CI 0.36-0.84, P = 0.01), mono-3-hydroxybutyl phthalate (OR = 0.37, 95% CI 0.18-0.76, P = 0.01), mono-n-butyl phthalate (OR = 0.55, 95% CI 0.42-0.73, P < 0.01) and monomethyl phthalate (OR = 0.39, 95% CI 0.26-0.60, P < 0.01) were inversely associated with high-quality blastocysts. A borderline statistically significant relationship was observed for male concentrations of mono(2-ethylhexyl) phthalate (OR = 0.52, 95% CI 0.27-1.00, P = 0.05) and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (OR = 0.21, 95% CI 0.04-1.03, P = 0.05) at the blastocyst stage. Similar inverse associations were observed between male urinary phthalate metabolite concentrations and likelihood of transferrable quality blastocysts. For female partners, select metabolites were positively associated with odds of high or transferrable blastocyst quality, but the observed associations were not consistent across blastocyst quality measures or between sex-specific and couples-level models. All models were adjusted for age of both partners, urinary metabolite concentrations of female partners and male infertility status, while models of blastocysts were additionally adjusted for embryo quality at cleavage stage. Our modest sample included only 50 couples contributing one cycle each. In addition, non-differential misclassification of exposure remains a concern given the single-spot urine collection and the short half-life of phthalates. Our results suggest an inverse association between male preconception concentrations of select phthalate metabolites and blastocyst quality, likely occurring after genomic activation. If corroborated with other studies, such findings will have public health and clinical significance for both the general population and those undergoing IVF. This work was generously supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests. N/A. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

1H NMR spectroscopy-based metabolomics analysis for the diagnosis of symptomatic E. coli-associated urinary tract infection (UTI).

PubMed

Lussu, Milena; Camboni, Tania; Piras, Cristina; Serra, Corrado; Del Carratore, Francesco; Griffin, Julian; Atzori, Luigi; Manzin, Aldo

2017-09-21

Urinary tract infection (UTI) is one of the most common diagnoses in girls and women, and to a lesser extent in boys and men younger than 50 years. Escherichia coli, followed by Klebsiella spp. and Proteus spp., cause 75-90% of all infections. Infection of the urinary tract is identified by growth of a significant number of a single species in the urine, in the presence of symptoms. Urinary culture is an accurate diagnostic method but takes several hours or days to be carried out. Metabolomics analysis aims to identify biomarkers that are capable of speeding up diagnosis. Urine samples from 51 patients with a prior diagnosis of Escherichia coli-associated UTI, from 21 patients with UTI caused by other pathogens (bacteria and fungi), and from 61 healthy controls were analyzed. The 1 H-NMR spectra were acquired and processed. Multivariate statistical models were applied and their performance was validated using permutation test and ROC curve. Orthogonal Partial Least Squares-discriminant Analysis (OPLS-DA) showed good separation (R 2 Y = 0.76, Q2=0.45, p < 0.001) between UTI caused by Escherichia coli and healthy controls. Acetate and trimethylamine were identified as discriminant metabolites. The concentrations of both metabolites were calculated and used to build the ROC curves. The discriminant metabolites identified were also evaluated in urine samples from patients with other pathogens infections to test their specificity. Acetate and trimethylamine were identified as optimal candidates for biomarkers for UTI diagnosis. The conclusions support the possibility of a fast diagnostic test for Escherichia coli-associated UTI using acetate and trimethylamine concentrations.

Association Between Variants in Arsenic (+3 Oxidation State) Methyltranserase (AS3MT) and Urinary Metabolites of Inorganic Arsenic: Role of Exposure Level

PubMed Central

Xu, Xiaofan; Drobná, Zuzana; Voruganti, V. Saroja; Barron, Keri; González-Horta, Carmen; Sánchez-Ramírez, Blanca; Ballinas-Casarrubias, Lourdes; Cerón, Roberto Hernández; Morales, Damián Viniegra; Terrazas, Francisco A. Baeza; Ishida, María C.; Gutiérrez-Torres, Daniela S.; Saunders, R. Jesse; Crandell, Jamie; Fry, Rebecca C.; Loomis, Dana; García-Vargas, Gonzalo G.; Del Razo, Luz M.; Stýblo, Miroslav; Mendez, Michelle A.

2016-01-01

Abstract Variants in AS3MT, the gene encoding arsenic (+3 oxidation state) methyltranserase, have been shown to influence patterns of inorganic arsenic (iAs) metabolism. Several studies have suggested that capacity to metabolize iAs may vary depending on levels of iAs exposure. However, it is not known whether the influence of variants in AS3MT on iAs metabolism also vary by level of exposure. We investigated, in a population of Mexican adults exposed to drinking water As, whether associations between 7 candidate variants in AS3MT and urinary iAs metabolites were consistent with prior studies, and whether these associations varied depending on the level of exposure. Overall, associations between urinary iAs metabolites and AS3MT variants were consistent with the literature. Referent genotypes, defined as the genotype previously associated with a higher percentage of urinary dimethylated As (DMAs%), were associated with significant increases in the DMAs% and ratio of DMAs to monomethylated As (MAs), and significant reductions in MAs% and iAs%. For 3 variants, associations between genotypes and iAs metabolism were significantly stronger among subjects exposed to water As >50 versus ≤50 ppb (water As X genotype interaction P < .05). In contrast, for 1 variant (rs17881215), associations were significantly stronger at exposures ≤50 ppb. Results suggest that iAs exposure may influence the extent to which several AS3MT variants affect iAs metabolism. The variants most strongly associated with iAs metabolism—and perhaps with susceptibility to iAs-associated disease—may vary in settings with exposure level. PMID:27370415

The Dose–Response Decrease in Heart Rate Variability: Any Association with the Metabolites of Polycyclic Aromatic Hydrocarbons in Coke Oven Workers?

PubMed Central

Deng, Huaxin; Zhang, Wangzhen; Kuang, Dan; Deng, Qifei; Dai, Xiayun; Lin, Dafeng; Huang, Suli; Xin, Lili; He, Yunfeng; Huang, Kun; He, Meian; Guo, Huan; Zhang, Xiaomin; Wu, Tangchun

2012-01-01

Background Air pollution has been associated with an increased risk of cardiopulmonary mortality and decreased heart rate variability (HRV). However, it is unclear whether coke oven emissions (COEs) and polycyclic aromatic hydrocarbons (PAHs) are associated with HRV. Objectives Our goal in the present study was to investigate the association of exposure to COEs and the urinary metabolite profiles of PAHs with HRV of coke oven workers. Methods We measured benzene soluble matter, carbon monoxide, sulfur dioxide, particulate matters, and PAHs at different workplaces of a coke oven plant. We determined 10 urinary PAH metabolites and HRV indices of 1333 workers using gas chromatography–mass spectrometry and a 3-channel digital Holter monitor, respectively. Results Our results showed that there was a significant COEs-related dose-dependent decrease in HRV, and an inverse relationship between the quartiles of urinary 2-hydroxynaphthalene and five HRV indices (p trend<0.01 for all). After adjustment for potential confounders, elevation per interquartile range (IQR) (1.81 µg/mmol creatinine) of urinary 2-hydroxynaphthalene was associated with a 5.46% (95% CI, 2.50–8.32) decrease in standard deviation of NN intervals (SDNN). As workers worked more years, SDNN gradually declined in the same quartiles of 2-hydroxynaphthalene levels (p trend = 1.40×10−4), especially in workers with the highest levels of 2-hydroxynaphthalene. Conclusions Occupational exposure to COEs is associated with a dose-response decrease in HRV. In particular, increased exposure to 2-hydroxynaphthalene is associated with significantly decreased HRV. Increase of working years and exposure levels has resulted in a gradual decline of HRV. PMID:23024753

The dose-response decrease in heart rate variability: any association with the metabolites of polycyclic aromatic hydrocarbons in coke oven workers?

PubMed

Li, Xiaohai; Feng, Yingying; Deng, Huaxin; Zhang, Wangzhen; Kuang, Dan; Deng, Qifei; Dai, Xiayun; Lin, Dafeng; Huang, Suli; Xin, Lili; He, Yunfeng; Huang, Kun; He, Meian; Guo, Huan; Zhang, Xiaomin; Wu, Tangchun

2012-01-01

Air pollution has been associated with an increased risk of cardiopulmonary mortality and decreased heart rate variability (HRV). However, it is unclear whether coke oven emissions (COEs) and polycyclic aromatic hydrocarbons (PAHs) are associated with HRV. Our goal in the present study was to investigate the association of exposure to COEs and the urinary metabolite profiles of PAHs with HRV of coke oven workers. We measured benzene soluble matter, carbon monoxide, sulfur dioxide, particulate matters, and PAHs at different workplaces of a coke oven plant. We determined 10 urinary PAH metabolites and HRV indices of 1333 workers using gas chromatography-mass spectrometry and a 3-channel digital Holter monitor, respectively. Our results showed that there was a significant COEs-related dose-dependent decrease in HRV, and an inverse relationship between the quartiles of urinary 2-hydroxynaphthalene and five HRV indices (p(trend)<0.01 for all). After adjustment for potential confounders, elevation per interquartile range (IQR) (1.81 µg/mmol creatinine) of urinary 2-hydroxynaphthalene was associated with a 5.46% (95% CI, 2.50-8.32) decrease in standard deviation of NN intervals (SDNN). As workers worked more years, SDNN gradually declined in the same quartiles of 2-hydroxynaphthalene levels (p(trend) = 1.40×10(-4)), especially in workers with the highest levels of 2-hydroxynaphthalene. Occupational exposure to COEs is associated with a dose-response decrease in HRV. In particular, increased exposure to 2-hydroxynaphthalene is associated with significantly decreased HRV. Increase of working years and exposure levels has resulted in a gradual decline of HRV.

Relevance of Urinary 3-Hydroxybenzo(a)pyrene and 1-Hydroxypyrene to Assess Exposure to Carcinogenic Polycyclic Aromatic Hydrocarbon Mixtures in Metallurgy Workers

PubMed Central

Barbeau, Damien; Persoons, Renaud; Marques, Marie; Hervé, Claire; Laffitte-Rigaud, Gilbert; Maitre, Anne

2014-01-01

Objectives: In metallurgy, workers are exposed to mixtures of polycyclic aromatic hydrocarbons (PAHs) in which some compounds are carcinogenic. Biomonitoring of PAH exposure has been performed by measuring urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene which is not carcinogenic. This study investigated the use of 3-hydroxybenzo(a)pyrene (3-OHBaP), a metabolite of benzo(a)pyrene (BaP) which is the main carcinogenic component in PAHs, to improve carcinogen exposure assessment. Methods: We included 129 metallurgy workers routinely exposed to PAHs during working hours. Urinary samples were collected at three sampling times at the beginning and at the end of the working week for 1-OHP and 3-OHBaP analyses. Results: Workers in anode production showed greater exposure to both biomarkers than those in cathode or silicon production, with respectively, 71, 40, and 30% of 3-OHBaP concentrations exceeding the value of 0.4 nmol mol−1 creatinine. No difference was observed between the 3-OHBaP levels found at the end of the penultimate workday shift and those at the beginning of the last workday shift. Within these plants, the 1-OHP/3-OHBaP ratios varied greatly according to the workers’ activity and emission sources. Using linear regression between these two metabolites, the 1-OHP level corresponding to the guidance value for 3-OHBaP ranged from 0.7 to 2.4 µmol mol−1 creatinine, depending on the industrial sector. Conclusions: This study emphasizes the interest of monitoring urinary 3-OHBaP at the end of the last workday shift when working week exposure is relatively steady, and the irrelevance of a single guideline value for 1-OHP when assessing occupational health risk. PMID:24504174

Quantitative analysis of urinary glycine conjugates by high performance liquid chromatography: excretion of hippuric acid and methylhippuric acids in the urine of subjects exposed to vapours of toluene and xylenes.

PubMed

Ogata, M; Taguchi, T

1986-01-01

A new method for the direct determination of hippuric acid (HA) and o-, m- and p-methylhippuric acids (MHAs) in the urine, metabolites of toluene and o-, m- and p-xylenes by high performance liquid chromatography (HPLC) is described. A stainless-steel column packed with silica gel having dinitrophenyl residue and a mixed solution of methanol/water/acetic acid (80/20/0.2) containing tetra-n-butylammonium bromide (0.2% w/v) as mobile phase was used. Concentrations of HA and MHAs were estimated from their peak height at a wave length of 225 nm. Urine can be analyzed directly without solvent extraction or pretreatment to obtain complete separation of HA and o-, m- and p-MHAs. Urine samples from male workers exposed to toluene or xylenes were analyzed for HA or MHAs. The urinary levels of HA and MHAs increased by exposure to toluene and xylenes in proportion to the environmental concentrations of the solvents, although there is a considerable variation in metabolite concentrations. The slope of regression line between toluene and HA and that between m-xylene and m-MHA were similar. The urinary concentrations of HA and MHAs corresponding to 100 ppm (TLV) of toluene was 2.35 g/g creatinine and that of m-MHA corresponding to 100 ppm (TLV) of m-xylene was 2.05 g/g creatinine. The warning levels of the urinary metabolite concentrations of a group of workers and that of an individual worker corresponding to TLV of organic solvent concentration is discussed.

Urinary phthalate metabolite concentrations among pregnant women in Northern Puerto Rico: distribution, temporal variability, and predictors.

PubMed

Cantonwine, David E; Cordero, José F; Rivera-González, Luis O; Anzalota Del Toro, Liza V; Ferguson, Kelly K; Mukherjee, Bhramar; Calafat, Antonia M; Crespo, Noe; Jiménez-Vélez, Braulio; Padilla, Ingrid Y; Alshawabkeh, Akram N; Meeker, John D

2014-01-01

Phthalate contamination exists in the North Coast karst aquifer system in Puerto Rico. In light of potential health impacts associated with phthalate exposure, targeted action for elimination of exposure sources may be warranted, especially for sensitive populations such as pregnant women. However, information on exposure to phthalates from a variety of sources in Puerto Rico is lacking. The objective of this study was to determine concentrations and predictors of urinary phthalate biomarkers measured at multiple times during pregnancy among women living in the Northern karst area of Puerto Rico. We recruited 139 pregnant women in Northern Puerto Rico and collected urine samples and questionnaire data at three separate visits (18 ± 2 weeks, 22 ± 2 weeks, and 26 ± 2 weeks of gestation). Urine samples were analyzed for eleven phthalate metabolites: mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate, mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono-benzyl phthalate, mono-isobutyl phthalate, mono-3-carboxypropyl phthalate (MCPP), mono carboxyisononyl phthalate (MCNP), and mono carboxyisooctyl phthalate (MCOP). Detectable concentrations of phthalate metabolites among pregnant women living in Puerto Rico was prevalent, and metabolite concentrations tended to be higher than or similar to those measured in women of reproductive age from the general US population. Intraclass correlation coefficients ranged from very weak (MCNP; 0.05) to moderate (MEP; 0.44) reproducibility among all phthalate metabolites. We observed significant or suggestive positive associations between urinary phthalate metabolite concentrations and water usage/storage habits (MEP, MCNP, MCOP), use of personal care products (MEP), and consumption of certain food items (MCPP, MCNP, and MCOP). To our knowledge this is the first study to report concentrations, temporal variability, and predictors of phthalate biomarkers among pregnant women in Puerto Rico. Preliminary results suggest several potentially important exposure sources to phthalates in this population and future analysis from this ongoing prospective cohort will help to inform targeted approaches to reduce exposure. © 2013.

Stress physiology of migrant birds during stopover in natural and anthropogenic woodland habitats of the Northern Prairie region.

PubMed

Liu, Ming; Swanson, David L

2014-01-01

Anthropogenic alterations of woodland habitat may influence stopover biology, which in turn could alter the stress physiology of migratory landbirds. Woodland stopover habitats are scarce in the Northern Prairie region of North America and consist of native riparian corridor woodlands (corridors) and smaller, more isolated woodlots of anthropogenic origin around farmsteads (woodlots). Corridor habitats have been greatly reduced since the time of European settlement, but woodlot habitats have appeared over this same time period. In this study, we compared stopover biology and stress physiology of migratory landbirds using natural and anthropogenic woodland habitats. We first tested for differences between birds in the two habitats for baseline corticosterone (CORTB) and the magnitude of the stress response for individual species, taxonomic families and foraging guilds. Plasma corticosterone increased significantly for all bird groups in both habitats following 30 min of restraint stress (CORT30), and neither CORTB nor the magnitude of the stress response (CORT30 - CORTB) differed significantly between birds in the two habitats. Secondly, because CORTB levels are often elevated and CORT secretion following a stressor is often suppressed for birds in poor body condition, we hypothesized that woodland migrants with higher fattening rates would show reduced CORTB and a robust stress response. We tested this hypothesis by assessing the relationships between plasma corticosterone and plasma metabolites associated with refuelling. We found that CORTB was negatively associated and the magnitude of the stress response positively associated with plasma triglycerides (an indicator of fat deposition), with opposite patterns for corticosterone and plasma β-hydroxybutyrate (an indicator of fat catabolism). These data suggest that both corridor and woodlot habitats serve as effective stopover habitat and that the reduction of corridor habitat and increased reliance on anthropogenic woodlots is not detrimental to the stress physiology of migrants in a region with limited woodland habitats.

The Effect of Feeding Purified versus Chow Diet on Bone Changes Produced by Hindlimb Suspension of Female Rats

NASA Technical Reports Server (NTRS)

Tou, Janet; Arnaud, Sara B.; Grindeland, Richard; Wade, Charles

2004-01-01

Spaceflight simulation studies use chow diets while spaceflight studies use a semi-purified &et. To determine whether the differences in these diets would affect the changes in unweighted bone, we compared the effects of purified vs chow diet on bone parameters, urinary calcium, plasma estradiol, and urinary corticosterone (CORT) in sexually mature female Sprague-Dawley rats. Rats fed purified AIN-93G or chow diet were kept ambulatory (AMB) or subjected to a spaceflight simulation model of unweighted hindlimbs (HLS) for 38 days. Body mass of treatment groups was similar although food intake and caloric density of the diets differed. Both HLS diet groups showed similar decreases in bone mineral content and mechanical strength in unweighted femurs compared to AMB (p<0.05). However, femur length was lower (p<0.05) in the chow-fed than AIN-93G fed groups. Urinary calcium excretion was greater in chow than AIN-93G fed rats, consistent with the higher level of calcium in the diet. Plasma estradiol was lower in HLS than in AMB fed AIN-93G, but similar in HLS and AMB chow fed groups. Femur mineral content was related to plasma estradiol (r(sup 2) =0.91, p<0.00l). Urinary CORT excretion was increased during initial HLS and elevated in HLS/chow-fed rats. Diets did not appear to affect the osteopenia induced by unweighting, but effects on bone growth, calcium excretion, plasma estradiol and urinary CORT do not support the view that these diets can by used interchangeably in bone studies.

In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms

NASA Astrophysics Data System (ADS)

Hao, Ling; Greer, Tyler; Page, David; Shi, Yatao; Vezina, Chad M.; Macoska, Jill A.; Marker, Paul C.; Bjorling, Dale E.; Bushman, Wade; Ricke, William A.; Li, Lingjun

2016-08-01

Lower urinary tract symptoms (LUTS) are a range of irritative or obstructive symptoms that commonly afflict aging population. The diagnosis is mostly based on patient-reported symptoms, and current medication often fails to completely eliminate these symptoms. There is a pressing need for objective non-invasive approaches to measure symptoms and understand disease mechanisms. We developed an in-depth workflow combining urine metabolomics analysis and machine learning bioinformatics to characterize metabolic alterations and support objective diagnosis of LUTS. Machine learning feature selection and statistical tests were combined to identify candidate biomarkers, which were statistically validated with leave-one-patient-out cross-validation and absolutely quantified by selected reaction monitoring assay. Receiver operating characteristic analysis showed highly-accurate prediction power of candidate biomarkers to stratify patients into disease or non-diseased categories. The key metabolites and pathways may be possibly correlated with smooth muscle tone changes, increased collagen content, and inflammation, which have been identified as potential contributors to urinary dysfunction in humans and rodents. Periurethral tissue staining revealed a significant increase in collagen content and tissue stiffness in men with LUTS. Together, our study provides the first characterization and validation of LUTS urinary metabolites and pathways to support the future development of a urine-based diagnostic test for LUTS.

Differential toxicity of arsenic on renal oxidative damage and urinary metabolic profiles in normal and diabetic mice.

PubMed

Yin, Jinbao; Liu, Su; Yu, Jing; Wu, Bing

2017-07-01

Diabetes is a common metabolic disease, which might influence susceptibility of the kidney to arsenic toxicity. However, relative report is limited. In this study, we compared the influence of inorganic arsenic (iAs) on renal oxidative damage and urinary metabolic profiles of normal and diabetic mice. Results showed that iAs exposure increased renal lipid peroxidation in diabetic mice and oxidative DNA damage in normal mice, meaning different effects of iAs exposure on normal and diabetic individuals. Nuclear magnetic resonance (NMR)-based metabolome analyses found that diabetes significantly changed urinary metabolic profiles of mice. Oxidative stress-related metabolites, such as arginine, glutamine, methionine, and β-hydroxybutyrate, were found to be changed in diabetic mice. The iAs exposure altered amino acid metabolism, lipid metabolism, carbohydrate metabolism, and energy metabolism in normal and diabetic mice, but had higher influence on metabolic profiles of diabetic mice than normal mice, especially for oxidative stress-related metabolites and metabolisms. Above results indicate that diabetes increased susceptibility to iAs exposure. This study provides basic information on differential toxicity of iAs on renal toxicity and urinary metabolic profiles in normal and diabetic mice and suggests that diabetic individuals should be considered as susceptible population in toxicity assessment of arsenic.

Biomonitoring of polycyclic aromatic compounds in the urine of mining workers occupationally exposed to diesel exhaust.

PubMed

Seidel, Albrecht; Dahmann, Dirk; Krekeler, Horst; Jacob, Juergen

2002-02-01

Diesel exhaust is considered a probable human carcinogen by the IARC. Biomonitoring of workers occupationally exposed to diesel exhaust was performed to determine their internal burden of diesel associated aromatic compounds. Personal air sampling also allowed to determine the exposure of the miners at their work place towards several polycyclic aromatic hydrocarbons (PAH) and nitro-arenes, the latter of which are thought to be specific constituents of diesel exhaust. For biomonitoring the urine of 18 underground salt miners was collected during and after their shift for 24-hours. half of the 18 miners were smokers. The urinary levels of 1-hydroxypyrene and hydroxylated phenanthrene metabolites were determined as biomarkers of PAH exposure, whereas urinary levels of some aromatic amines were chosen to monitor exposure towards specific nitro-arenes from diesel exhaust like 1-nitropyrene and 3-nitrobenzanthrone and to monitor the human burden by these compounds from inhaled cigarette smoke. Non-smoking workers exposed to diesel exhaust excrete an average level of about 4 micrograms phenanthrene metabolites, whereas the urinary levels in smokers were up to 3-fold higher. In summary the results indicate that (i) diesel exposure led to an increase of PAH metabolism in the workers examined, most probably by an induction of cytochrome P450 (ii) smokers could be identified in accordance with earlier studies by their increased ratio of phenanthrene metabolites derived from 1,2- and 3,4-oxidation and their higher amounts of excreted 1-naphthylamine, and (iii) the excreted amounts of aromatic amines found as metabolites of the nitro-arenes were about 5- to 10-fold higher as one might expect from the levels determined by personal air sampling at the workplace of the individuals.

Urinary naphthol metabolites and chromosomal aberrations in 5 yr old children

PubMed Central

Orjuela, Manuela A.; Liu, XinHua; Miller, Rachel L.; Warburton, Dorothy; Tang, DeLiang; Jobanputra, Vaidehi; Hoepner, Lori; Suen, Ida Hui; Diaz-Carreno, Silvia; Li, Zheng; Sjodin, Andreas; Perera, Frederica P.

2012-01-01

Background Exposure to naphthalene, an IARC-classified possible carcinogen and polycyclic aromatic hydrocarbon (PAH), is widespread, though resulting health effects are poorly understood. Metabolites of naphthalene, 1- and 2-naphthol, are measurable in urine and are biomarkers of personal exposure. Chromosomal aberrations (CAs), including translocations, are established markers of cancer risk and a bio-dosimeter of clastogenic exposures. Although prenatal (maternal) PAH exposure predicts CAs in cord blood, few studies have examined CAs in school-age children and none has examined their association with metabolites of specific PAHs. Methods Using Whole Chromosome Paint Fluorescent in Situ Hybridization, we documented CAs including translocations, in 113 five year old urban minority children and examined their association with concurrent concentrations of PAH metabolites measured in urine. Results We report that in lymphocytes, the occurrence and frequency of CAs including translocations are associated with levels of urinary 1- and 2-naphthol. When doubling the levels of urinary naphthols, gender-adjusted Odds Ratio (OR) for CAs are 1.63 (95%CI: 1.21, 2.19) and 1.44 (95%CI: 1.02, 2.04) for 1-and 2-naphthol respectively; and for translocations: OR=1.55 (95%CI: 1.11-2.17) and 1.92 (95%CI: 1.20-3.08) for 1- and 2-naphthol respectively. Conclusion Our results demonstrate that markers of exposure to naphthalene in children are associated with translocations in a dose related manner, and that naphthalene may be a clastogen. Impact Indoor exposure to elevated levels of naphthalene is prevalent in large regions of the world. This study is the first to present an association between a marker of naphthalene exposure and a pre-carcinogenic effect in humans. PMID:22573794

A urinary metabolite of phenanthrene as a biomarker of polycyclic aromatic hydrocarbon metabolic activation in workers exposed to residual oil fly ash.

PubMed

Kim, Jee Young; Hecht, Stephen S; Mukherjee, Sutapa; Carmella, Steven G; Rodrigues, Ema G; Christiani, David C

2005-03-01

Residual oil fly ash is a chemically complex combustion product containing a significant component of potentially carcinogenic transition metals and polycyclic aromatic hydrocarbons (PAH). Various biomarkers of PAH exposure have been investigated previously, most notably 1-hydroxypyrene (1-OHP), in urine. In this study, we assessed the utility of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (trans, anti-PheT), a metabolite of phenanthrene, to detect occupational PAH exposure. Urine samples collected across the workweek were analyzed for 1-OHP and trans, anti-PheT in boilermakers (n = 20) exposed to residual oil fly ash. Median baseline urinary trans, anti-PheT concentrations were 0.50 microg/g creatinine in current tobacco smokers and 0.39 microg/g creatinine in nonsmokers. Median baseline urinary 1-OHP concentrations in smokers and nonsmokers were 0.31 and 0.13 microg/g creatinine, respectively. To study further the effect of smoking exposure on the urinary PAH markers, urinary cotinine was used. Although urinary trans, anti-PheT and 1-OHP concentrations were correlated (Spearman r = 0.63; P < 0.001) for all subjects, the regression coefficient between log-transformed trans, anti-PheT and log 1-OHP was statistically significant only for subjects with low levels of urinary cotinine or for nonsmokers. Each 1-unit increase in log 1-OHP was associated with a 0.77-unit increase (95% confidence interval, 0.45-1.09) in log trans, anti-PheT in subjects with low levels of urinary cotinine (P < 0.001). In these subjects, dichotomized occupational exposure status was a significant predictor of log trans, anti-PheT (P = 0.02) but not of log 1-OHP (P = 0.2). In conclusion, we found that urinary trans, anti-PheT was detected in levels comparable with 1-OHP in occupationally exposed workers, particularly nonsmokers. This study shows that urinary trans, anti-PheT may be an effective biomarker of uptake and metabolic activation of PAHs.

Analysis of Multiple Metabolites of Tocopherols and Tocotrienols in Mice and Humans

PubMed Central

Zhao, Yang; Lee, Mao-Jung; Cheung, Connie; Ju, Ji-Hyeung; Chen, Yu-Kuo; Liu, Ba; Hu, Long-Qin; Yang, Chung S.

2010-01-01

Tocopherols and tocotrienols, collectively known as vitamin E, are essential antioxidant nutrients. The biological fates and metabolite profiles of the different forms are not clearly understood. The objective of this study is to simultaneously analyze the metabolites of different tocopherols and tocotrienols in mouse and human samples. Using HPLC/electrochemical detection and mass spectrometry, 18 tocopherol-derived and 24 tocotrienol-derived side-chain degradation metabolites were identified in fecal samples. Short-chain degradation metabolites, in particular γ- and δ- carboxyethyl hydroxychromans (CEHCs) and carboxymethylbutyl hydroxychromans (CMBHCs) were detected in urine, serum and liver samples, with tocopherols additionally detected in serum and liver samples. The metabolite profiles of tocotrienols and tocopherols were similar, but new tocotrienol metabolites with double bonds were identified. This is the first comprehensive report describing simultaneous analysis of different side-chain metabolites of tocopherols and tocotrienols in mice and humans. Urinary metabolites may serve as useful biomarkers for nutritional assessment of vitamin E. PMID:20222730

Preservation of urine free catecholamines and their free O-methylated metabolites with citric acid as an alternative to hydrochloric acid for LC-MS/MS-based analyses.

PubMed

Peitzsch, Mirko; Pelzel, Daniela; Lattke, Peter; Siegert, Gabriele; Eisenhofer, Graeme

2016-01-01

Measurements of urinary fractionated metadrenalines provide a useful screening test to diagnose phaeochromocytoma. Stability of these compounds and their parent catecholamines during and after urine collection is crucial to ensure accuracy of the measurements. Stabilisation with hydrochloric acid (HCl) can promote deconjugation of sulphate-conjugated metadrenalines, indicating a need for alternative preservatives. Urine samples with an intrinsically acidic or alkaline pH (5.5-6.9 or 7.1-8.7, respectively) were used to assess stability of free catecholamines and their free O-methylated metabolites over 7 days of room temperature storage. Stabilisation with HCl was compared with ethylenediaminetetraacetic acid/metabisulphite and monobasic citric acid. Catecholamines and metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Free catecholamines and their O-methylated metabolites were stable in acidic urine samples over 7 days of room temperature storage, independent of the presence or absence of any stabilisation method. In contrast, free catecholamines, but not the free O-methylated metabolites, showed rapid degradation within 24 h and continuing degradation over 7 days in urine samples with an alkaline pH. Adjustment of alkaline urine samples to a pH of 3-5 with HCl or 4.8-5.4 with citric acid completely blocked degradation of catecholamines. Ethylenediaminetetraacetic acid/metabisulphite, although reducing the extent of degradation of catecholamines in alkaline urine, was largely ineffectual as a stabiliser. Citric acid is equally effective as HCl for stabilisation of urinary free catecholamines and minimises hazards associated with use of strong inorganic acids while avoiding deconjugation of sulphate-conjugated metabolites during simultaneous LC-MS/MS measurements of free catecholamines and their free O-methylated metabolites.

Detection of metabolites of the new synthetic cannabinoid CUMYL-4CN-BINACA in authentic urine samples and human liver microsomes using high-resolution mass spectrometry.

PubMed

Öztürk, Yeter Erol; Yeter, Oya; Öztürk, Serkan; Karakus, Goksun; Ates, Ismail; Buyuk, Yalçın; Yurdun, Turkan

2018-03-01

CUMYL-4CN-BINACA(1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide) is a recently introduced indazole-3-carboxamide-type synthetic cannabinoid (SC) that was detected in herbal incense seized by of the Council of Forensic Medicine, Istanbul Narcotics Department, in May 2016 in Turkey. Recently introduced SCs are not detected in routine toxicological analysis; therefore, analytical methods to measure these compounds are in demand. The present study aims to identify urinary marker metabolites of CUMYL-4CN-BINACA by investigating its metabolism in human liver microsomes and to confirm the results in authentic urine samples (n = 80). In this study, 5 μM CUMYL-4CN-BINACA was incubated with human liver microsomes (HLMs) for up to 3 hours, and metabolites were identified using liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Less than 21% of the CUMYL-4CN-BINACA parent compound remained after 3 hours of incubation. We identified 18 metabolites that were formed via monohydroxylation, dealkylation, oxidative decyanation to aldehyde, alcohol, and carboxylic acid formation, glucuronidation or reaction combinations. CUMYL-4CN-BINACA N-butanoic acid (M16) was found to be major metabolite in HLMs. In urine samples CUMYL-4CN-BINACA was not detected; CUMYL-4CN-BINACA N-butanoic acid (M16) was major metabolite after β-glucuronidase hydrolysis. Based on these findings, we recommend using M16 (CUMYL-4CN-BINACA N-butanoic acid), M8 and M11 (hydroxylcumyl CUMYL-4CN-BINACA) as urinary marker metabolites to confirm CUMYL-4CN-BINACA intake. Copyright © 2017 John Wiley & Sons, Ltd.

Metabolism of 1-fluoro-1,1,2-trichloroethane, 1,2-dichloro-1,1-difluoroethane, and 1,1,1-trifluoro-2-chloroethane.

PubMed

Yin, H; Jones, J P; Anders, M W

1995-03-01

1-Fluoro-1,1,2-trichloroethane (HCFC-131a), 1,2-dichloro-1,1-difluoroethane (HCFC-132b), and 1,1,1-trifluoro-2-chloroethane (HCFC-133a) were chosen as models for comparative metabolism studies on 1,1,1,2-tetrahaloethanes, which are under consideration as replacements for ozone-depleting chlorofluorocarbons (CFCs). Male Fischer 344 rats were given 10 mmol/kg ip HCFC-131a or HCFC-132b or exposed by inhalation to 1% HCFC-133a for 2 h. Urine collected in the first 24 h after exposure was analyzed by 19F NMR and GC/MS and with a fluoride-selective ion electrode for the formation of fluorine-containing metabolites. Metabolites of HCFC-131a included 2,2-dichloro-2-fluoroethyl glucuronide, 2,2-dichloro-2-fluoroethyl sulfate, dichlorofluoroacetic acid, and inorganic fluoride. Metabolites of HCFC-132b were characterized as 2-chloro-2,2-difluoroethyl glucuronide, 2-chloro-2,2-difluoroethyl sulfate, chlorodifluoroacetic acid, chlorodifluoroacetaldehyde hydrate, chlorodifluoroacetaldehyde-urea adduct, and inorganic fluoride. HCFC-133a was metabolized to 2,2,2-trifluoroethyl glucuronide, trifluoroacetic acid, trifluoroacetaldehyde hydrate, trifluoroacetaldehyde-urea adduct, inorganic fluoride, and a minor, unidentified metabolite. With HCFC-131a and HCFC-132b, glucuronide conjugates of 2,2,2-trihaloethanols were the major urinary metabolites, whereas with HCFC-133a, a trifluoroacetaldehyde-urea adduct was the major urinary metabolite. Analysis of metabolite distribution in vivo indicated that aldehydic metabolites increased as fluorine substitution increased in the order HCFC-131a < HCFC-132b < HCFC-133a. With NADPH-fortified rat liver microsomes, HCFC-133a and HCFC-132b were biotransformed to trifluoroacetaldehyde and chlorodifluoroacetaldehyde, respectively, whereas HCFC-131a was converted to dichlorofluoroacetic acid. No covalently bound metabolites were detected by 19F NMR spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary metabotyping of bladder cancer using two-dimensional gas chromatography time-of-flight mass spectrometry.

PubMed

Pasikanti, Kishore Kumar; Esuvaranathan, Kesavan; Hong, Yanjun; Ho, Paul C; Mahendran, Ratha; Raman Nee Mani, Lata; Chiong, Edmund; Chan, Eric Chun Yong

2013-09-06

Cystoscopy is the gold standard clinical diagnosis of human bladder cancer (BC). As cystoscopy is expensive and invasive, it compromises patients' compliance toward surveillance screening and challenges the detection of recurrent BC. Therefore, the development of a noninvasive method for the diagnosis and surveillance of BC and the elucidation of BC progression become pertinent. In this study, urine samples from 38 BC patients and 61 non-BC controls were subjected to urinary metabotyping using two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOFMS). Subsequent to data preprocessing and chemometric analysis, the orthogonal partial least-squares discriminant analysis (OPLS-DA, R2X=0.278, R2Y=0.904 and Q2Y (cumulative)=0.398) model was validated using permutation tests and receiver operating characteristic (ROC) analysis. Marker metabolites were further screened from the OPLS-DA model using statistical tests. GC×GC-TOFMS urinary metabotyping demonstrated 100% specificity and 71% sensitivity in detecting BC, while 100% specificity and 46% sensitivity were observed via cytology. In addition, the model revealed 46 metabolites that characterize human BC. Among the perturbed metabolic pathways, our clinical finding on the alteration of the tryptophan-quinolinic metabolic axis in BC suggested the potential roles of kynurenine in the malignancy and therapy of BC. In conclusion, global urinary metabotyping holds potential for the noninvasive diagnosis and surveillance of BC in clinics. In addition, perturbed metabolic pathways gleaned from urinary metabotyping shed new and established insights on the biology of human BC.

Human urinary metabolic patterns of the designer benzodiazepines flubromazolam and pyrazolam studied by liquid chromatography-high resolution mass spectrometry.

PubMed

Pettersson Bergstrand, Madeleine; Meyer, Markus R; Beck, Olof; Helander, Anders

2018-03-01

Over the past ~8 years, hundreds of unregulated new psychoactive substances (NPS) of various chemical categories have been introduced as recreational drugs through mainly open online trade. This study was performed to further investigate the human metabolic pattern of the NPS, or designer benzodiazepines flubromazolam and pyrazolam, and to propose analytical targets for urine drug testing of these substances. The urine samples originated from patient samples confirmed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) analysis to contain flubromazolam or pyrazolam. The LC-HRMS/MS system consisted of a YMC-UltraHT Hydrosphere C18 column (YMC, Dinslaken, Germany) coupled to a Thermo Scientific (Waltham, MA, USA) Q Exactive Orbitrap MS operating in positive electrospray mode. The samples were analyzed both with and without enzymatic hydrolysis using β-glucuronidase. Besides the parent compounds, the main urinary excretion products were parent glucuronides, mono-hydroxy metabolites, and mono-hydroxy glucuronides. In samples prepared without hydrolysis, the most common flubromazolam metabolites were 1 of the mono-hydroxy glucuronides and 1 of the parent glucuronides. For pyrazolam, a parent glucuronide was the most common metabolite. These 3 metabolites were detected in all samples and were considered the primary targets for urine drug testing and confirmation of intake. After enzymatic hydrolysis of the urine samples, a 2-19-fold increase in the concentration of flubromazolam was found, highlighting the value of hydrolysis for this analyte. With hydrolysis, the flubromazolam hydroxy metabolites should be used as target metabolites. Copyright © 2017 John Wiley & Sons, Ltd.

Identification of Urinary Polyphenol Metabolite Patterns Associated with Polyphenol-Rich Food Intake in Adults from Four European Countries.

PubMed

Noh, Hwayoung; Freisling, Heinz; Assi, Nada; Zamora-Ros, Raul; Achaintre, David; Affret, Aurélie; Mancini, Francesca; Boutron-Ruault, Marie-Christine; Flögel, Anna; Boeing, Heiner; Kühn, Tilman; Schübel, Ruth; Trichopoulou, Antonia; Naska, Androniki; Kritikou, Maria; Palli, Domenico; Pala, Valeria; Tumino, Rosario; Ricceri, Fulvio; Santucci de Magistris, Maria; Cross, Amanda; Slimani, Nadia; Scalbert, Augustin; Ferrari, Pietro

2017-07-25

We identified urinary polyphenol metabolite patterns by a novel algorithm that combines dimension reduction and variable selection methods to explain polyphenol-rich food intake, and compared their respective performance with that of single biomarkers in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included 475 adults from four European countries (Germany, France, Italy, and Greece). Dietary intakes were assessed with 24-h dietary recalls (24-HDR) and dietary questionnaires (DQ). Thirty-four polyphenols were measured by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS-MS) in 24-h urine. Reduced rank regression-based variable importance in projection (RRR-VIP) and least absolute shrinkage and selection operator (LASSO) methods were used to select polyphenol metabolites. Reduced rank regression (RRR) was then used to identify patterns in these metabolites, maximizing the explained variability in intake of pre-selected polyphenol-rich foods. The performance of RRR models was evaluated using internal cross-validation to control for over-optimistic findings from over-fitting. High performance was observed for explaining recent intake (24-HDR) of red wine ( r = 0.65; AUC = 89.1%), coffee ( r = 0.51; AUC = 89.1%), and olives ( r = 0.35; AUC = 82.2%). These metabolite patterns performed better or equally well compared to single polyphenol biomarkers. Neither metabolite patterns nor single biomarkers performed well in explaining habitual intake (as reported in the DQ) of polyphenol-rich foods. This proposed strategy of biomarker pattern identification has the potential of expanding the currently still limited list of available dietary intake biomarkers.

Influence of delivery mode on the urinary excretion of nandrolone metabolites.

PubMed

Watson, Phillip; Houghton, Ed; Grace, Philip B; Judkins, Catherine; Dunster, Paula M; Maughan, Ronald J

2010-04-01

This study examined the influence of a supplement matrix on the excretion pattern of nandrolone metabolites in response to ingestion of a trace amount of 19-norandrostenedione. Ten male and nine female volunteers (mean ± SD: age = 26 ± 3 yr, height = 1.71 ± 0.09 m, body mass = 70.9 ± 13.2 kg) were recruited. On two occasions, subjects entered the laboratory in the morning after an overnight fast. After an initial urine collection, subjects ingested either 500 mL of plain water or a commercially available energy bar; 10 µg of 19-norandrostenedione was added to each. The volume of each urine sample passed during the next 24 h was measured, and an aliquot was retained for analysis. All samples were analyzed for the metabolites 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE) by gas chromatography-mass spectrometry. The total volume of urine passed was higher in the water trial (2.10 ± 0.52 L) than in the bar trial (1.85 ± 0.55 L; P = 0.040). Baseline urinary 19-NA concentrations were all below the limit of quantification for the assay. Peak urinary 19-NA was lower (P = 0.002) in the water trial (4.80 ± 2.84 ng·mL(-1)) than in the bar trial (8.46 ± 4.44 ng·mL(-1)). The time elapsed between ingestion of the supplement and the peak urinary 19-NA concentration was longer (P = 0.023) on the bar trial (4.6 ± 2.4 h) than on the water trial (2.8 ± 1.9 h). There was no difference in the total recovery of 19-NA + 19-NE between the liquid and solid supplements (water 30 ± 10%; bar 28 ± 12%; P < 0.140). Peak 19-NA concentrations were higher, and occurred later, when the 19-norandrostenedione was added to a solid supplement. This may be due to a slower rate of absorption and/or a reduced diuresis, resulting in a longer period for the metabolites to accumulate in the urine.

The selective determination of sulfates, sulfonates and phosphates in urine by CE-MS.

PubMed

Bunz, Svenja-Catharina; Weinmann, Wolfgang; Neusüss, Christian

2010-04-01

Metabolite identification and metabolite profiling are of major importance in the pharmaceutical and clinical context. However, highly polar and ionic substances are rarely included as analytical tools are missing. In this study, we present a new method for the determination of urinary sulfates, sulfonates, phosphates and other anions of strong acids. The method comprises a CE separation using an acidic BGE (pH

Urinary Concentrations of Insecticide and Herbicide Metabolites among Pregnant Women in Rural Ghana: A Pilot Study.

PubMed

Wylie, Blair J; Ae-Ngibise, Kenneth A; Boamah, Ellen A; Mujtaba, Mohammed; Messerlian, Carmen; Hauser, Russ; Coull, Brent; Calafat, Antonia M; Jack, Darby; Kinney, Patrick L; Whyatt, Robin; Owusu-Agyei, Seth; Asante, Kwaku P

2017-03-29

Use of pesticides by households in rural Ghana is common for residential pest control, agricultural use, and for the reduction of vectors carrying disease. However, few data are available about exposure to pesticides among this population. Our objective was to quantify urinary concentrations of metabolites of organophosphate (OP), pyrethroid, and select herbicides during pregnancy, and to explore exposure determinants. In 2014, 17 pregnant women from rural Ghana were surveyed about household pesticide use and provided weekly first morning urine voids during three visits ( n = 51 samples). A total of 90.1% (46/51) of samples had detectable OP metabolites [geometric mean, GM (95% CI): 3,5,6-trichloro-2-pyridinol 0.54 µg/L (0.36-0.81), para-nitrophenol 0.71 µg/L (0.51-1.00)], 75.5% (37/49) had detectable pyrethroid metabolites [GM: 3-phenoxybenzoic acid 0.23 µg/L (0.17, 0.32)], and 70.5% (36/51) had detectable 2,4-dichlorophenoxyacetic acid levels, a herbicide [GM: 0.46 µg/L (0.29-0.73)]. Concentrations of para-nitrophenol and 2,4-dichlorophenoxyacetic acid in Ghanaian pregnant women appear higher when compared to nonpregnant reproductive-aged women in a reference U.S. Larger studies are necessary to more fully explore predictors of exposure in this population.

Hplc-nmr identification of the human urinary metabolites of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analogue active against human immunodeficiency virus (HIV).

PubMed

Shockcor, J P; Wurm, R M; Frick, L W; Sanderson, P N; Farrant, R D; Sweatman, B C; Lindon, J C

1996-02-01

1. Human urine samples from a clinical trial of the anti-HIV compound (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cyto sin e (BW524W91) have been analysed using 19F-nmr and 1H-hplc-nmr spectroscopy. 2. The identities and relative levels of the xenobiotic species in the urine have been determined by 470-MHz 19F-nmr spectroscopy and by directly coupled 600-MHz 1H-hplc-nmr in the stop-flow mode with confirmation of the metabolite identities being made by comparison with nmr spectra of synthetic standard compounds. 3. The principal urinary xenobiotic was the unchanged drug, but the glucuronide ether conjugate at the 5' position of BW524W91, one of the two diastereomeric sulphoxides and the deaminated metabolite were also characterized. 4. The detection limit of directly coupled hplc-600-MHz 1H-nmr spectroscopy was evaluated by measuring two-dimensional nmr spectra of the glucuronide conjugate of BW524W91 and shown to be approximately 1 microgram material for 1H-1H-TOCSY and 20 micrograms metabolite for 1H-13C-HMQC spectra for overnight (16 h) acquisition.

Detection of rare species of volatile organic selenium metabolites in male golden hamster urine.

PubMed

Kwak, Jae; Ohrnberger, Sarah A; Valencak, Teresa G

2016-07-01

Selenium has been considered as an essential trace element in mammals and its intake comes mainly from food. Mammals can metabolize both inorganic and organic species, and urinary excretion is the primary elimination route of selenium. Selenosugars and trimethylselenonium ion have been identified as major urinary metabolites. Other metabolites have been reported, but they were detected in some studies and not in others. Still, a large portion of the ingested selenium eliminated from the body is unknown. Volatile selenium species may account for a certain portion of the unknown species since they can easily be lost during sample analyses. While we analyzed male golden hamster urine in search of potential volatile pheromone(s), four volatile selenium compounds were detected. They were dimethyl selenenylsulfide, dimethyl diselenide, dimethyl bis(thio)selenide, and dimethyl selenodisulfide. When the urine samples were aged and dried for 48 h, dimethyl selenodisulfide tended to increase, while others decreased. The increase might be due to the formation of dimethyl selenodisulfide via reaction of dimethyl diselenide and dimethyl trisulfide whose concentration increased as urine aged. To our knowledge, dimethyl bis(thio)selenide and dimethyl selenodisulfide have never been demonstrated in urine. It remains to be determined whether these species are common metabolites in other animals or hamster-specific.

Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation.

PubMed

Giskeødegård, Guro F; Davies, Sarah K; Revell, Victoria L; Keun, Hector; Skene, Debra J

2015-10-09

Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2-8 h intervals and analysed by (1)H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies.

Updated bioavailability and 48 h excretion profile of flavan-3-ols from green tea in humans.

PubMed

Calani, Luca; Del Rio, Daniele; Luisa Callegari, Maria; Morelli, Lorenzo; Brighenti, Furio

2012-08-01

Green tea is a popular beverage, prepared with infusion of unfermented dried leaves of Camellia sinensis, and is one of the most relevant sources of polyphenolic compounds in the human diet. This study reports green tea flavan-3-ol absorption, metabolism and complete urinary excretion up to 48 h in 20 healthy volunteers. Urinary and tea samples were analysed by high-performance liquid chromatography coupled with tandem mass spectrometry. Green tea contained monomeric flavan-3-ols and proanthocyanidins with a total polyphenol content of 728 μmol. A total of 41 metabolites were identified in urines, all present in conjugated forms. Among these, six colonic metabolites of green tea flavan-3-ols were identified for the first time after green tea consumption in humans. The average 48 h bioavailability was close to 62%, major contributors being microbial metabolites. Some volunteer showed a 100% absorption/excretion, whereas some others were unable to efficiently absorb/excrete this class of flavonoids. This suggests that colonic ring fission metabolism could be relevant in the putative bioactivity of green tea polyphenols.

Smoking modify the effects of polycyclic aromatic hydrocarbons exposure on oxidative damage to DNA in coke oven workers.

PubMed

Yang, Jin; Zhang, Hongjie; Zhang, Huitao; Wang, Wubin; Liu, Yanli; Fan, Yanfeng

2017-07-01

Coke oven emissions containing polycyclic aromatic hydrocarbons (PAHs) are predominant toxic constituents of particulate air pollution that have been linked to increased risk of lung cancer. Numerous epidemiological studies have suggested that oxidative DNA damage may play a pivotal role in the carcinogenic mechanism of lung cancer. Little is known about the effect of interaction between PAHs exposure and lifestyle on DNA oxidative damage. The study population is composed by coke oven workers (365) and water treatment workers (144), and their urinary levels of four PAH metabolites and 8-hydroxydeoxyguanosine (8-OHdG) were determined. Airborne samples of exposed sites (4) and control sites (3) were collected, and eight carcinogenic PAHs were detected by high-performance liquid chromatography. The median values of the sum of eight carcinogenic PAHs and BaP in exposed sites were significantly higher than control sites (P < 0.01). The study found that the urinary PAH metabolites were significantly elevated in coke oven workers (P < 0.01). Multivariate logistic regression analysis revealed that the risk of high levels of urinary 8-OHdG will increase with increasing age, cigarette consumption, and levels of urinary 1-hydroxypyrene, and P for trend were all <0.05. Smoking can significantly modify the effects of urinary 1-hydroxypyrene on high concentrations urinary 8-OHdG, during co-exposure to both light or heavy smoking and high 1-hydroxypyrene levels (OR 4.28, 95% CI 1.32-13.86 and OR 5.05, 95% CI 1.63-15.67, respectively). Our findings quantitatively demonstrate that workers exposed to coke oven fumes and smoking will cause more serious DNA oxidative damage.

The role of chromogranin A in the management of patients with phaeochromocytoma.

PubMed

Grossrubatscher, Erika; Dalino, Paolo; Vignati, Federico; Gambacorta, Marcello; Pugliese, Raffaele; Boniardi, Marco; Rossetti, Ornella; Marocchi, Alessandro; Bertuzzi, Michaela; Loli, Paola

2006-09-01

Chromogranin A (CgA) is the most accurate general marker of neuroendocrine tumours. Supranormal CgA concentrations have been recorded in patients with tumours of neuroectodermal origin such as phaeochromocytoma and paraganglioma. The present study was performed to assess the role of CgA determination in the management of patients with phaeochromocytoma, in comparison with urinary catecholamines and their metabolites. The patients studied included 22 cases with phaeochromocytoma at initial presentation or at relapse some years after surgical cure or during follow-up of a malignant phaeochromocytoma. Seventeen patients were evaluated before and after surgical removal of phaeochromocytoma. To assess the specificity of the hormonal parameters, 20 subjects were enrolled as controls; they were from a group of patients referred to our observation for possible phaeochromocytoma and who were subsequently proven not to have the disease. Urinary epinephrine and norepinephrine were supranormal in 82% and 77% of patients, respectively. Urinary metanephrines and normetanephrines were supranormal in 84% and 89% of patients, respectively. The combination of urinary metanephrine and normetanephrine had a sensitivity of 100% in identifying a phaeochromocytoma. CgA was supranormal in 91% of patients. Combining the results of CgA and urinary catecholamines (epinephrine and norepinephrine), the sensitivity for diagnosis of phaeochromocytoma was 100%. Urinary catecholamines, metabolites (metanephrine and normetanephrine) and CgA levels in patients with malignant phaeochromocytoma did not differ significantly from those of patients with benign lesions. In most cases, CgA normalized after surgery. Our results indicate that CgA is a good marker of phaeochromocytoma; measurement of CgA could have a role in the follow-up of patients operated on for phaeochromocytoma.

Biotransformation of the citrus flavone tangeretin in rats. Identification of metabolites with intact flavane nucleus.

PubMed

Nielsen, S E; Breinholt, V; Cornett, C; Dragsted, L O

2000-09-01

The present study was carried out in order to investigate the in vivo biotransformation and excretion of the flavone, tangeretin, found in citrus fruits, by analysing urine and faeces samples from rats after repeated administration of 100 mg/kg body weight/day tangeretin. The formed metabolites were separated and identified by HPLC and the structures elucidated by LC/MS and 1H NMR. Ten new, major metabolites with intact flavonoid structure were identified. The metabolites identified were either demethylated or hydroxylated derivatives of the parent compound and metabolic changes were found primarily to occur in the 4' position of the B-ring. The total urinary excretion of tangeretin metabolites with intact flavan nucleus was about 11% of the administered daily dose.

Vitamin E decreases extra-hepatic menaquinone-4 concentrations in rats fed menadione or phylloquinone.

PubMed

Farley, Sherry M; Leonard, Scott W; Labut, Edwin M; Raines, Hannah F; Card, David J; Harrington, Dominic J; Mustacich, Debbie J; Traber, Maret G

2012-06-01

The mechanism for increased bleeding and decreased vitamin K status accompanying vitamin E supplementation is unknown. We hypothesized that elevated hepatic α-tocopherol (α-T) concentrations may stimulate vitamin K metabolism and excretion. Furthermore, α-T may interfere with the side chain removal of phylloquinone (PK) to form menadione (MN) as an intermediate for synthesis of tissue-specific menaquinone-4 (MK-4). In order to investigate these hypotheses, rats were fed phylloquinone (PK) or menadione (MN) containing diets (2 μmol/kg) for 2.5 weeks. From day 10, rats were given daily subcutaneous injections of either α-T (100 mg/kg) or vehicle and were sacrificed 24 h after the seventh injection. Irrespective of diet, α-T injections decreased MK-4 concentrations in brain, lung, kidney, and heart; and PK in lung. These decreases were not accompanied by increased excretion of urinary 5C- or 7C-aglycone vitamin K metabolites, however, the urinary α-T metabolite (α-CEHC) increased ≥ 100-fold. Moreover, α-T increases were accompanied by downregulation of hepatic cytochrome P450 expression and modified expression of tissue ATP-binding cassette transporters. Thus, in rats, high tissue α-T depleted tissue MK-4 without significantly increasing urinary vitamin K metabolite excretion. Changes in tissue MK-4 and PK levels may be a result of altered regulation of transporters. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Metabolic Pathway Signatures Associated with Urinary Metabolite Biomarkers Differentiate Bladder Cancer Patients from Healthy Controls.

PubMed

Kim, Won Tae; Yun, Seok Joong; Yan, Chunri; Jeong, Pildu; Kim, Ye Hwan; Lee, Il Seok; Kang, Ho Won; Park, Sunghyouk; Moon, Sung Kwon; Choi, Yung Hyun; Choi, Young Deuk; Kim, Isaac Yi; Kim, Jayoung; Kim, Wun Jae

2016-07-01

Our previous high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry study identified bladder cancer (BCA)-specific urine metabolites, including carnitine, acylcarnitines, and melatonin. The objective of the current study was to determine which metabolic pathways are perturbed in BCA, based on our previously identified urinary metabolome. A total of 135 primary BCA samples and 26 control tissue samples from healthy volunteers were analyzed. The association between specific urinary metabolites and their related encoding genes was analyzed. Significant alterations in the carnitine-acylcarnitine and tryptophan metabolic pathways were detected in urine specimens from BCA patients compared to those of healthy controls. The expression of eight genes involved in the carnitine-acylcarnitine metabolic pathway (CPT1A, CPT1B, CPT1C, CPT2, SLC25A20, and CRAT) or tryptophan metabolism (TPH1 and IDO1) was assessed by RT-PCR in our BCA cohort (n=135). CPT1B, CPT1C, SLC25A20, CRAT, TPH1, and IOD1 were significantly downregulated in tumor tissues compared to normal bladder tissues (p<0.05 all) of patients with non-muscle invasive BCA, whereas CPT1B, CPT1C, CRAT, and TPH1 were downregulated in those with muscle invasive BCA (p<0.05), with no changes in IDO1 expression. Alterations in the expression of genes associated with the carnitine-acylcarnitine and tryptophan metabolic pathways, which were the most perturbed pathways in BCA, were determined.

Excretion of Avenanthramides, Phenolic Acids and their Major Metabolites Following Intake of Oat Bran

PubMed Central

Schär, Manuel Y.; Corona, Giulia; Soycan, Gulten; Dine, Clemence; Kristek, Angelika; Alsharif, Sarah N. S.; Behrends, Volker; Lovegrove, Alison; Shewry, Peter R.

2017-01-01

Scope Wholegrain has been associated with reduced chronic disease mortality, with oat intake particularly notable for lowering blood cholesterol and glycemia. To better understand the complex nutrient profile of oats, we studied urinary excretion of phenolic acids and avenanthramides after ingestion of oat bran in humans. Methods and results After a 2‐d (poly)phenol‐low diet, seven healthy men provided urine 12 h before and 48 h after consuming 60 g oat bran (7.8 μmol avenanthramides, 139.2 μmol phenolic acids) or a phenolic‐low (traces of phenolics) control in a crossover design. Analysis by ultra‐high performance liquid chromatography (UPLC)–MS/MS showed that oat bran intake resulted in an elevation in urinary excretion of 30 phenolics relative to the control, suggesting that they are oat bran‐derived. Mean excretion levels were elevated between 0–2 and 4–8 h, following oat bran intake, and amounted to a total of 33.7 ± 7.3 μmol total excretion (mean recovery: 22.9 ± 5.0%), relative to control. The predominant metabolites included: vanillic acid, 4‐ and 3‐hydroxyhippuric acids, and sulfate‐conjugates of benzoic and ferulic acids, which accounted collectively for two thirds of total excretion. Conclusion Oat bran phenolics follow a relatively rapid urinary excretion, with 30 metabolites excreted within 8 h of intake. These levels of excretion suggest that bound phenolics are, in part, rapidly released by the microbiota. PMID:29024323

Development of automated analytical capability for the early detection of diabetes mellitus

NASA Technical Reports Server (NTRS)

Zlatkis, A.

1976-01-01

The total profile of volatile metabolites in urine of patients with diabetes mellitus was studied. Because of the drastic abnormalities in the metabolism of carbohydrates, lipids, and proteins connected with diabetes it was expected that apart from acetone further characteristic abnormalities occur in the profiles if volatile urinary metabolites in cases of diabetes mellitus. Quantitative and qualitative changes were found in these urines as compared to the urines of normal subjects.

Arsenic Metabolites and Methylation Capacity Among Individuals Living in a Rural Area with Endemic Arseniasis in Inner Mongolia, China.

PubMed

Wei, Binggan; Yu, Jiangping; Li, Hairong; Yang, Linsheng; Xia, Yajuan; Wu, Kegong; Gao, Jianwei; Guo, Zhiwei; Cui, Na

2016-04-01

More than 0.3 million individuals are subject to chronic exposure to arsenic via their drinking water in Inner Mongolia, China. To determine arsenic methylation capacity profiles for such individuals, concentrations of urinary arsenic metabolites were measured for 548 subjects using high-performance liquid chromatography and a hydride generator combined with inductively coupled plasma-mass spectrometry. Mean urinary concentrations of dimethylarsonic acid (DMA), monomethylarsonic acid (MMA), inorganic arsenic (iAs), and total arsenic (TAs) were 200.50, 46.71, 52.96, and 300.17 μg/L, respectively. The %iAs, %DMA, and %MMA were 15.98, 69.72, and 14.29%. Mean urinary %iAs and %MMA were higher in males, while urinary %DMA was higher in females. There was a strong positive correlation between %iAs and %MMA, with negative correlations between %iAs and %DMA, and %iAs and %MMA. In addition, %iAs and %MMA were positively associated with total arsenic in drinking water (WAs), while %DMA was negatively related with WAs. Regression analysis indicated that the primary methylation index (PMI) and secondary methylation index (SMI) generally decreased with increasing WAs. Females had a higher arsenic methylation capacity compared to males. Younger subjects had lower primary arsenic methylation capacity. However, the secondary arsenic methylation capacity was hardly affected by age. Moreover, both primary and secondary arsenic methylation capacities were negatively related to WAs.

Co-exposure to polycyclic aromatic hydrocarbons, benzene and toluene and their dose-effects on oxidative stress damage in kindergarten-aged children in Guangzhou, China.

PubMed

Li, Junnan; Lu, Shaoyou; Liu, Guihua; Zhou, Yuanxiu; Lv, Yanshan; She, Jianwen; Fan, Ruifang

2015-08-15

Polycyclic aromatic hydrocarbons (PAHs), benzene and toluene (BT) are ubiquitous toxic pollutants in the environment. Children are sensitive and susceptible to exposure to these contaminants. To investigate the potential oxidative DNA damage from the co-exposure of PAHs and BT in children, 87 children (aged 3-6) from a kindergarten in Guangzhou, China, were recruited. Ten urinary PAHs and four BT metabolites, as well as 8-hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage)in urine, were determined using a liquid chromatography tandem mass spectrometer. The results demonstrated that the levels of PAHs and BT in children from Guangzhou were 2-30 times higher than those in children from the other countries based on a comparison with recent data from the literature. In particular, the difference is more substantial for pyrene and volatile BT. Co-exposure to PAHs and BT could lead to additive oxidative DNA damage. Significant dose-effects were observed between the sum concentration of urinary monohydroxylated metabolites of PAHs (∑OH-PAHs), the sum concentration of the metabolites of BT (∑BT) and 8-OHdG levels. Every one percent increase in urinary PAHs and BT generated 0.33% and 0.02% increases in urinary 8-OHdG, respectively. We also determined that the urinary levels of PAHs and BT were negatively associated with the age of the children. Moreover, significant differences in the levels of ∑OH-PAHs and ∑BT were determined between 3- and 6-year-old children (p<0.05), which may be caused by different metabolism capabilities or inhalation frequencies. In conclusion, exposure to PAHs or BT could lead to oxidative DNA damage, and 8-OHdG is a good biomarker for indicating the presence of DNA damage. There exists a significant dose-effect relationship between PAH exposure, BT exposure and the concentration of 8-OHdG in urine. Toddlers (3-4 years old) face a higher burden of PAH and BT exposure compared with older children. Copyright © 2015 Elsevier B.V. All rights reserved.

Major metabolite of F2-isoprostane in urine may be a more sensitive biomarker of oxidative stress than isoprostane itself1234

PubMed Central

Dorjgochoo, Tsogzolmaa; Gao, Yu-Tang; Chow, Wong-Ho; Shu, Xiao-ou; Yang, Gong; Cai, Qiuyin; Rothman, Nathaniel; Cai, Hui; Li, Honglan; Deng, Xinqing; Franke, Adrian; Roberts, L Jackson; Milne, Ginger; Zheng, Wei; Dai, Qi

2012-01-01

Background: There is limited literature on the contributors to isoprostane metabolite 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (15-F2t-IsoP-M) compared with F2-isoprostanes (F2-IsoPs) as an oxidative stress biomarker. Objective: The objective of this study was to investigate whether plasma concentrations of antioxidants, urinary excretion rates of polyphenols, and antioxidants in food and dietary supplements are attributable to both urinary F2-IsoP and 15-F2t-IsoP-M concentrations. Design: Dietary intake information and blood and urine samples were obtained from 845 healthy middle-aged and elderly female participants of the Shanghai Women's Health Study. Urinary isoprostanes (F2-IsoPs and 15-F2t-IsoP-M) were measured and adjusted for creatinine concentrations. Results: Urinary 15-F2t-IsoP-M and F2-IsoP concentrations were lower in subjects who used a multivitamin. Lower F2-IsoP concentrations were observed in ginseng users, whereas lower concentrations of 15-F2t-IsoP-M were shown in subjects who used a vitamin E supplement. Plasma concentrations of several antioxidants (ie, β-carotenes, both trans and cis β-carotenes, lycopene other than trans, 5-cis and 7-cis isomers, cis anhydrolutein, and cis β-cryptoxanthin) were inversely associated with 15-F2t-IsoP-M but not with F2-IsoPs, whereas β-, γ-, and δ-tocopherols were positively associated with 15-F2t-IsoP-M but not with F2-IsoPs. Urinary polyphenol quercetin was positively associated with both F2-IsoPs and 15-F2t-IsoP-M. Conclusion: The results suggest that the F2-IsoP major metabolite 15-F2t-IsoP-M may be a more sensitive marker of endogenous oxidative stress status than are F2-IsoPs in the assessment of effects of antioxidants on age-related diseases. PMID:22760572

Urinary nandrolone metabolites of endogenous origin in man: a confirmation by output regulation under human chorionic gonadotropin stimulation.

PubMed

Reznik, Y; Dehennin, L; Coffin, C; Mahoudeau, J; Leymarie, P

2001-01-01

19-Nortestosterone (nandrolone) is an anabolic steroid compound widely used as a doping agent by athletes. The analysis of its urinary metabolites, 19-norandrosterone (NA) and 19-noretiocholanolone (NE) glucuronides, allows the detection of surreptitious administration of nandrolone in sport. A threshold concentration at 2 microgram/L urinary nandrolone metabolites is advocated by the International Olympic Committee for the detection of doping, but some controversy concerning the validity of this threshold arose from the demonstration of endogenous production of nandrolone in mammals, including humans. The regulation of human nandrolone production and its contribution in vivo to the process of aromatization remain unknown. In the present study 10 healthy men were successively submitted to insulinic stress and gonadal stimulation by hCG administration. Urinary NA and NE concentrations were quantified by gas chromatography-mass spectrometry. NA was detected in basal urine samples from all subjects, with a mean urinary excretion rate (UER) of 3.17 +/- 0.35 ng/h, whereas NE was detected in 4 of 10 (UER range, 0.8-4.7 ng/h). Insulinic hypoglycemia did not significantly modify mean NA UER despite random intraindividual variations between timed urine collections. After hCG administration, NA UER increased by 250% (P < 0.01) and estradiol (E(2)) UER by 260% (P < 0.001). The maximum NA concentration obtained after stimulation was 0.43 microgram/L. NA UER, plasma E(2), and E(2)/T ratio peaked on day 1 after hCG administration, whereas plasma T peaked later on day 3. NA UER correlated with plasma E(2) (r = 0.61; P < 0.001) and E(2)/T (r = 0.51; P < 0.001), but not with plasma T. In conclusion, insulinic stress did not significantly alter nandrolone metabolism, whereas the effect of hCG was a stimulation of NA excretion in all subjects, which constitutes strong support for the endogenous origin of low basal NA excretion. The comparative kinetics of NA UER, plasma E(2), and E(2)/T ratio suggest a contribution of the aromatase process to nandrolone biosynthesis in man.

Urinary 3-hydroxypropyl mercapturic acid (3-HPMA) concentrations in dogs with acute spinal cord injury due to intervertebral disc herniation.

PubMed

Sangster, A M; Zheng, L; Bentley, R T; Shi, R; Packer, R A

2017-01-01

The aim of this study was to investigate urinary 3-hydroxypropyl mercapturic acid (3-HPMA), a metabolite of acrolein, as a novel biomarker in acute spinal cord injury (ASCI) due to intervertebral disc herniation in dogs. Urine from 10 client-owned dogs with ASCI collected at presentation and 10 control dogs was analyzed for 3-HPMA. The median urinary 3-HPMA concentration in ASCI dogs was significantly higher than in control dogs, but was not correlated with the severity of ASCI. The median urinary 3-HPMA concentration in intact dogs was higher than in neutered dogs. Higher urinary 3-HPMA concentrations in dogs after ASCI support a role for acrolein, a cytotoxic by-product of lipid peroxidation, in canine ASCI. Urinary 3-HPMA could be used as a biomarker in future clinical trials to measure the effect of therapeutic intervention of reducing acrolein after ASCI. Copyright © 2016. Published by Elsevier Ltd.

Impact of pesticide exposure misclassification on estimates of relative risks in the Agricultural Health Study.

PubMed

Blair, Aaron; Thomas, Kent; Coble, Joseph; Sandler, Dale P; Hines, Cynthia J; Lynch, Charles F; Knott, Charles; Purdue, Mark P; Zahm, Shelia Hoar; Alavanja, Michael C R; Dosemeci, Mustafa; Kamel, Freya; Hoppin, Jane A; Freeman, Laura Beane; Lubin, Jay H

2011-07-01

The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators and their spouses in Iowa and North Carolina. We evaluate the impact of occupational pesticide exposure misclassification on relative risks using data from the cohort and the AHS Pesticide Exposure Study (AHS/PES). We assessed the impact of exposure misclassification on relative risks using the range of correlation coefficients observed between measured post-application urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) and a chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications. Correlations between urinary levels of 2,4-D and a chlorpyrifos metabolite and algorithm estimated intensity scores were about 0.4 for 2,4-D (n=64), 0.8 for liquid chlorpyrifos (n=4) and 0.6 for granular chlorpyrifos (n=12). Correlations of urinary levels with kilograms of active ingredient used, duration of application, or number of acres treated were lower and ranged from -0.36 to 0.19. These findings indicate that a priori expert-derived algorithm scores were more closely related to measured urinary levels than individual exposure determinants evaluated here. Estimates of potential bias in relative risks based on the correlations from the AHS/PES indicate that non-differential misclassification of exposure using the algorithm would bias estimates towards the null, but less than that from individual exposure determinants. Although correlations between algorithm scores and urinary levels were quite good (ie, correlations between 0.4 and 0.8), exposure misclassification would still bias relative risk estimates in the AHS towards the null and diminish study power.

Exposure to organophosphate pesticides and male hormone profile in floriculturist of the state of Morelos, Mexico.

PubMed

Blanco-Muñoz, Julia; Morales, Magally Mayanin; Lacasaña, Marina; Aguilar-Garduño, Clemente; Bassol, Susana; Cebrián, Mariano E

2010-07-01

Studies on experimental animals have found that organophosphate (OP) pesticides may act as endocrine disruptors; however, their effects on the human hormonal profile have not yet been adequately characterized. We evaluate the association between exposure to OP pesticides, measured through dialkyl phosphate (DAP) metabolites urinary levels, and the male hormone profile. A cross-sectional study was performed in 104 floriculturists of Morelos, Mexico. A structured questionnaire was applied to get information on sociodemographic characteristics, anthropometry, clinical history, alcohol and tobacco consumption, and work history. DAP metabolites [dimethylphosphate (DMP), dimethylthiophosphate, dimethyldithiophosphate, diethylphosphate (DEP), diethylthiophosphate (DETP) and diethyldithiophosphate] were determined using gas-liquid chromatography. Serum levels of FSH, LH, prolactin, testosterone, inhibin B and estradiol were determined using enzyme-linked immunosorbent assay. Multiple linear regression was used to study the association between DAP metabolite levels and male hormonal profile. Data were adjusted by p,p'-dichlorodiphenyldichloroethene serum levels and other potential confounders. There was a negative association between inhibin B and urinary levels of DMP, DEP, DETP and total DAP metabolites. DEP levels were negatively associated with serum FSH concentrations, but marginally and positively associated with those of testosterone. DETP was marginally associated with lower LH serum levels. There were no other significant associations among OP metabolites and serum hormone levels. Inhibin B and FSH vary according to levels of DAP metabolites in men occupationally exposed to OP pesticides. These results suggest that OP pesticides could act as endocrine disruptors in humans; however, most hormonal values fell within the wide normal range and associations were small. There is, therefore, a need for further investigation to elucidate their biological and clinical relevance.

Urinary Biomarkers for Phthalates Associated with Asthma in Norwegian Children

PubMed Central

Carlsen, Karin C. Lødrup; Calafat, Antonia M.; Hoppin, Jane A.; Håland, Geir; Mowinckel, Petter; Carlsen, Kai-Håkon; Løvik, Martinus

2012-01-01

Background: High-molecular-weight phthalates in indoor dust have been associated with asthma in children, but few studies have evaluated phthalate biomarkers in association with respiratory outcomes. Objectives: We explored the association between urinary concentrations of phthalate metabolites and current asthma. Methods: In a cross-sectional analysis, 11 metabolites of 8 phthalates [including four metabolites of di(2-ethylhexyl) phthalate] were measured in one first morning void collected from 2001 through 2004 from 623 10-year-old Norwegian children. Logistic regression models controlling for urine specific gravity, sex, parental asthma, and income were used to estimate associations between current asthma and phthalate metabolite concentrations by quartiles or as log10-transformed variables. Results: Current asthma was associated with both mono(carboxyoctyl) phthalate (MCOP) and mono(carboxynonyl) phthalate (MCNP), although the association was limited to those in the highest quartile of these chemicals. The adjusted odds ratio (aOR) for current asthma was 1.9 (95% CI: 1.0, 3.3) for the highest MCOP quartile compared with the lowest quartile, and 1.3 (95% CI: 0.98, 1.7) for an interquartile-range increase. The aOR for current asthma was 2.2 (95% CI: 1.2, 4.0) for the highest MCNP quartile and 1.3 (95% CI: 1.0, 1.7) for an interquartile-range increase. The other phthalate metabolites were not associated with current asthma. Conclusions: Current asthma was associated with the highest quartiles of MCOP and MCNP, metabolites of two high molecular weight phthalates, diisononyl phthalate and diisodecyl phthalate, respectively. Given the short biological half-life of the phthalates and the cross-sectional design, our findings should be interpreted cautiously. PMID:23164678

A comparison of direct and indirect analytical approaches to measuring total nicotine equivalents in urine.

PubMed

Taghavi, Taraneh; Novalen, Maria; Lerman, Caryn; George, Tony P; Tyndale, Rachel F

2018-05-31

Total nicotine equivalents (TNE), the sum of nicotine and metabolites in urine, is a valuable tool for evaluating nicotine exposure. Most methods for measuring TNE involve two-step enzymatic hydrolysis for indirect quantification of glucuronide metabolites. Here, we describe a rapid, low-cost direct liquid chromatography - tandem mass spectrometry (LCMS) assay. In 139 smokers' urine samples, Bland-Altman, correlation, and regression analyses were used to investigate differences in quantification of nicotine and metabolites, TNE, and nicotine metabolite ratio (NMR) between direct and indirect LCMS methods. DNA from a subset (n=97 smokers) was genotyped for UGT2B10*2 and UGT2B17*2 and the known impact of these variants was evaluated using urinary ratios determined by the direct versus indirect method. The direct method showed high accuracy (0-9% bias) and precision (3-14% coefficient of variation) with similar distribution of nicotine metabolites to literary estimates and good agreement between the direct and indirect methods for nicotine, cotinine, and 3-hydroxycotinine (ratios 0.99-1.07), but less agreement for their respective glucuronides (ratios 1.16-4.17). The direct method identified urinary 3HC+3HC-GLUC/COT as having the highest concordance with plasma NMR and provided substantially better estimations of the established genetic impact of glucuronidation variants compared to the indirect method. Direct quantification of nicotine and metabolites is less time-consuming and less costly, and provides accurate estimates of nicotine intake, metabolism rate and the impact of genetic variation in smokers. Lower cost and maintenance combined with high accuracy and reproducibility make the direct method ideal for smoking biomarker, NMR and pharmacogenomics studies. Copyright ©2018, American Association for Cancer Research.

Simultaneous Quantification of Multiple Urinary Naphthalene Metabolites by Liquid Chromatography Tandem Mass Spectrometry

PubMed Central

Ayala, Daniel C.; Morin, Dexter; Buckpitt, Alan R.

2015-01-01

Naphthalene is an environmental toxicant to which humans are exposed. Naphthalene causes dose-dependent cytotoxicity to murine airway epithelial cells but a link between exposure and human pulmonary disease has not been established. Naphthalene toxicity in rodents depends on P450 metabolism. Subsequent biotransformation results in urinary elimination of several conjugated metabolites. Glucuronide and sulfate conjugates of naphthols have been used as markers of naphthalene exposure but, as the current studies demonstrate, these assays provide a limited view of the range of metabolites generated from the parent hydrocarbon. Here, we present a liquid chromatography tandem mass spectrometry method for measurement of the glucuronide and sulfate conjugates of 1-naphthol as well as the mercapturic acids and N-acetyl glutathione conjugates from naphthalene epoxide. Standard curves were linear over 2 log orders. On column detection limits varied from 0.91 to 3.4 ng; limits of quantitation from 1.8 to 6.4 ng. The accuracy of measurement of spiked urine standards was -13.1 to + 5.2% of target and intra-day and inter-day variability averaged 7.2 (± 4.5) and 6.8 (± 5.0) %, respectively. Application of the method to urine collected from mice exposed to naphthalene at 15 ppm (4 hrs) showed that glutathione-derived metabolites accounted for 60-70% of the total measured metabolites and sulfate and glucuronide conjugates were eliminated in equal amounts. The method is robust and directly measures several major naphthalene metabolites including those derived from glutathione conjugation of naphthalene epoxide. The assays do not require enzymatic deconjugation, extraction or derivatization thus simplifying sample work up. PMID:25853821

Determination of total concentration of chemically labeled metabolites as a means of metabolome sample normalization and sample loading optimization in mass spectrometry-based metabolomics.

PubMed

Wu, Yiman; Li, Liang

2012-12-18

For mass spectrometry (MS)-based metabolomics, it is important to use the same amount of starting materials from each sample to compare the metabolome changes in two or more comparative samples. Unfortunately, for biological samples, the total amount or concentration of metabolites is difficult to determine. In this work, we report a general approach of determining the total concentration of metabolites based on the use of chemical labeling to attach a UV absorbent to the metabolites to be analyzed, followed by rapid step-gradient liquid chromatography (LC) UV detection of the labeled metabolites. It is shown that quantification of the total labeled analytes in a biological sample facilitates the preparation of an appropriate amount of starting materials for MS analysis as well as the optimization of the sample loading amount to a mass spectrometer for achieving optimal detectability. As an example, dansylation chemistry was used to label the amine- and phenol-containing metabolites in human urine samples. LC-UV quantification of the labeled metabolites could be optimally performed at the detection wavelength of 338 nm. A calibration curve established from the analysis of a mixture of 17 labeled amino acid standards was found to have the same slope as that from the analysis of the labeled urinary metabolites, suggesting that the labeled amino acid standard calibration curve could be used to determine the total concentration of the labeled urinary metabolites. A workflow incorporating this LC-UV metabolite quantification strategy was then developed in which all individual urine samples were first labeled with (12)C-dansylation and the concentration of each sample was determined by LC-UV. The volumes of urine samples taken for producing the pooled urine standard were adjusted to ensure an equal amount of labeled urine metabolites from each sample was used for the pooling. The pooled urine standard was then labeled with (13)C-dansylation. Equal amounts of the (12)C-labeled individual sample and the (13)C-labeled pooled urine standard were mixed for LC-MS analysis. This way of concentration normalization among different samples with varying concentrations of total metabolites was found to be critical for generating reliable metabolome profiles for comparison.

Analyses of plasma for metabolic and hormonal changes in rats flown aboard Cosmos 2044

NASA Technical Reports Server (NTRS)

Merrill, Alfred H., Jr.; Wang, Elaine; Mullins, Richard E.; Grindeland, Richard E.; Popova, Irina A.

1992-01-01

Plasmas samples from rats flown aboard Cosmos 2044 were analyzed for the levels of key metabolites, electrolytes, enzymes, and hormones. The major differences between the flight group and the synchronous control were elevations in glucose, cholesterol, phosphate, creatinine, blood urea nitrogen, lactate dehydrogenase, and aspartate aminotransferase and decreased levels of thyroxine. Most of these differences were not mimicked by tail suspension of ground-based rats; however, both flight and suspended rats exhibited inhibited testosterone secretion. Corticosterone, immunoreactive growth hormone, and prolactin showed inconsistent differences from the various control groups, suggesting that the levels of these hormones were not due to actual or simulated microgravity.

Behavioural and physiological responses of birds to environmentally relevant concentrations of an antidepressant

PubMed Central

Bean, Tom G.; Boxall, Alistair B. A.; Lane, Julie; Herborn, Katherine A.; Pietravalle, Stéphane; Arnold, Kathryn E.

2014-01-01

Many wildlife species forage on sewage-contaminated food, for example, at wastewater treatment plants and on fields fertilized with sewage sludge. The resultant exposure to human pharmaceuticals remains poorly studied for terrestrial species. On the basis of predicted exposure levels in the wild, we administered the common antidepressant fluoxetine (FLUOX) or control treatment via prey to wild-caught starlings (Sturnus vulgaris) for 22 weeks over winter. To investigate responses to fluoxetine, birds were moved from their group aviaries into individual cages for 2 days. Boldness, exploration and activity levels showed no treatment effects but controls and FLUOX birds habituated differently to isolation in terms of the concentration of corticosterone (CORT) metabolites in faeces. The controls that excreted higher concentrations of CORT metabolites on day 1 lost more body mass by day 2 of isolation than those which excreted lower levels of CORT metabolites. CORT metabolites and mass loss were unrelated in FLUOX birds. When we investigated the movements of birds in their group aviaries, we found the controls made a higher frequency of visits to food trays than FLUOX birds around the important foraging periods of sunrise and sunset, as is optimal for wintering birds. Although individual variability makes interpreting the sub-lethal endpoints measured challenging, our data suggest that fluoxetine at environmentally relevant concentrations can significantly alter behaviour and physiology. PMID:25405964

Exposure to organophosphate flame retardants of hotel room attendants in Wuhan City, China.

PubMed

Tao, Yun; Shang, Yinzhu; Li, Jing; Feng, Jingwen; He, Zhenyu; Covaci, Adrian; Wang, Peng; Luo, Jing; Mao, Xiang; Shi, Bin; Hu, Liqin; Luo, Dan; Mei, Surong

2018-05-01

Indoor environments provide sources of exposure to organophosphate flame retardants (PFRs), which are artificially synthesized fire-protecting agents used as additives in interior products. As public spaces, hotels are required to meet stricter fire-precaution criteria. As such, room attendants may be exposed to higher levels of PFRs. Our goal was to characterize the exposure of hotel room attendants to PFRs by measuring metabolites in their urine and the corresponding parent PFRs in dust and hand-wipes collected from 27 hotels located in Wuhan City, China. The exposure of the attendants was found to be omnipresent: urinary metabolites of PFRs, such as DPHP (diphenyl phosphate), BDCIPP (bis(1,3-dichloro-2-propyl) phosphate), and DoCP (di-o-cresyl phosphate) & DpCP (di-p-cresyl phosphate) were detected with high frequency (87%, 79% and 87%, respectively). We observed that metabolites in post-shift urine were consistently present at higher levels than those in the first morning voids (p < 0.05 for BDCIPP and DPHP). Regarding external exposure, 10 PFRs were determined in both dust samples and hand-wipes, with TCIPP (tris(2-chloroisopropyl) phosphate) being the most abundant compound in both matrices. The levels of PFRs in hand-wipes and dust samples were not correlated. PFRs in dust and their corresponding urinary metabolites were not significantly correlated, while a moderate significant correlation of TDCIPP (tris(1,3-dichloro-2-propyl) phosphate) in hand-wipes and its urinary metabolite, BDCIPP, was observed in both morning void samples (p = 0.01) and post-shift urine (p = 0.002). Moreover, we found that participants from high-rise buildings (defined as > 7 stories) had significantly higher BDCIPP and DPHP concentrations than those from low-rise buildings. A possible reason is that high-rise buildings may use high-grade fireproof building materials to meet stricter fire restrictions. Overall, these results indicate that PFRs exposure in hotels is a contributor to the personal exposure of hotel room attendants. Copyright © 2018 Elsevier Ltd. All rights reserved.

Vitamin D, Hypercalciuria and Kidney Stones

PubMed Central

Letavernier, Emmanuel; Daudon, Michel

2018-01-01

The estimated lifetime risk of nephrolithiasis is growing nowadays, and the formation of kidney stones is frequently promoted by hypercalciuria. Vitamin D, and especially its active metabolite calcitriol, increase digestive calcium absorption—as urinary calcium excretion is directly correlated with digestive calcium absorption, vitamin D metabolites could theoretically increase calciuria and promote urinary stone formation. Nevertheless, there was, until recently, low evidence that 25-hydroxyvitamin D serum levels would be correlated with kidney stone formation, even if high calcitriol concentrations are frequently observed in hypercalciuric stone formers. Low 25-hydroxyvitamin D serum levels have been associated with a broad spectrum of diseases, leading to a huge increase in vitamin D prescription in the general population. In parallel, an increased frequency of kidney stone episodes has been observed in prospective studies evaluating vitamin D alone or in association with calcium supplements, and epidemiological studies have identified an association between high 25-hydroxyvitamin D serum levels and kidney stone formation in some groups of patients. Moreover, urinary calcium excretion has been shown to increase in response to vitamin D supplements, at least in some groups of kidney stone formers. It seems likely that predisposed individuals may develop hypercalciuria and kidney stones in response to vitamin D supplements. PMID:29562593

A metabolomics-driven approach to predict cocoa product consumption by designing a multimetabolite biomarker model in free-living subjects from the PREDIMED study.

PubMed

Garcia-Aloy, Mar; Llorach, Rafael; Urpi-Sarda, Mireia; Jáuregui, Olga; Corella, Dolores; Ruiz-Canela, Miguel; Salas-Salvadó, Jordi; Fitó, Montserrat; Ros, Emilio; Estruch, Ramon; Andres-Lacueva, Cristina

2015-02-01

The aim of the current study was to apply an untargeted metabolomics strategy to characterize a model of cocoa intake biomarkers in a free-living population. An untargeted HPLC-q-ToF-MS based metabolomics approach was applied to human urine from 32 consumers of cocoa or derived products (CC) and 32 matched control subjects with no consumption of cocoa products (NC). The multivariate statistical analysis (OSC-PLS-DA) showed clear differences between CC and NC groups. The discriminant biomarkers identified were mainly related to the metabolic pathways of theobromine and polyphenols, as well as to cocoa processing. Consumption of cocoa products was also associated with reduced urinary excretions of methylglutarylcarnitine, which could be related to effects of cocoa exposure on insulin resistance. To improve the prediction of cocoa consumption, a combined urinary metabolite model was constructed. ROC curves were performed to evaluate the model and individual metabolites. The AUC values (95% CI) for the model were 95.7% (89.8-100%) and 92.6% (81.9-100%) in training and validation sets, respectively, whereas the AUCs for individual metabolites were <90%. The metabolic signature of cocoa consumption in free-living subjects reveals that combining different metabolites as biomarker models improves prediction of dietary exposure to cocoa. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biochemical sensor tubing for point-of-care monitoring of intravenous drugs and metabolites.

PubMed

Choi, Charles J; Wu, Hsin-Yu; George, Sherine; Weyhenmeyer, Jonathan; Cunningham, Brian T

2012-02-07

In medical facilities, there is strong motivation to develop detection systems that can provide continuous analysis of fluids in medical tubing used to either deliver or remove fluids from a patient's body. Possible applications include systems that increase the safety of intravenous (IV) drug injection and point-of-care health monitoring. In this work, we incorporated a surface-enhanced Raman scattering (SERS) sensor comprised of an array of closely spaced metal nanodomes into flexible tubing commonly used for IV drug delivery and urinary catheters. The nanodome sensor was fabricated by a low-cost, large-area process that enables single use disposable operation. As exemplary demonstrations, the sensor was used to kinetically detect promethazine (pain medication) and urea (urinary metabolite) within their clinically relevant concentration ranges. Distinct SERS peaks for each analyte were used to demonstrate separate detection and co-detection of the analytes.

The tomato sauce making process affects the bioaccessibility and bioavailability of tomato phenolics: a pharmacokinetic study.

PubMed

Martínez-Huélamo, Miriam; Tulipani, Sara; Estruch, Ramón; Escribano, Elvira; Illán, Montserrat; Corella, Dolores; Lamuela-Raventós, Rosa M

2015-04-15

Tomato sauce is the most commonly consumed processed tomato product worldwide, but very little is known about how the manufacturing process may affect the phenolic composition and bioavailability after consumption. In a prospective randomised, cross-over intervention study, we analysed the plasma and urinary levels of tomato phenolic compounds and their metabolites after acute consumption of raw tomatoes and tomato sauce, enriched or not with refined olive oil during production. Respectively, eleven and four phenolic metabolites were found in urine and plasma samples. The plasma concentration and urinary excretion of naringenin glucuronide were both significantly higher after the consumption of tomato sauce than raw tomatoes. The results suggest that the mechanical and thermal treatments during tomato sauce manufacture may help to deliver these potentially bioactive phenolics from the food matrix more effectively than the addition of an oil component, thus increasing their bioavailability. Copyright © 2014 Elsevier Ltd. All rights reserved.

Selenium metabolite levels in human urine after dosing selenium in different chemical forms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hasunuma, Ryoichi; Tsuda, Morizo; Ogawa, Tadao

1993-11-01

It has been well known that selenium in marine fish such as tuna and swordfish protects the toxicity of methylmercury in vivo. The protective potency might depend on the chemical forms of selenium in the meat of marine fish sebastes and sperm whale. Little has been revealed, however, on the chemical forms of selenium in the meat of these animals or the selenium metabolites in urine, because the amount of the element is very scarce. Urine is the major excretory route for selenium. The chemical forms of urinary selenium may reflect the metabolism of the element. We have developed methodologymore » for analysis of selenium-containing components in human urine. Using this method, we have observed the time courses of excretory levels of urinary selenium components after a single dose of selenium as selenious acid, selenomethionine, trimethylselenonium ion or tuna meat. 14 refs., 6 figs., 1 tab.« less

Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke

PubMed Central

Hecht, S

2004-01-01

Objective: To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts. Method: Published reviews and the current literature were searched for relevant articles. Results: The most consistently elevated biomarker in people exposed to SHS was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc), urinary metabolites of the tobacco specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The tobacco specificity of this biomarker as well as its clear relation to an established lung carcinogen are particularly appropriate for its application in studies of SHS exposure. Conclusion: The results of the available carcinogen derived biomarker studies provide biochemical data which support the conclusion, based on epidemiologic investigations, that SHS causes lung cancer in non-smokers. PMID:14985617

Stereometabolism of ethylbenzene in man: gas chromatographic determination of urinary excreted mandelic acid enantiomers and phenylglyoxylic acid and their relation to the height of occupational exposure.

PubMed

Korn, M; Gfrörer, W; Herz, R; Wodarz, I; Wodarz, R

1992-01-01

Ethylbenzene is an important industrial solvent and a key substance in styrene production. Ethylbenzene metabolism leads to the formation of mandelic acid, which occurs in two enantiomeric forms, and phenylglyoxylic acid. To decide which enantiomer is preferably formed, 70 urine samples of exposed workers were taken at the end of shifts and--after 3-pentyl ester derivatisation--gas chromatographically analysed. The R/S ratio of mandelic acid enantiomers in urine amounts to 19:1, which means that R-mandelic acid is a major metabolite and S-mandelic acid is one of the minor urinary metabolites of ethylbenzene in man. The R/S ratio is independent of ambient air concentration of ethylbenzene within the investigated range. Compared to an ethylbenzene monoexposure the height of total mandelic acid excretion is decreased in the case of coexposure to other aromatic solvents.

Chromium supplementation improved post-stroke brain infarction and hyperglycemia.

PubMed

Chen, Wen-Ying; Mao, Frank Chiahung; Liu, Chia-Hsin; Kuan, Yu-Hsiang; Lai, Nai-Wei; Wu, Chih-Cheng; Chen, Chun-Jung

2016-04-01

Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia.

Relevance of urinary 3-hydroxybenzo(a)pyrene and 1-hydroxypyrene to assess exposure to carcinogenic polycyclic aromatic hydrocarbon mixtures in metallurgy workers.

PubMed

Barbeau, Damien; Persoons, Renaud; Marques, Marie; Hervé, Claire; Laffitte-Rigaud, Gilbert; Maitre, Anne

2014-06-01

In metallurgy, workers are exposed to mixtures of polycyclic aromatic hydrocarbons (PAHs) in which some compounds are carcinogenic. Biomonitoring of PAH exposure has been performed by measuring urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene which is not carcinogenic. This study investigated the use of 3-hydroxybenzo(a)pyrene (3-OHBaP), a metabolite of benzo(a)pyrene (BaP) which is the main carcinogenic component in PAHs, to improve carcinogen exposure assessment. We included 129 metallurgy workers routinely exposed to PAHs during working hours. Urinary samples were collected at three sampling times at the beginning and at the end of the working week for 1-OHP and 3-OHBaP analyses. Workers in anode production showed greater exposure to both biomarkers than those in cathode or silicon production, with respectively, 71, 40, and 30% of 3-OHBaP concentrations exceeding the value of 0.4 nmol mol(-1) creatinine. No difference was observed between the 3-OHBaP levels found at the end of the penultimate workday shift and those at the beginning of the last workday shift. Within these plants, the 1-OHP/3-OHBaP ratios varied greatly according to the workers' activity and emission sources. Using linear regression between these two metabolites, the 1-OHP level corresponding to the guidance value for 3-OHBaP ranged from 0.7 to 2.4 µmol mol(-1) creatinine, depending on the industrial sector. This study emphasizes the interest of monitoring urinary 3-OHBaP at the end of the last workday shift when working week exposure is relatively steady, and the irrelevance of a single guideline value for 1-OHP when assessing occupational health risk. © The Author 2014. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study

PubMed Central

Mukherjee, Dwaipayan; Royce, Steven G.; Alexander, Jocelyn A.; Buckley, Brian; Isukapalli, Sastry S.; Bandera, Elisa V.; Zarbl, Helmut; Georgopoulos, Panos G.

2014-01-01

Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population. PMID:25474635

Effect of pistachio consumption on the modulation of urinary gut microbiota-related metabolites in prediabetic subjects.

PubMed

Hernández-Alonso, Pablo; Cañueto, Daniel; Giardina, Simona; Salas-Salvadó, Jordi; Cañellas, Nicolau; Correig, Xavier; Bulló, Mònica

2017-07-01

The specific nutritional composition of nuts could affect different metabolic pathways involved in a broad range of metabolic diseases. We therefore investigated whether chronic consumption of pistachio nuts modifies the urine metabolome in prediabetic subjects. We designed a randomized crossover clinical trial in 39 prediabetic subjects. They consumed a pistachio-supplemented diet (PD, 50% carbohydrates, 33% fat, including 57 g/d of pistachios daily) and a control diet (CD, 55% carbohydrates, 30% fat) for 4 months each, separated by a 2-week wash-out. Nuclear magnetic resonance (NRM) was performed to determine changes in 24-h urine metabolites. Significant changes in urine metabolites according to the different intervention periods were found in uni- and multivariate analysis. Score plot of the first two components of the multilevel partial least squares discriminant analysis (ML-PLS-DA) showed a clear separation of the intervention periods. Three metabolites related with gut microbiota metabolism (i.e., hippurate, p-cresol sulfate and dimethylamine) were found decreased in PD compared with CD (P<.05). Moreover, cis-aconitate [intermediate of the tricarboxylic acid (TCA)] was also found decreased following PD compared with CD. Intragroup analysis showed that creatinine levels were significantly increased in PD (P=.023), whereas trimethylamine N-oxide (TMAO) was found significantly reduced following PD (P=.034). Our results suggest that chronic pistachio consumption may modulate some urinary metabolites related to gut microbiota metabolism and the TCA cycle; all associated with metabolic derangements associated with insulin resistance and Type 2 diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Urinary Excretion of Buprenorphine, Norbuprenorphine, Buprenorphine-Glucuronide, and Norbuprenorphine-Glucuronide in Pregnant Women Receiving Buprenorphine Maintenance Treatment

PubMed Central

Kacinko, Sherri L.; Jones, Hendree E.; Johnson, Rolley E.; Choo, Robin E.; Concheiro-Guisan, Marta; Huestis, Marilyn A.

2011-01-01

BACKGROUND Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. We investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum. METHODS We measured BUP, norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. Specimens were analyzed using a fully validated liquid chromatography-mass spectrometry method with limits of quantification of 5 µg/L for BUP and BUP-Gluc and 25 µg/L for NBUP and its conjugated metabolite. We examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy. RESULTS NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy. CONCLUSIONS These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation. PMID:19325013

Identification of a novel human deoxynivalenol metabolite enhancing proliferation of intestinal and urinary bladder cells

PubMed Central

Warth, Benedikt; Del Favero, Giorgia; Wiesenberger, Gerlinde; Puntscher, Hannes; Woelflingseder, Lydia; Fruhmann, Philipp; Sarkanj, Bojan; Krska, Rudolf; Schuhmacher, Rainer; Adam, Gerhard; Marko, Doris

2016-01-01

The mycotoxin deoxynivalenol (DON) is an abundant contaminant of cereal based food and a severe issue for global food safety. We report the discovery of DON-3-sulfate as a novel human metabolite and potential new biomarker of DON exposure. The conjugate was detectable in 70% of urine samples obtained from pregnant women in Croatia. For the measurement of urinary metabolites, a highly sensitive and selective LC-MS/MS method was developed and validated. The method was also used to investigate samples from a duplicate diet survey for studying the toxicokinetics of DON-3-sulfate. To get a preliminary insight into the biological relevance of the newly discovered DON-sulfates, in vitroexperiments were performed. In contrast to DON, sulfate conjugates lacked potency to suppress protein translation. However, surprisingly we found that DON-sulfates enhanced proliferation of human HT-29 colon carcinoma cells, primary human colon epithelial cells (HCEC-1CT) and, to some extent, also T24 bladder cancer cells. A proliferative stimulus, especially in tumorigenic cells raises concern on the potential impact of DON-sulfates on consumer health. Thus, a further characterization of their toxicological relevance should be of high priority. PMID:27659167

Association between Phthalate Exposure and the Use of Plastic Containers in Shanghai Adults.

PubMed

Dong, Rui Hua; Zhang, Han; Zhang, Mei Ru; Chen, Jing Si; Wu, Min; Li, Shu Guang; Chen, Bo

2017-10-01

Consuming phthalates may be due to the presence of food contact materials, such as plastic containers. In this study, we investigated the association between plastic container use and phthalate exposure in 2,140 Shanghai adults. Participants completed a questionnaire on the frequency of using plastic containers in different scenarios in the previous year (e.g., daily, weekly) and on the consumption of plastic-packaged foods in the previous three days (yes or no). Urinary phthalate metabolites were used to assess the association between phthalate exposure and the use of plastic containers. The metabolites of di-(2-ethylhexyl) phthalate (DEHP) were the most frequently detected in urine. The results revealed that phthalate exposure was associated with consumption of plastic-packaged breakfast or processed food items in the previous three days. The consumption of these two food items had strong synergistic effects on increasing urinary concentrations of most phthalate metabolites. Our results of plastic-packaged breakfast and processed food may be explained by the use of flexible plastic containers, indicating the importance of risk assessment for the application of flexible plastic containers. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Identification of a novel human deoxynivalenol metabolite enhancing proliferation of intestinal and urinary bladder cells

NASA Astrophysics Data System (ADS)

Warth, Benedikt; Del Favero, Giorgia; Wiesenberger, Gerlinde; Puntscher, Hannes; Woelflingseder, Lydia; Fruhmann, Philipp; Sarkanj, Bojan; Krska, Rudolf; Schuhmacher, Rainer; Adam, Gerhard; Marko, Doris

2016-09-01

The mycotoxin deoxynivalenol (DON) is an abundant contaminant of cereal based food and a severe issue for global food safety. We report the discovery of DON-3-sulfate as a novel human metabolite and potential new biomarker of DON exposure. The conjugate was detectable in 70% of urine samples obtained from pregnant women in Croatia. For the measurement of urinary metabolites, a highly sensitive and selective LC-MS/MS method was developed and validated. The method was also used to investigate samples from a duplicate diet survey for studying the toxicokinetics of DON-3-sulfate. To get a preliminary insight into the biological relevance of the newly discovered DON-sulfates, in vitroexperiments were performed. In contrast to DON, sulfate conjugates lacked potency to suppress protein translation. However, surprisingly we found that DON-sulfates enhanced proliferation of human HT-29 colon carcinoma cells, primary human colon epithelial cells (HCEC-1CT) and, to some extent, also T24 bladder cancer cells. A proliferative stimulus, especially in tumorigenic cells raises concern on the potential impact of DON-sulfates on consumer health. Thus, a further characterization of their toxicological relevance should be of high priority.

Evaluating Cumulative OP Pesticide Body Burden of Children: A National Case Study

PubMed Central

Payne-Sturges, Devon; Cohen, Jonathan; Castorina, Rosemary; Axelrad, Daniel A.; Woodruff, Tracey J.

2009-01-01

Biomonitoring is a valuable tool for identifying exposures to chemicals that pose potential harm to human health. However, to date there has been little published on ways to evaluate the relative public health significance of biomonitoring data for different chemicals, and even less on cumulative assessment of multiple chemicals. The objectives of our study are to develop a methodology for a health risk interpretation of biomonitoring data, and to apply it using NHANES 1999–2002 body burden data for organophosphorus (OP) pesticides. OP pesticides present a particularly challenging case given the non-specificity of many metabolites monitored through NHANES. We back-calculate OP pesticide exposures from urinary metabolite data, and compare cumulative dose estimates with available toxicity information for a common mechanism of action (brain cholinesterase inhibition) using data from U.S. EPA. Our results suggest that approximately 40% of children in the United States may have had insufficient margins of exposure (MOEs) for neurological impacts from cumulative exposures to OP pesticides (MOE less than 1,000). Limitations include uncertainty related to assumptions about likely precursor pesticide compounds of the urinary metabolites, sources of exposure, and intra-individual and temporal variability. PMID:19921915

The metabolic impact of methamphetamine on the systemic metabolism of rats and potential markers of methamphetamine abuse.

PubMed

Zheng, Tian; Liu, Linsheng; Shi, Jian; Yu, Xiaoyi; Xiao, Wenjing; Sun, Runbing; Zhou, Yahong; Aa, Jiye; Wang, Guangji

2014-07-01

Although the stimulating and psychotropic effects of methamphetamine (METH) on the nervous system are well documented, the impact of METH abuse on biological metabolism and the turnover of peripheral transmitters are poorly understood. Metabolomics has the potential to reveal the effect of METH abuse on systemic metabolism and potential markers suggesting the underlying mechanism of toxicity. In this study, male Sprague Dawley rats were intraperitoneally injected with METH at escalating doses of mg kg(-1) for 5 consecutive days and then were withdrawn for 2 days. The metabolites in the serum and urine were profiled and the systemic effects of METH on metabolic pathways were evaluated. Multivariate statistical analysis showed that METH caused distinct deviations, whereas the withdrawal of METH restored the metabolic patterns towards baseline. METH administration elevated energy metabolism, which was manifested by the distinct depletion of branched-chain amino acids, accelerated tricarboxylic-acid cycle and lipid metabolism, reduced serum glycerol-3-phosphate, and elevated serum and urinary 3-hydroxybutyrate and urinary glycerol. In addition to the increased serum levels of the excitatory amino acids glutamate and aspartate (the inhibitory neurotransmitters in the brain), a marked decline in serum alanine and glycine after METH treatment suggested the activation and decreased inhibition of the nervous system and hence elevated nervous activity. Withdrawal of METH for 2 days efficiently restored all but a few metabolites to baseline, including serum creatinine, citrate, 2-ketoglutarate, and urinary lactate. Therefore, these metabolites are potential markers of METH use, and they may be used to facilitate the diagnosis of METH abuse.

Metabolomics study of human urinary metabolome modifications after intake of almond (Prunus dulcis (Mill.) D.A. Webb) skin polyphenols.

PubMed

Llorach, Rafael; Garrido, Ignacio; Monagas, Maria; Urpi-Sarda, Mireia; Tulipani, Sara; Bartolome, Begona; Andres-Lacueva, Cristina

2010-11-05

Almond, as a part of the nut family, is an important source of biological compounds, and specifically, almond skins have been considered an important source of polyphenols, including flavan-3-ols and flavonols. Polyphenol metabolism may produce several classes of metabolites that could often be more biologically active than their dietary precursor and could also become a robust new biomarker of almond polyphenol intake. In order to study urinary metabolome modifications during the 24 h after a single dose of almond skin extract, 24 volunteers (n = 24), who followed a polyphenol-free diet for 48 h before and during the study, ingested a dietary supplement of almond skin phenolic compounds (n = 12) or a placebo (n = 12). Urine samples were collected before ((-2)-0 h) and after (0-2 h, 2-6 h, 6-10 h, and 10-24 h) the intake and were analyzed by liquid chromatography-mass spectrometry (LC-q-TOF) and multivariate statistical analysis (principal component analysis (PCA) and orthogonal projection to latent structures (OPLS)). Putative identification of relevant biomarkers revealed a total of 34 metabolites associated with the single dose of almond extract, including host and, in particular, microbiota metabolites. As far as we know, this is the first time that conjugates of hydroxyphenylvaleric, hydroxyphenylpropionic, and hydroxyphenylacetic acids have been identified in human samples after the consumption of flavan-3-ols through a metabolomic approach. The results showed that this non-targeted approach could provide new intake biomarkers, contributing to the development of the food metabolome as an important part of the human urinary metabolome.

Urinary levels of N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA), an acrylamide metabolite, in Korean children and their association with food consumption.

PubMed

Ji, Kyunghee; Kang, Sungeun; Lee, Gowoon; Lee, Saeram; Jo, Areum; Kwak, Kyunghee; Kim, Dohyung; Kho, Dohyun; Lee, Sangwoo; Kim, Sunmi; Kim, Sungkyoon; Hiuang, Yuh-Fang; Wu, Kuen-Yuh; Choi, Kyungho

2013-07-01

Acrylamide (AA), a probable human carcinogen, is present in high-temperature-processed foods, and has frequently been detected in humans worldwide. In the present study, the levels of a major AA metabolite, N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) were measured in urine samples collected in two separate events with 3d interval from Korean children (n=31, 10-13 years old), and their diets were surveyed for 4d period prior to the second urine sampling. Daily AA intake was estimated from AAMA urinary levels and the influence of food consumption on urinary AAMA levels was investigated. The concentrations of metabolite AAMA in urine ranged between 15.4 and 196.3 ng/mL, with a median level of 68.1 ng/mL, and the levels varied by day considerably even in a given child. Children who were exposed to environmental smoke at home exhibited significantly higher levels of AAMA in urine, suggesting the importance of passive smoking as a source of AA exposure among children. Median (95th percentile) values of daily AA intake in Korean children were 1.04 (2.47)μg/kgbodyweight/day, which is higher than those reported elsewhere. After adjustment for gender, body mass index, and smoking status of family members, the consumptions of cracker and chocolate were identified to be significantly associated with the concentrations of AAMA in urine. The result of this study will provide information useful for developing public health and safety management for AA. Copyright © 2013 Elsevier B.V. All rights reserved.

Non-targeted metabolomic biomarkers and metabotypes of type 2 diabetes: A cross-sectional study of PREDIMED trial participants.

PubMed

Urpi-Sarda, M; Almanza-Aguilera, E; Llorach, R; Vázquez-Fresno, R; Estruch, R; Corella, D; Sorli, J V; Carmona, F; Sanchez-Pla, A; Salas-Salvadó, J; Andres-Lacueva, C

2018-02-20

To characterize the urinary metabolomic fingerprint and multi-metabolite signature associated with type 2 diabetes (T2D), and to classify the population into metabotypes related to T2D. A metabolomics analysis using the 1 H-NMR-based, non-targeted metabolomic approach was conducted to determine the urinary metabolomic fingerprint of T2D compared with non-T2D participants in the PREDIMED trial. The discriminant metabolite fingerprint was subjected to logistic regression analysis and ROC analyses to establish and to assess the multi-metabolite signature of T2D prevalence, respectively. Metabotypes associated with T2D were identified using the k-means algorithm. A total of 33 metabolites were significantly different (P<0.05) between T2D and non-T2D participants. The multi-metabolite signature of T2D comprised high levels of methylsuccinate, alanine, dimethylglycine and guanidoacetate, and reduced levels of glutamine, methylguanidine, 3-hydroxymandelate and hippurate, and had a 96.4% AUC, which was higher than the metabolites on their own and glucose. Amino-acid and carbohydrate metabolism were the main metabolic alterations in T2D, and various metabotypes were identified in the studied population. Among T2D participants, those with a metabotype of higher levels of phenylalanine, phenylacetylglutamine, p-cresol and acetoacetate had significantly higher levels of plasma glucose. The multi-metabolite signature of T2D highlights the altered metabolic fingerprint associated mainly with amino-acid, carbohydrate and microbiota metabolism. Metabotypes identified in this patient population could be related to higher risk of long-term cardiovascular events and therefore require further studies. Metabolomics is a useful tool for elucidating the metabolic complexity and interindividual variation in T2D towards the development of stratified precision nutrition and medicine. Trial registration at www.controlled-trials.com: ISRCTN35739639. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Assessment of serum pharmacokinetics and urinary excretion of albendazole and its metabolites in human volunteers.

PubMed

Ceballos, Laura; Krolewiecki, Alejandro; Juárez, Marisa; Moreno, Laura; Schaer, Fabian; Alvarez, Luis I; Cimino, Rubén; Walson, Judd; Lanusse, Carlos E

2018-01-01

Soil Transmitted Helminth (STH) infections negatively impact physical and mental development in human populations. Current WHO guidelines recommend morbidity control of these infections through mass drug administration (MDA) using albendazole (ABZ) or mebendazole. Despite major reductions in STH associated morbidity globally, not all programs have demonstrated the expected impact on prevalence of parasite infections. These therapeutic failures may be related to poor programmatic coverage, suboptimal adherence or the exposure of parasites to sub-therapeutic drug concentrations. As part of the DeWorm3 project, we sought to characterize the serum disposition kinetics and pattern of urinary excretion of ABZ and its main metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) in humans, and the assessment of the duration and optimal time point where ABZ and/or its metabolites can be measured in urine as an indirect assessment of an individual's adherence to treatment. Consecutive venous blood and urine samples were collected from eight (8) human volunteers up to 72 h post-ABZ oral administration. ABZ/metabolites were quantified by HPLC. The ABZSO metabolite was the main analyte recovered both in serum and urine. ABZSO Cmax in serum was 1.20 ± 0.44 μg/mL, reached at 4.75 h post-treatment. In urine, ABZSO Cmax was 3.24 ± 1.51 μg/mL reached at 6.50 h post-ABZ administration. Pharmacokinetic data obtained for ABZ metabolites in serum and urine, including the recovery of the ABZ sulphoxide derivative up to 72 h in both matrixes and the recovery of the amino-ABZ sulphone metabolite in urine samples, are suggesting the possibility of developing a urine based method to assess compliance to ABZ treatment. Such an assay may be useful to optimize ABZ use in human patients. ClinicalTrials.gov NCT03192449.

Urinary phthalate and phthalate alternative metabolites and isoprostane among couples undergoing fertility treatment.

PubMed

Wu, Haotian; Olmsted, Alexandra; Cantonwine, David E; Shahsavari, Shahin; Rahil, Tayyab; Sites, Cynthia; Pilsner, J Richard

2017-02-01

Epidemiological data suggest associations between phthalate exposures to a variety of adverse reproductive outcomes including reduced sperm quality and reproductive success. While mechanisms of these associations are not fully elucidated, oxidative stress has been implicated as a potential mediator. We examined associations of urinary metabolites of phthalates and phthalate alternative plasticizers with oxidative stress among couples seeking fertility treatment. Seventeen urinary plasticizer metabolites and 15-F2t isoprostane, a biomarker of oxidative stress, were quantified in spot samples from 50 couples seeking fertility treatment who enrolled in the Sperm Environmental Epigenetics and Development Study during 2014-2015. In multivariable analyses, percent change in isoprostane was positively associated with interquartile range increases for the oxidative metabolites of di-2-ethylhexyl phthalate, [mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP; 20.0%, p=0.02), mono-2-ethyl-5-oxohexyl phthalate (MEOHP; 24.1%, p=0.01), and mono-2-ethyl-5-carboxypentyl phthalate (MECPP; 24.1%, p=0.004)], mono-isobutyl phthalate (MiBP; 17.8%, p=0.02), mono-hydroxyisobutyl phthalate (MHiBP; 27.5%, p=0.003), and cyclohexane-1,2-dicarboxylic acid mono-hydroxy-isononyl ester (MHINCH; 32.3%, p=0.002). Stratification of participants by sex revealed that isoprostane was positively associated with MHiBP (41.4%, p=0.01) and monocarboxy-isononyl phthalate (MCNP; 26.0%, p=0.02) among females and MEOHP (35.8%, p=0.03), MiBP (29.2%, p=0.01), MHiBP (34.7%, p=0.007) and MHINCH (49.0%, p=0.002) among males. Our results suggest that exposure to phthalates and phthalate replacements are associated with higher levels of oxidative stress in a sex-specific manner. Additional studies are needed to replicate our findings and to examine the potential health implications of the use of phthalates and alternative phthalates in consumer end products. Copyright © 2016 Elsevier Inc. All rights reserved.

Prenatal Phthalate Exposures and Childhood Fat Mass in a New York City Cohort.

PubMed

Buckley, Jessie P; Engel, Stephanie M; Mendez, Michelle A; Richardson, David B; Daniels, Julie L; Calafat, Antonia M; Wolff, Mary S; Herring, Amy H

2016-04-01

Experimental animal studies and limited epidemiologic evidence suggest that prenatal exposure to phthalates may be obesogenic, with potential sex-specific effects of phthalates having anti-androgenic activity. We aimed to assess associations between prenatal phthalate exposures and childhood fat mass in a prospective cohort study. We measured phthalate metabolite concentrations in third-trimester maternal urine in a cohort of women enrolled in New York City between 1998 and 2002 (n = 404). Among 180 children (82 girls and 98 boys), we evaluated body composition using a Tanita scale at multiple follow-up visits between ages 4 and 9 years (363 total visits). We estimated associations of standard deviation differences or tertiles of natural log phthalate metabolite concentrations with percent fat mass using linear mixed-effects regression models with random intercepts for repeated outcome measurements. We assessed associations in multiple metabolite models and adjusted for covariates including prepregnancy body mass index, gestational weight gain, maternal smoking during pregnancy, and breastfeeding. We did not observe associations between maternal urinary phthalate concentrations and percent body fat in models examining continuous exposures. Fat mass was 3.06% (95% CI: -5.99, -0.09%) lower among children in the highest tertile of maternal urinary concentrations of summed di(2-ethylhexyl) phthalate (ΣDEHP) metabolites than in children in the lowest tertile. Though estimates were imprecise, there was little evidence that associations between maternal urinary phthalate concentrations and percent fat mass were modified by child's sex. Prenatal phthalate exposures were not associated with increased body fat among children 4-9 years of age, though high prenatal DEHP exposure may be associated with lower fat mass in childhood. Buckley JP, Engel SM, Mendez MA, Richardson DB, Daniels JL, Calafat AM, Wolff MS, Herring AH. 2016. Prenatal phthalate exposures and childhood fat mass in a New York City cohort. Environ Health Perspect 124:507-513; http://dx.doi.org/10.1289/ehp.1509788.

Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism.

PubMed

Engström, Karin; Vahter, Marie; Mlakar, Simona Jurkovic; Concha, Gabriela; Nermell, Barbro; Raqib, Rubhana; Cardozo, Alejandro; Broberg, Karin

2011-02-01

Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases. We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 µg/L] and in rural Bangladesh (n = 361; U-As, 100 µg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays. Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression. Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children.

PubMed

Philippat, Claire; Bennett, Deborah; Calafat, Antonia M; Picciotto, Irva Hertz

2015-07-01

Certain phenols and phthalates are used in many consumer products including personal care products (PCPs). We aimed to study the associations between the use of PCPs and urinary concentrations of biomarkers of select phenols and phthalates among Californian adults and their children. As an additional aim we compared phenols and phthalate metabolites concentrations measured in adults and children urine samples collected the same day. Our study relied on a subsample of 90 adult-child pairs participating in the Study of Use of Products and Exposure Related Behavior (SUPERB). Each adult and child provided one to two urine samples in which we measured concentrations of selected phenols and phthalate metabolites. We computed Spearman correlation coefficients to compare concentrations measured in adults and children urine samples collected the same day. We used adjusted linear and Tobit regression models to study the associations between the use of PCPs in the past 24h and biomarker concentrations. Benzophenone-3 and parabens concentrations were higher in adults compared to their children. Conversely children had higher mono-n-butyl phthalate and mono-isobutyl phthalate concentrations. No significant difference was observed for the other compounds. The total number of different PCPs used was positively associated with urinary concentrations of methyl, propyl and butyl parabens and the main metabolite of diethyl phthalate in adults. Among children, the use of a few specific products including liquid soap, hair care products and sunscreen was positively associated with urinary concentrations of some phenols or phthalate metabolites. These results strengthen the body of evidence suggesting that use of PCPs is an important source of exposure to parabens and diethyl phthalate in adults and provide data on exposure to selected phenols and phthalates through use of PCPs in children. Copyright © 2015 Elsevier Inc. All rights reserved.

Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children

PubMed Central

Philippat, Claire; Bennett, Deborah; Calafat, Antonia M.; Picciotto, Irva Hertz

2016-01-01

Introduction Certain phenols and phthalates are used in many consumer products including personal care products (PCPs). Aims We aimed to study the associations between the use of PCPs and urinary concentrations of bio-markers of select phenols and phthalates among Californian adults and their children. As an additional aim we compared phenols and phthalate metabolites concentrations measured in adults and children urine samples collected the same day. Methods Our study relied on a subsample of 90 adult–child pairs participating in the Study of Use of Products and Exposure Related Behavior (SUPERB). Each adult and child provided one to two urine samples in which we measured concentrations of selected phenols and phthalate metabolites. We computed Spearman correlation coefficients to compare concentrations measured in adults and children urine samples collected the same day. We used adjusted linear and Tobit regression models to study the associations between the use of PCPs in the past 24 h and biomarker concentrations. Results Benzophenone-3 and parabens concentrations were higher in adults compared to their children. Conversely children had higher mono-n-butyl phthalate and mono-isobutyl phthalate concentrations. No significant difference was observed for the other compounds. The total number of different PCPs used was positively associated with urinary concentrations of methyl, propyl and butyl parabens and the main metabolite of diethyl phthalate in adults. Among children, the use of a few specific products including liquid soap, hair care products and sunscreen was positively associated with urinary concentrations of some phenols or phthalate metabolites. Discussion These results strengthen the body of evidence suggesting that use of PCPs is an important source of exposure to parabens and diethyl phthalate in adults and provide data on exposure to selected phenols and phthalates through use of PCPs in children. PMID:25929801

Longer period of oral administration of aspartame on cytokine response in Wistar albino rats.

PubMed

Choudhary, Arbind Kumar; Sheela Devi, Rathinasamy

2015-03-01

Aspartame is a non-nutritive sweetener particularly used in 'diet' and 'low calorie' products and also in a variety of foods, drugs and hygiene products. Aspartame is metabolized by gut esterases and peptidases to three common chemicals: the amino acids, aspartic acid and phenylalanine, and small amounts of methanol. The aim of the present study was to assess potential changes in molecular mediators of aspartame as a chemical stressor in rats. The effects of long-term administration of aspartame (40 mg/kg body weight/day) were tested in Wistar Albino rats. The treatment effects were assessed in different conditions, including control groups. After 90 days of treatment, circulating concentrations of different parameters were assessed: corticosterone, lipid peroxidation, antioxidant activity, nitric oxide, reduced glutathione and cytokines (interleukin 2, interleukin 4, tumor necrosis factor-α and interferon-γ). The results show that there was a significant increase in plasma corticosterone, serum lipid peroxidation and nitric oxide level along with a decrease in enzymatic and non-enzymatic antioxidant as well as significant decrease in interleukin 2, tumor necrosis factor-α and interferon-γ. There was also a significant increase in interleukin 4 irrespective of whether the animals were immunized or not. The findings clearly point out that aspartame acts as a chemical stressor because of increased corticosterone level and increased lipid peroxidation and nitric oxide level induce generation of free radicals in serum which may be the reason for variation of cytokine level and finally results in alteration of immune function. Aspartame metabolite methanol or formaldehyde may be the causative factors behind the changes observed. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Effect of the glucocorticoid receptor antagonist RU486 on MK-801 induced behavioural sensitisation

PubMed Central

Lefevre, Emilia M.; Medley, Gregory A.; Reeks, Timothy; Alexander, Suzy; Burne, Thomas H. J.; Eyles, Darryl W.

2017-01-01

Stress is known to modulate sensitisation to repeated psychostimulant exposure. However, there is no direct evidence linking glucocorticoids and sensitisation achieved by repeated administration of the NMDA receptor antagonist MK-801. We tested the hypothesis that co-administration of RU486, a glucocorticoid receptor (GR) antagonist, prior to repeated daily MK-801 injections would block the expression of locomotor sensitisation due to its dual effects on corticosterone and dopamine. We employed a repeated MK-801 administration locomotor sensitisation paradigm in male Sprague Dawley rats. RU486 or a dimethyl sulfoxide (DMSO) vehicle was co-administered with MK-801 or saline during the induction phase. Subsequent to withdrawal, rats were challenged with MK-801 alone to test for the expression of sensitisation. In a separate cohort of rats, plasma corticosterone levels were quantified from blood samples taken on the 1st, 4th and 7th day of induction and at expression. One day after challenge, nucleus accumbens tissue levels of dopamine and its metabolites DOPAC and HVA were measured. During the induction phase, RU486 progressively enhanced locomotor sensitisation to MK-801. RU486 and MK-801 both showed stimulatory effects on corticosterone levels and this was further augmented when given in combination. Contrary to our hypothesis, RU486 did not block the expression of locomotor sensitisation to MK-801 and actually increased levels of dopamine, DOPAC and HVA in nucleus accumbens tissue. Our results showed that RU486 has augmentative rather than inhibitory effects on MK-801-induced sensitisation. This study indicates a divergent role for glucocorticoids in sensitisation to MK-801 compared to sensitisation with other psychostimulants. PMID:28430805

CURRENT-USE PESTICIDES: ASSESSING EXPOSURE AND SPERMATOXICITY

EPA Science Inventory

We recently reported that higher levels of urinary metabolite (mercapturates) of the current-use pesticides alachlor, atrazine and diazinon were significantly associated with decreased semen quality in fertile men from mid-Missouri. The primary goal of this stud...

Corticosterone facilitates begging and affects resource allocation in the black-legged kittiwake

USGS Publications Warehouse

Kitaysky, A.S.; Wingfield, J.C.; Piatt, John F.

2001-01-01

Parent black-legged kittiwakes (Rissa tridactyla) and their dependent chicks respond to food shortages by increasing circulating levels of corticosterone. To examine the behavioral significance of corticosterone release, we experimentally increased levels of circulating corticosterone in parents and chicks up to the levels observed during food shortages. We found that corticosterone-implanted chicks begged more frequently than sham-implanted controls. Corticosterone-implanted chicks in broods of two begged more frequently than singletons. Parent kittiwakes then responded to the increase in corticosterone levels in their chicks by increasing chick-feeding rates. However, feeding rates were not different among corticosterone-implanted chicks in broods of two and singletons. We also found that corticosterone-implanted parents spent more time away from the nest - perhaps foraging - and less time brooding/guarding chicks than sham-implanted controls. Untreated mates of the corticosterone-implanted bird did not compensate for the change in their partner's behavior; consequently, chicks were left unattended about 20% of the time compared to 1% at the control nests. However, corticosterone-implanted parents did not decrease their chick-feeding rates. Our findings suggest two functional implications of the increased corticosterone secretion during food shortages in the black-legged kittiwake: it facilitates begging in chicks, and it affects time allocated by parents to guarding young at the nest. Thus, release of corticosterone might provide a mechanistic link between physiological condition and behavioral interactions among adults and their young.

Comparisons among serum, egg albumin and yolk concentrations of corticosterone as biomarkers of basal and stimulated adrenocortical activity of laying hens.

PubMed

Cook, N J; Renema, R; Wilkinson, C; Schaefer, A L

2009-09-01

1. Serial blood samples from individual birds were analysed for corticosterone concentrations under basal and stimulated conditions, and matched to eggs from the same birds for comparison to albumin and yolk concentrations of corticosterone. 2. Serum corticosterone exhibited increases in response to stimulation by ACTH and Handling stress. There were no significant increases in egg albumin or yolk concentrations of corticosterone following stimulation. 3. Several significant correlations were observed between the mean and area under the curve (AUC) measurements of serum corticosterone concentrations with albumin and yolk corticosterone concentrations in eggs laid from 1 to 2 d later. 4. The results demonstrated a relationship between endogenous concentrations of serum corticosterone that reflected daily adrenocortical output with albumin and yolk corticosterone concentrations in eggs laid the following day. 5. The results do not support the concept of albumin and yolk concentrations of corticosterone as biomarkers of acute adrenocortical responses to stimulation.

Exposure to Bisphenol A and Other Phenols in Neonatal Intensive Care Unit Premature Infants

PubMed Central

Calafat, Antonia M.; Weuve, Jennifer; Ye, Xiaoyun; Jia, Lily T.; Hu, Howard; Ringer, Steven; Huttner, Ken; Hauser, Russ

2009-01-01

Objective We previously demonstrated that exposure to polyvinyl chloride plastic medical devices containing di(2-ethylhexyl) phthalate (DEHP) was associated with higher urinary concentrations of several DEHP metabolites in 54 premature infants in two neonatal intensive care units than in the general population. For 42 of these infants, we evaluated urinary concentrations of several phenols, including bisphenol A (BPA), in association with the use of the same medical devices. Measurements We measured the urinary concentrations of free and total (free plus conjugated) species of BPA, triclosan, benzophenone-3, methyl paraben, and propyl paraben. Results The percentage of BPA present as its conjugated species was > 90% in more than three-quarters of the premature infants. Intensity of use of products containing DEHP was strongly associated with BPA total concentrations but not with any other phenol. Adjusting for institution and sex, BPA total concentrations among infants in the group of high use of DEHP-containing products were 8.75 times as high as among infants in the low use group (p < 0.0001). Similarly, after adjusting for sex and DEHP-containing product use category, BPA total concentrations among infants in Institution A were 16.6 times as high as those among infants in Institution B (p < 0.0001). Conclusion BPA geometric mean urinary concentration (30.3 μg/L) among premature infants undergoing intensive therapeutic medical interventions was one order of magnitude higher than that among the general population. Conjugated species were the primary urinary metabolites of BPA, suggesting that premature infants have some capacity to metabolize BPA. The differences in exposure to BPA by intensity of use of DEHP-containing medical products highlight the need for further studies to determine the specific source(s) of exposure to BPA. PMID:19440505

Urinary metabolomics analysis identifies key biomarkers of different stages of nonalcoholic fatty liver disease

PubMed Central

Dong, Shu; Zhan, Zong-Ying; Cao, Hong-Yan; Wu, Chao; Bian, Yan-Qin; Li, Jian-Yuan; Cheng, Gen-Hong; Liu, Ping; Sun, Ming-Yu

2017-01-01

AIM To identify a panel of biomarkers that can distinguish between non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and explore molecular mechanism involved in the process of developing NASH from NAFLD. METHODS Biomarkers may differ during stages of NAFLD. Urine and blood were obtained from non-diabetic subjects with NAFLD and steatosis, with normal liver function (n = 33), from patients with NASH, with abnormal liver function (n = 45), and from healthy age and sex-matched controls (n = 30). Samples were subjected to metabolomic analysis to identify potential non-invasive biomarkers. Differences in urinary metabolic profiles were analyzed using liquid chromatography tandem mass spectrometry with principal component analysis and partial least squares-discriminate analysis. RESULTS Compared with NAFLD patients, patients with NASH had abnormal liver function and high serum lipid concentrations. Urinary metabonomics found differences in 31 metabolites between these two groups, including differences in nucleic acids and amino acids. Pathway analysis based on overlapping metabolites showed that pathways of energy and amino acid metabolism, as well as the pentose phosphate pathway, were closely associated with pathological processes in NAFLD and NASH. CONCLUSION These findings suggested that a panel of biomarkers could distinguish between NAFLD and NASH, and could help to determine the molecular mechanism involved in the process of developing NASH from NAFLD. Urinary biomarkers may be diagnostic in these patients and could be used to assess responses to therapeutic interventions. PMID:28487615

Levels of Urinary Metabolites of Organophosphate Flame Retardants, TDCIPP, and TPHP, in Pregnant Women in Shanghai

PubMed Central

Ouyang, Fengxiu; Liu, Liangpo; Wang, Xu; Wang, Xia; Li, Yi-Ju; Murtha, Amy; Shen, Heqing; Zhang, Junfeng; Zhang, Jun Jim

2016-01-01

Flame retardants are widely used in consumer products to reduce their flammability. Previously used flame retardants have been sequentially banned due to their environmental and human toxicity. Currently, tris(1,3-dichloropropyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) are among the most commonly used flame retardants. TDCIPP and TPHP are reproductive toxins and have carcinogenic, neurotoxic, and endocrine-disrupting properties. Although high levels of TDCIPP and TPHP have been found in drinking water, seawater, and office air in China, data regarding human exposure are lacking. In this study, we assessed the level of urinary TPHP and TDCIPP metabolites (DPHP and BDCIPP, resp.) in a cohort of pregnant women (N = 23) from Shanghai, China, using liquid chromatography-tandem mass spectrometry. DPHP were detected in 100% urine samples, while only four urine samples had detectable level of BDCIPP in this cohort (17% detected). Geometric means of DPHP and BDCIPP concentrations were 1.1 ng/mL (interquartile range [IQR]: 0.6, 1.5 ng/mL) and 1.2 ng/mL (IQR: 0.6, 2.2 ng/mL), respectively. In this small cohort, urinary DPHP and BDCIPP levels were not significantly correlated with miscarriages, neonatal birthweight, gestational diabetes, or maternal age. These data suggest that exposure to TPHP is widespread, and they demonstrate the feasibility of using urinary biomarkers to measure exposures to modern flame-retardant chemicals. PMID:28115951

Polycyclic aromatic hydrocarbons at fire stations: firefighters' exposure monitoring and biomonitoring, and assessment of the contribution to total internal dose.

PubMed

Oliveira, Marta; Slezakova, Klara; Alves, Maria José; Fernandes, Adília; Teixeira, João Paulo; Delerue-Matos, Cristina; Pereira, Maria do Carmo; Morais, Simone

2017-02-05

This work characterizes levels of eighteen polycyclic aromatic hydrocarbons (PAHs) in the breathing air zone of firefighters during their regular work shift at eight Portuguese fire stations, and the firefighters' total internal dose by six urinary monohydroxyl metabolites (OH-PAHs). Total PAHs (ΣPAHs) concentrations varied widely (46.4-428ng/m 3 ), mainly due to site specificity (urban/rural) and characteristics (age and layout) of buildings. Airborne PAHs with 2-3 rings were the most abundant (63.9-95.7% ΣPAHs). Similarly, urinary 1-hydroxynaphthalene and 1-hydroxyacenaphthene were the predominant metabolites (66-96% ΣOH-PAHs). Naphthalene contributed the most to carcinogenic ΣPAHs (39.4-78.1%) in majority of firehouses; benzo[a]pyrene, the marker of carcinogenic PAHs, accounted with 1.5-10%. Statistically positive significant correlations (r≥0.733, p≤0.025) were observed between ΣPAHs and urinary ΣOH-PAHs for firefighters of four fire stations suggesting that, at these sites, indoor air was their major exposure source of PAHs. Firefighter's personal exposure to PAHs at Portuguese fire stations were well below the existent occupational exposure limits. Also, the quantified concentrations of post-shift urinary 1-hydroxypyrene in all firefighters were clearly lower than the benchmark level (0.5μmol/mol) recommended by the American Conference of Governmental Industrial Hygienists. Copyright © 2016 Elsevier B.V. All rights reserved.

Urinary Arsenic Speciation in Children and Pregnant Women from Spain.

PubMed

Signes-Pastor, Antonio J; Carey, Manus; Vioque, Jesus; Navarrete-Muñoz, Eva M; Rodríguez-Dehli, Cristina; Tardón, Adonina; Begoña-Zubero, Miren; Santa-Marina, Loreto; Vrijheid, Martine; Casas, Maribel; Llop, Sabrina; Gonzalez-Palacios, Sandra; Meharg, Andrew A

2017-01-01

Inorganic arsenic (i-As) is a non-threshold human carcinogen that has been associated with several adverse health outcomes. Exposure to i-As is of particular concern among pregnant women, infants and children, as they are specifically vulnerable to the adverse health effects of i-As, and in utero and early-life exposure, even low to moderate levels of i-As, may have a marked effect throughout the lifespan. Ion chromatography-mass spectrometry detection (IC-ICP-MS) was used to analyse urinary arsenic speciation, as an exposure biomarker, in samples of 4-year-old children with relatively low-level arsenic exposure living in different regions in Spain including Asturias, Gipuzkoa, Sabadell and Valencia. The profile of arsenic metabolites in urine was also determined in samples taken during pregnancy (1st trimester) and in the children from Valencia of 7 years old. The median of the main arsenic species found in the 4-year-old children was 9.71 μg/l (arsenobetaine-AsB), 3.97 μg/l (dimethylarsinic acid-DMA), 0.44 μg/l (monomethylarsonic acid-MMA) and 0.35 μg/l (i-As). Statistically significant differences were found in urinary AsB, MMA and i-As according to the study regions in the 4-year-old, and also in DMA among pregnant women and their children. Spearman's correlation coefficient among urinary arsenic metabolites was calculated, and, in general, a strong methylation capacity to methylate i-As to MMA was observed.

Dietary predictors of urinary environmental biomarkers in young girls, BCERP, 2004-7.

PubMed

Mervish, Nancy; McGovern, Kathleen J; Teitelbaum, Susan L; Pinney, Susan M; Windham, Gayle C; Biro, Frank M; Kushi, Lawrence H; Silva, Manori J; Ye, Xiaoyun; Calafat, Antonia M; Wolff, Mary S

2014-08-01

Exposures of children to phthalates, parabens, and bisphenol-A (BPA) are of concern because of their hormonal potential. These agents are found in a wide range of foods and packaging. We investigated whether intake of certain foods predict exposures to these chemicals in young girls. Among 1101 girls (6-8 years at enrollment) from the Breast Cancer and Environment Research Program (BCERP) study, we measured urinary exposure biomarkers for phthalates, parabens, and BPA and assessed dietary intake using 24-h recall 2-4 times. We examined the average daily servings of major and minor food groups categorized as 0 to <0.5, 0.5 to <1 and ≥ 1 servings per day. Items included dairy, eggs, fats, fish, fruit, single grains, meat, non-poultry meats, pasta, poultry and vegetables. Covariate-adjusted least squares geometric means and 95% confidence intervals of creatinine-corrected phthalate and phenol metabolite concentrations in urine were calculated in relation to food intake. Grains, flour and dry mixes and total fish consumption were positively associated with BPA and the sum of four di-2-ethylhexylphthalate (DEHP) urinary metabolite concentrations. Non-fresh vegetables and poultry were both positively associated with BPA and paraben urinary concentrations. Fats, oils and poultry consumption were positively associated with BPA. Whole-fat dairy consumption was associated with ΣDEHP. Some foods may contribute to child exposures to certain chemicals, and this may constitute modifiable means to reduce these environmental exposures. Copyright © 2014 Elsevier Inc. All rights reserved.

Identification of fentanyl metabolites in rat urine by gas chromatography-mass spectrometry with stable-isotope tracers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goromaru, T.; Matsuura, H.; Furuta, T.

The metabolites of fentanyl (l), which has been widely used as a neuroleptic analgesic agent, were identified in urine of rats by gas chromatography-mass spectrometry combined with a stable-isotope tracer technique. After the oral administration of an equimolar mixture of l and deuterium-labeled l (l/l-d5), the urinary metabolites were extracted with chloroform at pH 9.0. Extracts were derivatized and analyzed by GC/MS. Metabolites were identified by the presence of doublet ion peaks separated by 5 amu, and chemical structures were established from analyses of fragmentation pathways. The metabolites were identified as 4-N-(N-propionylanilino)-piperidine, 4-N-(N-hydroxypropionylanilino)piperidine, 4-N-(N-propionylanilino) hydroxypiperidine, 1-(2-phenethyl)-4-N-(N-hydroxypropionylanilino)piperidine and 1-(2-phenethyl)-4-N-(N-propionylanilino)hydroxypiperidine. These metabolites,more » together with unchanged l, were also detected in urine of rats receiving l/l-d5 intravenously, by selected-ion monitoring of the specific cluster ions.« less

Measurement of vitamin D3 metabolites in smelter workers exposed to lead and cadmium

PubMed Central

Chalkley, S. R.; Richmond, J.; Barltrop, D.

1998-01-01

OBJECTIVES: To investigate the effects of lead and cadmium on the metabolic pathway of vitamin D3. METHODS: Blood and urinary cadmium and urinary total proteins were measured in 59 smelter workers occupationally exposed to lead and cadmium. In 19 of these workers, the plasma vitamin D3 metabolites, (25-hydroxycholecalciferol (25 OHD3), 24R, 25-dihydroxycholecalciferol (24R,25(OH)2D3) and 1 alpha,25- dihydroxycholecalciferol (1 alpha, 25(OH)2D3)) were measured together with blood lead. Vitamin D3 metabolites were measured by radioimmunoassay, (RIA), lead and cadmium by atomic absorption spectrophotometry, and total proteins with a test kit. RESULTS: Ranges for plasma 25(OH)D3, 24R,25(OH)2D3 and 1 alpha,25(OH)2D3 were 1.0-51.9 ng/ml, 0.6-5.8 ng/ml, and 0.1-75.7 pg/ml, respectively. Ranges for blood lead were 1-3.7 mumol/l, (21-76 micrograms/dl), blood cadmium 6- 145 nmol/l, and urinary cadmium 3-161 nmol/l. Total proteins in random urine samples were 2.1-32.6 mg/dl. Concentrations of lead and cadmium in blood showed no correlation (correlation coefficient -0.265) but there was a highly significant correlation between blood and urinary cadmium. Concentrations for 24R,25(OH)2D3 were depressed below the normal range as blood and urinary cadmium increased, irrespective of lead concentrations. High cadmium concentrations were associated with decreased plasma 1 alpha,25(OH)2D3 when lead concentrations were < 1.9 mumol/l and with above normal plasma 1 alpha,25(OH)2D3 when lead concentrations were > 1.9 mumol/l, Kruskal-Wallis analysis of variance (K-W ANOVA) chi 2 = 10.3, p = 0.006. Plasma 25(OH)D3 was negatively correlated with both urinary total proteins and urinary cadmium, but showed no correlation with plasma 24R,25(OH)2D3, 1 alpha,25(OH)2D3, blood lead, or blood cadmium. CONCLUSION: Continuous long term exposure to cadmium may result in a state of equilibrium between blood and urinary cadmium. Cadmium concentrations in blood could be predicted from the cadmium concentration of the urine, (regression coefficient +0.35 SE 0.077). Exposure to cadmium alone decreased the concentrations of 1 alpha,25(OH)2D3 and 24R,25(OH)2D3, whereas exposure to both cadmium and lead increased the concentrations of 1 alpha,25(OH)2D3. It has been suggested that cadmium and lead interact with renal mitochondrial hydroxylases of the vitamin D3 endocrine complex. Perturbation of the vitamin D metabolic pathway by cadmium may result in health effect, such as osteoporosis or osteomalacia, risks which are possibly increased in the presence of lead.   PMID:9816377

Identification of Furan Metabolites Derived from Cysteine-cis-2-Butene-1,4-Dial-Lysine Crosslinks

PubMed Central

Lu, Ding; Peterson, Lisa A.

2010-01-01

Furan is a rodent hepatotoxicant and carcinogen. Since this compound is an important industrial intermediate and has been detected in heat-processed foods and smoke, humans are likely exposed to this toxic compound. Characterization of urinary metabolites of furan will lead to the development of biomarkers to assess human health risks associated with furan exposure. Previous studies indicate that furan is oxidized to a reactive α, β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA), in a reaction catalyzed by cytochrome P450. Five previously characterized metabolites are derived from the reaction of BDA with cellular nucleophiles such as glutathione and protein. They include the mono-glutathione reaction product, N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine cyclic sulfide and its downstream metabolite, S-[1-(1,3-dicarboxypropyl)-1H-pyrrol-3-yl]methylthiol as well as R-2-acetylamino-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid and N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine and its sulfoxide. The last two compounds are downstream metabolites of a BDA-derived cysteine-lysine crosslink, S-[1-(5-amino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine. In this report, we present the characterization of seven additional urinary furan metabolites, all of which are derived from this crosslink. The cysteinyl residue is subject to several biotransformation reactions, including N-acetylation and S-oxidation. Alternatively, it can undergo β-elimination followed by S-methylation to a methylthiol intermediate that is further oxidized to a sulfoxide. The lysine portion of the crosslink is either N-acetylated or undergoes an oxidative transamination reaction to generate an α-ketoacid metabolite that undergoes oxidative decarboxylation. Some of these metabolites are among the most abundant furan metabolites present in urine as judged by LC-MS/MS analysis, indicating that the oxidation of furan to BDA and BDA’s subsequent reaction with cellular cysteine and lysine residues may represent a significant in vivo pathway of furan biotransformation. Since they are derived from cellular BDA reaction products, these metabolites are markers of furan exposure and bioactivation and could be explored as potential biomarkers in human studies. PMID:20043645

The effects of maternal corticosterone levels on offspring behavior in fast- and slow-growth garter snakes (Thamnophis elegans).

PubMed

Robert, Kylie A; Vleck, Carol; Bronikowski, Anne M

2009-01-01

During embryonic development, viviparous offspring are exposed to maternally circulating hormones. Maternal stress increases offspring exposure to corticosterone and this hormonal exposure has the potential to influence developmental, morphological and behavioral traits of the resulting offspring. We treated pregnant female garter snakes (Thamnophis elegans) with low levels of corticosterone after determining both natural corticosterone levels in the field and pre-treatment levels upon arrival in the lab. Additional measurements of plasma corticosterone were taken at days 1, 5, and 10 during the 10-day exposure, which occurred during the last third of gestation (of 4-month gestation). These pregnant snakes were from replicate populations of fast- and slow-growth ecotypes occurring in Northern California, with concomitant short and long lifespans. Field corticosterone levels of pregnant females of the slow-growth ecotype were an order of magnitude higher than fast-growth dams. In the laboratory, corticosterone levels increased over the 10 days of corticosterone manipulation for animals of both ecotypes, and reached similar plateaus for both control and treated dams. Despite similar plasma corticosterone levels in treated and control mothers, corticosterone-treated dams produced more stillborn offspring and exhibited higher total reproductive failure than control dams. At one month of age, offspring from fast-growth females had higher plasma corticosterone levels than offspring from slow-growth females, which is opposite the maternal pattern. Offspring from corticosterone-treated mothers, although unaffected in their slither speed, exhibited changes in escape behaviors and morphology that were dependent upon maternal ecotype. Offspring from corticosterone-treated fast-growth females exhibited less anti-predator reversal behavior; offspring from corticosterone-treated slow-growth females exhibited less anti-predator tail lashing behavior.

Metabolism of growth hormone releasing peptides.

PubMed

Thomas, Andreas; Delahaut, Philippe; Krug, Oliver; Schänzer, Wilhelm; Thevis, Mario

2012-12-04

New, potentially performance enhancing compounds have frequently been introduced to licit and illicit markets and rapidly distributed via worldwide operating Internet platforms. Developing fast analytical strategies to follow these new trends is one the most challenging issues for modern doping control analysis. Even if reference compounds for the active drugs are readily obtained, their unknown metabolism complicates effective testing strategies. Recently, a new class of small C-terminally amidated peptides comprising four to seven amino acid residues received considerable attention of sports drug testing authorities due to their ability to stimulate growth hormone release from the pituitary. The most promising candidates are the growth hormone releasing peptide (GHRP)-1, -2, -4, -5, -6, hexarelin, alexamorelin, and ipamorelin. With the exemption of GHRP-2, the entity of these peptides represents nonapproved pharmaceuticals; however, via Internet providers, all compounds are readily available. To date, only limited information on the metabolism of these substances is available and merely one metabolite for GHRP-2 is established. Therefore, a comprehensive in vivo (po and iv administration in rats) and in vitro (with human serum and recombinant amidase) study was performed in order to generate information on urinary metabolites potentially useful for routine doping controls. The urine samples from the in vivo experiments were purified by mixed-mode cation-exchange solid-phase extraction and analyzed by ultrahigh-performance liquid chromatography (UHPLC) separation followed by high-resolution/high-accuracy mass spectrometry. Combining the high resolution power of a benchtop Orbitrap mass analyzer for the first metabolite screening and the speed of a quadrupole/time-of-flight (Q-TOF) instrument for identification, urinary metabolites were screened by means of a sensitive full scan analysis and subsequently confirmed by high-accuracy product ion scan experiments. Two deuterium-labeled internal standards (triply deuterated GHRP-4 and GHRP-2 metabolite) were used to optimize the extraction and analysis procedure. Overall, 28 metabolites (at least three for each GHRP) were identified from the in vivo samples and main metabolites were confirmed by the human in vitro model. All identified metabolites were formed due to exopeptidase- (amino- or carboxy-), amidase-, or endopeptidase activity.

Prenatal phthalate exposure and reduced masculine play in boys.

PubMed

Swan, S H; Liu, F; Hines, M; Kruse, R L; Wang, C; Redmon, J B; Sparks, A; Weiss, B

2010-04-01

Foetal exposure to antiandrogens alters androgen-sensitive development in male rodents, resulting in less male-typical behaviour. Foetal phthalate exposure is also associated with male reproductive development in humans, but neurodevelopmental outcomes have seldom been examined in relation to phthalate exposure. To assess play behaviour in relation to phthalate metabolite concentration in prenatal urine samples, we recontacted participants in the Study for Future Families whose phthalate metabolites had been measured in mid-pregnancy urine samples. Mothers completed a questionnaire including the Pre-School Activities Inventory, a validated instrument used to assess sexually dimorphic play behaviour. We examined play behaviour scores (masculine, feminine and composite) in relationship to (log(10)) phthalate metabolite concentrations in mother's urine separately for boys (N = 74) and girls (N = 71). Covariates (child's age, mother's age and education and parental attitude towards atypical play choices) were controlled using multivariate regression models. Concentrations of dibutyl phthalate metabolites, mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) and their sum, were associated with a decreased (less masculine) composite score in boys (regression coefficients -4.53,-3.61 and -4.20, p = 0.01, 0.07 and 0.04 for MnBP, MiBP and their sum respectively). Concentrations of two urinary metabolites of di(2-ethylhexyl) phthalate (DEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the sum of these DEHP metabolites plus mono(2-ethylhexyl) phthalate were associated with a decreased masculine score (regression coefficients -3.29,-2.94 and -3.18, p = 0.02, 0.04 and 0.04) for MEHHP, MEOHP and the sum respectively. No strong associations were seen between behaviour and urinary concentrations of any other phthalate metabolites in boys, or between girls' scores and any metabolites. These data, although based on a small sample, suggest that prenatal exposure to antiandrogenic phthalates may be associated with less male-typical play behaviour in boys. Our findings suggest that these ubiquitous environmental chemicals have the potential to alter androgen-responsive brain development in humans.

The effect of long-term corticosterone treatment on blood cell differentials and function in laboratory and wild-caught amphibian models.

PubMed

Falso, Paul G; Noble, Christopher A; Diaz, Jesus M; Hayes, Tyrone B

2015-02-01

The effect of long-term stress on amphibian immunity is not well understood. We modeled a long-term endocrine stress scenario by elevating plasma corticosterone in two species of amphibians and examined effects on white blood cell differentials and innate immune activity. Plasma corticosterone was elevated in American bullfrogs (Lithobates catesbeianus) by surgically implanting corticosterone capsules and in African clawed frogs (Xenopus laevis) by immersion in corticosterone-treated water. To provide a context for our results within endogenous corticosterone fluctuations, diurnal plasma corticosterone cycles were determined. A daily low of corticosterone was observed in X. laevis at 12:00, while a significant pattern was not observed in L. catesbeianus. Elevated plasma corticosterone levels increased the ratio of peripheral neutrophils to lymphocytes, in both species, and decreased eosinophil concentrations in L. catesbeianus over a long-term period. Whole blood oxidative burst generally correlated with neutrophil concentrations, and thus was increased with corticosterone treatment, significantly in L. catesbeianus. In L. catesbeianus, an endogenous response of eosinophils and lymphocytes to implanted empty (sham) capsules was observed, but this effect was attenuated by corticosterone. Peripheral monocyte and basophil concentrations were not significantly altered by corticosterone treatment in either species. Our results show that long-term stress can alter amphibian immune parameters for extended periods and may play a role in susceptibility to disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Fecal corticosterone reflects serum corticosterone in Florida sandhill cranes.

PubMed

Ludders, J W; Langenberg, J A; Czekala, N M; Erb, H N

2001-07-01

Florida sandhill cranes (Grus canadensis pratensis) were conditioned to confinement 6 hr/day for 7 days. On day 8, each bird's jugular vein was catheterized, blood samples were drawn, and each crane was confined for 6 hr. Using a randomized, restricted cross-over design, cranes were injected intravenously with either 0.9% NaCl solution or ACTH (cosyntropin; Cortrosyn; 0.25 mg). During the 6 hr of confinement, fecal samples (feces and urine) were collected from each of five cranes immediately after defecation. Individual fecal samples were collected approximately at hourly intervals and assayed for corticosterone. We showed previously that serum corticosterone did not vary significantly following saline injection, but peaked significantly 60 min after ACTH injection. Maximal fecal corticosterone concentrations (ng/g) were greater (P < 0.10; median 1087 ng/g) following ACTH stimulation compared to maximal fecal corticosterone concentrations at the end of acclimation (day 7; median 176) and following saline treatment (median 541). In cranes under controlled conditions, fecal corticosterone concentration reflects serum corticosterone levels, fecal corticosterone, Grus canadensis pratensis, sandhill cranes, serum corticosterone levels.

Oxybuprocaine and five metabolites simultaneously determined in urine by gas chromatography and gas chromatography-mass spectrometry after extraction with Extrelut.

PubMed

Kasuya, F; Igarashi, K; Fukui, M

1987-05-01

We describe a gas-liquid chromatographic (GC) method for determination of oxybuprocaine, and a gas chromatographic-mass spectrometric (GC-MS) method for simultaneous determination of four of its nine metabolites in urine. We used an Extrelut column to simply and rapidly extract oxybuprocaine and its metabolites from urine. For the GC-MS analyses, we monitored the characteristic fragment ions at m/z 353, 395, 369, 411, and 235 for 3-butoxy-4-aminobenzoic acid (metabolite 2, M-2), 3-butoxy-4-acetylaminobenzoic acid (M-3), 3-hydroxy-4-aminobenzoic acid (M-4), 3-hydroxy-4-acetylaminobenzoic acid (M-5), and methaqualone (internal standard), respectively. We quantified the glucuronide of M-2 after enzymic treatment. The assay's selectivity and reproducibility (within-day and between-day CVs less than 8% for all metabolites) make it applicable to determine oxybuprocaine and its metabolites in human urine. Mean 9-h urinary excretion of oxybuprocaine and its five metabolites from four healthy volunteers was 89.2% after a 100-mg oral dose.

Corticosterone administration and high-energy feed results in enhanced fat accumulation and insulin resistance in broiler chickens.

PubMed

Yuan, L; Lin, H; Jiang, K J; Jiao, H C; Song, Z G

2008-07-01

1. Two experiments were conducted to investigate the effects of exogenous corticosterone administration (30 mg/kg diet) and dietary energy level on feed or energy intake and fat deposition in broiler chickens of 1 and 4 weeks of age. 2. Corticosterone treatment significantly suppressed body weight (BW) gain and reduced feed and caloric efficiencies. The retarded growth may conceal the stimulatory effect of corticosterone on feed consumption or metabolisable energy (ME) intake. A high-energy diet may increase energy intake and partially alleviate the suppressing effect of corticosterone on growth of broilers. 3. Corticosterone administration promoted the conservation of energy stores as fat at both abdominal and subcutaneous sites and this process occurred regardless of dietary energy level in ad libitum feeding status. A high-energy diet increased fat accumulation and showed no significant interaction with corticosterone treatment. 4. The suppressed development of breast and thigh muscles by corticosterone treatment was observed only in 1-week-old chickens fed on the low-energy diet. In contrast, the yield of breast muscle but not thigh muscle was significantly decreased by corticosterone in 4-week-old chickens, suggesting that the tissue specificity to corticosterone challenge is age dependent. 5. Plasma concentrations of glucose, insulin, triglyceride, non-esterified fatty acids (NEFA) and very low density lipoprotein were increased by corticosterone treatment regardless of diet treatment. A high-energy diet increased plasma levels of NEFA and resulted in hyperinsulinism in 4-week-old chickens but not in 1-week-old chickens. 6. Lipoprotein lipase (LPL) activities in adipose tissues may have been up-regulated by corticosterone treatment and showed tissue specificity. The increased LPL activities at ad libitum feeding status were not necessarily linked with the increased fat accumulation in corticosterone challenged chickens. 7. Corticosterone resulted in augmented energy consumption and altered energy redistribution toward lipid deposition. The induced insulin resistance and enhanced hepatic de novo lipogenesis by corticosterone are likely to be responsible for the increased fat deposition.

Concentrations of nandrolone metabolites in urine after the therapeutic administration of an ophthalmic solution.

PubMed

Avois, Lidia; Mangin, Patrice; Saugy, Martial

2007-05-09

Nandrolone, an anabolic steroid, is used for the treatment of several diseases and is available in various pharmaceutical formulations. The most widely used pharmaceutical formulation is Deca-Durabolin, but other products, such as Keratyl eye drops solution, are also currently administered. Nandrolone is one of the most abused anabolic steroid in sports. Analyses for this anabolic steroid according to the World Anti-Doping Agency (WADA) protocol are based on the identification of the nandrolone two main urinary metabolites which, in humans, are glucuronides of 19-norandrosterone and 19-noretiocholanolone. A positive cut off limit of 2 ng/mL has been set by the anti-doping code for the first metabolite, 19-norandrosterone. In this preliminary study, an eye drops solution (Keratyl) containing a therapeutic dose of a nandrolone sodium sulphate was administered to several male volunteers during 3 days and urines were collected during 3 weeks. Surprisingly, contrary to all expectations, the urinary concentrations measured in urines reached 450 ng/mL and 70 ng/mL for norandrosterone and noretiocholanolone, respectively. Moreover, concentration levels near to 2 ng/mL were found, more than 2 weeks after the last administration, depending on individual metabolism. Inter-variability as well as intra-variability of nandrolone excretion kinetic, regarding this particular administration mode, were also evaluated. Quantification of nandrolone metabolites was performed by GC-MS. The method was previously validated in terms of specificity, precision, linearity, LOD, LOQ, robustness, accuracy and the expanded uncertainty was also evaluated.

Use of mass spectrometry fingerprinting to identify urinary metabolites after consumption of specific foods.

PubMed

Lloyd, Amanda J; Favé, Gaëlle; Beckmann, Manfred; Lin, Wanchang; Tailliart, Kathleen; Xie, Long; Mathers, John C; Draper, John

2011-10-01

The lack of robust biological markers of dietary exposure hinders the quantitative understanding of causal relations between diet and health. We aimed to develop an efficient procedure to discover metabolites in urine that may have future potential as biomarkers of acute exposure to foods of high public health importance. Twenty-four participants were provided with a test breakfast in which the cereal component of a standardized breakfast was replaced by 1 of 4 foods of high public health importance; 1.5-, 3-, and 4.5-h postprandial urine samples were collected. Flow infusion electrospray-ionization mass spectrometry followed by supervised multivariate data analysis was used to discover signals resulting from consumption of each test food. Fasted-state urine samples provided a universal comparator for food biomarker lead discovery in postprandial urine. The filtering of data features associated with consumption of the common components of the standardized breakfast improved discrimination models and readily identified metabolites that showed consumption of specific test foods. A combination of trimethylamine-N-oxide and 1-methylhistidine was associated with salmon consumption. Novel ascorbate derivatives were discovered in urine after consumption of either broccoli or raspberries. Sulphonated caffeic acid and sulphonated methyl-epicatechin concentrations increased dramatically after consumption of raspberries. This biomarker lead discovery strategy can identify urinary metabolites associated with acute exposure to individual foods. Future studies are required to validate the specificity and utility of potential biomarkers in an epidemiologic context.

The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid.

PubMed Central

Tormey, W. P.; FitzGerald, R. J.

1995-01-01

Over a five-and-a-half-year period, there were 298 laboratory requests for urinary 5-hydroxyindoleacetic acid (5-HIAA). The clinical and laboratory associations of the 24 patients in which there were 43 urinary 5-HIAA 24-h collection results greater than the laboratory upper reference limit are detailed. Four were confirmed carcinoid tumours and two were phaeochromocytomas. Flushing was a prominent symptom in 46% and diarrhoea or altered bowel habit in 37%. Associated with the raised urinary 5-HIAA values were increased levels of 4-hydroxy-3-methoxymandelic acid and homovanillic acid in 14.3% and 21%, respectively, of those collections where the metabolites were requested. Diagnostic imaging was performed in 57%. While the specificity was 88%, 5-HIAA is relatively insensitive in the diagnosis of carcinoid tumours and a more widespread use of diagnostic imaging including isotope scanning with labelled metaiodo-benzylguanidine, vasoactive intestinal peptide and octreotide is suggested. PMID:7479466

Pregnancy and Lactation Alter Biomarkers of Biotin Metabolism in Women Consuming a Controlled Diet123

PubMed Central

Perry, Cydne A; West, Allyson A; Gayle, Antoinette; Lucas, Lauren K; Yan, Jian; Jiang, Xinyin; Malysheva, Olga; Caudill, Marie A

2014-01-01

Background: Biotin functions as a cofactor for several carboxylase enzymes with key roles in metabolism. At present, the dietary requirement for biotin is unknown and intake recommendations are provided as Adequate Intakes (AIs). The biotin AI for adults and pregnant women is 30 μg/d, whereas 35 μg/d is recommended for lactating women. However, pregnant and lactating women may require more biotin to meet the demands of these reproductive states. Objective: The current study sought to quantify the impact of reproductive state on biotin status response to a known dietary intake of biotin. Methods: To achieve this aim, we measured a panel of biotin biomarkers among pregnant (gestational week 27 at study entry; n = 26), lactating (postnatal week 5 at study entry; n = 28), and control (n = 21) women who participated in a 10- to 12-wk feeding study providing 57 μg of dietary biotin/d as part of a mixed diet. Results: Over the course of the study, pregnant women excreted 69% more (vs. control; P < 0.001) 3-hydroxyisovaleric acid (3-HIA), a metabolite that accumulates during the catabolism of leucine when the activity of biotin-dependent methylcrotonyl–coenzyme A carboxylase is impaired. Interestingly, urinary excretion of 3-hydroxyisovaleryl-carnitine (3-HIA-carnitine), a downstream metabolite of 3-HIA, was 27% lower (P = 0.05) among pregnant (vs. control) women, a finding that may arise from carnitine inadequacy during gestation. No differences (P > 0.05) were detected in plasma biotin, urinary biotin, or urinary bisnorbiotin between pregnant and control women. Lactating women excreted 76% more (vs. control; P = 0.001) of the biotin catabolite bisnorbiotin, indicating that lactation accelerates biotin turnover and loss. Notably, with respect to control women, lactating women excreted 23% less (P = 0.04) urinary 3-HIA and 26% less (P = 0.05) urinary 3-HIA-carnitine, suggesting that lactation reduces leucine catabolism and that these metabolites may not be useful indicators of biotin status during lactation. Conclusions: Overall, these data demonstrate significant alterations in markers of biotin metabolism during pregnancy and lactation and suggest that biotin intakes exceeding current recommendations are needed to meet the demands of these reproductive states. This trial was registered at clinicaltrials.gov as NCT01127022. PMID:25122647

Endocrine regulation of the immune response to influenza virus infection with a metabolite of DHEA-androstenediol.

PubMed

Padgett, D A; Loria, R M; Sheridan, J F

1997-09-01

In these studies the influence of androstenediol on the course of an experimental virus infection was examined. Pretreatment with 320 mg/kg AED protected male mice from lethal influenza virus infection. In addition, AED enhanced antigen-induced trafficking of mononuclear cells into the draining lymph node and augmented antigen-specific activation of helper-T cells, which are important for control of viral pathogenesis. Furthermore, AED prevented the characteristic increase in serum corticosterone noted during influenza A virus infection. Although steroid hormones, at least corticosteroids, typically suppress host immune and inflammatory responses in vivo, these data suggest that AED may function to augment host immune and inflammatory responses in contrast to corticosteroids.

ESTIMATES OF AGE-SPECIFIC URINARY EXCRETION RATES FOR CREATININE AMONG CHILDREN

EPA Science Inventory

The results of this study suggest that naïve adjustment by creatinine concentration, without consideration of the age-dependence of the physiological mechanisms controlling its excretion, may introduce sizeable error and is inappropriate when comparing metabolite concentrations a...

Methodologies for Estimating Cumulative Human Exposures to Current-Use Pyrethroid Pesticides

EPA Science Inventory

We estimated cumulative residential pesticide exposures for a group of nine young children (4–6 years) using three different methodologies developed by the US Environmental Protection Agency and compared the results with estimates derived from measured urinary metabolite concentr...

DIETARY EXPOSURE TO PYRETHROIDS IN THE U.S POPULATION

EPA Science Inventory

We examined the contribution of pyrethroid residues in food as an important driver of exposure. The levels of urinary metabolites of pyrethroids reported in NHANES were used as a general estimate of population exposure to pyrethroids. Dietary exposure to pyrethroids was estimat...

Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth

PubMed Central

Ferguson, Kelly K.; McElrath, Thomas F.; Ko, Yi-An; Mukherjee, Bhramar; Meeker, John D.

2014-01-01

Background Preterm birth is a significant public health problem, affecting over 1 in 10 live births and contributing largely to infant mortality and morbidity. Everyday exposure to environmental chemicals such as phthalates could contribute, and may be modifiable. In the present study we examine variability in phthalate exposure across gestation and identify windows of susceptibility for the relationship with preterm birth. Methods Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Women’s Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points during gestation for phthalate measurement, and birth outcomes were recorded at delivery. From this population we selected all 130 cases of preterm birth, defined as delivery before 37 weeks completed gestation, as well as 352 random controls. Results Urinary phthalate metabolite levels were moderately variable over pregnancy, but levels measured at multiple time points were associated with increased odds of preterm birth. Adjusted odds ratios (aOR) for spontaneous preterm birth were strongest in association with phthalate metabolite concentrations measured at the beginning of the third trimester (aOR for summed di-2-ethylhexyl phthalate metabolites [∑DEHP]=1.33, 95% confidence interval [CI]=1.02, 1.73). Odds ratios for placental preterm birth, defined as delivery with presentation of preeclampsia or intrauterine growth restriction, were slightly elevated in the first trimester for DEHP metabolites (aOR for ∑DEHP=1.33, 95% CI=0.99, 1.78). Conclusions Pregnant women with exposure to phthalates both early and late in pregnancy are at increased risk of delivering preterm, but mechanisms may differ based on etiology. PMID:24934852

Phthalate metabolites and bisphenol-A in association with circulating angiogenic biomarkers across pregnancy

PubMed Central

Ferguson, Kelly K.; McElrath, Thomas F.; Cantonwine, David E.; Mukherjee, Bhramar; Meeker, John D.

2015-01-01

Introduction Phthalates and bisphenol-a (BPA) are endocrine disrupting compounds with widespread exposure that have been linked in a number of epidemiologic studies to adverse birth outcomes and developmental effects. We hypothesized that these associations may be mediated in part through altered placental development and function consequent to exposure. To investigate this question, we examined associations between plasma biomarkers of angiogenesis and urinary biomarkers of exposure to phthalates and bisphenol-a (BPA) measured at repeated time points across pregnancy. Methods We utilized a nested case-control population consisting of 130 mothers who delivered preterm and 352 who delivered term from a prospective birth cohort. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in plasma samples collected from up to four visits during pregnancy (median 10, 18, 26, and 35 weeks). Phthalate metabolites and BPA were measured in urine samples collected at the same visits as indices of exposure. Results In linear mixed effects models adjusted for urine dilution and gestational age at sample collection, oxidized di-2-ethylhexyl phthalate (DEHP) metabolites were associated with decreases in PlGF as well as increases in the sFlt-1 to PlGF ratio. These results were slightly attenuated in fully adjusted models. Other phthalate metabolites did not show consistent relationships with either sFlt-1 or PlGF. BPA, however, was associated with increased sFlt-1 as well as the sFlt-1 to PlGF ratio in both crude and adjusted models. Discussion We observed associations between urinary DEHP metabolites and BPA and biomarkers of angiogenesis during pregnancy that may be indicative of disrupted placental development and/or function during gestation. PMID:25913709

Identification of N-Acetyltaurine as a Novel Metabolite of Ethanol through Metabolomics-guided Biochemical Analysis*

PubMed Central

Shi, Xiaolei; Yao, Dan; Chen, Chi

2012-01-01

The influence of ethanol on the small molecule metabolome and the role of CYP2E1 in ethanol-induced hepatotoxicity were investigated using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics platform and Cyp2e1-null mouse model. Histological and biochemical examinations of ethanol-exposed mice indicated that the Cyp2e1-null mice were more resistant to ethanol-induced hepatic steatosis and transaminase leakage than the wild-type mice, suggesting CYP2E1 contributes to ethanol-induced toxicity. Metabolomic analysis of urinary metabolites revealed time- and dose-dependent changes in the chemical composition of urine. Along with ethyl glucuronide and ethyl sulfate, N-acetyltaurine (NAT) was identified as a urinary metabolite that is highly responsive to ethanol exposure and is correlated with the presence of CYP2E1. Subsequent stable isotope labeling analysis using deuterated ethanol determined that NAT is a novel metabolite of ethanol. Among three possible substrates of NAT biosynthesis (taurine, acetyl-CoA, and acetate), the level of taurine was significantly reduced, whereas the levels of acetyl-CoA and acetate were dramatically increased after ethanol exposure. In vitro incubation assays suggested that acetate is the main precursor of NAT, which was further confirmed by the stable isotope labeling analysis using deuterated acetate. The incubations of tissues and cellular fractions with taurine and acetate indicated that the kidney has the highest NAT synthase activity among the tested organs, whereas the cytosol is the main site of NAT biosynthesis inside the cell. Overall, the combination of biochemical and metabolomic analysis revealed NAT is a novel metabolite of ethanol and a potential biomarker of hyperacetatemia. PMID:22228769

A metabolomic study of low estimated GFR in non-proteinuric type 2 diabetes mellitus.

PubMed

Ng, D P K; Salim, A; Liu, Y; Zou, L; Xu, F G; Huang, S; Leong, H; Ong, C N

2012-02-01

We carried out a urinary metabolomic study to gain insight into low estimated GFR (eGFR) in patients with non-proteinuric type 2 diabetes. Patients were identified as being non-proteinuric using multiple urinalyses. Cases (n = 44) with low eGFR and controls (n = 46) had eGFR values <60 and ≥60 ml min(-1) 1.73 m(-2), respectively, as calculated using the Modification of Diet in Renal Disease formula. Urine samples were analysed by liquid chromatography/mass spectrometry (LC/MS) and GC/MS. False discovery rates were used to adjust for multiple hypotheses testing, and selection of metabolites that best predicted low eGFR status was achieved using least absolute shrinkage and selection operator logistic regression. Eleven GC/MS metabolites were strongly associated with low eGFR after correction for multiple hypotheses testing (smallest adjusted p value = 2.62 × 10(-14), largest adjusted p value = 3.84 × 10(-2)). In regression analysis, octanol, oxalic acid, phosphoric acid, benzamide, creatinine, 3,5-dimethoxymandelic amide and N-acetylglutamine were selected as the best subset for prediction and allowed excellent classification of low eGFR (AUC = 0.996). In LC/MS, 19 metabolites remained significant after multiple hypotheses testing had been taken into account (smallest adjusted p value = 2.04 × 10(-4), largest adjusted p value = 4.48 × 10(-2)), and several metabolites showed stronger evidence of association relative to the uraemic toxin, indoxyl sulphate (adjusted p value = 3.03 × 10(-2)). The potential effect of confounding on the association between metabolites was excluded. Our study has yielded substantial new insight into low eGFR and provided a collection of potential urinary biomarkers for its detection.

Milk decreases urinary excretion but not plasma pharmacokinetics of cocoa flavan-3-ol metabolites in humans.

PubMed

Mullen, William; Borges, Gina; Donovan, Jennifer L; Edwards, Christine A; Serafini, Mauro; Lean, Michael E J; Crozier, Alan

2009-06-01

Cocoa drinks containing flavan-3-ols are associated with many health benefits, and conflicting evidence exists as to whether milk adversely affects the bioavailability of flavan-3-ols. The objective was to determine the effect of milk on the bioavailability of cocoa flavan-3-ol metabolites. Nine human volunteers followed a low-flavonoid diet for 2 d before drinking 250 mL of a cocoa beverage, made with water or milk, that contained 45 micromol (-)-epicatechin and (-)-catechin. Plasma and urine samples were collected for 24 h, and flavan-3-ol metabolites were analyzed by HPLC with photodiode array and mass spectrometric detection. Milk affected neither gastric emptying nor the transit time through the small intestine. Two flavan-3-ol metabolites were detected in plasma and 4 in urine. Milk had only minor effects on the plasma pharmacokinetics of an (epi)catechin-O-sulfate and had no effect on an O-methyl-(epi)catechin-O-sulfate. However, milk significantly lowered the excretion of 4 urinary flavan-3-ol metabolites from 18.3% to 10.5% of the ingested dose (P = 0.016). Studies that showed protective effects of cocoa and those that showed no effect of milk on bioavailability used products that have a much higher flavan-3-ol content than does the commercial cocoa used in the present study. Most studies of the protective effects of cocoa have used drinks with a very high flavan-3-ol content. Whether similar protective effects are associated with the consumption of many commercial chocolate and cocoa products containing substantially lower amounts of flavan-3-ols, especially when absorption at lower doses is obstructed by milk, remains to be determined.

Increased Urinary Phthalate Levels in Women with Uterine Leiomyoma: A Case-Control Study.

PubMed

Kim, Young Ah; Kho, Younglim; Chun, Kyoung Chul; Koh, Jae Whoan; Park, Jeong Woo; Bunderson-Schelvan, Melisa; Cho, Yoon Hee

2016-12-15

We assessed the urinary concentration of 16 phthalate metabolites in 57 women with and without uterine leiomyoma ( n = 30 and 27; respectively) to determine the association between phthalate exposure and uterine leiomyoma. To evaluate exposure to di-(2-ethylhexyl) phthalate (DEHP); we calculated the molar sum of DEHP metabolites; ∑3-DEHP (combining mono-(2-ethylhexyl) phthalate (MEHP); mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); and mono-(2-ethyl-5-oxohexyl) phthalate); ∑4-DEHP (∑3-DEHP plus mono-(2-ethyl-5-carboxypentyl) phthalate); and ∑5-DEHP (∑4-DEHP plus mono (2-(carboxylmethyl)hexyl) phthalate (2cx-MMHP)). The log transformed urinary levels of MEHP; MEHHP; 2cx-MMHP; ∑3-DEHP; ∑4-DEHP; and ∑5-DEHP in the leiomyoma group were significantly higher than those of controls. When we adjusted for age; waist circumference; and parity using multiple logistic regression analyses; we found log ∑3-DEHP (OR = 10.82; 95% CI = 1.25; 93.46) and ∑4-DEHP (OR = 8.78; 95% CI = 1.03; 75.29) were significantly associated with uterine leiomyoma. Our findings suggest an association between phthalate exposure and uterine leiomyoma. However; larger studies are needed to investigate potential interactions between phthalate exposure and uterine leiomyoma.

Hebei Spirit Oil Spill Exposure and Subjective Symptoms in Residents Participating in Clean-Up Activities

PubMed Central

Cheong, Hae-Kwan; Lee, Jong Seong; Kwon, Hojang; Ha, Eun-Hee; Hong, Yun-Chul; Choi, Yeyong; Jeong, Woo-Chul; Hur, Jongil; Lee, Seung-Min; Kim, Eun-Jung; Im, Hosub

2011-01-01

Objectives This study was conducted to examine the relationship between crude oil exposure and physical symptoms among residents participating in clean-up work associated with the Hebei Spirit oil spill, 2007 in Korea. Methods A total of 288 residents responded to a questionnaire regarding subjective physical symptoms, sociodemographic characteristics and clean-up activities that occurred between two and eight weeks after the accident. Additionally, the urine of 154 of the respondents was analyzed for metabolites of volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) and heavy metals. To compare the urinary levels of exposure biomarkers, the urine of 39 inland residents who were not directly exposed to the oil spill were analyzed. Results Residents exposed to oil remnants through clean-up work showed associations between physical symptoms and the exposure levels defined in various ways, including days of work, degree of skin contamination, and levels of some urinary exposure biomarkers of VOCs, metabolites and metals, although no major abnormalities in urinary exposure biomarkers were observed. Conclusions This study provides evidence of a relationship between crude oil exposure and acute human health effects and suggests the need for follow-up to evaluate the exposure status and long-term health effects of clean-up participants. PMID:22125768

Increased Urinary Phthalate Levels in Women with Uterine Leiomyoma: A Case-Control Study

PubMed Central

Kim, Young Ah; Kho, Younglim; Chun, Kyoung Chul; Koh, Jae Whoan; Park, Jeong Woo; Bunderson-Schelvan, Melisa; Cho, Yoon Hee

2016-01-01

We assessed the urinary concentration of 16 phthalate metabolites in 57 women with and without uterine leiomyoma (n = 30 and 27; respectively) to determine the association between phthalate exposure and uterine leiomyoma. To evaluate exposure to di-(2-ethylhexyl) phthalate (DEHP); we calculated the molar sum of DEHP metabolites; ∑3-DEHP (combining mono-(2-ethylhexyl) phthalate (MEHP); mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP); and mono-(2-ethyl-5-oxohexyl) phthalate); ∑4-DEHP (∑3-DEHP plus mono-(2-ethyl-5-carboxypentyl) phthalate); and ∑5-DEHP (∑4-DEHP plus mono (2-(carboxylmethyl)hexyl) phthalate (2cx-MMHP)). The log transformed urinary levels of MEHP; MEHHP; 2cx-MMHP; ∑3-DEHP; ∑4-DEHP; and ∑5-DEHP in the leiomyoma group were significantly higher than those of controls. When we adjusted for age; waist circumference; and parity using multiple logistic regression analyses; we found log ∑3-DEHP (OR = 10.82; 95% CI = 1.25; 93.46) and ∑4-DEHP (OR = 8.78; 95% CI = 1.03; 75.29) were significantly associated with uterine leiomyoma. Our findings suggest an association between phthalate exposure and uterine leiomyoma. However; larger studies are needed to investigate potential interactions between phthalate exposure and uterine leiomyoma. PMID:27983712

Nandrolone excretion in sedentary vs physically trained young women.

PubMed

Enea, C; Boisseau, N; Bayle, M L; Flament, M M; Grenier-Loustalot, M F; Denjean, A; Diaz, V; Dugué, B

2010-02-01

We investigated the effects of the menstrual cycle, oral contraception and physical training on exhaustive exercise-induced changes in the excretion of nandrolone metabolites [19-norandrosterone (19-NA), and 19-noretiocholanolone (19-NE)] in young women. Twenty-eight women were allocated to an untrained group (n=16) or a trained group (n=12), depending on their physical training background. The untrained group was composed of nine oral contraceptive users (OC+) and seven eumenorrheic women (OC-), while the trained group was entirely composed of OC+ subjects. Three laboratory sessions were conducted in a randomized order: a prolonged exercise test, a short-term exercise test and a control session. Urine specimens were collected before and 30, 60 and 90 min after the exercise test and at the same times of the day during the control session. Urinary concentrations of nandrolone metabolites were determined by gas chromatography coupled to mass spectrometry. Urinary concentrations of 19-NA and 19-NE ranged from undetectable levels to 1.14 and 0.47 ng/mL, respectively. Nandrolone excretion was not affected by the menstrual cycle phase (early follicular vs mid-luteal), prior physical training, oral contraception or acute physical exercise. Therefore, a urinary concentration of 2 ng/mL of 19-NA appears to be fair as the upper acceptable limit in doping control tests for female athletes.

Gestation-specific reference intervals for comprehensive spot urinary steroid hormone metabolite analysis in normal singleton pregnancy and 6 weeks postpartum.

PubMed

Mistry, Hiten D; Eisele, Nicole; Escher, Geneviève; Dick, Bernhard; Surbek, Daniel; Delles, Christian; Currie, Gemma; Schlembach, Dietmar; Mohaupt, Markus G; Gennari-Moser, Carine

2015-09-04

Normal pregnancy depends on pronounced adaptations in steroid hormone concentrations. Although in recent years, the understanding of these hormones in pregnancy has improved, the interpretation is hampered by insufficient reference values. Our aim was to establish gestation-specific reference intervals for spot urinary steroid hormone levels in normal singleton pregnancies and 6 weeks postpartum. Cross-sectional multicentre observational study. Women recruited between 2008 and 2013 at 3 University Hospitals in Switzerland (Bern), Scotland (Glasgow) and Austria (Graz). Spot urine was collected from healthy women undergoing a normal pregnancy (age, 16-45 years; mean, 31 years) attending routine antenatal clinics at gestation weeks 11, 20, and 28 and approximately 6 weeks postpartum. Urine steroid hormone levels were analysed using gas-chromatography mass spectrometry. Creatinine was also measured by routine analysis and used for normalisation. From the results, a reference interval was calculated for each hormone metabolite at each trimester and 6 weeks postpartum. Changes in these concentrations between trimesters and postpartum were also observed for several steroid hormones and followed changes proposed for index steroid hormones. Normal gestation-specific reference values for spot urinary steroid hormones throughout pregnancy and early postpartum are now available to facilitate clinical management and research approaches to steroid hormone metabolism in pregnancy and the early postpartum period.

Dietary protein-induced increases in urinary calcium are accompanied by similar increases in urinary nitrogen and urinary urea: a controlled clinical trial.

PubMed

Bihuniak, Jessica D; Simpson, Christine A; Sullivan, Rebecca R; Caseria, Donna M; Kerstetter, Jane E; Insogna, Karl L

2013-03-01

To determine the usefulness of urinary urea as an index of dietary protein intake, 10 postmenopausal women were enrolled in and completed a randomized, double-blind, cross-over feeding trial from September 2008 to May 2010 that compared 10 days of a 45-g whey supplement with 10 days of a 45-g maltodextrin control. Urinary nitrogen, urinary calcium, urinary urea, and bone turnover markers were measured at days 0, 7, and 10. Paired sample t tests, Pearson's correlation statistic, and simple linear regression were used to assess differences between treatments and associations among urinary metabolites. Urinary nitrogen/urinary creatinine rose from 12.3±1.7 g/g (99.6±13.8 mmol/mmol) to 16.8±2.2 g/g (135.5±17.8 mmol/mmol) with whey supplementation, but did not change with maltodextrin. Whey supplementation caused urinary calcium to rise by 4.76±1.84 mg (1.19±0.46 mmol) without a change in bone turnover markers. Because our goal was to estimate protein intake from urinary nitrogen/urinary creatinine, we used our data to develop the following equation: protein intake (g/day)=71.221+1.719×(urinary nitrogen, g)/creatinine, g) (R=0.46, R(2)=0.21). As a more rapid and less costly alternative to urinary nitrogen/urinary creatinine, we next determined whether urinary urea could predict protein intake and found that protein intake (g/day)=63.844+1.11×(urinary urea, g/creatinine, g) (R=0.58, R(2)=0.34). These data indicate that urinary urea/urinary creatinine is at least as good a marker of dietary protein intake as urinary nitrogen and is easier to quantitate in nutrition intervention trials. Copyright © 2013 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Experimentally reduced corticosterone release promotes early breeding in black-legged kittiwakes.

PubMed

Goutte, Aurélie; Clément-Chastel, Céline; Moe, Børge; Bech, Claus; Gabrielsen, Geir Wing; Chastel, Olivier

2011-06-15

Breeding at the right time is important for successful reproduction. In birds, stressful environmental conditions are known to delay the timing of breeding but the underlying mechanisms are poorly understood. The stress hormone corticosterone appears to be a good candidate for mediating egg-laying date according to early environmental conditions and physiological state. By experimentally reducing the release of corticosterone in black-legged kittiwakes during the pre-laying period, we tested whether egg-laying date was mechanistically linked to corticosterone levels. Male and female kittiwakes were implanted with a low dose of exogenous corticosterone to inhibit endogenous corticosterone production. According to our predictions, the experimental reduction of corticosterone release was paralleled by a significant advancement of egg laying in females (around 4 days earlier). In addition, females with experimentally reduced corticosterone release gained mass during the pre-laying period compared with controls. Ultimately, the advancement of egg laying in females with experimentally reduced corticosterone levels was associated with an enhanced breeding success. This effect was strongly sex specific. In corticosterone-treated male kittiwakes, egg-laying date and reproductive success were not affected, but breeding probability was lower than in controls. This corticosterone treatment did not influence immediate clutch size, or return rate and breeding decision the following year. Our results support the hypothesis that corticosterone secretion during the pre-laying period mediates the timing of breeding in this long-lived seabird, possibly through the dynamics of energy reserves.

The relationships between pesticide metabolites and neurobehavioral test performance in the third National Health and Nutrition Examination Survey.

PubMed

Krieg, Edward F

2013-01-01

Regression analysis was used to estimate and test for relationships between urinary pesticide metabolites and neurobehavioral test performance in adults, 20 to 59 years old, participating in the third National Health and Nutrition Examination Survey. The 12 pesticide metabolites included 2 naphthols, 8 phenols, a phenoxyacetic acid, and a pyridinol. The 3 neurobehavioral tests included in the survey were simple reaction time, symbol-digit substitution, and serial digit learning. As the 2,4-dichlorophenol, 2,5-dichlorophenol, and the pentachlorophenol concentrations increased, performance on the serial digit learning test improved. As the 2,5-dichlorophenol concentration increased, performance on the symbol-digit substitution test improved. At low concentrations, the parent compounds of these metabolites may act at acetylcholine and γ-aminobutyric acid synapses in the central nervous system to improve neurobehavioral test performance.

Urinary DAP metabolite levels in Thai farmers and their families and exposure to pesticides from agricultural pesticide spraying.

PubMed

Hanchenlaksh, Chalalai; Povey, Andrew; O'Brien, Sarah; de Vocht, Frank

2011-08-01

We conducted a biomarker study to characterise exposure to pesticides among farmers and their families in Thailand to assess the relative importance of the dermal exposure route and to identify important factors that determine exposure levels within farmers' families. Sixteen farmers' families (eight vegetable and eight fruit farmers) participated in the study. Three morning spot urine samples were collected during a pesticide spraying week. Spot samples were grouped by individual and analysed for dialkylphosphate (DAP) metabolites and creatinine. Additional information on exposure and lifestyle was collected by means of questionnaires. Dermal exposure was assessed using a semi-quantitative observational method (DREAM). Urinary DAP levels varied 20-fold between farmers, with average (geometric mean) levels of 51.1 μg/g for vegetable and 122.2 μg/g for fruit farmers. A moderate correlation (r(s)∼0.45) was found between log(e)-transformed DREAM scores and DAP levels. Farmers' urinary metabolite levels were not correlated with those of their spouses (r(s)∼-0.30) or children (r(s)∼-0.00) collected on the same days. Detectable spouses' DAP levels were on average (geometric mean) 13.0 μg/g and those of children 7.6 μg/g. Farmers in Thailand as well as their families are exposed to pesticides in the spraying season and dermal exposure is an important route. The main route of exposure for farmers' families seems to be through transfer from the farmer to family members or contamination of the home environment, rather than family members helping or playing on the farm. Showering or washing immediately after pesticide spraying greatly reduces the potential exposure of family members to pesticide residues.

Urinary Arsenic Metabolites in Children and Adults Exposed to Arsenic in Drinking Water in Inner Mongolia, China

PubMed Central

Sun, Guifan; Xu, Yuanyuan; Li, Xin; Jin, Yaping; Li, Bing; Sun, Xiance

2007-01-01

Background We report the concentrations and distributions of urinary arsenic (As) metabolites in 233 residents exposed to 20, 90, or 160 μg/L inorganic arsenic (iAs) in drinking water from three villages in Hohhot, Inner Mongolia, China, that formed one control and two exposed groups. Methods We used hydride generation-atomic absorption spectrometry (HGAAS) to determine iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA). Results The concentrations of each urinary As species in the two exposed groups were significantly higher than in the control group for both children and adults. Both children and adults in exposed groups had higher percent iAs and MMA and lower percent DMA, and low primary and secondary methylation indices (PMI and SMI, respectively) than those in the control group. However, children showed significant increases in percent DMA and the SMI as well as decreases in the percent MMA when the iAs exposure level increased from 90 to 160 μg/L. In addition, children in the two exposed groups showed lower percent MMA but higher percent DMA and higher SMI than adults in the same exposed group. No significant differences in As metabolite concentrations and distributions were found between males and females in each group. A significant correlation was also found in the SMI between 11 pairs of children and their mothers from the 160-μg/L–exposed group. Conclusions Children had higher a capacity for secondary methylation of As than adults when exposed to the same concentrations of iAs in drinking water. Exposure to As may increase the capacity for methylation in children to some extent. PMID:17450238

Arsenic Metabolism in Children Differs From That in Adults

PubMed Central

Skröder Löveborn, Helena; Lu, Ying; Ahmed, Sultan; Kuehnelt, Doris; Raqib, Rubhana; Vahter, Marie

2016-01-01

Arsenic toxicity in adults is associated with methylation efficiency, influenced by factors such as gender, genetics, and nutrition. The aim of this study was to evaluate influencing factors for arsenic metabolism in children. For 488 children (9 years), whose mothers participated in a study on arsenic exposure during pregnancy (nested into the MINIMat trial) in rural Bangladesh, we measured urinary concentrations of inorganic arsenic (iAs) and its metabolites methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by HPLC-HG-ICPMS. Methylation efficiency was assessed by relative amounts (%) of the metabolites. We evaluated the impact of factors such as maternal urinary metabolite pattern, arsenic exposure, gender, socioeconomic status, season of sampling, and nutritional factors, including erythrocyte selenium (Ery-Se), and plasma folate and vitamin B12. Children had higher %DMA and lower %iAs in urine compared to their mothers, unrelated to their lower exposure [median urinary arsenic (U-As) 53 vs 78 µg/l]. Surprisingly, selenium status (Ery-Se) was strongly associated with children’s arsenic methylation; an increase in Ery-Se from the 5–95th percentile was associated with: +1.8 percentage points (pp) for %iAs (P  =  .001), +1.4 pp for %MMA (P  =  .003), and −3.2 pp for %DMA (P  <  .001). Despite this, Ery-Se was positively associated with U-As (5–95th percentile: +41 µg/l, P  =  .026). As expected, plasma folate was inversely associated with %iAs (5–95th percentile: −1.9 pp, P  =  .001) and positively associated with %DMA (5–95th percentile: +2.2 pp, P  =  .008). Children methylated arsenic more efficiently than their mothers. Also influencing factors, mainly selenium and folate, differed. This warrants further research. PMID:27056082

The Adrenocortical Response of Greater Sage Grouse (Centrocercus urophasianus) to Capture, ACTH Injection, and Confinement, as Measured in Fecal Samples

PubMed Central

Jankowski, M. D.; Wittwer, D. J.; Heisey, D. M.; Franson, J. C.; Hofmeister, E. K.

2009-01-01

Investigators of wildlife populations often utilize demographic indicators to understand the relationship between habitat characteristics and population viability. Assessments of corticosterone may enable earlier detection of populations at risk of decline because physiological adjustments to habitat disturbance occur before reproductive diminutions. Noninvasive methods to accomplish these assesments are important in species of concern, such as the greater sage grouse (GRSG). Therefore, we validated a radioimmunoassay that measures immunoreactive corticosterone metabolites (ICM) in fecal samples and used it to characterize the adrenocortical response of 15 GRSG exposed to capture, intravenous injection of 50 IU/kg adrenocorticotrophic hormone (ACTH) or saline, and 22 h of confinement. Those animals injected with ACTH exhibited a more sustained (P = 0.0139) and less variable (P = 0.0012) response than those injected with saline, indicating different levels of adrenocortical activity. We also found that potential field-collection protocols of fecal samples did not alter ICM concentrations: samples held at 4°C for up to 16 h contained similar levels of ICM as those frozen (−20°C) immediately. This study demonstrates a multiphasic adrenocortical response that varied with the level of stimulation and indicates that the assay used to measure this phenomenon is applicable for studies of wild GRSG. PMID:19199814

Characterizing the nutritional strategy of incubating king eiders Somateria spectabilis in northern Alaska

USGS Publications Warehouse

Bentzen, R.L.; Powell, A.N.; Williams, T.D.; Kitaysky, A.S.

2008-01-01

We measured plasma concentrations of variables associated with lipid metabolism (free fatty acids, glycerol, triglyceride, and ??- hydroxybutyrate), protein metabolism (uric acid), and baseline corticosterone to characterize the nutritional state of incubating king eiders Somateria spectabilis and relate this to incubation constancy at two sites, Kuparuk and Teshekpuk, in northern Alaska. King eiders at both sites appeared to employ a partial-income incubation strategy, relying on both endogenous and exogenous energy resources. Females maintained high invariant levels of free fatty acids, ??-hydroxybutyrate, and glycerol throughout incubation, indicating that fat reserves were a major energy source, and not completely depleted during incubation. Similarly, uric acid did not increase, suggesting effective protein sparing or protein ingestion and adequate lipid reserves throughout incubation. Baseline corticosterone and triglyceride levels increased during incubation, indicative of an increase in foraging during late stages of incubation. Incubating females at Kuparuk had higher triglyceride concentrations but also had higher ??-hydroxybutyrate concentrations than females at Teshekpuk. This dichotomy may reflect a short-term signal of feeding overlaying the longer-term signal of reliance on endogenous lipid reserves due to higher food intake yet higher metabolic costs at Kuparuk because of its colder environment. Incubation constancy was not correlated with plasma concentrations of lipid or protein metabolites. ?? 2008 The Authors.

Effects of population density on corticosterone levels of prairie voles in the field

PubMed Central

Blondel, Dimitri V.; Wallace, Gerard N.; Calderone, Stefanie; Gorinshteyn, Marija; St. Mary, Colette M.; Phelps, Steven M.

2015-01-01

High population density is often associated with increased levels of stress-related hormones, such as corticosterone (CORT). Prairie voles (Microtus ochrogaster) are a socially monogamous species known for their large population density fluctuations in the wild. Although CORT influences the social behavior of prairie voles in the lab, the effect of population density on CORT has not previously been quantified in this species in the field. We validated a non-invasive hormone assay for measuring CORT metabolites in prairie vole feces. We then used semi-natural enclosures to experimentally manipulate population density, and measured density effects on male space use and fecal CORT levels. Our enclosures generated patterns of space use and social interaction that were consistent with previous prairie vole field studies. Contrary to the positive relationship between CORT and density typical of other taxa, we found that lower population densities (80 animals/ha) produced higher fecal CORT than high densities (240/ha). Combined with prior work in the lab and field, the data suggest that high prairie vole population densities indicate favorable environments, perhaps through reduced predation risk. Lastly, we found that field animals had lower fecal CORT levels than laboratory-living animals. The data emphasize the usefulness of prairie voles as models for integrating ecological, evolutionary and mechanistic questions in social behavior. PMID:26342968

The adrenocortical response of greater sage grouse (Centrocercus urophasianus) to capture, ACTH injection, and confinement, as measured in fecal samples

USGS Publications Warehouse

Jankowski, M.D.; Wittwer, D.J.; Heisey, D.M.; Franson, J. Christian; Hofmeister, Erik K.

2009-01-01

Investigators of wildlife populations often utilize demographic indicators to understand the relationship between habitat characteristics and population viability. Assessments of corticosterone may enable earlier detection of populations at risk of decline because physiological adjustments to habitat disturbance occur before reproductive diminutions. Noninvasive methods to accomplish these assesments are important in species of concern, such as the greater sage grouse (GRSG). Therefore, we validated a radioimmunoassay that measures immunoreactive corticosterone metabolites (ICM) in fecal samples and used it to characterize the adrenocortical response of 15 GRSG exposed to capture, intravenous injection of 50 IU/kg adrenocorticotrophic hormone (ACTH) or saline, and 22 h of confinement. Those animals injected with ACTH exhibited a more sustained (P = 0.0139) and less variable (P = 0.0012) response than those injected with saline, indicating different levels of adrenocortical activity. We also found that potential field-collection protocols of fecal samples did not alter ICM concentrations: samples held at 4??C for up to 16 h contained similar levels of ICM as those frozen (-20??C) immediately. This study demonstrates a multiphasic adrenocortical response that varied with the level of stimulation and indicates that the assay used to measure this phenomenon is applicable for studies of wild GRSG. ?? 2009 by The University of Chicago. All rights reserved.

Protecting embryos from stress: Corticosterone effects and the corticosterone response to capture and confinement during pregnancy in a live-bearing lizard (Hoplodactylus maculatus)

USGS Publications Warehouse

Cree, A.; Tyrrell, C.L.; Preest, M.R.; Thorburn, D.; Guillette, L.J.

2003-01-01

Hormones in the embryonic environment, including those of the hypothalamo-pituitary-adrenal (HPA) axis, have profound effects on development in eutherian mammals. However, little is known about their effects in reptiles that have independently evolved viviparity. We investigated whether exogenous corticosterone affected embryonic development in the viviparous gecko Hoplodactylus maculatus, and whether pregnant geckos have a corticosterone response to capture and confinement that is suppressed relative to that in non-pregnant (vitellogenic) females and males. Corticosterone implants (5 mg, slow-release) administered to females in mid-pregnancy caused a large elevation of corticosterone in maternal plasma (P<0.001), probable reductions in embryonic growth and development (P=0.069-0.073), developmental abnormalities and eventual abortions. Cool temperature produced similar reductions in embryonic growth and development (P???0.036 cf. warm controls), but pregnancies were eventually successful. Despite the potentially harmful effects of elevated plasma corticosterone, pregnant females did not suppress their corticosterone response to capture and confinement relative to vitellogenic females, and both groups of females had higher responses than males. Future research should address whether lower maternal doses of corticosterone produce non-lethal effects on development that could contribute to phenotypic plasticity. Corticosterone implants also led to increased basking in pregnant females (P<0.001), and basal corticosterone in wild geckos (independent of reproductive condition) was positively correlated with body temperature (P<0.001). Interactions between temperature and corticosterone may have broad significance to other terrestrial ectotherms, and body temperature should be considered as a variable influencing plasma corticosterone concentrations in all future studies on reptiles. ?? 2003 Elsevier Inc. All rights reserved.

Androgen and androgen metabolite levels in serum and urine of East African chimpanzees (Pan troglodytes schweinfurthii): comparison of EIA and LC-MS analyses.

PubMed

Preis, Anna; Mugisha, Lawrence; Hauser, Barbara; Weltring, Anja; Deschner, Tobias

2011-12-01

The primary male androgen testosterone (T) is often used as an endocrinological marker to investigate androgen-behaviour interactions in males. In chimpanzees and bonobos, studies investigating the relationship between T levels and dominance rank or aggressive behaviour have revealed contradictory results. The immunoassays used in these studies were originally developed for the measurement of steroids in serum. Their application to non-invasively collected samples, however, can lead to methodological problems due to cross-reacting metabolites, which might occur in urine or faeces but not in blood. The overall aim of this study, therefore, is to clarify whether a T enzyme immunoassay (EIA) is an applicable method to monitor testicular function in adult male chimpanzees. To estimate the impact of cross-reacting androgens on the used T EIA, we compared the results of an EIA measurement with a set of androgen metabolite levels measured by LC-MS. In urine from male chimpanzees, cross-reactivities appear to exist mainly with T and its exclusive metabolites, 5α-dihydrotestosterone (5α-DHT) and 5α-androstanediol (androstanediol). Both urinary and serum T levels of male chimpanzees were significantly higher than female T levels when measured with the T EIA, indicating a reliable measurement of testicular androgens and their exclusive metabolites with the used EIA. In urine from female chimpanzees, the comparison between LC-MS and T EIA results indicated a higher impact of cross-reactions with adrenal androgen metabolites. Therefore, the investigation of urinary T levels in female chimpanzees with a T EIA seems to be problematic. Overall our results show that a T EIA can be a reliable method to monitor testicular function in male chimpanzee urine and that LC-MS is a valuable tool for the validation of immunoassays. Copyright © 2011 Elsevier Inc. All rights reserved.

Study of tamoxifen urinary metabolites in rat by ultra-high-performance liquid chromatography time-of-flight mass spectrometry.

PubMed

Domínguez-Romero, Juan C; García-Reyes, Juan F; Beneito-Cambra, Miriam; Martínez-Romero, Rubén; Martinez-Lara, Esther; Del Moral-Leal, María L; Molina-Díaz, Antonio

2015-08-01

Tamoxifen (TMX) is a nonsteroidal estrogen antagonist drug used for the treatment of breast cancer. It is also included in the list of banned substances of the World Anti Doping Agency (WADA) prohibited in and out of competition. In this work, the excretion of urinary metabolites of TMX after a single therapeutic dose administration in rats has been studied using ultra-high-performance liquid chromatography electrospray time-of-flight mass spectrometry (UHPLC-TOFMS). A systematic strategy based on the search of typical biotransformations that a xenobiotic can undergo in living organisms, based on their corresponding molecular formula modification and accurate mass shifts, was applied for the identification of TMX metabolites. Prior to UHPLC-TOFMS analyses, a solid-phase extraction step with polymeric cartridges was applied to urine samples. Up to 38 TMX metabolites were detected. Additional collision induced dissociation (CID) MS/MS fragmentation was performed using UHPLC-QTOFMS. Compared with recent previous studies in human urine and plasma, new metabolites have been reported for the first time in urine. Metabolites identified in rat urine include the oxygen addition, owing to different possibilities for the hydroxylation of the rings in different positions (m/z 388.2271), the incorporation of two oxygen atoms (m/z 404.2220) (including dihydroxylated derivatives or alternatives such as epoxidation plus hydroxylation or N-oxidation and hydroxylation), epoxide formation or hydroxylation and dehydrogenation [m/z 386.2114 (+O -H2 )], hydroxylation of the ring accompanied by N-desmethylation (m/z 374.2115), combined hydroxylation and methoxylation (m/z 418.2377), desaturated TMX derivate (m/z 370.2165) and its N-desmethylated derivate (m/z 356.2009), the two latter modifications not previously being reported in urine. These findings confirm the usefulness of the proposed approach based on UHPLC-TOFMS. Copyright © 2015 John Wiley & Sons, Ltd.

Efficiency control of dietary pesticide intake reduction by human biomonitoring.

PubMed

Göen, Thomas; Schmidt, Lukas; Lichtensteiger, Walter; Schlumpf, Margret

2017-03-01

In spite of food safety controls for pesticide residues, a conventional diet still leads to a noticeable exposure of the general population to several pesticides. In a pilot study the response of exposure reduction by organic diet intervention on the urinary levels of pesticide metabolites was investigated. In the study two adult individuals were kept on a conventional diet for 11days and morning urine voids were collected at the last four days of the period. Afterwards, the participants switched to exclusively organic food intake for 18days and likewise morning urine samples were collected at the last four days of this period. In the urine samples six pyrethroid metabolites, six dialkylphosphates, four phenolic parameter for organophosphate pesticides and carbamates, 6-chloronicotinic acid (ClNA) as parameter for neonicotinoid insecticides, seven phenoxy herbicides, glyphosate and its metabolite AMPA were quantified using gas chromatographic mass spectrometric methods. Generally, the comparative analyses revealed greater shares as well as higher levels of the parameters in the samples taken during the common diet period compared to the organic diet period. Considerable decrease of the levels was found for almost all pyrethroid metabolites, dialkyphosphates and phenoxy herbicids, as well as for the phenolic metabolites 4-nitrophenol and 3,5,6-trichloropyridinol. In contrast, higher values were found for the organic diet period for ClNA and the metabolite of coumaphos in one of the volunteers. The present study confirms the results of former studies which indicated that an organic diet intervention results in considerable lower exposure to organophosphate pesticides and pyrethroids. It also verifies the former experience that monitoring of urinary parameters for non-persistent pesticides permits a reliable efficiency control of short-time effects by dietary interventions. Additionally to former studies, the results of the present study highlight the need of an extension of the parameter spectrum to all prominent pesticide groups. Copyright © 2016 Elsevier GmbH. All rights reserved.

Urinary Phthalate Metabolite Concentrations and Breast Cancer Incidence and Survival following Breast Cancer: The Long Island Breast Cancer Study Project.

PubMed

Parada, Humberto; Gammon, Marilie D; Chen, Jia; Calafat, Antonia M; Neugut, Alfred I; Santella, Regina M; Wolff, Mary S; Teitelbaum, Susan L

2018-04-26

Phthalates, known endocrine disruptors, may play a role in breast carcinogenesis. Few studies have examined phthalates in relation to breast cancer (BC), and, to our knowledge, none have considered survival following BC. We examined 11 urinary phthalate metabolites, individually and as molar sum groupings, in association with BC incidence and subsequent survival. Our study includes 710 women diagnosed with first primary BC in 1996-1997 and 598 women without BC from Long Island, New York. Within 3 mo of diagnosis, participants provided spot urine samples. Nine phthalate metabolites were measured in all women; two [monocarboxyoctyl phthalate (MCOP) and monocarboxy-isononyl phthalate (MCNP)] were measured in 320 women with and 205 without BC. Women with BC were followed since diagnosis using the National Death Index; during follow-up (median=17.6 y), we identified 271 deaths (98 BC related). We examined creatinine-corrected metabolite concentrations in association with: BC, using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and all-cause/BC-specific mortality, using Cox regression to estimate hazard ratios (HRs) and 95% CIs. We also examined effect modification by body mass index (BMI) and estrogen receptor (ER) status. The highest (vs. lowest) quintiles of mono(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), MCNP, and MCOP were associated with BC ORs ranging from 0.71-0.73. The highest (vs. lowest) quintiles of mono(2-ethylhexyl) phthalate (MEHP) and MCOP were associated with BC-specific mortality HRs of 0.54 (95% CI: 0.28, 1.04) and 0.55 (95% CI: 0.23, 1.35), respectively. For BC-specific mortality, interactions were significant between BMI and mono(2-ethyl-5-oxyhexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), with positive associations among women with BMI<25 and inverse associations among women with BMI≥25.0 kg/m 2 . Consistent with laboratory evidence, we observed inverse associations between urinary concentrations of several phthalate metabolites and BC and subsequent survival; however, these results should be interpreted with caution given that biospecimen collection among women with BC occurred after diagnosis, which may be of particular concern for our case-control findings. https://doi.org/10.1289/EHP2083.

Circadian Rhythms of Oxidative Stress Markers and Melatonin Metabolite in Patients with Xeroderma Pigmentosum Group A.

PubMed

Miyata, Rie; Tanuma, Naoyuki; Sakuma, Hiroshi; Hayashi, Masaharu

2016-01-01

Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2'-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm.

Circadian Rhythms of Oxidative Stress Markers and Melatonin Metabolite in Patients with Xeroderma Pigmentosum Group A

PubMed Central

Sakuma, Hiroshi

2016-01-01

Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2′-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm. PMID:27213030

Corticosterone predicts foraging behavior and parental care in macaroni penguins.

PubMed

Crossin, Glenn T; Trathan, Phil N; Phillips, Richard A; Gorman, Kristen B; Dawson, Alistair; Sakamoto, Kentaro Q; Williams, Tony D

2012-07-01

Corticosterone has received considerable attention as the principal hormonal mediator of allostasis or physiological stress in wild animals. More recently, it has also been implicated in the regulation of parental care in breeding birds, particularly with respect to individual variation in foraging behavior and provisioning effort. There is also evidence that prolactin can work either inversely or additively with corticosterone to achieve this. Here we test the hypothesis that endogenous corticosterone plays a key physiological role in the control of foraging behavior and parental care, using a combination of exogenous corticosterone treatment, time-depth telemetry, and physiological sampling of female macaroni penguins (Eudyptes chrysolophus) during the brood-guard period of chick rearing, while simultaneously monitoring patterns of prolactin secretion. Plasma corticosterone levels were significantly higher in females given exogenous implants relative to those receiving sham implants. Increased corticosterone levels were associated with significantly higher levels of foraging and diving activity and greater mass gain in implanted females. Elevated plasma corticosterone was also associated with an apparent fitness benefit in the form of increased chick mass. Plasma prolactin levels did not correlate with corticosterone levels at any time, nor was prolactin correlated with any measure of foraging behavior or parental care. Our results provide support for the corticosterone-adaptation hypothesis, which predicts that higher corticosterone levels support increased foraging activity and parental effort.

Mangiferin prevents corticosterone-induced behavioural deficits via alleviation of oxido-nitrosative stress and down-regulation of indoleamine 2,3-dioxygenase (IDO) activity.

PubMed

Luo, Gao-Quan; Liu, Ling; Gao, Qu-Wen; Wu, Xiao-Na; Xiang, Wei; Deng, Wen-Ting

2017-08-01

In recent years, a substantial amount of experimental studies have demonstrated that exogenous administration of corticosterone causes anxiety and depressive-like behaviour in rodents which involves hypothalamic-pituitary-adrenal axis dysregulation. Our present study aimed to explore the neuroprotective potential of mangiferin against corticosterone-induced anxiety and depressive-like behaviour. Corticosterone (40 mg/kg; subcutaneously) was administered once daily in swiss albino mice for 21 days. Mice were treated simultaneously with mangiferin (40 mg/kg; p.o.), 30 min prior to the corticosterone injection. Chronic administration of corticosterone caused anxiety and depressive-like behaviour in mice which was significantly alleviated by mangiferin treatment. Biochemical analysis revealed that mangiferin treatment significantly attenuated corticosterone-induced oxido-nitrosative stress and neuroinflammation in the hippocampus region. Furthermore, concomitant treatment with mangiferin significantly enhanced the hippocampal brain-derived neurotrophic factor (BDNF) level and decreased the serum corticosterone level in the corticosterone-treated animals. Western blotting analysis revealed that corticosterone administration significantly up-regulated the indoleamine 2,3-dioxygenase (IDO) protein expression level in the hippocampus which was significantly reduced by mangiferin treatment. Taken together, our results suggest that mangiferin exerts anti-anxiety and antidepressant effect in corticosterone-treated rats, which is probably mediated through up-regulation of BDNF level along with inhibition of oxido-nitrosative stress, neuroinflammation and IDO up-regulation in the hippocampus region.

Recent Biologic Studies on Suicide.

ERIC Educational Resources Information Center

Roy, Alex

1994-01-01

Reviews studies on suicidal behavior in depressed patients, including study showing that depressed patients who had attempted suicide had significantly reduced CSF concentrations of dopamine metabolite homovanillic acid (HVA) and significantly lower urinary outputs of HVA than patients who had not attempted suicide. Considers role of diminished…

INTERPRETATION OF BENZENE URINARY BIOMARKER DATA FOR RISK ASSESSMENT: A CASE STUDY

EPA Science Inventory

Human biomonitoring is an effective tool in assessing exposure to hundreds of chemicals. Too often, however, biomarkers such as parent or metabolite concentrations in blood or urine are reported without information on doses associated with the biomarkers and implications for hum...

Determination of albumin adducts of 4,4'-methylenediphenyl diisocyanate after specific inhalative challenge tests in workers.

PubMed

Sabbioni, Gabriele; Dongari, Nagaraju; Kumar, Anoop; Baur, Xaver

2016-10-17

4,4'-Methylenediphenyl diisocyanate (MDI) is the most important isocyanate used in the industry. Lung sensitization with bronchial asthma is the main disorder in exposed workers. Albumin adducts of MDI might be involved in specific immunological reactions. MDI adducts with lysine (MDI-Lys) of albumin have been found in MDI-workers and construction workers. MDI-Lys is an isocyanate-specific adduct of MDI with albumin. In the present study, we report MDI-adducts in workers undergoing diagnostic MDI challenge tests. The workers were exposed for 2h to 5ppb of MDI. The adduct levels increase significantly after the exposure to MDI in the challenge chamber. About 0.6% of the dose was bound to albumin. So far, only urinary metabolites of MDI were measured to monitor isocyanate workers. However, such urinary metabolites are not isocyanate specific. Therefore, we propose to measure albumin adducts for monitoring MDI exposed subjects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system

PubMed Central

Kirkby, Nicholas S.; Lundberg, Martina H.; Harrington, Louise S.; Leadbeater, Philip D. M.; Milne, Ginger L.; Potter, Claire M. F.; Al-Yamani, Malak; Adeyemi, Oladipupo; Warner, Timothy D.; Mitchell, Jane A.

2012-01-01

Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice. PMID:23045674

Metabonomics approach to determine metabolic differences between green tea and black tea consumption.

PubMed

Van Dorsten, Ferdi A; Daykin, Clare A; Mulder, Theo P J; Van Duynhoven, John P M

2006-09-06

The purpose of this study was to compare the effects of black and green tea consumption on human metabolism. Seventeen healthy male volunteers consumed black tea, green tea, or caffeine in a randomized crossover study. Twenty-four-hour urine and blood plasma samples were analyzed by NMR-based metabonomics, that is, high-resolution 1H NMR metabolic profiling combined with multivariate statistics. Green and black tea consumption resulted in similar increases in urinary excretion of hippuric acid and 1,3-dihydroxyphenyl-2-O-sulfate, both of which are end products of tea flavonoid degradation by colonic bacteria. Several unidentified aromatic metabolites were detected in urine specifically after green tea intake. Interestingly, green and black tea intake also had a different impact on endogenous metabolites in urine and plasma. Green tea intake caused a stronger increase in urinary excretion of several citric acid cycle intermediates, which suggests an effect of green tea flavanols on human oxidative energy metabolism and/or biosynthetic pathways.

Effects of maternal exposure to phthalates and bisphenol A during pregnancy on gestational age.

PubMed

Weinberger, Barry; Vetrano, Anna M; Archer, Faith E; Marcella, Stephen W; Buckley, Brian; Wartenberg, Daniel; Robson, Mark G; Klim, Jammie; Azhar, Sana; Cavin, Sarah; Wang, Lu; Rich, David Q

2014-03-01

Phthalates and bisphenol A (BPA) are ubiquitous environmental toxicants, present in high concentrations in numerous consumer products. We hypothesized that maternal exposure to phthalates and BPA in pregnancy is associated with shortened gestation. Urinary phthalate and BPA metabolites from 72 pregnant women were measured at the last obstetric clinic visit prior to delivery. Using linear regression models, we estimated the change in gestational age associated with each interquartile range (IQR) increase in phthalate and BPA metabolite concentration. IQR increases in urinary mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and BPA concentrations were associated with 4.2 and 1.1 d decreases in gestation, respectively. When stratified by gender, these alterations were found only in male infants. We conclude that MEHHP and BPA (free + glucuronide) are associated with reductions in gestation, with effects observed only in males. Our findings are consistent with the idea that these agents induce gender-specific alterations in signaling via PPAR-γ transcription factor, androgen precursors and/or inflammatory mediators during the initiation of labor.

CS Riot Control Agent Exposure in US Army Mask Confidence Training: Association Between Exposure to O-Chlorobenzylidene Malononitrile (CS) and Urinary Metabolite 2-Chlorophippuric Acid

DTIC Science & Technology

2016-05-20

9 Figure 3. Major and Minor Metabolic Pathway of CS in the Body (37) .......................... 11 Figure 4. OSHA Versatile Sampler...the primary metabolite of CS in the body (8). This study will utilize Method ERB-2537 for quantification of CHA levels in exposed test subjects...intermediate that serves as a source of high energy in skeletal muscle and the brain (38). Creatine is produced in the body , can be consumed through foods

Effects of diet and exposure to hindlimb suspension on estrous cycling in Sprague-Dawley rats

NASA Technical Reports Server (NTRS)

Tou, Janet C L.; Grindeland, Richard E.; Wade, Charles E.

2004-01-01

Various factors can disrupt the female reproductive cycle resulting in subfertility. The primary objective of this study was to determine whether physiological changes associated with exposure to hypogravity disrupt reproductive cycles. The hindlimb suspension (HLS) model was used to simulate the major physiological effects of hypogravity in female Sprague-Dawley rats. Also, to determine whether diet may influence reproductive results, rats were fed purified American Institute of Nutrition (AIN)-93G or chow diet. Rats (n = 9-11/group) subjected to HLS had lengthened estrous cycles due to prolonged diestrus, indicating hypoestrogenism. Interestingly, HLS rats fed AIN-93G but not chow diet had significantly reduced time spent in estrus and decreased plasma estradiol. Attenuation of hypoestrogenism in the chow-fed rats suggested that diet provided an exogenous source of estrogen. The mechanism involved in the disruption of estrous cycling remains to be determined. HLS increased urinary corticosterone (CORT) levels during the initial 4 days of HLS, suggesting that physiological responses to acute stress may be a potential mechanism in the disruption of estrous cycles. Higher basal urinary CORT was observed in rats fed chow vs. AIN-93G diet. HLS resulted in increased urinary CORT. However, two-way ANOVA indicated a significant HLS effect (P < 0.001) but no effect of HLS x diet effect on urinary CORT levels, suggesting that estrogenic activity associated with the chow diet did not enhance the stress response. The results of this study indicate that HLS, diet, and the combination of HLS and diet influence estrous cycling. This has important implications for future reproductive success in the hypogravity environment of space.

Contribution of creatine to protein homeostasis in athletes after endurance and sprint running.

PubMed

Tang, Fu-Chun; Chan, Chun-Chen; Kuo, Po-Ling

2014-02-01

Few studies have focused on the metabolic changes induced by creatine supplementation. This study investigated the effects of creatine supplementation on plasma and urinary metabolite changes of athletes after endurance and sprint running. Twelve male athletes (20.3 ± 1.4 y) performed two identical (65-70 % maximum heart rate reserved) 60 min running exercises (endurance trial) before and after creatine supplementation (12 g creatine monohydrate/day for 15 days), followed by a 5-day washout period. Subsequently, they performed two identical 100 m sprint running exercises (power trial) before and after 15 days of creatine supplementation in accordance with the supplementary protocol of the endurance trial. Body composition measurements were performed during the entire study. Plasma samples were examined for the concentrations of glucose, lactate, branched-chain amino acids (BCAAs), free-tryptophan (f-TRP), glutamine, alanine, hypoxanthine, and uric acid. Urinary samples were examined for the concentrations of hydroxyproline, 3-methylhistidine, urea nitrogen, and creatinine. Creatine supplementation significantly increased body weights of the athletes of endurance trial. Plasma lactate concentration and ratio of f-TRP/BCAAs after recovery from endurance running were significantly decreased with creatine supplementation. Plasma purine metabolites (the sum of hypoxanthine and uric acid), glutamine, urinary 3-methylhistidine, and urea nitrogen concentrations tended to decrease before running in trials with creatine supplements. After running, urinary hydroxyproline concentration significantly increased in the power trial with creatine supplements. The findings suggest that creatine supplementation tended to decrease muscle glycogen and protein degradation, especially after endurance exercise. However, creatine supplementation might induce collagen proteolysis in athletes after sprint running.

Extreme urinary betaine losses in type 2 diabetes combined with bezafibrate treatment are associated with losses of dimethylglycine and choline but not with increased losses of other osmolytes.

PubMed

Lever, Michael; McEntyre, Christopher J; George, Peter M; Slow, Sandy; Elmslie, Jane L; Lunt, Helen; Chambers, Stephen T; Parry-Strong, Amber; Krebs, Jeremy D

2014-10-01

Betaine deficiency is a probable cardiovascular risk factor and a cause of elevated homocysteine. Urinary betaine excretion is increased by fibrate treatment, and is also often elevated in diabetes. Does fibrate further increase betaine excretion in diabetes, and does it affect the plasma concentrations and excretions of related metabolites and of other osmolytes? Samples from a previous study of type 2 diabetes were selected if participants were taking bezafibrate (n = 32). These samples were compared with participants matched for age and gender and not on a fibrate (comparator group, n = 64). Betaine, related metabolites, and osmolytes were measured in plasma and urine samples from these 96 participants. Median urinary betaine excretion in those on bezafibrate was 5-fold higher than in the comparator group (p < 0.001), itself 3.5-fold higher than the median reported for healthy populations. In the bezafibrate group, median dimethylglycine excretion was higher (9-fold, p < 0.001). Excretions of choline, and of the osmolytes myo-inositol, taurine and glycerophosphorylcholine, were not significantly different between groups. Some participants excreted more betaine than usual dietary intakes. Several betaine fractional clearances were >100 %. Betaine excretion correlated with excretions of the osmolytes myo-inositol and glycerophosphorylcholine, and also with the excretion of choline and N,N-dimethylglycine, but it was inconclusive whether these relationships were affected by bezafibrate therapy. Increased urinary betaine excretions in type 2 diabetes are further increased by fibrate treatment, sometimes to more than their dietary intake. Concurrent betaine supplementation may be beneficial.

Arsenic Exposure in Relation to Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study.

PubMed

Tsinovoi, Cari L; Xun, Pengcheng; McClure, Leslie A; Carioni, Vivian M O; Brockman, John D; Cai, Jianwen; Guallar, Eliseo; Cushman, Mary; Unverzagt, Frederick W; Howard, Virginia J; He, Ka

2018-01-01

The purpose of this case-cohort study was to examine urinary arsenic levels in relation to incident ischemic stroke in the United States. We performed a case-cohort study nested within the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort. A subcohort (n=2486) of controls was randomly sampled within region-race-sex strata while all incident ischemic stroke cases from the full REGARDS cohort (n=671) were included. Baseline urinary arsenic was measured by inductively coupled plasma-mass spectrometry. Arsenic species, including urinary inorganic arsenic and its metabolites monomethylarsonic acid and dimethylarsinic acid, were measured in a random subset (n=199). Weighted Cox's proportional hazards models were used to calculate hazard ratios and 95% confidence intervals of ischemic stroke by arsenic and its species. The average follow-up was 6.7 years. Although incident ischemic stroke showed no association with total arsenic or total inorganic arsenic, for each unit higher level of urinary monomethylarsonic acid on a log-scale, after adjustment for potential confounders, ischemic stroke risk increased ≈2-fold (hazard ratio=1.98; 95% confidence interval: 1.12-3.50). Effect modification by age, race, sex, or geographic region was not evident. A metabolite of arsenic was positively associated with incident ischemic stroke in this case-cohort study of the US general population, a low-to-moderate exposure area. Overall, these findings suggest a potential role for arsenic methylation in the pathogenesis of stroke, having important implications for future cerebrovascular research. © 2017 American Heart Association, Inc.

Simultaneous Quantification of Free and Glucuronidated Cannabinoids in Human Urine by Liquid Chromatography-Tandem Mass Spectrometry

PubMed Central

Scheidweiler, Karl B.; Desrosiers, Nathalie A.; Huestis, Marilyn A.

2012-01-01

Background Cannabis is the most commonly abused drug of abuse and is commonly quantified during urine drug testing. We conducted a controlled drug administration studies investigating efficacy of urinary cannabinoid glucuronide metabolites for documenting recency of cannabis intake and for determining stability of urinary cannabinoids. Methods A liquid chromatography tandem mass spectrometry method was developed and validated quantifying Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide and THCCOOH-glucuronide in 0.5 ml human urine via supported-liquid extraction. Chromatography was performed on an Ultra Biphenyl column with a gradient of 10 mmol/l ammonium acetate, pH 6.15 and 15% methanol in acetonitrile at 0. 4ml/min. Analytes were monitored by positive and negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. Results Linear ranges were 0.5–50 ng/ml for THC-glucuronide, 1–100 ng/ml for THCCOOH, 11-OH-THC and cannabidiol, 2–100 ng/ml for THC and cannabinol, and 5–500 ng/ml for THCCOOH-glucuronide (R2>0.99). Mean extraction efficiencies were 34–73% with analytical recovery (bias) 80.5–118.0% and total imprecision 3.0–10.2% coefficient of variation. Conclusion This method simultaneously quantifies urinary cannabinoids and phase II glucuronide metabolites, and enables evaluation of urinary cannabinoid glucuronides for documenting recency of cannabis intake and cannabinoid stability. The assay is applicable for routine urine cannabinoid testing. PMID:22771478

Genotoxicity following Organophosphate Pesticides Exposure among Orang Asli Children Living in an Agricultural Island in Kuala Langat, Selangor, Malaysia.

PubMed

Sutris, J M; How, V; Sumeri, S A; Muhammad, M; Sardi, D; Mohd Mokhtar, M T; Muhammad, H; Ghazi, H F; Isa, Z M

2016-01-01

Agriculture is an important sector for the Malaysian economy. The use of pesticides in agriculture is crucial due to its function in keeping the crops from harmful insects. Children living near agricultural fields are at risk of pesticide poisoning. To evaluate the genotoxic risk among children who exposed to pesticides and measure DNA damage due to pesticides exposure. In a cross-sectional study 180 Orang Asli Mah Meri children aged between 7 and 12 years were studied. They were all living in an agricultural island in Kuala Langat, Selangor, Malaysia. The data for this study were collected via modified validated questionnaire and food frequency questionnaire, which consisted of 131 food items. 6 urinary organophosphate metabolites were used as biomarkers for pesticides exposure. For genotoxic risk or genetic damage assessment, the level of DNA damage from exfoliated buccal mucosa cells was measured using the comet assay electrophoresis method. Out of 180 respondents, 84 (46.7%) showed positive traces of organophosphate metabolites in their urine. Children with detectable urinary pesticide had a longer tail length (median 43.5; IQR 30.9 to 68.1 μm) than those with undetectable urinary pesticides (median 24.7; IQR 9.5 to 48.1 μm). There was a significant association between the extent of DNA damage and the children's age, length of residence in the area, pesticides detection, and frequency of apple consumption. The organophosphate genotoxicity among children is associated with the amount of exposure (detectability of urinary pesticide) and length of residence in (exposure) the study area.

An association between feather damaging behavior and corticosterone metabolite excretion in captive African grey parrots (Psittacus erithacus)

PubMed Central

De Marco, Michele; Nucera, Daniele M.; Gasco, Laura

2016-01-01

Background African grey parrots (Psittacus erithacus) are kept as pets and are frequently hand-reared. It has been observed that hand-reared African grey parrots may develop behavioral disorders such as feather damaging behavior (FDB). It is well known that chronic stress is involved in behavioral disorders in captive parrots. The main glucocorticoid in birds is corticosterone; its quantification provides information about adrenocortical activity and is considered to be a reliable indicator of stress levels in birds. We analyzed the differences in the excretion of corticosterone metabolites (CM) in the droppings of African grey parrots characterized by: 1. different rearing histories (parent rearing vs. hand rearing); and 2. the presence or absence of FDB in hand-reared parrots. Methods A total of 82 African grey parrots that were kept in captivity were considered. According to breeding methods, three groups of birds were defined: 1. The parent-reared (PR) parrots included birds kept in pairs (n = 30 pairs) with a conspecific partner of the opposite sex. All of these birds were healthy and never showed FDB signs; 2. The healthy hand-reared parrots (H-HR) included pet parrots individually kept, that were hand-reared and did not display any sign of FDB (n = 11, 7 males and 4 females); 3. The FDB hand-reared parrot (FDB-HR) included pet parrots individually kept, that were hand-reared and displayed FDB (n = 11, 7 males and 4 females). Droppings were collected in the morning over three alternating days in autumn 2014 and spring 2015. The CM were determined using a multi-species corticosterone enzyme immunoassay kit. Split-plot repeated-measure ANOVA was used to examine any differences using group, season and group × season as the main factors. Results Different quantities of CM in droppings were found for the three groups. The mean CM value was 587 ng/g in the PR parrots, 494 ng/g in the H-HR parrots and 1,744 ng/g in the FDB-HR parrots, irrespective of the season. The excretion of CM in FDB-HR was significantly higher than in PR or H-HR parrots. CM in droppings were not influenced by the season (autumn vs. spring); furthermore, the interaction between group and sampling season was not significant. Limited to the H-HR and FDB-HR groups, a trend in the significance of the difference in the mean CM excreted by male and female birds was observed, with the levels excreted by males being higher than those excreted by females. When the effect of age was considered (in the two separate groups), there was a statistically significant positive correlation only for H-HR. Conclusions The highest amount of CM excretion was found in FDB-HR parrots, and a positive correlation between age and CM excretion was found in H-HR. Given that the CM excretion of both PR and H-HR parrots was similar in our study, future research is recommended to investigate the specific aspects of hand-rearing to improve parrot welfare. PMID:27672512

Influence of immobilization and forced swim stress on the neurotoxicity of lambda-cyhalothrin in rats: Effect on brain biogenic amines and BBB permeability.

PubMed

Shukla, Rajendra K; Dhuriya, Yogesh K; Chandravanshi, Lalit P; Gupta, Richa; Srivastava, Pranay; Pant, Aditya B; Kumar, Ajay; Pandey, Chandra M; Siddiqui, M Haris; Khanna, Vinay K

2017-05-01

Experimental studies have been carried out on rats to understand the influence of immobilization stress (IMS), a psychological stressor and forced swim stress (FSS), a physical stressor in the neurotoxicity of lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid with extensive applications. No significant change in plasma corticosterone levels and blood brain barrier (BBB) permeability was observed in rats subjected to IMS (one session of 15min/day), FSS (one session of 3min/day) for 28days or LCT treatment (3.0mg/kg body weight, p.o. suspended in groundnut oil) for 3days (26th, 27th and 28th day) as compared to controls. Marginal changes in the levels of biogenic amines and their metabolites (NE, EPN, DA, HVA, DOPAC, 5-HT) in hypothalamus, frontal cortex, hippocampus, and corpus striatum were observed in rats subjected to IMS or FSS or LCT alone as compared to controls. It was interesting to note that pre-exposure to IMS or FSS followed by LCT treatment for 3days caused a marked increase in plasma corticosterone levels associated with disruption in the BBB permeability as compared to rats exposed to IMS or FSS or LCT alone. Pre-exposure to IMS or FSS followed by LCT treatment for 3days resulted to alter the levels of biogenic amines and their metabolites in hypothalamus, frontal cortex, hippocampus, and corpus striatum as compared to rats exposed to IMS or FSS or LCT alone. Although neurochemical changes were more intense in rats pre-exposed to IMS as compared to those subjected to FSS on LCT treatment, the results indicate that both psychological and physical stress could be important influencing factors in the neurotoxicity of LCT. Copyright © 2016. Published by Elsevier B.V.

Potential antiproliferative activity of polyphenol metabolites against human breast cancer cells and their urine excretion pattern in healthy subjects following acute intake of a polyphenol-rich juice of grumixama (Eugenia brasiliensis Lam.).

PubMed

Teixeira, L L; Costa, G R; Dörr, F A; Ong, T P; Pinto, E; Lajolo, F M; Hassimotto, N M A

2017-06-21

The bioavailability and metabolism of anthocyanins and ellagitannins following acute intake of grumixama fruit, native Brazilian cherry, by humans, and its in vitro antiproliferative activity against breast cancer cells (MDA-MB-231) were investigated. A single dose of grumixama juice was administered to healthy women (n = 10) and polyphenol metabolites were analyzed in urine and plasma samples collected over 24 h. The majority of the metabolites circulating and excreted in urine were phenolic acids and urolithin conjugates, the gut microbiota catabolites of both classes of polyphenols, respectively. According to pharmacokinetic parameters, the subjects were divided into two distinct groups, high and low urinary metabolite excretors. The pool of polyphenol metabolites found in urine samples showed a significant inhibition of cell proliferation and G2/M cell cycle arrest in MDA-MB-231 cells. Our findings demonstrate the large interindividual variability concerning the polyphenol metabolism, which possibly could reflect in health promotion.

Measuring urinary N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (IPMA3) as a potential biomarker of isoprene exposure.

PubMed

Alwis, K Udeni; Bailey, T Liz; Patel, Dhrusti; Wang, Liqun; Blount, Benjamin C

2016-10-19

Isoprene, the 2-methyl analog of 1,3-butadiene, is identified as a possible human carcinogen by the International Agency for Research on Cancer (IARC). Isoprene is ubiquitous in the environment with numerous natural and anthropogenic sources. Tobacco smoke is the main exogenous source of isoprene exposure in indoor environments. Among smoke constituents, isoprene is thought to contribute significantly to cancer risk; however, no selective urinary biomarkers of isoprene exposure have been identified for humans. In this manuscript, we measured the minor isoprene metabolite IPMA1 (mixture of N-acetyl-S-(1-[hydroxymethyl]-2-methyl-2-propen-1-yl)-L-cysteine and N-acetyl-S-(2-hydroxy-3-methyl-3-buten-1-yl)-L-cysteine), and we identified IPMA3 (N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine) as a major isoprene metabolite and novel isoprene exposure biomarker for humans. Urinary isoprene metabolites were measured using ultra high performance liquid chromatography coupled with electrospray ionization triple quad tandem mass spectrometry (UPLC/ESI-MSMS). The detection rates of IPMA1 and IPMA3 are <20% and 82%, respectively. The selectivity and abundance of IPMA3 make it a useful urinary biomarker of isoprene exposure. The limit of detection of IPMA3 in urine was 0.5 ng mL -1 . IPMA3 was stable under different storage temperatures and following ten freeze-thaw cycles. The average recovery of urine spiked with IPMA3 at three different levels was 99%. IPMA3 was measured in urine samples received from 75 anonymous subjects; the median (25th percentile, 75th percentile) IPMA3 level in smokers was 36.2 (18.2, 56.8) ng mL -1 and non-smokers 2.31 (2.31, 4.38) ng mL -1 . Application of this method to large population studies will help to characterize isoprene exposure and assess potential health impact. Published by Elsevier B.V.

MARKERS OF OXIDATIVE STRESS AND SYSTEMIC VASOCONSTRICTION IN PREGNANT WOMEN DRINKING ≥ 48 GRAMS OF ALCOHOL PER DAY

PubMed Central

Signore, Caroline; Aros, Sofía; Morrow, Jason D.; Troendle, James; Conley, Mary R.; Flanigan, Elizabeth Y.; Cassorla, Fernando; Mills, James L.

2008-01-01

Background The precise pathway by which alcohol causes the characteristic features of fetal alcohol spectrum disorders (FASD) is unknown. Proposed mechanisms for fetal injury from maternal alcohol use include cellular damage from oxidative stress and impaired fetal oxygenation related to maternal systemic vasoconstriction. Our objective was to compare levels of urinary markers of oxidative stress and systemic vasoconstriction between women consuming large amounts of alcohol during pregnancy and women who did not drink alcohol during pregnancy. Methods Pregnant women consuming ≥ 48g alcohol/day (n=29) on average and pregnant women who abstained from alcohol use (n=39) were identified using detailed interviews and home visits. Random maternal urine specimens were collected. Urinary levels of the oxidative stress marker, 8-isoprostane F2α, and of the vasoactive prostaglandin metabolites, 2,3-dinor-6-keto-prostaglandin F1α (a vasodilator) and 11-dehydro-thromboxane B2 (a vasoconstrictor), were measured using mass spectrometric methods. All analyte levels were corrected for urinary creatinine. Results In crude analyses, there was no significant difference in 8-isoprostane F2α between pregnant drinkers and nondrinkers (2.16 vs. 2.08 ng/mg creatinine respectively, P=.87). There were no significant differences between the drinking and non-drinking groups in levels of 2,3-dinor-6-keto-prostaglandin F1α (1.03 vs. 1.17 ng/mg creatinine repectively, P=.50), 11-dehydro-thromboxane B2 (0.72 vs. 0.59 ng/mg creatinine respectively, P=.21), or the ratio of vasodilatory metabolite to vasoconstrictive metabolite (1.73 vs. 2.72 respectively, P=.14). Adjusting for maternal age, marital status, smoking, and gestational age at sampling did not substantially alter the results. Conclusion Our results show no difference in levels of urinary eicosanoid markers of oxidative stress and systemic vasoconstriction between pregnant women who drink heavily and pregnant women who abstain. These findings speak against a role for maternal oxidative stress or systemic vasoconstriction in the pathogenesis of alcohol damage to the fetus. PMID:18715278

Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance.

PubMed

Dinis-Oliveira, Ricardo Jorge

2017-02-01

Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT) 2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis.

Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration

EPA Science Inventory

Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic inmice after acute oral administration. Adult fema...

Organophosphorus and Pyrethroid Insecticide Urinary Metabolite Concentrations in Young Children Living in a Southeastern United States City

EPA Science Inventory

Biomonitoring studies provide valuable information on exposures to chemical contaminants, including pesticides. They can help to identify highly exposed populations and may be used to develop hypotheses about sources and pathways for exposure. A biomonitoring study was conducte...

URINARY METABOLITES OF DI-N-OCTYL PHTHALATE IN RATS

EPA Science Inventory

Di-n-octyl phthalate (DnOP) is a plasticizer used in polyvinyl chloride plastics, cellulose esters, and polystyrene resins. The metabolism of DnOP results in the hydrolysis of one ester linkage to produce mono-n-octyl phthalate (MnOP), which subsequently metabolizes to form oxida...

An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

NASA Technical Reports Server (NTRS)

Vailas, Arthur C.; Martinez, Daniel A.

1999-01-01

Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, media] gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

The Human Fetus Preferentially Secretes Corticosterone, Rather than Cortisol, in Response to Intra-Partum Stressors

PubMed Central

Wynne-Edwards, Katherine E.; Edwards, Heather E.; Hancock, Trina M.

2013-01-01

Context Fetal stress is relevant to newborn outcomes. Corticosterone is rarely quantified in human clinical endocrinology and is found at much lower concentrations than cortisol. However, fetal corticosterone is a candidate hormone as a fetal stress signal. Objective Test the hypothesis that preferential fetal corticosterone synthesis occurs in response to fetal intra-partum stress. Design Cross-sectional comparison of paired serum corticosteroid concentrations in umbilical artery and vein from 300 women providing consent at admission to a General Hospital Labor and Delivery unit. Pre-term and multiple births were excluded, leaving 265 healthy deliveries. Main Outcome Measures Corticosterone and cortisol concentrations determined by LC-MS/MS for umbilical cord venous (V) and arterial (A) samples and used to calculate fetal synthesis (A−V) and proportional fetal synthesis ([A−V]/V). Chart-derived criteria stratified samples by type of delivery, maternal regional analgesia, augmentation of contractions, and clinical rationale for emergent Caesarian delivery. Results Cortisol concentrations were higher than corticosterone concentrations; however, the fetus preferentially secretes corticosterone (148% vs 49% proportional increase for cortisol) and differentially secretes corticosterone as fetal stress increases. Fetal corticosterone synthesis is elevated after passage through the birth canal relative to Caesarian deliveries. For vaginal deliveries, augmentation of contractions does not affect corticosteroid concentrations whereas maternal regional analgesia decreases venous (maternal) concentrations and increases fetal synthesis. Fetal corticosterone synthesis is also elevated after C-section indicated by cephalopelvic disproportion after labor, whereas cortisol is not. Conclusions The full-term fetus preferentially secretes corticosterone in response to fetal stress during delivery. Fetal corticosterone could serve as a biomarker of fetal stress. PMID:23798989

Effects of anesthesia with halothane and methoxyflurane on plasma corticosterone concentration in rats at rest and after exercise.

PubMed

Carlberg, K A; Gwosdow, A R; Alvin, B L

1995-10-01

To determine whether halothane and methoxyflurane are suitable anesthetics for cardiac puncture in studies of plasma corticosterone concentration in rats, four experiments were done. Blood samples were taken immediately after rats became anesthetized with halothane or methoxyflurane. Decapitation without anesthesia was used to determine baseline corticosterone concentration. Another group of rats was anesthetized with ether as a positive control (known to stimulate corticosterone secretion). Corticosterone values in halothane- and methoxyflurane-treated rats were not significantly different from those measured after decapitation. Corticosterone concentration in halothane-treated rats was significantly lower than that in either methoxyflurane- or ether-treated rats. Cardiac puncture was done after 3 min of exposure to each of the three anesthetics. The results indicated that there were no differences in corticosterone values among the three anesthetics, suggesting that corticosterone concentration was lower immediately after halothane was used as the anesthetic, because halothane induced anesthesia in less time than that required for activation of adrenocortical secretion. To determine whether there was a difference among anesthetics in stimulating corticosterone secretion when anesthesia was maintained for a period before blood sample collection, cardiac puncture was done after 15 min of exposure to each of the three anesthetics. Corticosterone values were similar, suggesting that any of the three anesthetics was acceptable in this situation. To determine whether halothane or methoxyflurane affected exercise-induced increases in corticosterone values, exercise-trained rats were run for 30 min; then blood samples were collected by cardiac puncture immediately after induction of anesthesia with halothane, methoxyflurane, or ether, or after decapitation without anesthesia. Corticosterone values were not different among the three anesthetics or decapitation.

Discovery of urine biomarkers for bladder cancer via global metabolomics.

PubMed

Shi, Hangchuan; Li, Xiang; Zhang, Qingyang; Yang, Hongmei; Zhang, Xiaoping

2016-11-01

Bladder cancer (BC) is latent in its early stage and lethal in its late stage. Therefore, early diagnosis and intervention are essential for successful BC treatment. Considering the limitations of current diagnostic tools, noninvasive biomarkers that are both highly sensitive and specific are needed to improve the overall survival and quality of life of patients. With the advent of systems biology, "-omics" technologies have been developed over the past few decades. As a promising member, global metabolomics has increasingly been found to have clear potential for biomarker discovery. However, urinary metabolomics studies related to BC have lagged behind those of other urinary cancers, and major findings have not been systematically reported. The objective of this review is to comprehensively list the currently identified potential urinary metabolite biomarkers for BC.

Polymorphisms in Arsenic(+III Oxidation State) Methyltransferase (AS3MT) Predict Gene Expression of AS3MT as Well as Arsenic Metabolism

PubMed Central

Engström, Karin; Vahter, Marie; Mlakar, Simona Jurkovic; Concha, Gabriela; Nermell, Barbro; Raqib, Rubhana; Cardozo, Alejandro; Broberg, Karin

2011-01-01

Background Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases. Objectives We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 μg/L] and in rural Bangladesh (n = 361; U-As, 100 μg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays. Results Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression. Conclusions Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. PMID:21247820

Urinary levels of eight phthalate metabolites and bisphenol A in mother-child pairs from two Spanish locations.

PubMed

Cutanda, Francisco; Koch, Holger M; Esteban, Marta; Sánchez, Jinny; Angerer, Jürgen; Castaño, Argelia

2015-01-01

Exposure to some phthalate diesters and bisphenol A in the general population is a cause of increasing concern because of their potential adverse effects on the reproductive and endocrine systems and their broad presence in foodstuff and consumer products. The aims of this work are to assess patterns of exposure to phthalates and bisphenol A in a pilot sample of Spanish mothers and their children, and to provide basic information to address priorities in future Spanish surveys/research. Urinary levels of eight phthalate metabolites and bisphenol A have been measured in samples from 120 mother-child pairs in one rural and one urban location in central Spain, recruited as part of the European project DEMOCOPHES. More than 96% of the participants were exposed to all the compounds studied here with generally higher levels in children than their mothers. The sum of secondary DEHP metabolites gave a GM of 33.3μg/g creatinine (95% CI 30.2-36.6) for mothers and 63.0μg/g creatinine (95% CI 56.8-69.8) for children. Mono-ethyl phthalate (MEP) was the metabolite with the highest levels, with geometric means (GM) of 150.8μg/g creatinine (95% CI 124.0-183.5) for mothers and 198.9μg/g creatinine (95% CI 165.2-239.6) for children. Bisphenol A urinary levels were relatively low with geometric means of 2.0μg/g (95% CI 1.6-2.4) for mothers and 2.01μg/g (95% CI 1.7-2.4) for children. Personal care products like body lotions and fragrances showed associations with MEHP, MEP, MnBP and cx-MiNP and canteen food with MBzP and bisphenol A. Exposure of mothers and their children are correlated, except for MEP. As phthalates and bisphenol A are non-persistent chemicals, a daily, intermittent exposure of the population is taking place. Copyright © 2014 Elsevier GmbH. All rights reserved.

Analytical Method for Pyrethroid Metabolites in Urine of the Non-Occupationally Exposed Population by Gas Chromatography/Mass Spectrometry.

PubMed

Yoshida, Toshiaki

2017-10-01

Pyrethroids are widely being used as household insecticides or mothproof repellents. An analytical method is described for determination of urinary metabolites as biomarkers for monitoring exposure to the pyrethroids. In total, 11 urinary metabolites, 3-(2-carboxyprop-1-enyl)-2,2-dimethylcyclopropanecarboxylic acid, 3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylic acid, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylic acid, 4-fluoro-3-phenoxybenzoic acid, 4-methoxymethyl-2,3,5,6-tetrafluorobenzly alcohol, 2-methyl-3-phenylbenzoic acid, 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol, 3-phenoxybenzoic acid, 2,3,5,6-tetrafluorobenzoic acid and 2,2,3,3-tetramethylcyclopropanecarboxylic acid, were enzymatically hydrolyzed and extracted with toluene. After transformation to their tert-butyldimethylsilyl or trimethylsilyl derivatives, they were analyzed by gas chromatography/mass spectrometry in electron impact ionization mode. The calibration curves for the metabolite were linear over the concentration range of 0-30 μg/L in urine. They could be determined accurately and precisely (detection limits: 0.01-0.12 μg/L, quantification limits: 0.04-0.41 μg/L). The urine samples collected could be stored for up to 1 month at -20°C in a freezer. The proposed method was applied to determine urine samples from several health volunteers. The method was considered to be available for monitoring pyrethroid exposure in the general population. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PVC flooring is related to human uptake of phthalates in infants.

PubMed

Carlstedt, F; Jönsson, B A G; Bornehag, C-G

2013-02-01

Polyvinyl chloride (PVC) flooring material contains phthalates, and it has been shown that such materials are important sources for phthalates in indoor dust. Phthalates are suspected endocrine-disrupting chemicals (EDCs). Consecutive infants between 2 and 6 months old and their mothers were invited. A questionnaire about indoor environmental factors and family lifestyle was used. Urinary metabolites of the phthalates diethyl phthalate (DEP), dibutyl phthalate (DBP), butylbenzyl phthalate (BBzP), and dietylhexyl phthalate (DEHP) were measured in the urine of the children. Of 209 invited children, 110 (52%) participated. Urine samples were obtained from 83 of these. Urine levels of the BBzP metabolite monobenzyl phthalate (MBzP) was significantly higher in infants with PVC flooring in their bedrooms (P < 0.007) and related to the body area of the infant. Levels of the DEHP metabolites MEHHP (P < 0.01) and MEOHP (P < 0.04) were higher in the 2-month-old infants who were not exclusively breast-fed when compared with breast-fed children. The findings indicate that the use of soft PVC as flooring material may increase the human uptake of phthalates in infants. Urinary levels of phthalate metabolites during early life are associated with the use of PVC flooring in the bedroom, body area, and the use of infant formula. This study shows that the uptake of phthalates is not only related to oral uptake from, for example, food but also to environmental factors such as building materials. This new information should be considered when designing indoor environment, especially for children. © 2012 John Wiley & Sons A/S.

Plasma amine oxidase activities in Norrie disease patients with an X-chromosomal deletion affecting monoamine oxidase.

PubMed

Murphy, D L; Sims, K B; Karoum, F; Garrick, N A; de la Chapelle, A; Sankila, E M; Norio, R; Breakefield, X O

1991-01-01

Two individuals with an X-chromosomal deletion were recently found to lack the genes encoding monoamine oxidase type A (MAO-A) and MAO-B. This abnormality was associated with almost total (90%) reductions in the oxidatively deaminated urinary metabolites of the MAO-A substrate, norepinephrine, and with marked (100-fold) increases in an MAO-B substrate, phenylethylamine, confirming systemic functional consequences of the genetic enzyme deficiency. However, urinary concentrations of the deaminated metabolites of dopamine and serotonin (5-HT) were essentially normal. To investigate other deaminating systems besides MAO-A and MAO-B that might produce these metabolites of dopamine and 5-HT, we examined plasma amine oxidase (AO) activity in these two patients and two additional patients with the same X-chromosomal deletion. Normal plasma AO activity was found in all four Norrie disease-deletion patients, in four patients with classic Norrie disease without a chromosomal deletion, and in family members of patients from both groups. Marked plasma amine metabolite abnormalities and essentially absent platelet MAO-B activity were found in all four Norrie disease-deletion patients, but in none of the other subjects in the two comparison groups. These results indicate that plasma AO is encoded by gene(s) independent of those for MAO-A and MAO-B, and raise the possibility that plasma AO, and perhaps the closely related tissue AO, benzylamine oxidase, as well as other atypical AOs or MAOs encoded independently from MAO-A and MAO-B may contribute to the oxidative deamination of dopamine and 5-HT in humans.

Exposure sources and their relative contributions to urinary phthalate metabolites among children in Taiwan.

PubMed

Chen, Chu-Chih; Wang, Yin-Han; Wang, Shu-Li; Huang, Po-Chin; Chuang, Shu-Chun; Chen, Mei-Huei; Chen, Bai-Hsiun; Sun, Chien-Wen; Fu, Hsiao-Chun; Lee, Ching-Chang; Wu, Ming-Tsang; Chen, Mei-Lien; Hsiung, Chao A

2017-07-01

Phthalate exposure is omnipresent and known to have developmental and reproductive effects in children. The aim of this study was to determine the phthalate exposure sources and their relative contributions among children in Taiwan. During the first wave of the Risk Assessment of Phthalate Incident in Taiwan (RAPIT), in 2012, we measured 8 urinary phthalate metabolites in 226 children aged 1-11 years old and in 181 children from the same cohort for the wave 2 study in 2014. A two-stage statistical analysis approach was adopted. First, a stepwise regression model was used to screen 80 questions that explored the exposure frequency and lifestyle for potential associations. Second, the remaining questions with positive regression coefficients were grouped into the following 6 exposure categories: plastic container/packaging, food, indoor environment, personal care products, toys, and eating out. A mixed model was then applied to assess the relative contributions of these categories for each metabolite. The use of plastic container or food packaging were dominant exposure sources for mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and mono-n-butyl phthalate (MnBP). The indoor environment was a major exposure source of mono-methyl phthalate (MMP), mono-benzyl phthalate (MBzP), and mono-isobutyl phthalate (MiBP). The consumption of seafood showed a significant correlation with MEHP. The children's modified dietary behavior and improved living environment in the second study wave were associated with lower phthalate metabolite levels, showing that phthalate exposures can be effectively reduced. Copyright © 2017 Elsevier GmbH. All rights reserved.

Neonatal methamphetamine-induced corticosterone release in rats is inhibited by adrenal autotransplantation without altering the effect of the drug on hippocampal serotonin

PubMed Central

Grace, Curtis E.; Schaefer, Tori L.; Gudelsky, Gary A.; Williams, Michael T.; Vorhees, Charles V.

2010-01-01

Rat neonatal methamphetamine exposure results in corticosterone release and learning and memory impairments in later life; effects also observed after neonatal stress. Previous attempts to test the role of corticosterone release after methamphetamine using corticosterone inhibitors were unsuccessful and adrenalectomy caused reductions in hippocampal serotonin greater than those caused by methamphetamine alone. Here we tested whether adrenal autotransplantation could be used to attenuate methamphetamine-induced corticosterone release without also altering the effects of the drug on serotonin. Adrenal autotransplantation surgery occurred on postnatal day 9 followed by methamphetamine or saline treatment from postnatal day 11–20 (10 mg/kg/dose x 4/day). Plasma corticosterone and hippocampal serotonin and 5-hydroxyindoleacetic acid were determined 30 min following the first treatment on each day between postnatal days 11–20. Adrenal autotransplantation attenuated neonatal methamphetamine-induced corticosterone release by ~70% initially, ~55% midway through treatment, and ~25% by the end of treatment. Methamphetamine reduced serotonin and 5-hydroxyindoleacetic acid in the hippocampus to the same degree as in sham-surgery rats. The data show that neonatal adrenal autotransplantation is an effective method for partially reducing treatment-induce corticosterone release while providing sufficient corticosterone to sustain normal growth and development. The method should is applicable to other models of developmental stress/corticosterone release. PMID:20153424

ATTRIBUTION OF PARTICLE EXPOSURE AND RISK TO COMBUSTION SOURCE EMISSIONS BASED ON PERSONAL PAH EXPOSURE AND URINARY METABOLITES

EPA Science Inventory

Personal airborne exposures to carcinogenic particulate PAH have been significantly correlated with exposure to respirable fine particle mass (PM 2.5) in several studies. All combustion sources emit PAH, however the relative concentrations of different PAH and other organic tr...