EFFECTS OF MIXTURES OF PHTHALATES AND OTHER TOXICANTS ON SEXUAL DIFFERENTIATON IN RATS: A RISK FRAMEWORK BASED UPON DISRUPTION OF COMMON DEVELOPING SYSTEMS

EPA Science Inventory

Since humans are exposed to more than one chemical at a time, concern has arisen about the effects ofmixtures ofphthalates and other chemicals on human reproduction and development. We are conducting studies to determine 1) what effects associated with in utero phthalate exposure...

Human Fetal Testis Xenografts Are Resistant to Phthalate-Induced Endocrine Disruption

PubMed Central

Heger, Nicholas E; Hall, Susan J; Sandrof, Moses A; McDonnell, Elizabeth V; Hensley, Janan B; McDowell, Erin N; Martin, Kayla A; Gaido, Kevin W; Johnson, Kamin J

2012-01-01

Background: In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common male reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male rats exposed in utero to certain phthalate plasticizers exhibit multinucleated germ cell (MNG) induction and suppressed steroidogenic gene expression and testosterone production in the fetal testis, causing TDS-consistent effects of hypospadias and cryptorchidism. Mice exposed to phthalates in utero exhibit MNG induction only. This disparity in response demonstrates a species-specific sensitivity to phthalate-induced suppression of fetal Leydig cell steroidogenesis. Importantly, ex vivo phthalate exposure of the fetal testis does not recapitulate the species-specific endocrine disruption, demonstrating the need for a new bioassay to assess the human response to phthalates. Objectives: In this study, we aimed to develop and validate a rat and mouse testis xenograft bioassay of phthalate exposure and examine the human fetal testis response. Methods: Fetal rat, mouse, and human testes were xenografted into immunodeficient rodent hosts, and hosts were gavaged with a range of phthalate doses over multiple days. Xenografts were harvested and assessed for histopathology and steroidogenic end points. Results: Consistent with the in utero response, phthalate exposure induced MNG formation in rat and mouse xenografts, but only rats exhibited suppressed steroidogenesis. Across a range of doses, human fetal testis xenografts exhibited MNG induction but were resistant to suppression of steroidogenic gene expression. Conclusions: Phthalate exposure of grafted human fetal testis altered fetal germ cells but did not reduce expression of genes that regulate fetal testosterone biosynthesis. PMID:22511013

Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls.

PubMed

Watkins, Deborah J; Sánchez, Brisa N; Téllez-Rojo, Martha Maria; Lee, Joyce M; Mercado-García, Adriana; Blank-Goldenberg, Clara; Peterson, Karen E; Meeker, John D

2017-11-01

Over the past several decades, the age of pubertal onset in girls has shifted downward worldwide. As early pubertal onset is associated with increased risky behavior and psychological issues during adolescence and cardiometabolic disease and cancer in adulthood, this is an important public health concern. Exposure to endocrine disrupting chemicals during critical windows of in utero development may play a role in this trend. Our objective was to investigate trimester-specific phthalate and BPA exposure in relation to pubertal development among girls in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort. We measured maternal urinary phthalate metabolites and BPA in samples collected during the first, second, and third trimesters of pregnancy. To assess reproductive development among their female children, we measured serum testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone-binding globulin (SHBG), and assessed sexual maturation, including Tanner staging for breast and pubic hair development and menarche status, at age 8-13 years (n = 120). We used linear and logistic regression to examine measures of trimester-specific in utero exposure as predictors of peripubertal hormone levels and pubertal onset, respectively. In secondary analyses, we evaluated estimated exposure at the midpoint of the first trimester and rates of change in exposure across pregnancy in relation to outcomes. Several phthalate metabolites measured throughout in utero development were associated with higher serum testosterone concentrations, while a number of metabolites measured in the third trimester were associated with higher DHEA-S. For example, an interquartile range (IQR) increase in mean monoethyl phthalate (MEP) levels across pregnancy was associated with 44% higher peripubertal testosterone (95% CI: 13-83%), while an IQR increase in di-2-ethylhexyl phthalate metabolites (ΣDEHP) specifically in the third trimester was associated with 25% higher DHEA-S (95%CI: 4.7-47%). In IQR increase in mean mono-2-ethylhexyl phthalate (MEHP) levels across pregnancy was associated with lower odds of having a Tanner Stage >1 for breast development (OR = 0.32, 95%CI: 0.11-0.95), while MEHP in the third trimester was associated with higher odds of having a Tanner Stage >1 for pubic hair development (OR = 3.76, 95%CI: 1.1-12.8). Results from secondary analyses were consistent with findings from our main analysis. These findings suggest that female reproductive development may be more vulnerable to the effects of phthalate or BPA exposure during specific critical periods of in utero development. This highlights the need for comprehensive characterizations of in utero exposure and consideration of windows of susceptibility in developmental epidemiological studies. Future research should consider repeated measures of in utero phthalate and BPA exposure within each trimester and across pregnancy. Copyright © 2017 Elsevier Inc. All rights reserved.

In utero exposure to carcinogens: Epigenetics, developmental disruption and consequences in later life.

PubMed

Waring, R H; Harris, R M; Mitchell, S C

2016-04-01

The uterine environment is often viewed as a relatively safe haven, being guarded by the placenta which acts as a filter, permitting required materials to enter and unwanted products to be removed. However, this defensive barrier is sometimes breached by potential chemical hazards to which the mother may be subjected. Many of these toxins have immediate and recognisable deleterious effects on the embryo, foetus or neonate, but a few are insidious and leave a legacy of health issues that may emerge in later life. Several substances, falling into the categories of metals and metalloids, endocrine disruptors, solvents and other industrial chemicals, have been implicated in the development of long-term health problems in the offspring following maternal and subsequent in utero exposure. The mechanisms involved are complex but often involve epigenetic changes which disrupt normal cell processes leading to the development of cancers and also dysregulation of biochemical pathways. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Adverse effects of a mixture of 15 pesticides and phthalates on reproductive tract development in the male rat

EPA Science Inventory

This presentation highlights our "supermix" study which included 15 different environmental anti-androgens (6 pesticides and 9 phthalates) with a dosing structure based on the individual chemical NOAELs. Exposures were conducted in utero (dam oral gavage) during the ma...

CHANGES IN THE DNA-BINDING OF SEVERAL TRANSCRIPTION FACTORS IN THE DEVELOPING RAT CEREBELLUM BY PCBS.

EPA Science Inventory

PCBs are a class of persistent halogenated aromatic hydrocarbon chemical pollutants and considered as one of the major environmental contaminants resulting from intensive industrial use and inadequate disposal. In utero exposure to PCBs has been known to cause delayed neuronal de...

Maternal in utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate affects the blood pressure of adult male offspring

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

Martinez–Arguelles, D.B.; Department of Medicine, McGill University, Montreal, Quebec, Canada H3G 1A4; McIntosh, M.

Di-(2-ethylhexyl) phthalate (DEHP) is used industrially to add flexibility to polyvinyl chloride (PVC) polymers and is ubiquitously found in the environment, with evidence of prenatal, perinatal and early infant exposure in humans. In utero exposure to DEHP decreases circulating testosterone levels in the adult rat. In addition, DEHP reduces the expression of the angiotensin II receptors in the adrenal gland, resulting in decreased circulating aldosterone levels. The latter may have important effects on water and electrolyte balance as well as systemic arterial blood pressure. Therefore, we determined the effects of in utero exposure to DEHP on systemic arterial blood pressuremore » in the young (2 month-old) and older (6.5 month-old) adult rats. Sprague-Dawley pregnant dams were exposed from gestational day 14 until birth to 300 mg DEHP/kg/day. Blood pressure, heart rate, and activity data were collected using an intra-aortal transmitter in the male offspring at postnatal day (PND) 60 and PND200. A low (0.01%) and high-salt (8%) diet was used to challenge the animals at PND200. In utero exposure to DEHP resulted in reduced activity at PND60. At PND200, systolic and diastolic systemic arterial pressures as well as activity were reduced in response to DEHP exposure. This is the first evidence showing that in utero exposure to DEHP has cardiovascular and behavioral effects in the adult male offspring. Highlights: ► In utero exposure to 300 mg DEHP/kg/day decreases activity at postnatal day 60. ► In utero exposure to DEHP decreases aldosterone levels at postnatal day 200. ► In utero exposure to DEHP decreases systolic blood pressure at postnatal day 200. ► An 8% salt diet recovers the decreased blood pressure at postnatal day 200.« less

Chemical mixtures: Evaluation of risk for child-specific exposures in a multi-stressor environment

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

Pohl, H.R.; Abadin, H.G.

Evaluating the health impact from exposure to chemical mixtures is multifaceted. One component is exposure. Exposure, and consequently risk assessment for mixtures and chemicals in general, are often viewed in terms of a given exposure to a given population at a given location over a given time period. However, environmental exposures are present throughout human lifetime. As a result, an evaluation of risk must include the distinctive characteristics related to chemical exposures which will impact risk depending upon the particular life stage where exposure occurs. Risks to offspring may be associated with unique exposures in utero, during infancy, childhood, ormore » adolescent periods. For example, exposure of infants to anthropogenic chemicals via breast milk may be of concern. The Agency for Toxic Substances and Disease Registry's (ATSDR's) approach to evaluating risks associated with exposure to mixtures of chemicals is presented. In addition to the breast milk issues, indoor exposure to combined air pollutants, drinking water contaminants, and soil and dust contaminants are discussed. The difference between a mixture's risk evaluation for children and adults is in the distinct exposure scenarios resulting from variations in behavior, physiology, and/or pharmacokinetics between adults and children rather than in the method for the specific mixtures evaluation per se.« less

In Utero Exposure to Low-Dose Alcohol Induces Reprogramming of Mammary Development and Tumor Risk in MMTV-erbB-2 Transgenic Mice

PubMed Central

Ma, Zhikun; Blackwelder, Amanda J.; Lee, Harry; Zhao, Ming; Yang, Xiaohe

2015-01-01

There is increasing evidence that prenatal exposure to environmental factors may modify breast cancer risk later in life. This study aimed to investigate the effects of in utero exposure to low-dose alcohol on mammary development and tumor risk. Pregnant MMTV-erbB-2 mice were exposed to alcohol (6 g/kg/day) between day 13 and day 19 of gestation, and the female offspring were examined for tumor risk. Whole mount analysis indicated that in utero exposure to low-dose alcohol induced significant increases in ductal extension at 10 weeks of age. Molecular analysis showed that in utero alcohol exposure induced upregulation of ERα signaling and activation of Akt and Erk1/2 in pubertal mammary glands. However, enhanced signaling in the EGFR/erbB-2 pathway appeared to be more prominent in 10-week-old glands than did signaling in the other pathways. Interestingly, tumor development in mice with in utero exposure to low-dose alcohol was slightly delayed compared to control mice, but tumor multiplicity was increased. The results indicate that in utero exposure to low-dose alcohol induces the reprogramming of mammary development by mechanisms that include altered signaling in the estrogen receptor (ER) and erbB-2 pathways. The intriguing tumor development pattern might be related to alcohol dose and exposure conditions, and warrants further investigation. PMID:25853264

Endocrine disrupting chemicals and growth of children.

PubMed

Botton, Jérémie; Kadawathagedara, Manik; de Lauzon-Guillain, Blandine

2017-06-01

According to the "environmental obesogen hypothesis", early-life (including in utero) exposure to endocrine disrupting chemicals (EDCs) may disturb the mechanisms involved in adipogenesis or energy storage, and thus may increase the susceptibility to overweight and obesity. Animal models have shown that exposure to several of these chemicals could induce adipogenesis and mechanisms have been described. Epidemiological studies are crucial to know whether this effect could also be observed in humans. We aimed at summarizing the literature in epidemiology on the relationship between EDCs exposure and child's growth. Overall, epidemiological studies suggest that pre- and/or early postnatal exposure to some EDCs may increase the risk of overweight or obesity during childhood. In that review, we present some limitations of these studies, mainly in exposure assessment, that currently prevent to conclude about causality. Recent advances in epidemiology should bring further knowledge. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chronic respiratory symptoms in children following in utero and early life exposure to arsenic in drinking water in Bangladesh

PubMed Central

Smith, Allan H; Yunus, Mohammad; Khan, Al Fazal; Ercumen, Ayse; Yuan, Yan; Smith, Meera Hira; Liaw, Jane; Balmes, John; von Ehrenstein, Ondine; Raqib, Rubhana; Kalman, David; Alam, Dewan S; Streatfield, Peter K; Steinmaus, Craig

2013-01-01

Background Arsenic exposure via drinking water increases the risk of chronic respiratory disease in adults. However, information on pulmonary health effects in children after early life exposure is limited. Methods This population-based cohort study set in rural Matlab, Bangladesh, assessed lung function and respiratory symptoms of 650 children aged 7–17 years. Children with in utero and early life arsenic exposure were compared with children exposed to less than 10 µg/l in utero and throughout childhood. Because most children drank the same water as their mother had drunk during pregnancy, we could not assess only in utero or only childhood exposure. Results Children exposed in utero to more than 500 µg/l of arsenic were more than eight times more likely to report wheezing when not having a cold [odds ratio (OR) = 8.41, 95% confidence interval (CI): 1.66–42.6, P < 0.01] and more than three times more likely to report shortness of breath when walking on level ground (OR = 3.86, 95% CI: 1.09–13.7, P = 0.02) and when walking fast or climbing (OR = 3.19, 95% CI: 1.22–8.32, P < 0.01]. However, there was little evidence of reduced lung function in either exposure category. Conclusions Children with high in utero and early life arsenic exposure had marked increases in several chronic respiratory symptoms, which could be due to in utero exposure or to early life exposure, or to both. Our findings suggest that arsenic in water has early pulmonary effects and that respiratory symptoms are a better marker of early life arsenic toxicity than changes in lung function measured by spirometry. PMID:24062297

Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development.

PubMed

Brown, Traci Ann; Holian, Andrij; Pinkerton, Kent E; Lee, Joong Won; Cho, Yoon Hee

2016-07-01

Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual's lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development.

Comparison of fetal testosterone production in various tissues of the male sprague dawley rat dosed in utero with dipentyl phthalate during the critical window of sexual differentiation

EPA Science Inventory

Phthalate esters are high-production volume chemicals used in the manufacture of numerous plastics and consumer products, which generates major concern for potential human exposure and environmental contamination. Several studies have demonstrated adverse effects associated with ...

In utero exposure to pets is associated with asthma and wheezing in Mexican American children.

PubMed

Eldeirawi, Kamal; Kunzweiler, Colin; Combs, Angela M T; Persky, Victoria W

2016-01-01

To examine the associations of in utero and early life exposure to cats/dogs and birds with the risk of lifetime doctor-diagnosed asthma and other respiratory conditions in a sample of Mexican American (MA) children 4-18 years of age. This study is a population-based cross-sectional investigation of 1816 MA children. We conducted multiple logistic models examining the relationship of asthma and wheezing with exposures to cats/dogs and birds in utero, infancy and at the time of the survey adjusted for country of birth, family history of asthma/allergies, antibiotics use in infancy and other covariates. In adjusted analyses, in utero exposure to cats/dogs and birds jointly was associated with increased odds of asthma (adjusted odds ratio (aOR): 2.89; 95% confidence interval (CI): 1.34-6.23), ever wheezing (aOR: 1.96; 95% CI: 1.11-3.46) and current exercise-induced wheezing (aOR: 3.16; 95% CI: 1.27-7.85) compared to children not exposed to these pets in utero. Children who were exposed to both cats/dogs and birds in utero had an elevated, albeit statistically non-significant, odds of current wheezing. Exposures in infancy and at the time of the survey to cats/dogs and birds were not associated with asthma or wheezing. In utero exposure to pets might be associated with an increased risk of asthma and respiratory conditions in a sample of non-affluent MA children.

Second Trimester Amniotic Fluid Bisphenol A Concentration is Associated with Decreased Birth Weight in Term Infants

PubMed Central

Pinney, Sara E.; Mesaros, Clementina A.; Snyder, Nathaniel W.; Busch, Christine M.; Xiao, Rui; Aijaz, Sara; Ijaz, Naila; Blair, Ian A.; Manson, Jeanne M.

2016-01-01

Bisphenol A (BPA) is an endocrine disrupting chemical with ubiquitous environmental exposure. Animal studies have demonstrated that in utero BPA exposure leads to increased adult body weight. Our aim was to characterize human fetal BPA exposure by measuring BPA concentration in second trimester amniotic fluid (AF) samples and to study its relationship with birth weight (BW) in full term infants. To achieve these goals, we developed a total BPA assay utilizing derivatization with pentafluorobenzyl followed by analysis with LC-ECAPCI-MS/MS with a limit of detection of 0.08 ng/mL and limit of quantification (LOQ) of 0.25 ng/mL. The mean BW of infants with AF BPA 0.40-2.0 ng/mL was 241.8 grams less than infants with AF BPA less than the LOQ after controlling for covariates (p=0.049). No effect was seen outside this range indicating a non-monotonic effect. Our data suggest that low level BPA exposure in utero decreases BW and needs further study. PMID:27829162

Male reprotoxicity and endocrine disruption

PubMed Central

Campion, Sarah; Catlin, Natasha; Heger, Nicholas; McDonnell, Elizabeth V.; Pacheco, Sara E.; Saffarini, Camelia; Sandrof, Moses A.; Boekelheide, Kim

2013-01-01

Mammalian reproductive tract development is a tightly regulated process that can be disrupted following exposure to drugs, toxicants, endocrine disrupting chemicals or other compounds via alterations to gene and protein expression or epigenetic regulation. Indeed, the impacts of developmental exposure to certain toxicants may not be fully realized until puberty or adulthood when the reproductive tract becomes sexually mature and altered functionality is manifested. Exposures that occur later in life, once development is complete, can also disrupt the intricate hormonal and paracrine interactions responsible for adult functions, such as spermatogenesis. In this chapter, the biology and toxicology of the male reproductive tract is explored, proceeding through the various life stages including in utero development, puberty, adulthood and senescence. Special attention is given to the discussion of endocrine disrupting chemicals, chemical mixtures, low dose effects, transgenerational effects, and potential exposure-related causes of male reproductive tract cancers. PMID:22945574

Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development

PubMed Central

Brown, Traci A.; Holian, Andrij; Pinkerton, Kent E.; Lee, Joong Won; Cho, Yoon Hee

2016-01-01

Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual’s lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development. PMID:27138493

In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse

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

Wang, Wei, E-mail: weiwang2@illinois.edu; Hafner, Katlyn S., E-mail: katlynhafner@gmail.com; Flaws, Jodi A., E-mail: jflaws@illinois.edu

Bisphenol A (BPA) is a known reproductive toxicant in rodents. However, the effects of in utero BPA exposure on early ovarian development and the consequences of such exposure on female reproduction in later reproductive life are unclear. Thus, we determined the effects of in utero BPA exposure during a critical developmental window on germ cell nest breakdown, a process required for establishment of the finite primordial follicle pool, and on female reproduction. Pregnant FVB mice (F0) were orally dosed daily with tocopherol-striped corn oil (vehicle), diethylstilbestrol (DES; 0.05 μg/kg, positive control), or BPA (0.5, 20, and 50 μg/kg) from gestationalmore » day 11 until birth. Ovarian morphology and gene expression profiles then were examined in F1 female offspring on postnatal day (PND) 4 and estrous cyclicity was examined daily after weaning for 30 days. F1 females were also subjected to breeding studies with untreated males at three to nine months. The results indicate that BPA inhibits germ cell nest breakdown via altering expression of selected apoptotic factors. BPA also significantly advances the age of first estrus, shortens the time that the females remain in estrus, and increases the time that the females remain in metestrus and diestrus compared to controls. Further, F1 females exposed to low doses of BPA exhibit various fertility problems and have a significantly higher percentage of dead pups compared to controls. These results indicate that in utero exposure to low doses of BPA during a critical ovarian developmental window interferes with early ovarian development and reduces fertility with age. - Highlights: • In utero BPA exposure inhibits germ cell nest breakdown in female mouse offspring. • In utero BPA exposure alters expression of apoptosis regulators in the ovaries of mouse offspring. • In utero BPA exposure advances first estrus age and alters cyclicity in mouse offspring. • In utero BPA exposure causes various fertility problems in female mouse offspring.« less

Comparison of Fetal Testosterone Production in Various Tissues of the Male Sprague Dawley Rat dosed In Utero with Dipentyl Phthalate during the Critical Window of Sexual Differentiation###

EPA Science Inventory

Phthalate esters are high-production volume chemicals used in the manufacture of numerci plastics and consumer products, which generates major concern for potential human exposure and environmental contamination. Several studies have demonstrated adverse effects associated with p...

The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice

PubMed Central

Berger, Amelia; Ziv-Gal, Ayelet; Cudiamat, Jonathan; Wang, Wei; Zhou, Changqing; Flaws, Jodi A.

2016-01-01

Bisphenol A is used in polycarbonate plastics and epoxy resins. Previous studies show that in utero BPA exposure inhibits germ cell nest breakdown in the F1 generation of mice, but its effects on germ cell nest breakdown and on the ovary in the F2–F3 generations were unknown. Thus, we tested the hypothesis that BPA has transgenerational effects on the ovary. Mice were exposed to BPA in utero (BPA 0.5, 20, or 50 µg/kg/day), and ovaries were collected at postnatal days (PND) 4 and 21 from the F1–F3 generations and subjected to histological evaluation and gene expression analyses. In utero BPA exposure did not have transgenerational effects on germ cell nest breakdown and gene expression on PND 4, but it caused transgenerational changes in expression in multiple genes on PND 21. Collectively, these data indicate that in utero BPA exposure has some transgenerational effects in mice. PMID:26746108

Reproductive Outcomes Among Women Exposed to a Brominated Flame Retardant In Utero

PubMed Central

Small, Chanley M.; Murray, Deanna; Terrell, Metrecia L.; Marcus, Michele

2014-01-01

The authors studied 194 women exposed to polybrominated biphenyls (PBB) in utero when their mothers consumed products accidentally contaminated in Michigan in 1973. Generalized estimating equations were used to examine the effect of in utero PBB exposure on adult pregnancy-related outcomes. Compared to those with the lowest exposure (≤1 ppb), those with mid-range (>1–3.16 ppb) and high (≥3.17 ppb) PBB exposure had increased odds of spontaneous abortion with wide confidence intervals (odds ratio [OR] = 2.75, 95% confidence interval [CI] = 0.64–11.79, OR = 4.08, 95% CI = 0.94–17.70; respectively; p for trend = .05). Exposure during infancy to PBB-contaminated breast milk further increased this risk. Time to pregnancy and infertility were not associated with in utero exposure to PBB. Future studies should examine the suggested relationship between spontaneous abortion and other brominated flame retardants. PMID:22014192

Evolution of our understanding of methylmercury as a health threat.

PubMed Central

Watanabe, C; Satoh, H

1996-01-01

Methylmercury (MeHg) is recognized as one of the most hazardous environmental pollutants, primarily due to endemic disasters that have occurred repeatedly. A review of the earlier literature on the Minamata outbreak shows how large-scale poisoning occurred and why it could not be prevented. With the repeated occurrences of MeHg poisoning, it gradually became clear that the fetus is much more susceptible to the toxicity of this compound than the adult. Thus, recent epidemiologic studies in several fish-eating populations have focused on the effects of in utero exposure to MeHg. Also, there have been many studies on neurobehavioral effects of in utero exposure to methylmercury in rodents and nonhuman primates. The results of these studies revealed that the effects encompass a wide range of behavioral categories without clear identification of the functional categories distinctively susceptible to MeHg. The overall neurotoxicity of MeHg in humans, nonhuman primates, and rodents appears to have similarities. However, several gaps exist between the human and animal studies. By using the large body of neurotoxicologic data obtained in human populations and filling in such gaps, we can use MeHg as a model agent for developing a specific battery of tests of animal behavior to predict human risks resulting from in utero exposure to other chemicals with unknown neurotoxicity. Approaches developing such a battery are also discussed. PMID:9182044

PROSTATE REGULATION: MODELING ENDOGENOUS ...

EPA Pesticide Factsheets

ALTERATIONS IN PROSTATE WEIGHT AND HISTOPATHOLOGY ARE OBSERVED FOLLOWING IN UTERO, PUBERTAL AND ADULT EXPOSURES TO ANTIANDROGENS. ALTERATIONS IN PROSTATE WEIGHT AND HISTOPATHOLOGY ARE OBSERVED FOLLOWING IN UTERO, PUBERTAL AND ADULT EXPOSURES TO ANTIANDROGENS.

The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice

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

Ziv-Gal, Ayelet, E-mail: zivgal1@illinois.edu; Wang, Wei, E-mail: weiwang2@illinois.edu; Zhou, Changqing, E-mail: czhou27@illinois.edu

In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50 μg/kg/day) or diethylstilbestrol (DES; 0.05 μg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9 months were conducted to evaluate reproductive capacity over time. Further, studiesmore » were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50 μg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05 μg/kg/day) and BPA (50 μg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5 μg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature. - Highlights: • In utero BPA delayed vaginal opening in the F3 generation compared to control. • In utero BPA delayed estrus in the F3 generation compared to control. • In utero BPA reduced the ability of F1 and F2 female mice to maintain pregnancies. • In utero BPA compromised the ability of F3 female mice to become pregnant. • Some effects of in utero BPA may be transgenerational in nature.« less

In Utero Exposure to Exosomal and B-Cell Alloantigens Lessens Alloreactivity of Recipients' Lymphocytes Rather than Confers Allograft Tolerance.

PubMed

Chen, Jeng-Chang; Ou, Liang-Shiou; Chan, Cheng-Chi; Kuo, Ming-Ling; Tseng, Li-Yun; Chang, Hsueh-Ling

2018-01-01

According to actively acquired tolerance, antigen exposure before full immune development in fetal or early neonatal life will cause tolerance to this specific antigen. In this study, we aimed to examine whether allogeneic tolerance could be elicited by in utero exposure to surface MHC antigens of allogenic cells or soluble form of MHC exosomes. Gestational day 14 FVB/N fetuses were subjected to intraperitoneal injection of allogeneic major histocompatibility complex (MHC) exosomes or highly enriched B-cells. Postnatally, the recipients were examined for the immune responses to donor alloantigens by lymphocyte proliferative reactions and skin transplantation. In utero exposure to allogeneic MHC exosomes abolished the alloreactivity of recipients' lymphocytes to the alloantigens, but could not confer skin allograft tolerance. In utero transplantation of highly enriched allogeneic B-cells generated low-level B-cell chimerism in the recipients. However, it only extended the survivals of skin allograft by a few days despite the lack of donor-specific alloreactivity of recipients' lymphocyte. Thus, an early in utero contact with exosomal or B-cell alloantigens did not lead to full skin tolerance but rather, at best, only to delayed skin rejection in the presence of microchimerism made by B-cell inocula. These results argued against the theory of actively acquired tolerance, and implicated that in utero exposure to marrow cells in previous studies was a unique model of allo-tolerance induction that involved the establishment of significant hematopoietic chimerism. Taken together with the discovery of in utero sensitization to ovalbumin in our previous studies, the immunological consequences of fetal exposure to foreign antigens might vary according to the type or nature of antigens introduced.

Hershey Medical Center Technical Workshop Report: optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure.

PubMed

Amler, Robert W; Barone, Stanley; Belger, Aysenil; Berlin, Cheston M; Cox, Christopher; Frank, Harry; Goodman, Michael; Harry, Jean; Hooper, Stephen R; Ladda, Roger; LaKind, Judy S; Lipkin, Paul H; Lipsitt, Lewis P; Lorber, Matthew N; Myers, Gary; Mason, Ann M; Needham, Larry L; Sonawane, Babasaheb; Wachs, Theodore D; Yager, Janice W

2006-09-01

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings.

DEHP exposure in utero disturbs sex determination and is potentially linked with precocious puberty in female mice.

PubMed

Wang, Yongan; Yang, Qing; Liu, Wei; Yu, Mingxi; Zhang, Zhou; Cui, Xiaoyu

2016-09-15

Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, β-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

In utero and lactational exposure to bisphenol A, in contrast to ethinyl estradiol, does not alter sexually dimorphic behavior, puberty, fertility, and anatomy of female LE rats.

EPA Science Inventory

Many chemicals released into the environment display estrogenic activity including the oral contraceptive ethinyl estradiol (EE2) and the plastic monomer bisphenol A (BPA). EE2 is present in some aquatic systems at concentrations sufficient to alter reproductive function of fishe...

DDT Exposure in Utero and Breast Cancer.

PubMed

Cohn, Barbara A; La Merrill, Michele; Krigbaum, Nickilou Y; Yeh, Gregory; Park, June-Soo; Zimmermann, Lauren; Cirillo, Piera M

2015-08-01

Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation. In utero exposure to DDT is associated with an increased risk of breast cancer. This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year). Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study. Daughters' breast cancer diagnosed by age 52 years as of 2012 was measured. Maternal o,p'-DDT predicted daughters' breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5-9.0). Mothers' lipids, weight, race, age, and breast cancer history did not explain the findings. This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk.

Bisphenol A (BPA) Exposure In Utero Leads to Immunoregulatory Cytokine Dysregulation in the Mouse Mammary Gland: A Potential Mechanism Programming Breast Cancer Risk.

PubMed

Fischer, Catha; Mamillapalli, Ramanaiah; Goetz, Laura G; Jorgenson, Elisa; Ilagan, Ysabel; Taylor, Hugh S

2016-08-01

Bisphenol-A (BPA) is a ubiquitous estrogen-like endocrine disrupting compound (EDC). BPA exposure in utero has been linked to breast cancer and abnormal mammary gland development in mice. The recent rise in incidence of human breast cancer and decreased age of first detection suggests a possible environmental etiology. We hypothesized that developmental programming of carcinogenesis may involve an aberrant immune response. Both innate and adaptive immunity play a role in tumor suppression through cytolytic CD8, NK, and Th1 T-cells. We hypothesized that BPA exposure in utero would lead to dysregulation of both innate and adaptive immunity in the mammary gland. CD1 mice were exposed to BPA in utero during gestation (days 9-21) via osmotic minipump. At 6 weeks, the female offspring were ovariectomized and estradiol was given at 8 weeks. RNA and protein were extracted from the posterior mammary glands, and the mRNA and protein levels were measured by PCR array, qRT-PCR, and western blot. In mouse mammary tissue, BPA exposure in utero significantly decreased the expression of members of the chemokine CXC family (Cxcl2, Cxcl4, Cxcl14, and Ccl20), interleukin 1 (Il1) gene family (Il1β and Il1rn), interleukin 2 gene family (Il7 receptor), and interferon gene family (interferon regulatory factor 9 (Irf9), as well as immune response gene 1 (Irg1). Additionally, BPA exposure in utero decreased Esr1 receptor gene expression and increased Esr2 receptor gene expression. In utero exposure of BPA resulted in significant changes to inflammatory modulators within mammary tissue. We suggest that dysregulation of inflammatory cytokines, both pro-inflammatory and anti-inflammatory, leads to a microenvironment that may promote disordered cell growth through inhibition of the immune response that targets cancer cells.

Early-life chemical exposures and risk of metabolic syndrome.

PubMed

De Long, Nicole E; Holloway, Alison C

2017-01-01

The global prevalence of obesity has been increasing at a staggering pace, with few indications of any decline, and is now one of the major public health challenges worldwide. While obesity and metabolic syndrome (MetS) have historically thought to be largely driven by increased caloric intake and lack of exercise, this is insufficient to account for the observed changes in disease trends. There is now increasing evidence to suggest that exposure to synthetic chemicals in our environment may also play a key role in the etiology and pathophysiology of metabolic diseases. Importantly, exposures occurring in early life (in utero and early childhood) may have a more profound effect on life-long risk of obesity and MetS. This narrative review explores the evidence linking early-life exposure to a suite of chemicals that are common contaminants associated with food production (pesticides; imidacloprid, chlorpyrifos, and glyphosate) and processing (acrylamide), in addition to chemicals ubiquitously found in our household goods (brominated flame retardants) and drinking water (heavy metals) and changes in key pathways important for the development of MetS and obesity.

Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure

PubMed Central

Jorgensen, Elisa M.; Alderman, Myles H.; Taylor, Hugh S.

2016-01-01

Bisphenol-A (BPA) is an environmentally ubiquitous estrogen-like endocrine-disrupting compound. Exposure to BPA in utero has been linked to female reproductive disorders, including endometrial hyperplasia and breast cancer. Estrogens are an etiological factor in many of these conditions. We sought to determine whether in utero exposure to BPA altered the global CpG methylation pattern of the uterine genome, subsequent gene expression, and estrogen response. Pregnant mice were exposed to an environmentally relevant dose of BPA or DMSO control. Uterine DNA and RNA were examined by using methylated DNA immunoprecipitation methylation microarray, expression microarray, and quantitative PCR. In utero BPA exposure altered the global CpG methylation profile of the uterine genome and subsequent gene expression. The effect on gene expression was not apparent until sexual maturation, which suggested that estrogen response was the primary alteration. Indeed, prenatal BPA exposure preferentially altered adult estrogen-responsive gene expression. Changes in estrogen response were accompanied by altered methylation that preferentially affected estrogen receptor-α (ERα)–binding genes. The majority of genes that demonstrated both altered expression and ERα binding had decreased methylation. BPA selectively altered the normal developmental programming of estrogen-responsive genes via modification of the genes that bind ERα. Gene–environment interactions driven by early life xenoestrogen exposure likely contributes to increased risk of estrogen-related disease in adults.—Jorgensen, E. M., Alderman, M. H., III, Taylor, H. S. Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure. PMID:27312807

DDT Exposure in Utero and Breast Cancer

PubMed Central

La Merrill, Michele; Krigbaum, Nickilou Y.; Yeh, Gregory; Park, June-Soo; Zimmermann, Lauren; Cirillo, Piera M.

2015-01-01

Context: Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation. Hypothesis: In utero exposure to DDT is associated with an increased risk of breast cancer. Design: This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year). Setting and Participants: Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study. Main Outcome Measure: Daughters' breast cancer diagnosed by age 52 years as of 2012 was measured. Results: Maternal o,p′-DDT predicted daughters' breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5–9.0). Mothers' lipids, weight, race, age, and breast cancer history did not explain the findings. Conclusions: This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk. PMID:26079774

In Utero Exposure to a Cardiac Teratogen Causes Reversible Deficits in Postnatal Cardiovascular Function, But Altered Adaptation to the Burden of Pregnancy.

PubMed

Aasa, Kristiina L; Maciver, Rebecca D; Ramchandani, Shyamlal; Adams, Michael A; Ozolinš, Terence R S

2015-11-01

Congenital heart defects (CHD) are the most common birth anomaly and while many resolve spontaneously by 1 year of age, the lifelong burden on survivors is poorly understood. Using a rat model of chemically induced CHD that resolve postnatally, we sought to characterize the postnatal changes in cardiac function, and to investigate whether resolved CHD affects the ability to adapt to the increased the cardiovascular (CV) burden of pregnancy. To generate rats with resolved CHD, pregnant rats were administered distilled water or dimethadione (DMO) [300 mg/kg b.i.d. on gestation day (gd) 9 and 10] and pups delivered naturally. To characterize structural and functional changes in the heart, treated and control offspring were scanned by echocardiography on postnatal day 4, 21, and 10-12 weeks. Radiotelemeters were implanted for continuous monitoring of hemodynamics. Females were mated and scanned by echocardiography on gd12 and gd18 during pregnancy. On gd18, maternal hearts were collected for structural and molecular assessment. Postnatal echocardiography revealed numerous structural and functional differences in treated offspring compared with control; however, these resolved by 10-12 weeks of age. The CV demand of pregnancy revealed differences between treated and control offspring with respect to mean arterial pressure, CV function, cardiac strain, and left ventricular gene expression. In utero exposure to DMO also affected the subsequent generation. Gd18 fetal and placental weights were increased in treated F2 offspring. This study demonstrates that in utero chemical exposure may permanently alter the capacity of the postnatal heart to adapt to pregnancy and this may have transgenerational effects. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

DEHP exposure in utero disturbs sex determination and is potentially linked with precocious puberty in female mice

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

Wang, Yongan

Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposuremore » levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2 mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2 mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, β-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism. - Highlights: • Maternal exposure to di (2-ethylhexyl) phthalate disturbs fetus sex determination. • DEHP upregulated Foxl2 expression potentially disturbs postnatal granulosa cell differentiation. • DEHP accelerated medulla follicular atresia potentially leading to precocious puberty.« less

In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1

PubMed Central

Mitsuhashi, Takayuki; Yonemoto, Junzo; Sone, Hideko; Kosuge, Yasuhiro; Kosaki, Kenjiro; Takahashi, Takao

2010-01-01

Dioxins have been reported to exert various adverse effects, including cell-cycle dysregulation in vitro and impairment of spatial learning and memory after in utero exposure in rodents. Furthermore, children born to mothers who are exposed to dioxin analogs polychlorinated dibenzofurans or polychlorinated biphenyls have developmental impairments in cognitive functions. Here, we show that in utero exposure to dioxins in mice alters differentiation patterns of neural progenitors and leads to decreased numbers of non-GABAergic neurons and thinner deep neocortical layers. This reduction in number of non-GABAergic neurons is assumed to be caused by accumulation of cyclin-dependent kinase inhibitor p27Kip1 in nuclei of neural progenitors. Lending support to this presumption, mice lacking p27Kip1 are not susceptible to in utero dioxin exposure. These results show that environmental pollutants may affect neocortical histogenesis through alterations of functions of specific gene(s)/protein(s) (in our case, dioxins), exerting adverse effects by altering functions of p27Kip1. PMID:20805476

Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response

PubMed Central

Bromer, Jason G.; Zhou, Yuping; Taylor, Melissa B.; Doherty, Leo; Taylor, Hugh S.

2010-01-01

Bisphenol-A (BPA) is a nonsteroidal estrogen that is ubiquitous in the environment. The homeobox gene Hoxa10 controls uterine organogenesis, and its expression is affected by in utero BPA exposure. We hypothesized that an epigenetic mechanism underlies BPA-mediated alterations in Hoxa10 expression. We analyzed the expression pattern and methylation profile of Hoxa10 after in utero BPA exposure. Pregnant CD-1 mice were treated with BPA (5 mg/kg IP) or vehicle control on d 9–16 of pregnancy. Hoxa10 mRNA and protein expression were increased by 25% in the reproductive tract of mice exposed in utero. Bisulfite sequencing revealed that cytosine-guanine dinucleotide methylation was decreased from 67 to 14% in the promoter and from 71 to 3% in the intron of Hoxa10 after in utero BPA exposure. Decreased DNA methylation led to an increase in binding of ER-α to the Hoxa10 ERE both in vitro as and in vivo as determined by EMSA and chromatin immunoprecipitation, respectively. Diminished methylation of the ERE-containing promoter sequence resulted in an increase in ERE-driven gene expression in reporter assays. We identify altered methylation as a novel mechanism of BPA-induced altered developmental programming. Permanent epigenetic alteration of ERE sensitivity to estrogen may be a general mechanism through which endocrine disruptors exert their action.—Bromer, J. G., Zhou, Y., Taylor, M. B., Doherty, L., Taylor, H. S.. Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. PMID:20181937

Protecting children from toxic chemicals: putting it on Australia's public health agenda.

PubMed

Lantz, Sarah

2013-11-01

The high volume and widespread use of industrial chemicals, the backlog of internationally untested chemicals, the uptake of synthetic chemicals found in babies in utero, cord blood, and in breast milk, and the lack of a unified and comprehensive regulatory framework all necessitate developing policies that protect the most vulnerable in our society - our children. Australia's failure to do so raises profound intergenerational ethical issues. This article tells a story of international policy, and where Australia is falling down. It demonstrates that we can learn from countries already taking critical steps to reduce the toxic chemical exposure, and that the development of a comprehensive, child-centered chemical regulation framework is central to turning around Australia's failure.

EXPOSURE PARAMETERS FOR DELAYED PUBERTY AND MAMMARY GLAND DEVELOPMENT IN LONG-EVANS RATS EXPOSED IN UTERO TO ATRAZINE

EPA Science Inventory

Exposure Parameters For Delayed Puberty And Mammary Gland Development In Long-Evans Rats Exposed In Utero To Atrazine

Jennifer L. Rayner1 and Suzanne E. Fenton2

1 UNC-Chapel Hill, DESE, Chapel Hill, NC, and 2 RTD, USEPA, NHEERL/ORD, RTP,NC

Prenatal exposure ...

Detection of polybrominated biphenyl ethers (PBDEs) in pediatric hair as a tool for determining in utero exposure.

PubMed

Aleksa, Katarina; Carnevale, Amanda; Goodyer, Cynthia; Koren, Gideon

2012-05-10

Cryptorchidism, or undescended/maldescended testis, is the most common birth defect of male genitalia. Its prevalence has been increasing over the past few decades. This may be due to an increase in the prevalence of anti-androgenic chemicals such as polychlorinated biphenyls, organochloride pesticides, plasticizers and fungicides. A newer group of chemicals, brominated flame retardants (BFRs), are being implicated as endocrine-disrupting chemicals. These chemicals are used worldwide in polymers that are incorporated into a variety of consumer products (e.g., textile, computers and televisions, insulating foam, electrical equipment and kitchen appliances). In order to quantify BFRs we introduce the use of hair levels of polybrominated diphenyl esters (PBDEs) as biomarkers of systemic exposure. This approach will allow for the estimation of in utero BFR exposure, in the process of evaluating the potential link between the incidence of cryptorchidism in newborn males and level of exposure of the pregnant mother to environmentally relevant BFRs. For that end we have developed a GC/MS assay in which children's hair is analyzed for the presence of polybrominated biphenyl ethers (PBDEs). In this pilot, 10-40mg of hair from 24 children (12 newborn and 12 from children 1 to 15 years) was extracted overnight at 40°C with 4N HCl and hexane (4:1). The samples were eluted from 2g NaSO(4):2g Florisil SPE columns with 8mL hexane. Dried samples are reconstituted with anhydrous isooctane and injected onto a GC/MS and analyzed for BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154, BDE-183 and BDE-209. PBDEs were detected in all of the newborn and child hair. The ΣPBDE ranged from 0.038 to 1.01pg/mg newborn hair and from 0.208 to 2.695ng/mg child hair. The most abundant PBDE in newborn hair was BDE-153 while in child hair the variable PBDEs were BDE-47 and BDE-99. The highest molecular weight congener BDE-209 was detected in 10/24 pediatric hair samples. The LOQ is 0.0625pg/mg (BDE-209 0.625pg/mg) and the efficiency of extraction was between 70 and 90%. This GC/MS method is sufficiently sensitive to detect the presence of all 8 PBDE congeners tested in as little as 10mg of pediatric hair. The results show that PBDEs are present in newborn hair, making this matrix useful in examining in utero exposure to PBDEs and linking it to cryptorchidism. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Varying Susceptibility of the Female Mammary Gland to In Utero Windows of BPA Exposure.

PubMed

Hindman, Andrea R; Mo, Xiaokui Molly; Helber, Hannah L; Kovalchin, Claire E; Ravichandran, Nanditha; Murphy, Alina R; Fagan, Abigail M; St John, Pamela M; Burd, Craig J

2017-10-01

In utero exposure to the endocrine disrupting compound bisphenol A (BPA) is known to disrupt mammary gland development and increase tumor susceptibility in rodents. It is unclear whether different periods of in utero development might be more susceptible to BPA exposure. We exposed pregnant CD-1 mice to BPA at different times during gestation that correspond to specific milestones of in utero mammary gland development. The mammary glands of early-life and adult female mice, exposed in utero to BPA, were morphologically and molecularly (estrogen receptor-α and Ki67) evaluated for developmental abnormalities. We found that BPA treatment occurring before mammary bud invasion into the mesenchyme [embryonic day (E)12.5] incompletely resulted in the measured phenotypes of mammary gland defects. Exposing mice up to the point at which the epithelium extends into the precursor fat pad (E16.5) resulted in a nearly complete BPA phenotype and exposure during epithelial extension (E15.5 to E18.5) resulted in a partial phenotype. Furthermore, the relative differences in phenotypes between exposure windows highlight the substantial correlations between early-life molecular changes (estrogen receptor-α and Ki67) in the stroma and the epithelial elongation defects in mammary development. These data further implicate BPA action in the stroma as a critical mediator of epithelial phenotypes. Copyright © 2017 Endocrine Society.

In utero exposure to radiation and haematological malignancies: pooled analysis of Southern Urals cohorts

PubMed Central

Schüz, Joachim; Deltour, Isabelle; Krestinina, Lyudmila Y; Tsareva, Yulia V; Tolstykh, Evgenia I; Sokolnikov, Mikhail E; Akleyev, Alexander V

2017-01-01

Background: It is scientifically uncertain whether in utero exposure to low-dose ionising radiation increases the lifetime risk of haematological malignancies. Methods: We pooled two cohorts from the Southern Urals comprising offspring of female workers of a large nuclear facility (the Mayak Production Association) and of women living in areas along the Techa River contaminated by nuclear accidents/waste from the same facility, with detailed dosimetry. Results: The combined cohort totalled 19 536 subjects with 700 504 person-years at risk over the period of incidence follow-up, and slightly more over the period of mortality follow-up, yielding 58 incident cases and 36 deaths up to age 61 years. Risk was increased in subjects who received in utero doses of ⩾80 mGy (excess relative risk (ERR): 1.27; 95% confidence interval (CI): −0.20 to 4.71), and the risk increased consistently per 100 mGy of continuous exposure in utero (ERR: 0.77; CI: 0.02 to 2.56). No association was apparent in mortality-based analyses. Results for leukaemia and lymphoma were similar. A very weak positive association was observed between incidence and postnatal exposure. Conclusions: In summary, the results suggest a positive association between in utero exposure to ionising radiation and risk of haematological malignancies, but the small number of outcomes and inconsistent incidence and mortality findings preclude firm conclusions. PMID:27855443

Association between prenatal and postnatal tobacco smoke exposure and allergies in young children.

PubMed

Tanaka, Keiko; Miyake, Yoshihiro

2011-06-01

Many studies have shown a positive association between environmental tobacco smoke (ETS) exposure and allergic disorders, whereas epidemiological evidence of the effect of maternal smoking during pregnancy on allergic diseases is inconsistent. We investigated the independent and joint effects of in utero exposure to maternal smoking and postnatal ETS exposure at home on allergic disorders among Japanese children. Study subjects were 1951 children aged 3 years. Data on maternal smoking during pregnancy and postnatal exposure to ETS at home, allergic symptoms, and potential confounders were collected through the use of a questionnaire. Outcomes were defined according to the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC). The prevalence values of symptoms of wheeze, asthma, and eczema in the previous 12 months were 22.0%, 8.8%, and 17.2%, respectively. We found that postnatal ETS exposure at home in the absence of in utero exposure to maternal smoking was associated with a higher prevalence of wheeze (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.01-1.67). In contrast, in utero exposure without subsequent postnatal ETS exposure at home or exposure to postnatal ETS at home in addition to in utero exposure to maternal smoking was not associated with the prevalence of wheeze. No measurable associations were observed between fetal, postnatal, or joint exposure and the prevalence of asthma or eczema. Data from this study indicate that ETS at home may be associated with a higher prevalence of wheeze among young Japanese children.

In utero exposure to low dose arsenic via drinking water impairs early life lung mechanics in mice.

PubMed

Ramsey, Kathryn A; Larcombe, Alexander N; Sly, Peter D; Zosky, Graeme R

2013-02-18

Exposure to arsenic via drinking water is a significant environmental issue affecting millions of people around the world. Exposure to arsenic during foetal development has been shown to impair somatic growth and increase the risk of developing chronic respiratory diseases. The aim of this study was to determine if in utero exposure to low dose arsenic via drinking water is capable of altering lung growth and postnatal lung mechanics. Pregnant C57BL/6 mice were given drinking water containing 0, 10 (current World Health Organisation (WHO) maximum contaminant level) or 100 μg/L arsenic from gestational day 8 to birth. Birth outcomes and somatic growth were monitored. Plethysmography and the forced oscillation technique were used to collect measurements of lung volume, lung mechanics, pressure-volume curves and the volume dependence of lung mechanics in male and female offspring at two, four, six and eight weeks of age. In utero exposure to low dose arsenic via drinking water resulted in low birth weight and impaired parenchymal lung mechanics during infancy. Male offspring were more susceptible to the effects of arsenic on growth and lung mechanics than females. All alterations to lung mechanics following in utero arsenic exposure were recovered by adulthood. Exposure to arsenic at the current WHO maximum contaminant level in utero impaired somatic growth and the development of the lungs resulting in alterations to lung mechanics during infancy. Deficits in growth and lung development in early life may contribute to the increased susceptibility of developing chronic respiratory disease in arsenic exposed human populations.

In utero exposure to low dose arsenic via drinking water impairs early life lung mechanics in mice

PubMed Central

2013-01-01

Background Exposure to arsenic via drinking water is a significant environmental issue affecting millions of people around the world. Exposure to arsenic during foetal development has been shown to impair somatic growth and increase the risk of developing chronic respiratory diseases. The aim of this study was to determine if in utero exposure to low dose arsenic via drinking water is capable of altering lung growth and postnatal lung mechanics. Methods Pregnant C57BL/6 mice were given drinking water containing 0, 10 (current World Health Organisation (WHO) maximum contaminant level) or 100μg/L arsenic from gestational day 8 to birth. Birth outcomes and somatic growth were monitored. Plethysmography and the forced oscillation technique were used to collect measurements of lung volume, lung mechanics, pressure-volume curves and the volume dependence of lung mechanics in male and female offspring at two, four, six and eight weeks of age. Results In utero exposure to low dose arsenic via drinking water resulted in low birth weight and impaired parenchymal lung mechanics during infancy. Male offspring were more susceptible to the effects of arsenic on growth and lung mechanics than females. All alterations to lung mechanics following in utero arsenic exposure were recovered by adulthood. Conclusions Exposure to arsenic at the current WHO maximum contaminant level in utero impaired somatic growth and the development of the lungs resulting in alterations to lung mechanics during infancy. Deficits in growth and lung development in early life may contribute to the increased susceptibility of developing chronic respiratory disease in arsenic exposed human populations. PMID:23419080

NORMAL MAMMARY GLAND MORPHOLOGY IN PUBERTAL FEMALE MICE FOLLOWING IN UTERO AND LACTATIONAL EXPOSURE TO GENISTEIN AT LEVELS COMPARABLE TO HUMAN DIETARY EXPOSURE. (R827402)

EPA Science Inventory

The objective of the study was to determine the effect of in utero and lactational exposure to genistein (0, 0.1, 0.5, 2.5 and 10 mg/kg/day) on mammary gland morphology in female B6D2F1 mice at levels comparable to or greater than human exposures. The effect of diethylstilbest...

Child development following in utero exposure

PubMed Central

Shallcross, R.; Bromley, R.L.; Irwin, B.; Bonnett, L.J.; Morrow, J.

2011-01-01

Objective: Children born to women with epilepsy (WWE), exposed in utero to levetiracetam (LEV, n = 51), were assessed for early cognitive development and compared to children exposed to sodium valproate in utero (VPA, n = 44) and a group of children representative of the general population (n = 97). Methods: Children were recruited prospectively from 2 cohorts in the United Kingdom and assessed using the Griffiths Mental Development Scale (1996), aged <24 months. Information regarding maternal demographics were collected and controlled for. This is an observational study with researchers not involved in the clinical management of the WWE. Results: On overall developmental ability, children exposed to LEV obtained higher developmental scores when compared to children exposed to VPA (p < 0.001). When compared, children exposed to LEV did not differ from control children (p = 0.62) on overall development. Eight percent of children exposed to LEV in utero fell within the below average range (DQ score of <84), compared with 40% of children exposed to VPA. After controlling for maternal epilepsy and demographic factors using linear regression analysis, exposure to LEV in utero was not associated with outcome (p = 0.67). Conversely, when compared with VPA exposure, LEV exposure was associated with higher scores for the overall developmental quotient (p < 0.001). Conclusion: Children exposed to LEV in utero are not at an increased risk of delayed early cognitive development under the age of 24 months. LEV may therefore be a preferable drug choice, where appropriate, for WWE prior to and of childbearing age. PMID:21263139

Hypermethylation of Homeobox A10 by in Utero Diethylstilbestrol Exposure: An Epigenetic Mechanism for Altered Developmental Programming

PubMed Central

Bromer, Jason G.; Wu, Jie; Zhou, Yuping; Taylor, Hugh S.

2009-01-01

Diethylstilbestrol (DES) is a nonsteroidal estrogen that induces developmental anomalies of the female reproductive tract. The homeobox gene HOXA10 controls uterine organogenesis, and its expression is altered after in utero DES exposure. We hypothesized that an epigenetic mechanism underlies DES-mediated alterations in HOXA10 expression. We analyzed the expression pattern and methylation profile of HOXA10 after DES exposure. Expression of HOXA10 is increased in human endometrial cells after DES exposure, whereas Hoxa10 expression is repressed and shifted caudally from its normal location in mice exposed in utero. Cytosine guanine dinucleotide methylation frequency in the Hoxa10 intron was higher in DES-exposed offspring compared with controls (P = 0.017). The methylation level of Hoxa10 was also higher in the caudal portion of the uterus after DES exposure at the promoter and intron (P < 0.01). These changes were accompanied by increased expression of DNA methyltransferases 1 and 3b. No changes in methylation were observed after in vitro or adult DES exposure. DES has a dual mechanism of action as an endocrine disruptor; DES functions as a classical estrogen and directly stimulates HOXA10 expression with short-term exposure, however, in utero exposure results in hypermethylation of the HOXA10 gene and long-term altered HOXA10 expression. We identify hypermethylation as a novel mechanism of DES-induced altered developmental programming. PMID:19299448

Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice

PubMed Central

Rodriguez, Karina F.; Ungewitter, Erica K.; Crespo-Mejias, Yasmin; Liu, Chang; Nicol, Barbara; Kissling, Grace E.; Yao, Humphrey Hung-Chang

2015-01-01

Background Mice exposed to high levels of arsenic in utero have increased susceptibility to tumors such as hepatic and pulmonary carcinomas when they reach adulthood. However, the effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear. Objectives We evaluated the effects of in utero exposure to inorganic arsenic at the U.S. Environmental Protection Agency (EPA) drinking water standard (10 ppb) and at tumor-inducing levels (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reached adulthood. Methods Pregnant CD-1 mice were exposed to sodium arsenite [none (control), 10 ppb, or 42.5 ppm] in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) in the exposed females when they reached adulthood. Results Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10-ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10-ppb and 42.5-ppm groups, arsenic-exposed females had significantly greater body weight gain, body fat content, and glucose intolerance. Conclusion Our findings revealed unexpected effects of in utero exposure to arsenic: exposure to both a human-relevant low dose and a tumor-inducing level led to early onset of vaginal opening and to obesity in female CD-1 mice. Citation Rodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH. 2016. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ Health Perspect 124:336–343; http://dx.doi.org/10.1289/ehp.1509703 PMID:26295903

Concurrent primaries of vaginal clear cell adenocarcinoma and endometrial adenocarcinoma in a 39-year old woman with in utero diethylstilbestrol exposure.

PubMed

Keller, C; Nanda, R; Shannon, R L; Amit, A; Kaplan, A L

2001-01-01

Diethylstilbestrol (DES) was used widely in the late 1940s in an attempt to prevent adverse pregnancy outcomes. In 1971 the US Food and Drug Administration proscribed its use for pregnancy support secondary to its association with clear cell adenocarcinoma of the vagina. Several studies in animal models demonstrated an association with endometrial cancer among offspring following in utero DES exposure. To date, there is only one case report of endometrial cancer in women exposed to DES in utero. We present the first case, to our knowledge, of a woman exposed to DES in utero who presented with double primaries of clear cell cancer of the vagina concomitant with endometrial cancer.

EFFECTS OF DIBUTYL PHTHALATE IN MALE RABBITS FOLLOWING IN UTERO, ADOLESCENT OR POST-PUBERTAL EXPOSURE

EPA Science Inventory

Effects of dibutyl phthalate in male rabbits following in utero, adolescent, or post-pubertal exposure
Ty T. Higuchi1, Jennifer S. Palmer1, L. Earl Gray Jr2., and D. N. Rao Veeramachaneni1
1Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort

The effect of diesel (DE) exposure in utero on reproductive and developmental immunotoxicity

EPA Science Inventory

Epidemiology studies are beginning to show that in utero exposure to traffic related pollutants might increase the incidence of immune mediated lung diseases. Time pregnant BALB/c mice were exposed to air or two concentrations of diesel exhaust (0.5 and 2 mg/m³...

Developmental exposure to second-hand smoke increases adult atherogenesis and alters mitochondrial DNA copy number and deletions in apoE(-/-) mice.

PubMed

Fetterman, Jessica L; Pompilius, Melissa; Westbrook, David G; Uyeminami, Dale; Brown, Jamelle; Pinkerton, Kent E; Ballinger, Scott W

2013-01-01

Cardiovascular disease is a major cause of morbidity and mortality in the United States. While many studies have focused upon the effects of adult second-hand smoke exposure on cardiovascular disease development, disease development occurs over decades and is likely influenced by childhood exposure. The impacts of in utero versus neonatal second-hand smoke exposure on adult atherosclerotic disease development are not known. The objective of the current study was to determine the effects of in utero versus neonatal exposure to a low dose (1 mg/m(3) total suspended particulate) of second-hand smoke on adult atherosclerotic lesion development using the apolipoprotein E null mouse model. Consequently, apolipoprotein E null mice were exposed to either filtered air or second-hand smoke: (i) in utero from gestation days 1-19, or (ii) from birth until 3 weeks of age (neonatal). Subsequently, all animals were exposed to filtered air and sacrificed at 12-14 weeks of age. Oil red-O staining of whole aortas, measures of mitochondrial damage, and oxidative stress were performed. Results show that both in utero and neonatal second-hand smoke exposure significantly increased adult atherogenesis in mice compared to filtered air controls. These changes were associated with changes in aconitase and mitochondrial superoxide dismutase activities consistent with increased oxidative stress in the aorta, changes in mitochondrial DNA copy number and deletion levels. These studies show that in utero or neonatal exposure to second-hand smoke significantly influences adult atherosclerotic lesion development and results in significant alterations to the mitochondrion and its genome that may contribute to atherogenesis.

Developmental Exposure to Second-Hand Smoke Increases Adult Atherogenesis and Alters Mitochondrial DNA Copy Number and Deletions in apoE−/− Mice

PubMed Central

Fetterman, Jessica L.; Pompilius, Melissa; Westbrook, David G.; Uyeminami, Dale; Brown, Jamelle; Pinkerton, Kent E.; Ballinger, Scott W.

2013-01-01

Cardiovascular disease is a major cause of morbidity and mortality in the United States. While many studies have focused upon the effects of adult second-hand smoke exposure on cardiovascular disease development, disease development occurs over decades and is likely influenced by childhood exposure. The impacts of in utero versus neonatal second-hand smoke exposure on adult atherosclerotic disease development are not known. The objective of the current study was to determine the effects of in utero versus neonatal exposure to a low dose (1 mg/m3 total suspended particulate) of second-hand smoke on adult atherosclerotic lesion development using the apolipoprotein E null mouse model. Consequently, apolipoprotein E null mice were exposed to either filtered air or second-hand smoke: (i) in utero from gestation days 1–19, or (ii) from birth until 3 weeks of age (neonatal). Subsequently, all animals were exposed to filtered air and sacrificed at 12–14 weeks of age. Oil red-O staining of whole aortas, measures of mitochondrial damage, and oxidative stress were performed. Results show that both in utero and neonatal second-hand smoke exposure significantly increased adult atherogenesis in mice compared to filtered air controls. These changes were associated with changes in aconitase and mitochondrial superoxide dismutase activities consistent with increased oxidative stress in the aorta, changes in mitochondrial DNA copy number and deletion levels. These studies show that in utero or neonatal exposure to second-hand smoke significantly influences adult atherosclerotic lesion development and results in significant alterations to the mitochondrion and its genome that may contribute to atherogenesis. PMID:23825571

Epigenetic effects of endocrine-disrupting chemicals on female reproduction: An ovarian perspective

PubMed Central

Zama, Aparna Mahakali; Uzumcu, Mehmet

2010-01-01

The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the epigenetic mechanisms involved in mediating the effects of EDCs on female reproduction are gathering momentum. In this review, we describe the developmental processes that are susceptible to EDC exposures in female reproductive system, with a special emphasis on the ovary. We discuss studies with select EDCs that have been shown to have physiological and correlated epigenetic effects in the ovary, neuroendocrine system, and uterus. Importantly, EDCs that can directly target the ovary can alter epigenetic mechanisms in the oocyte, leading to transgenerational epigenetic effects. The potential mechanisms involved in such effects are also discussed. PMID:20609371

Chemical exposure and respiratory health of children in an industrial setting.

PubMed

McCarty, Kathleen M; Cleveland, Rebecca J; Franklin, Peter; Sly, Peter D

2014-01-01

Parental exposures to chemicals, and the interplay between chemical exposures in utero and in infancy leading to respiratory disease in childhood, are not yet fully understood. In this study we investigated the impact of chemical exposures to the parent in occupational settings and to the child in the home and children's respiratory health. A cross-sectional study of lung function and respiratory health was conducted in primary school children in the Kwinana industrial area, south of Perth, Western Australia. Respiratory health was assessed using a standardized questionnaire and lung function was measured using the forced oscillation technique before and after inhaling 200 μg of salbutamol. Univariate logistic regression models were used to explore the relationship between the child's respiratory health (asthma, lung function, bronchodilator response) and exposures to ceramics, dry cleaning fluid, electroplating fluid, glues, leather, fabrics, dyes, insecticides, plastics, metal cleaning fluid, petrol, paint, photochemicals, electric wiring, machining, welding, X-rays, cleaning products, nail products, and "other exposures". The impact of cigarette smoking in the home and family history on respiratory health were also investigated. No associations were found between parental occupational exposures or child's exposures in the home and respiratory health. Significant associations were observed between current smoking in the home and cigarette exposure in the first year of life and poor respiratory health in the children. We found no strong evidence of main effects of occupational exposures in impairing the respiratory health of primary school-aged children.

EXPOSURE PARAMETERS NECESSARY FOR DELAYED PUBERTY AND MAMMARY GLAND DEVELOPMENT IN LONG-EVANS RATS EXPOSED IN UTERO TO ATRAZINE

EPA Science Inventory

Exposure Parameters Necessary For Delayed Puberty And Mammary Gland Development In Long-Evans Rats Exposed In Utero To Atrazine

Jennifer L. Rayner1, 2, Carmen Wood2, and Suzanne E. Fenton2

1 Department of Environmental Sciences and Engineering, School of Public Heal...

FETAL TESTOSTERONE LEVELS ARE DIFFERENTIALLY AFFECTED IN MALE SPRAGUE DAWLEY AND WISTAR RATS AFTER IN UTERO EXPOSURE TO DIETHYLHEXYL PHTHALATE: A DOSE RESPONSE STUDY.

EPA Science Inventory

Exposure to phthalate esters during sexual differentiation disrupts testosterone resulting in malformations of androgen-dependent tissues. We have found that gubernacular lesions are more prevalent in in utero diethylhexyl phthalate (DEHP)-treated Wistar male than in the SD rat o...

IN UTERO EXPOSURE TO ATRAZINE INDUCES DELAYED PUBERTY OF LONG EVANS RATS: DAM-MEDIATED EFFECTS IN FEMALES

EPA Science Inventory

IN UTERO EXPOSURE TO ATRAZINE INDUCES DELAYED PUBERTY OF LONG EVANS RATS: DAM-MEDIATED EFFECTS IN FEMALES.

J L Rayner1 and S E Fenton2.

1 University of North Carolina at Chapel Hill, School of Public Health, Chapel Hill, NC, and 2 Reproductive Toxicology Divisio...

PRESENTED AT SOCIETY OF TOXICOLOGY 2006: THE HERBICIDE LINURON REDUCES FETAL TESTOSTERONE PRODUCTION DURING BOTH IN UTERO AND IN VITRO EXPOSURES

EPA Science Inventory

Previous studies in our lab have shown that in utero exposure to Linuron, a urea-based herbicide, results in malformations of androgen dependent tissues in adult male offspring. The pattern of malformations, however, differs somewhat from that typically seen with a pure androgen...

Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity.

PubMed

Odorizzi, Pamela M; Feeney, Margaret E

2016-10-01

Pregnancy-associated malaria, including placental malaria, causes significant morbidity and mortality worldwide. Recently, it has been suggested that in utero exposure of the fetus to malaria antigens may negatively impact the developing immune system and result in tolerance to malaria. Here, we review our current knowledge of fetal immunity to malaria, focusing on the dynamic interactions between maternal malaria infection, placental development, and the fetal immune system. A better understanding of the long-term impact of in utero malaria exposure on the development of natural immunity to malaria, immune responses to other childhood pathogens, and vaccine immunogenicity is urgently needed. This may guide the implementation of novel chemoprevention strategies during pregnancy and facilitate the push toward malaria vaccines. Published by Elsevier Ltd.

[Impact of chemical and physical environmental factors on the course and outcome of pregnancy].

PubMed

Slama, R; Cordier, S

2013-09-01

We review the epidemiological literature on the possible impact of chemical and physical factors on pregnancy outcome. Effects of in-utero exposures on child health are not considered here. The highest levels of evidence concern the effects of passive smoking (on fetal growth), of lead (pregnancy-induced hypertension, fetal growth), of some Polychlorinated Biphenyls (PCB; on fetal growth) and, to a lesser extent, of atmospheric pollutants (on fetal growth and preterm delivery). For the other compounds, in particular non-persistent chemicals, the literature, which is generally based on poor exposure assessment, is less informative. In conclusion, the last decades have witnessed the development of mother-child cohorts in which exposure biomarkers have been assayed, allowing a large number of publications. For some persistent compounds, for which efficient exposure assessment approaches have been used, the literature indicates a likely impact on pregnancy outcomes. With the exception of air pollutants, the literature on non-persistent compounds is little conclusive; the assay of exposure biomarkers in repeated biological samples collected at relevant time points could help further increase knowledge regarding any health impact. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Cosmetics as endocrine disruptors: are they a health risk?

PubMed

Nicolopoulou-Stamati, Polyxeni; Hens, Luc; Sasco, Annie J

2015-12-01

Exposure to chemicals from different sources in everyday life is widespread; one such source is the wide range of products listed under the title "cosmetics", including the different types of popular and widely-advertised sunscreens. Women are encouraged through advertising to buy into the myth of everlasting youth, and one of the most alarming consequences is in utero exposure to chemicals. The main route of exposure is the skin, but the main endpoint of exposure is endocrine disruption. This is due to many substances in cosmetics and sunscreens that have endocrine active properties which affect reproductive health but which also have other endpoints, such as cancer. Reducing the exposure to endocrine disruptors is framed not only in the context of the reduction of health risks, but is also significant against the background and rise of ethical consumerism, and the responsibility of the cosmetics industry in this respect. Although some plants show endocrine-disrupting activity, the use of well-selected natural products might reduce the use of synthetic chemicals. Instruments dealing with this problem include life-cycle analysis, eco-design, and green labels; in combination with the committed use of environmental management systems, they contribute to "corporate social responsibility".

Differential Responses of Hippocampal Neurons and Astrocytes to Nicotine and Hypoxia in the Fetal Guinea Pig

PubMed Central

Blutstein, Tamara; Castello, Michael A.; Viechweg, Shaun S.; Hadjimarkou, Maria M.; McQuail, Joseph A.; Holder, Mary; Thompson, Loren P.; Mong, Jessica A.

2012-01-01

In utero exposure to cigarette smoke has severe consequences for the developing fetus, including increased risk of birth complications and behavioral and learning disabilities later in life. Evidence from animal models suggests that the cognitive deficits may be a consequence of in utero nicotine exposure in the brain during critical developmental periods. However, maternal smoking exposes the fetus to not only nicotine but also a hypoxic intrauterine environment. Thus, both nicotine and hypoxia are capable of initiating cellular cascades, leading to long-term changes in synaptic patterning that have the potential to affect cognitive functions. The present study investigates the combined effect of in utero exposure to nicotine and hypoxia on neuronal and glial elements in the hippocampal CA1 field. Fetal guinea pigs were exposed in utero to normoxic or hypoxic conditions in the presence or absence of nicotine. Hypoxia increased the protein levels of matrix metalloproteinase-9 (MMP-9) and synaptophysin and decreased the neural density as measured by NeuN immunoreactivity (ir). Nicotine exposure had no effect on these neuronal parameters but dramatically increased the density of astrocytes immunopositive for glial fibrillary acidic protein (GFAP). Further investigation into the effects of in utero nicotine exposure revealed that both GFAP-ir and NeuN-ir in the CA1 field were significantly reduced in adulthood. Taken together, our data suggest that prenatal exposure to nicotine and hypoxia not only alters synaptic patterning acutely during fetal development, but that nicotine also has long-term consequences that are observed well into adulthood. Moreover, these effects most likely take place through distinct mechanisms. PMID:23192463

Prenatal versus Postnatal Tobacco Smoke Exposure and Intensive Care Use in Children Hospitalized with Bronchiolitis

PubMed Central

Stevenson, Michelle D.; Mansbach, Jonathan M.; Mowad, Eugene; Dunn, Michelle; Clark, Sunday; Piedra, Pedro A.; Sullivan, Ashley F.; Camargo, Carlos A.

2016-01-01

Objective Among children hospitalized with bronchiolitis, we examined the associations between in utero exposure to maternal cigarette smoking, postnatal tobacco smoke exposure, and risk of admission to the intensive care unit (ICU). Methods We performed a 16-center, prospective cohort study of hospitalized children age <2 years with a physician admitting diagnosis of bronchiolitis. For 3 consecutive years, from November 1, 2007 until March 31, 2010, site teams collected data from participating families, including information about prenatal maternal smoking and postnatal tobacco exposure. Analyses used χ2, Fisher's exact, and Kruskal-Wallis tests and multivariable logistic regression. Results Among 2,207 enrolled children, 216 (10%) had isolated in utero exposure to maternal smoking, 168 (8%) had isolated postnatal tobacco exposure, while 115 (5%) experienced both. Adjusting for age, sex, race, birth weight, viral etiology, apnea, initial severity of retractions, initial oxygen saturation, oral intake, and postnatal tobacco exposure, children with in utero exposure to maternal smoking had greater odds of being admitted to the ICU (adjusted odds ratio (aOR) 1.51 [95% CI 1.14-2.00]). Among children with in utero exposure to maternal smoking, those with additional postnatal tobacco exposure had a greater likelihood of ICU admission (aOR 1.95 [95% CI 1.13-3.37]) compared with children without postnatal tobacco smoke exposure (aOR 1.47 [95% CI 1.05-2.04]). Conclusions Maternal cigarette smoking during pregnancy puts children hospitalized with bronchiolitis at significantly higher risk of requiring intensive care use. Postnatal tobacco smoke exposure may exacerbate this risk. Health care providers should incorporate this information into counseling messages. PMID:26555856

Animal models for probing the developmental basis of disease and dysfunction paradigm.

PubMed

Heindel, Jerrold J

2008-02-01

There is a major paradigm shift taking place in science that while simple is profound. The new paradigm suggests that susceptibility to disease is set in utero or neonatally as a result of the influences of nutrition and exposures to environmental stressors/toxicants. In utero nutrition and/or in utero or neonatal exposures to environmental toxicants alter susceptibility to disease later in life as a result of their ability to affect the programming of tissue function that occurs during development. This concept, which is still a hypothesis undergoing scientific testing and scrutiny, is called the developmental basis of health and disease. If true, then it says that the focus on disease prevention and intervention must change from the time of disease onset to perhaps decades prior: during the in utero and neonatal period. Perhaps the reason it has been so difficult to link environmental exposure to disease susceptibility is that scientists have been looking at the wrong time! Certainly, not all exposures that result in increased disease or dysfunction occur during development. This paradigm shift just suggests that this is a sensitive window of exposure that should be examined more thoroughly. This overview focuses on animal models for the assessment of this new scientific paradigm and the animal data that now supports it.

In utero arsenic exposure induces early onset of atherosclerosis in ApoE−/− mice

PubMed Central

Srivastava, Sanjay; D’Souza, Stanley E.; Sen, Utpal; States, J. Christopher

2007-01-01

Consumption of arsenic contaminated drinking water has been linked to higher rates of coronary disease, stroke, and peripheral arterial disease. Recent evidence suggests that early life exposures may play a significant role in the onset of chronic adult diseases. To investigate the potential for in utero exposure to accelerate the onset of cardiovascular disease we exposed pregnant ApoE-knockout (ApoE−/−) mice to arsenic in their drinking water and examined the aortic trees of their male offspring for evidence of early disease 10 and 16 weeks after birth. Mice were maintained on normal chow after weaning. ApoE−/− mice are a commonly used model for atherogenesis and spontaneously develop atherosclerotic disease. Mice exposed to arsenic in utero showed a >2-fold increase in lesion formation in the aortic roots as well as the aortic arch compared to control mice at both 10 and 16 weeks of age. The mice exposed to arsenic also had a 20 – 40% decrease in total triglycerides, but no change in total cholesterol, phospholipids and total abundance of VLDL or HDL particles. Subfractionation of VLDL particles showed a decrease in large VLDL particles. In addition, the arsenic exposed mice showed a vasorelaxation defect in response to acetylcholine suggesting disturbance of endothelial cell signalling. These results indicate that in utero arsenic exposure induces an early onset of atherosclerosis in ApoE−/− mice without a hyperlipidemic diet and support the hypothesis that in utero arsenic exposure may be atherogenic in humans. PMID:17317095

PAH Particles Perturb Prenatal Processes and Phenotypes: Protection from Deficits in Object Discrimination Afforded by Dampening of Brain Oxidoreductase Following In Utero Exposure to Inhaled Benzo(a)pyrene

PubMed Central

Chadalapaka, Gayathri; Ramesh, Aramandla; Khoshbouei, Habibeh; Maguire, Mark; Safe, Stephen; Rhoades, Raina E.; Clark, Ryan; Jules, George; McCallister, Monique; Aschner, Michael; Hood, Darryl B.

2012-01-01

The wild-type (WT) Cprlox/lox (cytochrome P450 oxidoreductase, Cpr) mouse is an ideal model to assess the contribution of P450 enzymes to the metabolic activation and disposition of environmental xenobiotics. In the present study, we examined the effect of in utero exposure to benzo(a)pyrene [B(a)P] aerosol on Sp4 and N-methyl-D-aspartate (NMDA)–dependent systems as well as a resulting behavioral phenotype (object discrimination) in Cpr offspring. Results from in utero exposure of WT Cprlox/lox mice were compared with in utero exposed brain-Cpr-null offspring mice. Null mice were used as they do not express brain cytochrome P4501B1–associated NADPH oxidoreductase (CYP1B1-associated NADPH oxidoreductase), thus reducing their capacity to produce neural B(a)P metabolites. Subsequent to in utero (E14–E17) exposure to B(a)P (100 μg/m3), Cprlox/lox offspring exhibited: (1) elevated B(a)P metabolite and F2-isoprostane neocortical tissue burdens, (2) elevated concentrations of cortical glutamate, (3) premature developmental expression of Sp4, (4) decreased subunit ratios of NR2B:NR2A, and (5) deficits in a novelty discrimination phenotype monitored to in utero exposed brain-Cpr-null offspring. Collectively, these findings suggest that in situ generation of metabolites by CYP1B1-associated NADPH oxidoreductase promotes negative effects on NMDA-mediated signaling processes during the period when synapses are first forming as well as effects on a subsequent behavioral phenotype. PMID:21987461

Early-Onset Endocrine Disruptor–Induced Prostatitis in the Rat

PubMed Central

Cowin, Prue A.; Foster, Paul; Pedersen, John; Hedwards, Shelley; McPherson, Stephen J.; Risbridger, Gail P.

2008-01-01

Background Androgens are critical for specifying prostate development, with the fetal prostate sensitive to altered hormone levels and endocrine-disrupting chemicals (EDCs) that exhibit estrogenic or antiandrogenic properties. Prostatic inflammation (prostatitis) affects 9% of men of all ages, and > 90% of cases are of unknown etiology. Objectives In this study we aimed to evaluate effects of in utero exposure to the antiandrogenic EDC vinclozolin, during the period of male reproductive tract development, on neonatal, prepubertal, and postpubertal prostate gland function of male offspring. Methods Fetal rats were exposed to vinclozolin (100 mg/kg body weight) or vehicle control (2.5 mL/kg body weight) in utero from gestational day 14 (GD14) to GD19 via oral administration to pregnant dams. Tissue analysis was carried out when male offspring were 0, 4, or 8 weeks of age. Results In utero exposure to vinclozolin was insufficient to perturb prostatic development and branching, although expression of androgen receptor and mesenchymal fibroblast growth factor-10 was down-regulated. Prostate histology remained normal until puberty, but 100% of animals displayed prostatitis postpubertally (56 days of age). Prostatic inflammation was associated with phosphorylation and nuclear translocation of nuclear factor-kappa B (NFκB) and postpubertal activation of proinflammatory NFκB-dependent genes, including the chemokine interleukin-8 and the cytokine transforming growth factor-β1. Significantly, inflammation arising from vinclozolin exposure was not associated with the emergence of premalignant lesions, such as prostatic intra-epithelial neoplasia or proliferative inflammatory atrophy, and hence mimics nonbacterial early-onset prostatitis that commonly occurs in young men. Conclusions These data are the first to unequivocally implicate EDCs as a causative factor and fill an important knowledge gap on the etiology of prostatitis. PMID:18629315

COMBINED ENDOCRINE EFFECTS OF IN UTERO EXPOSURE TO THE ANTIANDROGENS BUTYLBENZYL PHTHALATE (BBP) AND LINURON (LIN) ON FETAL TESTOSTERONE (T) SYNTHESIS AND REPRODUCTIVE TRACT DEVELOPMENT

EPA Science Inventory

COMBINED ENDOCRINE EFFECTS OF IN UTERO EXPOSURE TO THE ANTIANDROGENS BUTYLBENZYL PHTHALATE (BBP) AND LINURON (Lin) ON FETAL TESTOSTERONE (T) SYNTHESIS AND REPRODUCTIVE TRACT DEVELOPMENT
Parks LG , Hotchkiss AK, Ostby J, Lambright C and Gray LE, Jr.

Lin and BBP are toxic...

The Long-Term Economic Impact of in Utero and Postnatal Exposure to Malaria

ERIC Educational Resources Information Center

Barreca, Alan I.

2010-01-01

I use an instrumental-variables identification strategy and historical data from the United States to estimate the long-term economic impact of in utero and postnatal exposure to malaria. My research design matches adults in the 1960 Decennial Census to the malaria death rate in their respective state and year of birth. To address potential…

Bioanalytical procedures for monitoring in utero drug exposure

PubMed Central

Gray, Teresa

2009-01-01

Drug use by pregnant women has been extensively associated with adverse mental, physical, and psychological outcomes in their exposed children. This manuscript reviews bioanalytical methods for in utero drug exposure monitoring for common drugs of abuse in urine, hair, oral fluid, blood, sweat, meconium, amniotic fluid, umbilical cord tissue, nails, and vernix caseosa; neonatal matrices are particularly emphasized. Advantages and limitations of testing different maternal and neonatal biological specimens including ease and invasiveness of collection, and detection time frames, sensitivities, and specificities are described, and specific references for available analytical methods included. Future research involves identifying metabolites unique to fetal drug metabolism to improve detection rates of in utero drug exposure and determining relationships between the amount, frequency, and timing of drug exposure and drug concentrations in infant biological fluids and tissues. Accurate bioanalytical procedures are vital to defining the scope of and resolving this important public health problem. PMID:17370066

Investigating the effects of in utero benzene exposure on epigenetic modifications in maternal and fetal CD-1 mice.

PubMed

Philbrook, Nicola A; Winn, Louise M

2015-11-15

Exposure to the ubiquitous environmental pollutant benzene is positively correlated with leukemia in adults and may be associated with childhood leukemia following in utero exposure. While numerous studies implicate oxidative stress and DNA damage as playing a role in benzene-mediated carcinogenicity, emerging evidence suggests that alterations in epigenetic regulations may be involved. The present study aimed to determine whether DNA methylation and/or various histone modifications were altered following in utero benzene exposure in CD-1 mice. Global DNA methylation and promoter-specific methylation of the tumor suppressor gene, p15, were assessed. Additionally, levels of acetylated histones H3, H4, and H3K56, as well as methylated histones H3K9 and H3K27 were assessed by Western blotting. A significant decrease in global DNA methylation of maternal bone marrow was observed following benzene exposure; however no effect on global DNA methylation was detected in fetal livers. Additionally, no effect of benzene exposure was observed on p15 promoter methylation or any measured histone modifications in both maternal bone marrow and fetal livers. These results suggest that the methodology used in the present study did not reveal alterations in DNA methylation and histone modifications following in utero exposure to benzene; however further experimentation investigating these modifications at the whole genome/epigenome level, as well as at later stages of benzene-induced carcinogenesis, are warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

An Evaluation of Transplacental Carcinogenesis for Human ...

EPA Pesticide Factsheets

Risk assessments take into account the sensitivity of the postnatal period to carcinogens through the application of age-dependent adjustment factors (ADAFs) (Barton et al. 2005). The prenatal period is also recognized to be sensitive but is typically not included into risk assessments (NRC, 2009). An analysis by California OEHHA (2008) contrasted prenatal, postnatal and adult sensitivity to 23 different carcinogens across 37 studies. That analysis found a wide range of transplacental sensitivity with some agents nearly 100 fold more potent in utero than in adults while others had an in utero/adult ratio adult only exposure). Five carcinogens had more modest ratios to adult potency in both pre- and postnatal testing (vinyl chloride, ethylnitroso biuret, 3-methylcholanthrene, urethane, diethylnitrosamine, 3-10 fold). Only one chemical showed a pre- vs postnatal divergence (butylnitrosourea, prenataladult). Based upon this limited set of genotoxic carcinogens, it appears that the prenatal period often has a sensitivity that approximates what has been found for postnatal, and the maternal system does not offer substantial protection against transplacental carcinogenesis in most cases. This suggests that the system of ADAFs developed for postnatal exposure may be considered for prenatal exposures as well. An alternative approach may be to calculate cancer risk for the period of pregnancy rather than blend this risk into the calculation of lifetime risk. This

Hair as a biomarker of polybrominated diethyl ethers' exposure in infants, children and adults.

PubMed

Aleksa, Katarina; Liesivuori, Jyrki; Koren, Gideon

2012-04-25

Over the last 20 years hair has moved from being a highly questionable biological matrix to mainstream and acceptable biomarker in forensic sciences where it is primarily used to determine past and present exposure to illicit drugs. In contrast, the use of hair to assess exposure to pesticides and persistent environmental pollutants is still not common. The applicability of this matrix to assess an individual's body burden of chemicals such as polybrominated diethyl ethers (PBDEs) can provide critical insight into current, but also to past exposure levels, which is not possible with more conventional matrices such as blood and urine. Furthermore, as PBDEs cross the placenta and since the hair the fetus is born with begins to grow during the third trimester, this matrix can be used to assess in utero exposure. These features of hair may therefore be used to determine the potential roles of chemicals such as PBDEs in mediating physiological or anatomical abnormalities in infants, children or adults. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Developmental origins of type 2 diabetes: a perspective from China.

PubMed

Ma, R C W; Tsoi, K Y; Tam, W H; Wong, C K C

2017-07-01

There has been a marked increase in the prevalence of diabetes in Asia, including China, over the last few decades. While the increased prevalence of diabetes has often been attributed to the nutritional transition associated with recent economic development, emerging data suggest that early-life exposures also play a major role in shaping developmental trajectories, and contributes to alter an individual's susceptibility to diabetes and other non-communicable diseases (NCDs). Early-life exposures such as in utero exposure to undernutrition has been consistently linked with later risk of diabetes and obesity. Furthermore, in utero exposure to maternal hyperglycemia, maternal obesity and excess gestational weight gain are all linked with increased childhood obesity and later risk of diabetes. Emerging data have also highlighted the potential link between early-feeding practices, the role of one-carbon metabolism in metabolic programming and endocrine disrupting chemicals (EDCs) with later risk of diabetes. These different developmental exposures may all be highly relevant to the current epidemic of diabetes in China. For example, the prevalence of gestational diabetes has increased markedly over the last two decades, and may contribute to the diabetes epidemic by driving macrosomia, childhood obesity and later risk of diabetes. In order to address the current burden of diabetes, a lifecourse perspective, incorporating multisectoral efforts from public health policy down to the individuals, will be needed. Several major initiatives have been launched in China as part of its national plans for NCD prevention and treatment, and the experience from these efforts would be invaluable.

Exposure to Ambient Fine Particulate Air Pollution in Utero as a Risk Factor for Child Stunting in Bangladesh

PubMed Central

Canning, David

2017-01-01

Pregnant mothers in Bangladesh are exposed to very high and worsening levels of ambient air pollution. Maternal exposure to fine particulate matter has been associated with low birth weight at much lower levels of exposure, leading us to suspect the potentially large effects of air pollution on stunting in children in Bangladesh. We estimate the relationship between exposure to air pollution in utero and child stunting by pooling outcome data from four waves of the nationally representative Bangladesh Demographic and Health Survey conducted between 2004 and 2014, and calculating children’s exposure to ambient fine particulate matter in utero using high resolution satellite data. We find significant increases in the relative risk of child stunting, wasting, and underweight with higher levels of in utero exposure to air pollution, after controlling for other factors that have been found to contribute to child anthropometric failure. We estimate the relative risk of stunting in the second, third, and fourth quartiles of exposure as 1.074 (95% confidence interval: 1.014–1.138), 1.150 (95% confidence interval: 1.069–1.237, and 1.132 (95% confidence interval: 1.031–1.243), respectively. Over half of all children in Bangladesh in our sample were exposed to an annual ambient fine particulate matter level in excess of 46 µg/m3; these children had a relative risk of stunting over 1.13 times that of children in the lowest quartile of exposure. Reducing air pollution in Bangladesh could significantly contribute to the Sustainable Development Goal of reducing child stunting. PMID:29295507

Exposure to Ambient Fine Particulate Air Pollution in Utero as a Risk Factor for Child Stunting in Bangladesh.

PubMed

Goyal, Nihit; Canning, David

2017-12-23

Pregnant mothers in Bangladesh are exposed to very high and worsening levels of ambient air pollution. Maternal exposure to fine particulate matter has been associated with low birth weight at much lower levels of exposure, leading us to suspect the potentially large effects of air pollution on stunting in children in Bangladesh. We estimate the relationship between exposure to air pollution in utero and child stunting by pooling outcome data from four waves of the nationally representative Bangladesh Demographic and Health Survey conducted between 2004 and 2014, and calculating children's exposure to ambient fine particulate matter in utero using high resolution satellite data. We find significant increases in the relative risk of child stunting, wasting, and underweight with higher levels of in utero exposure to air pollution, after controlling for other factors that have been found to contribute to child anthropometric failure. We estimate the relative risk of stunting in the second, third, and fourth quartiles of exposure as 1.074 (95% confidence interval: 1.014-1.138), 1.150 (95% confidence interval: 1.069-1.237, and 1.132 (95% confidence interval: 1.031-1.243), respectively. Over half of all children in Bangladesh in our sample were exposed to an annual ambient fine particulate matter level in excess of 46 µg/m³; these children had a relative risk of stunting over 1.13 times that of children in the lowest quartile of exposure. Reducing air pollution in Bangladesh could significantly contribute to the Sustainable Development Goal of reducing child stunting.

Detection of vulnerable neurons damaged by environmental insults in utero

PubMed Central

Torii, Masaaki; Chang, Yu-Wen; Ishii, Seiji; Waxman, Stephen G.; Kocsis, Jeffery D.; Rakic, Pasko; Hashimoto-Torii, Kazue

2017-01-01

Development of prognostic biomarkers for the detection of prenatally damaged neurons before manifestations of postnatal disorders is an essential step for prevention and treatment of susceptible individuals. We have developed a versatile fluorescence reporter system in mice enabling detection of Heat Shock Factor 1 activation in response to prenatal cellular damage caused by exposure to various harmful chemical or physical agents. Using an intrautero electroporation-mediated reporter assay and transgenic reporter mice, we are able to identify neurons that survive prenatal exposure to harmful agents but remain vulnerable in postnatal life. This system may provide a powerful tool for exploring the pathogenesis and treatment of multiple disorders caused by exposure to environmental stress before symptoms become manifested, exacerbated, and/or irreversible. PMID:28123061

The Scourge of Asian Flu: In Utero Exposure to Pandemic Influenza and the Development of a Cohort of British Children

ERIC Educational Resources Information Center

Kelly, Elaine

2011-01-01

This paper examines the impact of in utero exposure to the Asian influenza pandemic of 1957 upon childhood development. Outcome data are provided by the National Child Development Study (NCDS), a panel study where all members were potentially exposed in the womb. Epidemic effects are identified using geographic variation in a surrogate measure of…

Infant Head Growth and Cognitive Status at 36 Months in Children with In-Utero Drug Exposure

ERIC Educational Resources Information Center

Butz, Arlene M.; Pulsifer, Margaret; Belcher, Harolyn M. E.; Leppert, Mary; Donithan, Michele; Zeger, Scott

2005-01-01

Previous studies of children with in-utero drug exposure (IUDE) raise concerns that decreased head circumference (HC) at birth increases the child's risk for later compromised cognitive functioning. The purpose of this study was to determine if HC at birth and HC growth change are associated with cognitive functioning (IQ) at 36 months of age in…

The effects of in utero bisphenol A exposure on ovarian follicle numbers and steroidogenesis in the F1 and F2 generations of mice.

PubMed

Mahalingam, Sharada; Ther, Laura; Gao, Liying; Wang, Wei; Ziv-Gal, Ayelet; Flaws, Jodi A

2017-12-01

Bisphenol A (BPA) is a commonly used plasticizer. Previous studies show that in utero exposure to BPA affects reproductive outcomes in the F1-F3 generations of mice. However, its multigenerational effects on ovarian histology and steroidogenesis over the reproductive lifespan are unknown. Thus, we tested the hypothesis that BPA has multigenerational effects on follicle numbers and steroidogenesis. Mice were exposed in utero to vehicle control or BPA (0.5, 20, and 50μg/kg/day). Ovaries were collected for histological and gene expression analyses and sera were collected for hormone assays. In utero BPA exposure decreased preantral follicle numbers, cytochrome P450 aromatase mRNA levels, and estradiol levels in the F1 generation, whereas it decreased testosterone levels and altered steroidogenic acute regulatory protein, cytochrome P450 cholesterol side-chain cleavage, 3β-hydroxysteroid dehydrogenase 1, and cytochrome P450 aromatase mRNA levels in the F2 generation. These data suggest that BPA has multigenerational effects on the ovary in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression.

PubMed

Winterbottom, Emily F; Koestler, Devin C; Fei, Dennis Liang; Wika, Eric; Capobianco, Anthony J; Marsit, Carmen J; Karagas, Margaret R; Robbins, David J

2017-06-14

Sex-specific factors play a major role in human health and disease, including responses to environmental stresses such as toxicant exposure. Increasing evidence suggests that such sex differences also exist during fetal development. In a previous report using the resources of the New Hampshire Birth Cohort Study (NHBCS), we found that low-to-moderate in utero exposure to arsenic, a highly toxic and widespread pollutant, was associated with altered expression of several key developmental genes in the fetal portion of the placenta. These associations were sex-dependent, suggesting that in utero arsenic exposure differentially impacts male and female fetuses. In the present study, we investigated the molecular basis for these sex-specific responses to arsenic. Using NanoString technology, we further analyzed the fetal placenta samples from the NHBCS for the expression of genes encoding arsenic transporters and metabolic enzymes. Multivariable linear regression analysis was used to examine their relationship with arsenic exposure and with key developmental genes, after stratification by fetal sex. We found that maternal arsenic exposure was strongly associated with expression of the AQP9 gene, encoding an aquaglyceroporin transporter, in female but not male fetal placenta. Moreover, AQP9 expression associated with that of a subset of female-specific arsenic-responsive genes. Our results suggest that AQP9 is upregulated in response to arsenic exposure in female, but not male, fetal placenta. Based on these results and prior studies, increased AQP9 expression may lead to increased arsenic transport in the female fetal placenta, which in turn may alter the expression patterns of key developmental genes that we have previously shown to be associated with arsenic exposure. Thus, this study suggests that AQP9 may play a role in the sex-specific effects of in utero arsenic exposure.

Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk

PubMed Central

Leung, Yuet-Kin; Govindarajah, Vinothini; Cheong, Ana; Veevers, Jennifer; Song, Dan; Gear, Robin; Zhu, Xuegong; Ying, Jun; Kendler, Ady; Medvedovic, Mario; Belcher, Scott

2017-01-01

In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogen-induced mammary cancer risk in offspring, and its dose–response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming. PMID:28487351

[Meconium as a new biological material for detecting intrauterine exposure to toxic substances].

PubMed

Lisowska-Myjak, Barbara

2005-07-01

The use of licit and illicit drugs and exposure to other xenobiotic agents during pregnancy is common. These substances are known to have adverse effects on the pregnancy and fetus; however information on fetal exposure is sparse due to the lack of an appropriate measure of exposure. Meconium analysis is a new method for identifying in utero exposure of infants to a number of illicit and legal drugs, alcohol, nicotine, heavy metals, pesticides, congenital infections. It's testing is non-invasive, highly accurate and able to detect prior exposure in utero during 12-40 weeks of gestation. This has implications for toxicology to develop improved methods to identify exposed infants.

What Aircrews Should Know About Their Occupational Exposure to Ionizing Radiation

DTIC Science & Technology

2003-10-01

aircrews, and their children irradiated in utero , the principal health concern is a small increase in the lifetime risk of fatal cancer . For both of...from cancer : adults, p.301; all ages, p.303. — Risks from irradiation in utero , p.302. — Inherited genetic defects from parental...Aircrews, Ionizing Radiation, Galactic Cosmic Radiation, Cancer Risk, Hereditary Risks, Radiation Exposure Limits Springfield, Virginia 22161 19

Cardiac effects of in-utero exposure to antiretroviral therapy in HIV-uninfected children born to HIV-infected mothers.

PubMed

Lipshultz, Steven E; Williams, Paige L; Zeldow, Bret; Wilkinson, James D; Rich, Kenneth C; van Dyke, Russell B; Seage, George R; Dooley, Laurie B; Kaltman, Jonathan R; Siberry, George K; Mofenson, Lynne M; Shearer, William T; Colan, Steven D

2015-01-02

We evaluated the potential cardiac effects of in-utero exposures to antiretroviral drugs in HIV-exposed but uninfected (HEU) children. We compared echocardiographic parameters of left ventricular function (ejection fraction, fractional shortening, and stress-velocity index) and structure (left ventricular dimension, posterior wall/septal thickness, mass, thickness-to-dimension ratio, and wall stress) (expressed as Z-scores to account for age and body surface area) between HEU and HIV-unexposed cohorts from the Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring for ART Toxicities study. Within the HEU group, we investigated the associations between the echocardiographic Z-scores and in-utero exposures to maternal antiretroviral drugs. There were no significant differences in echocardiographic Z-scores between 417 HEU and 98 HIV-unexposed children aged 2-7 years. Restricting the analysis to HEU children, first-trimester exposures to combination antiretroviral therapy (a regimen including at least three antiretroviral drugs) and to certain specific antiretroviral drugs were associated with significantly lower stress-velocity Z-scores (mean decreases of 0.22-0.40 SDs). Exposure to combination antiretroviral therapy was also associated with lower left ventricular dimension Z-scores (mean decrease of 0.44 SD). First-trimester exposure to combination antiretroviral therapy was associated with higher mean left ventricular posterior wall thickness and lower mean left ventricular wall stress Z-scores. There was no evidence of significant cardiac toxicity of perinatal combination antiretroviral therapy exposure in HEU children. Subclinical differences in left ventricular structure and function with specific in-utero antiretroviral exposures indicate the need for a longitudinal cardiac study in HEU children to assess long-term cardiac risk and cardiac monitoring recommendations.

Clear cell adenocarcinoma of the ovary associated with in utero diethylstilbestrol exposure: case report and clinical overview.

PubMed

Dasanu, Constantin A; Herzog, Thomas J

2009-01-01

Clear cell adenocarcinoma of the vagina and cervix were previously shown to be tumors occurring in female offspring exposed prenatally to diethylstilbestrol. This report describes the first clinical case of clear cell adenocarcinoma of the ovary linked to early diethylstilbestrol exposure in utero. A 45-year-old woman presented with a self-discovered lump in the lower abdominal quadrant. She underwent surgery and staging that revealed clear cell adenocarcinoma confined to the left ovary. Foci of high-grade squamous neoplastic proliferation, inflammation, and a paratubal cyst were also present on the pathology specimen. Medical records established unequivocally that the patient's mother received diethylstilbestrol therapy throughout the pregnancy. Our case is consistent with clear cell adenocarcinoma, probably related to diethylstilbestrol exposure in utero. It reinforces the need for continued vigilance in individuals prenatally exposed to this drug.

Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms.

PubMed

Rodgers, Kathryn M; Udesky, Julia O; Rudel, Ruthann A; Brody, Julia Green

2018-01-01

Many common environmental chemicals are mammary gland carcinogens in animal studies, activate relevant hormonal pathways, or enhance mammary gland susceptibility to carcinogenesis. Breast cancer's long latency and multifactorial etiology make evaluation of these chemicals in humans challenging. For chemicals previously identified as mammary gland toxicants, we evaluated epidemiologic studies published since our 2007 review. We assessed whether study designs captured relevant exposures and disease features suggested by toxicological and biological evidence of genotoxicity, endocrine disruption, tumor promotion, or disruption of mammary gland development. We systematically searched the PubMed database for articles with breast cancer outcomes published in 2006-2016 using terms for 134 environmental chemicals, sources, or biomarkers of exposure. We critically reviewed the articles. We identified 158 articles. Consistent with experimental evidence, a few key studies suggested higher risk for exposures during breast development to dichlorodiphenyltrichloroethane (DDT), dioxins, perfluorooctane-sulfonamide (PFOSA), and air pollution (risk estimates ranged from 2.14 to 5.0), and for occupational exposure to solvents and other mammary carcinogens, such as gasoline components (risk estimates ranged from 1.42 to 3.31). Notably, one 50-year cohort study captured exposure to DDT during several critical windows for breast development (in utero, adolescence, pregnancy) and when this chemical was still in use. Most other studies did not assess exposure during a biologically relevant window or specify the timing of exposure. Few studies considered genetic variation, but the Long Island Breast Cancer Study Project reported higher breast cancer risk for polycyclic aromatic hydrocarbons (PAHs) in women with certain genetic variations, especially in DNA repair genes. New studies that targeted toxicologically relevant chemicals and captured biological hypotheses about genetic variants or windows of breast susceptibility added to evidence of links between environmental chemicals and breast cancer. However, many biologically relevant chemicals, including current-use consumer product chemicals, have not been adequately studied in humans. Studies are challenged to reconstruct exposures that occurred decades before diagnosis or access biological samples stored that long. Other problems include measuring rapidly metabolized chemicals and evaluating exposure to mixtures. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

In utero and postnatal exposure to arsenic alters pulmonary structure and function

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

Lantz, R. Clark; Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ 85721; BIO5 Institute, University of Arizona, Tucson, AZ 85721

2009-02-15

In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airwaymore » reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 {mu}m in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.« less

Prenatal DDT exposure and child adiposity at age 12: The CHAMACOS study.

PubMed

Warner, Marcella; Ye, Morgan; Harley, Kim; Kogut, Katherine; Bradman, Asa; Eskenazi, Brenda

2017-11-01

Using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort study, we assessed the association of in utero exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenylethylene (DDE) with child adiposity at age 12. We included 240 children with o,p'-DDT, p,p'-DDT, and p,p'-DDE concentrations measured in maternal serum collected during pregnancy (ng/g lipid) and complete 12-year follow-up data. Age- and sex-specific body mass index (BMI) z-scores were calculated from CDC growth charts. Children with BMI z-scores ≥ 85th percentile were classified as overweight or obese. At 12 years, BMI z-score averaged 1.09 (±1.03) and 55.4% of children were overweight or obese. Prenatal DDT and DDE exposure was associated with several adiposity measures in boys but not girls. Among boys, 10-fold increases in prenatal DDT and DDE concentrations were associated with increased BMI z-score (o,p'-DDT, adj-β=0.37, 95% CI: 0.08, 0.65; p,p'-DDT, adj-β = 0.26, 95% CI: 0.03, 0.48; p,p'-DDE, adj-β = 0.31, 95% CI: 0.02, 0.59). Results for girls were nonsignificant. The difference by sex persisted after considering pubertal status. These results support the chemical obesogen hypothesis, that in utero exposure to DDT and DDE may increase risk of obesity in males later in life. Copyright © 2017. Published by Elsevier Inc.

Medical Toxicology and Public Health-Update on Research and Activities at the Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry : Environmental Exposures among Arctic Populations: The Maternal Organics Monitoring Study in Alaska.

PubMed

Anwar, Mehruba; Ridpath, Alison; Berner, James; Schier, Joshua G

2016-09-01

Evidence suggests that in-utero exposure to environmental chemicals, such as persistent organic pollutants (POPs), heavy metals, and radionuclides, that might bioaccumulate in the mother may increase a newborn's risk of adverse developmental, neurological, and immunologic effects. Chemical contamination of bodies of water and strong ocean currents worldwide can drive these chemicals from lower latitudes to Arctic waters where they accumulate in common traditional subsistence foods. In response to concerns of the people from Alaska of the effects of bio-accumulated chemicals on their children, the Maternal Organics Monitoring Study(MOMS) was developed. The objective of the study was to assess the risks and benefits associated with the population's subsistence diet. Data analysis of biological samples at the CDC's NCEH laboratory and maternal questionnaires is ongoing. Results will be provided to Alaska Native communities to help support public health actions and inform future interventions and research.

Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure

PubMed Central

Sinha-Hikim, Indrani; Shen, Ruoqing; Nzenwa, Ify; Gelfand, Robert; Mahata, Sushil K.

2015-01-01

This study investigates the molecular mechanisms by which minocycline, a second generation tetracycline, prevents cardiac myocyte death induced by in utero cocaine exposure. Timed mated pregnant Sprague-Dawley (SD) rats received one of the following treatments twice daily from embryonic (E) day 15–21 (E15–E21): (i) intraperitoneal (IP) injections of saline (control); (ii) IP injections of cocaine (15 mg/kg BW); and (iii) IP injections of cocaine + oral administration of 25 mg/kg BW of minocycline. Pups were killed on postnatal day 15 (P15). Additional pregnant dams received twice daily IP injections of cocaine (from E15–E21) + oral administration of a relatively higher (37.5 mg/kg BW) dose of minocycline. Minocycline treatment continued from E15 until the pups were sacrificed on P15. In utero cocaine exposure resulted in an increase in oxidative stress and fetal cardiac myocyte apoptosis through activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK)-mediated mitochondria-dependent apoptotic pathway. Continued minocycline treatment from E15 through P15 significantly prevented oxidative stress, kinase activation, perturbation of BAX/BCL-2 ratio, cytochrome c release, caspase activation, and attenuated fetal cardiac myocyte apoptosis after prenatal cocaine exposure. These results demonstrate in vivo cardioprotective effects of minocycline in preventing fetal cardiac myocyte death after prenatal cocaine exposure. Given its proven clinical safety and ability to cross the placental barrier and enter into the fetal circulation, minocycline may be an effective therapy for preventing cardiac consequences of in utero cocaine exposure. PMID:21424555

Molecular epidemiology of childhood leukemia with emphasis on chemical exposures

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

Buffler, P.A.; Smith, M.T.; Wood, S.

1996-12-31

Developing markets in the Pacific Basin depend heavily on the production and export of consumer goods. The generation of hazardous waste as a by-product of industrial production can be linked to adverse health outcomes, such as childhood leukemia, in ways that are presently unknown. In California, exposures resulting from hazardous waste disposal are of concern in the etiology of childhood cancer. Approximately 63% of the 57 hazardous waste sites that the U.S. Environmental Protection Agency (USEPA) included in the national priority list under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) statute were in the six-county San Francisco Baymore » area. This area includes California`s Silicon Valley, where a disproportionate majority of these sites are located. Although only one study links hazardous waste disposal to childhood leukemia evidence is accumulating that in utero and maternal pesticide exposures as well as chemical exposures during childhood are important in the etiology of childhood leukemia. This study investigates whether children with leukemia have common genetic changes, whether children with genetic changes experience common chemical exposures, and whether the occurrences of these genetic changes correspond to the same temporal sequence as exposure. The purpose of this paper is to describe the study design and report on the status of research activity. 10 refs., 1 fig., 3 tabs.« less

Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal.

PubMed

Donovan, L E; Cundy, T

2015-03-01

The idea that exposure to hyperglycaemia in utero is an important factor in the development of obesity and diabetes in the offspring has become entrenched as popular belief. To appraise the literature supporting this hypothesis in the light of recent studies that have clarified the main drivers of obesity in children and adolescents. A review of published evidence from animal studies, human observational studies, systematic reviews and experimental trials that address the impact of diabetes (Types 1 and 2, genetic or gestational) on the future risk of obesity and/or glucose intolerance in the offspring. Some animal studies support a relationship between exposure to hyperglycaemia in utero and future development of obesity and diabetes, but the results are inconsistent. Most of the human studies claiming to show a relationship have not taken into account important known confounders, such as maternal and paternal BMI. Evidence supporting a dose-response relationship between maternal hyperglycaemia exposure and obesity and diabetes in the offspring is weak, and there is no convincing evidence that treating gestational diabetes reduces the later risk of offspring obesity or glucose intolerance. Exposure to hyperglycaemia in utero has minimal direct effect on the later risk of obesity and Type 2 diabetes. The increased risk of obesity in the offspring of women with Type 2 or gestational diabetes can be explained by confounding factors, such as parental obesity. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

In utero methanesulfonyl fluoride differentially affects learning and maze performance in the absence of long-lasting cholinergic changes in the adult rat.

PubMed

Carcoba, Luis M; Santiago, Miguel; Moss, Donald E; Cabeza, Rafael

2008-02-01

There is increasing evidence that acetylcholinesterase (AChE) may have various specific developmental roles in brain development. Nevertheless, specific effects of AChE inhibition during early brain development have not been adequately described. Therefore, methanesulfonyl fluoride (MSF), an irreversible AChE inhibitor that shows high selectivity for the CNS was used to produce AChE inhibition in utero to study subsequent adult behaviors, sleep, and cholinergic markers. Rats exposed to MSF in utero showed a deficit in spatial learning tasks using appetitive motivation but, surprisingly, they performed equally well or better than controls when aversive motivation was used. One hypothesis was that MSF treatment in utero affected the response to stress. Tests of anxiety however showed no differences in basal levels of anxiety. Studies of sleep behavior, however, indicated a higher level of REM sleep which is only seen during the light phase of male rats exposed to MSF in utero as compared to controls. No differences in cholinergic markers in the brains of adults were found except that females exposed to MSF in utero had a higher level of ChAT activity in the synaptosomal fraction of the hippocampus. Even so, whether cholinergic alterations accompany the in utero MSF exposure remains to be determined. The failure to find widespread changes in cholinergic markers in the adult brains suggests changes in behaviors should be further investigated by testing the participation of postsynaptic mechanisms, measuring of cholinergic markers during earlier development periods and the possible participation of other neurotransmitter systems to clearly reveal the role of the cholinergic system following in utero MSF exposure.

In utero methanesulfonyl fluoride differentially affects learning and maze performance in the absence of long-lasting cholinergic changes in the adult rat

PubMed Central

Carcoba, Luis M .; Santiago, Miguel; Moss, Donald E.; Cabeza, Rafael

2008-01-01

There is increasing evidence that acetylcholinesterase (AChE) may have various specific developmental roles in brain development. Nevertheless, specific effects of AChE inhibition during early brain development have not been adequately described. Therefore, methanesulfonyl fluoride (MSF), an irreversible AChE inhibitor that shows high selectivity for the CNS was used to produce AChE inhibition in utero to study subsequent adult behaviors, sleep, and cholinergic markers. Rats exposed to MSF in utero showed a deficit in spatial learning tasks using appetitive motivation but, surprisingly, they performed equally well or better than controls when aversive motivation was used. One hypothesis was that MSF treatment in utero affected the response to stress. Tests of anxiety however showed no differences in basal levels of anxiety. Studies of sleep behavior, however, indicated a higher level of REM sleep which is only seen during the light phase of male rats exposed to MSF in utero as compared to controls. No differences in cholinergic markers in the brains of adults were found except that females exposed to MSF in utero had a higher level of ChAT activity in the synaptosomal fraction of the hippocampus. Even so, whether cholinergic alterations accompany the in utero MSF exposure remains to be determined. The failure to find widespread changes in cholinergic markers in the adult brains suggests changes in behaviors should be further investigated by testing the participation of postsynaptic mechanisms, measuring of cholinergic markers during earlier development periods and the possible participation of other neurotransmitter systems to clearly reveal the role of the cholinergic system following in utero MSF exposure. PMID:17920111

The educational impact of shocks in utero: Evidence from Rwanda.

PubMed

Bundervoet, Tom; Fransen, Sonja

2018-05-01

Research on the impact of violence and conflict on education typically focuses on exposure among a cohort of school-aged children. In line with the fetal origins hypothesis, this paper studies the long-run effect of exposure to adverse maternal health shocks while still in the womb. Exploiting the sudden and discrete nature of the Rwandan genocide and an identification strategy based on temporal and spatial variation, we find that the cohort in utero during the genocide reported on average 0.3 fewer years of schooling in the 2012 Rwanda. Population and Housing Census and was 8% points less likely to finish primary school relative to the cohort in utero just a couple of months later. Copyright © 2018 Elsevier B.V. All rights reserved.

Exposure to a novel feedstuff by goat dams during pregnancy and lactation versus pregnancy alone does not further improve post-weaning acceptance of this feedstuff by their kids.

PubMed

Vu Hai, Phan; Schonewille, J Thomas; Dam Van, Tien; Everts, Henk; Hendriks, Wouter H

2016-04-01

Previous experiments demonstrated the existence of in utero learning in goats. However, in contrast to other animal species, in goats there is no information about the potential of flavour transmission from maternal feed to goat kids during lactation. The aim of the current study was to assess the role of post-natal exposure of Chromonaela odorata leaf meal (COLM) in relation to the preferences to this feedstuff by goat kids after weaning. It was hypothesised that exposure of COLM to the dams during both pregnancy and lactation versus pregnancy alone, additionally affects post-weaning intake of COLM by their offspring. Consumption of COLM by the goat kids was similar during the first week post-weaning for all treatments. However, after 4 weeks the intake of COLM was at least 1.8 times greater when kids were exposed to COLM during pregnancy whereas it remained virtually unchanged when kids were exposed to COLM during lactation only. The increase in COLM consumption was in line with the observations on latency to eat and meal size. Transmission of feeding behaviour from goat dams to offspring does not occur during lactation. However, the concept of in utero learning in goats was confirmed. © 2015 Society of Chemical Industry.

The Intrauterine and Nursing Period Is a Window of Susceptibility for Development of Obesity and Intestinal Tumorigenesis by a High Fat Diet in Min/+ Mice as Adults

PubMed Central

Ngo, Ha Thi; Hetland, Ragna Bogen; Steffensen, Inger-Lise

2015-01-01

We studied how obesogenic conditions during various life periods affected obesity and intestinal tumorigenesis in adult C57BL/6J-Min (multiple intestinal neoplasia)/+ mice. The mice were given a 10% fat diet throughout life (negative control) or a 45% fat diet in utero, during nursing, during both in utero and nursing, during adult life, or during their whole life-span, and terminated at 11 weeks for tumorigenesis (Min/+) or 23 weeks for obesogenic effect (wild-type). Body weight at 11 weeks was increased after a 45% fat diet during nursing, during both in utero and nursing, and throughout life, but had normalized at 23 weeks. In the glucose tolerance test, the early exposure to a 45% fat diet in utero, during nursing, or during both in utero and nursing, did not affect blood glucose, whereas a 45% fat diet given to adults or throughout life did. However, a 45% fat diet during nursing or during in utero and nursing increased the number of small intestinal tumors. So did exposures to a 45% fat diet in adult life or throughout life, but without increasing the tumor numbers further. The intrauterine and nursing period is a window of susceptibility for dietary fat-induced obesity and intestinal tumor development. PMID:25874125

Similar causes of various reproductive disorders in early life.

PubMed

Svechnikov, Konstantin; Stukenborg, Jan-Bernd; Savchuck, Iuliia; Söder, Olle

2014-01-01

During the past few decades, scientific evidence has been accumulated concerning the possible adverse effects of the exposure to environmental chemicals on the well-being of wildlife and human populations. One large and growing group of such compounds of anthropogenic or natural origin is referred to as endocrine-disrupting chemicals (EDCs), due to their deleterious action on the endocrine system. This concern was first focused on the control of reproductive function particularly in males, but has later been expanded to include all possible endocrine functions. The present review describes the underlying physiology behind the cascade of developmental events that occur during sexual differentiation of males and the specific role of androgen in the masculinization process and proper organogenesis of the external male genitalia. The impact of the genetic background, environmental exposures and lifestyle factors in the etiology of hypospadias, cryptorchidism and testicular cancer are reviewed and the possible role of EDCs in the development of these reproductive disorders is discussed critically. Finally, the possible direct and programming effects of exposures in utero to widely use therapeutic compounds, environmental estrogens and other chemicals on the incidence of reproductive abnormalities and poor semen quality in humans are also highlighted.

In Utero Oxcarbazepine Exposure and Neonatal Abstinence Syndrome: Case Report and Brief Review of the Literature.

PubMed

Chen, Chao-Yang; Li, Xing; Ma, Ling-Yue; Wu, Peng-Hui; Zhou, Ying; Feng, Qi; Cui, Yi-Min

2017-07-01

Oxcarbazepine is a second-generation antiepileptic drug that is used to treat partial seizures. Although it has been increasingly used in pregnant women, its fetal safety has not been fully validated. We describe a 12-hour-old neonate who developed neonatal abstinence syndrome (NAS) after intrauterine exposure to oxcarbazepine. The neonate was born via cesarean section to a mother who took oxcarbazepine 300 mg/day for treatment of seizures throughout her pregnancy. Approximately 12 hours after birth, the infant developed paroxysmal jitter, which mainly presented as increased excitability, irritability, limb shaking, and increased muscle tone. These symptoms resolved by day 9 of life. Although NAS occurs most often after in utero exposure to opioids, exposure to other drugs during pregnancy may contribute to a small proportion of NAS cases. To our knowledge, this is the second case report of oxcarbazepine-induced NAS. Pregnant women with epilepsy should weigh the pros and cons of continuing oxcarbazepine during their pregnancy when they are prescribed this drug. For infants with in utero oxcarbazepine exposure, comprehensive assessments and examinations are necessary for screening oxcarbazepine-induced NAS. © 2017 The Authors. Pharmacotherapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.

Effects of fetal microwave radiation exposure on offspring behavior in mice

PubMed Central

Zhang, Yanchun; Li, Zhihui; Gao, Yan; Zhang, Chenggang

2015-01-01

Abstract The recent rapid development of electronic communication techniques is resulting in a marked increase in exposure of humans to electromagnetic fields (EMFs). This has raised public concerns about the health hazards of long-term environmental EMF exposure for fetuses and children. Some studies have suggested EMF exposure in children could induce nervous system disorders. However, gender-dependent effects of microwave radiation exposure on cognitive dysfunction have not previously been reported. Here we investigated whether in utero exposure to 9.417-GHz microwave throughout gestation (Days 3.5–18) affected behavior, using the open field test (OFT), elevated-plus maze (EPM), tail suspension test (TST), forced swimming test (FST) and Morris water maze (MWM). We found that mice showed less movement in the center of an open field (using the OFT) and in an open arm (using the EPM) after in utero exposure to 9.417-GHz radiation, which suggested that the mice had increased anxiety-related behavior. Mice demonstrated reduced immobility in TST and FST after in utero exposure to 9.417-GHz radiation, which suggested that the mice had decreased depression-related behavior. From the MWM test, we observed that male offspring demonstrated decreased learning and memory, while females were not affected in learning and memory, which suggested that microwaves had gender-dependent effects. In summary, we have provided the first experimental evidence of microwaves inducing gender-dependent effects. PMID:25359903

The herbicide linuron reduces testosterone production from the fetal rat testis both in utero and in vitro

EPA Science Inventory

In utero exposure to linuron, an urea-based herbicide, results in a pattern of malformations of androgen-dependent tissues in adult male rat offspring resembling that produced by some phthalate esters which are known to decrease fetal testosterone production. This study investiga...

THE HERBICIDE LINURON REDUCES FETAL TESTOSTERONE PRODUCTION DURING BOTH IN UTERO AND IN VITRO EXPOSURES

EPA Science Inventory

Linuron, a urea-based herbicide, is a weak antagonist for the androgen receptor. Previous studies in our lab have shown that in utero exposureresults in malformations of androgen dependent tissues in adult male offspring. The pattern of malformations, however, differs somewha...

Fetal Onset of Aberrant Gene Expression Relevant to Pulmonary Carcinogenesis in Lung Adenocarcinoma Development Induced by In Utero Arsenic Exposure

PubMed Central

Shen, Jun; Liu, Jie; Xie, Yaxiong; Diwan, Bhalchandra A.; Waalkes, Michael P.

2009-01-01

Arsenic is a human pulmonary carcinogen. Our work indicates that in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in drinking water from days 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-α (ER-α) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2, and the steroid metabolism genes 17-β-hydroxysteroid dehydrogenase type 5 and aromatase. The insulin growth factor system, which can be influenced by ER and has been implicated in the pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. in utero arsenic exposure also induced overexpression of α-fetoprotein, epidermal growth factor receptor, L-myc, and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed widespread, intense nuclear ER-α expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-α expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-α activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programing in the lung leading eventually to lung tumor formation much later in adulthood. PMID:17077188

Fetal onset of aberrant gene expression relevant to pulmonary carcinogenesis in lung adenocarcinoma development induced by in utero arsenic exposure.

PubMed

Shen, Jun; Liu, Jie; Xie, Yaxiong; Diwan, Bhalchandra A; Waalkes, Michael P

2007-02-01

Arsenic is a human pulmonary carcinogen. Our work indicates that in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in drinking water from days 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-alpha (ER-alpha) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2, and the steroid metabolism genes 17-beta-hydroxysteroid dehydrogenase type 5 and aromatase. The insulin growth factor system, which can be influenced by ER and has been implicated in the pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. In utero arsenic exposure also induced overexpression of alpha-fetoprotein, epidermal growth factor receptor, L-myc, and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed widespread, intense nuclear ER-alpha expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-alpha expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-alpha activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programing in the lung leading eventually to lung tumor formation much later in adulthood.

Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure.

PubMed

Sinha-Hikim, Indrani; Shen, Ruoqing; Nzenwa, Ify; Gelfand, Robert; Mahata, Sushil K; Sinha-Hikim, Amiya P

2011-06-01

This study investigates the molecular mechanisms by which minocycline, a second generation tetracycline, prevents cardiac myocyte death induced by in utero cocaine exposure. Timed mated pregnant Sprague-Dawley (SD) rats received one of the following treatments twice daily from embryonic (E) day 15-21 (E15-E21): (i) intraperitoneal (IP) injections of saline (control); (ii) IP injections of cocaine (15 mg/kg BW); and (iii) IP injections of cocaine + oral administration of 25 mg/kg BW of minocycline. Pups were killed on postnatal day 15 (P15). Additional pregnant dams received twice daily IP injections of cocaine (from E15-E21) + oral administration of a relatively higher (37.5 mg/kg BW) dose of minocycline. Minocycline treatment continued from E15 until the pups were sacrificed on P15. In utero cocaine exposure resulted in an increase in oxidative stress and fetal cardiac myocyte apoptosis through activation of c-Jun-NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK)-mediated mitochondria-dependent apoptotic pathway. Continued minocycline treatment from E15 through P15 significantly prevented oxidative stress, kinase activation, perturbation of BAX/BCL-2 ratio, cytochrome c release, caspase activation, and attenuated fetal cardiac myocyte apoptosis after prenatal cocaine exposure. These results demonstrate in vivo cardioprotective effects of minocycline in preventing fetal cardiac myocyte death after prenatal cocaine exposure. Given its proven clinical safety and ability to cross the placental barrier and enter into the fetal circulation, minocycline may be an effective therapy for preventing cardiac consequences of in utero cocaine exposure.

Prevalence of Congenital Anomalies in Infants with in Utero Exposure to Antiretrovirals

PubMed Central

KNAPP, KATHERINE M.; BROGLY, SUSAN B.; MUENZ, DANIEL G.; SPIEGEL, HANS M.; CONWAY, DANIEL H.; SCOTT, GWENDOLYN B.; TALBOT, JEFFREY T.; SHAPIRO, DAVID E.; READ, JENNIFER S.

2011-01-01

Background While use of efficacious interventions, including antiretrovirals (ARVs), has reduced dramatically the rate of mother-to-child transmission (MTCT) of HIV, the safety of in utero ARV exposure remains of concern. Methods Data regarding 1112 infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) protocol P1025 born between 2002 and 2007 were analyzed for this study. Congenital anomalies were classified based on the Metropolitan Atlanta Congenital Defects Program (MACDP) guidelines. Associations between congenital anomalies and timing of first in utero exposure to ARVs were evaluated by logistic regression analysis. Results 61 of the 1112 infants had congenital anomalies identified and confirmed, resulting in a prevalence of 5.49/100 live births (95%CI: 4.22–6.99). Among the 80 anomalies identified, the organ systems involved included: cardiovascular (n=33), musculoskeletal (n=15), renal (n=9), genitourinary (n=6), craniofacial (n=4), and central nervous system (n=2). First trimester exposure to efavirenz was associated with a significantly increased risk of congenital anomalies (OR 2.84, 95%CI: 1.13–7.16). No significant associations were observed between exposure to other individual ARVs or classes of ARVs started at any time during pregnancy and infant congenital anomalies. Conclusions The observed rate of congenital anomalies in this cohort is higher than previously reported for the general population, but is consistent with rates observed in other recent studies of children born to HIV-infected women. Cardiovascular anomalies occurred most frequently. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero exposure to ARVs and congenital anomalies were identified. PMID:21983213

Associations of maternal exposure to triclosan, parabens, and other phenols with prenatal maternal and neonatal thyroid hormone levels.

PubMed

Berger, Kimberly; Gunier, Robert B; Chevrier, Jonathan; Calafat, Antonia M; Ye, Xiaoyun; Eskenazi, Brenda; Harley, Kim G

2018-05-24

Environmental phenols and parabens are commonly used in personal care products and other consumer products and human exposure to these chemicals is widespread. Although human and animal studies suggest an association between exposure to phenols and parabens and thyroid hormone levels, few studies have investigated the association of in utero exposure to these chemicals and thyroid hormones in pregnant women and their neonates. We measured four environmental phenols (triclosan, benzophenone-3, and 2,4- and 2,5-dichlorophenol), and three parabens (methyl-, propyl-, and butyl paraben) in urine collected from mothers at two time points during pregnancy as part of the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) study. We measured free thyroxine (T4), total T4, and thyroid-stimulating hormone (TSH) in serum of the pregnant women (N = 454) and TSH in their neonates (N = 365). We examined potential confounding by a large number of additional chemical exposures and used Bayesian Model Averaging (BMA) to select the most influential chemicals to include in regression models. We observed negative associations of prenatal urinary concentrations of propyl paraben and maternal TSH (β for two-fold increase = -3.26%, 95% CI: -5.55, -0.90) and negative associations of 2,4-dichlorophenol and maternal free T4 (β for two-fold increase = -0.05, 95% CI: -0.08, -0.02), after controlling for other chemical exposures. We observed negative associations of triclosan with maternal total T4 after controlling for demographic variables, but this association became non-significant after controlling for other chemicals (β for two-fold increase = -0.05, 95% CI: -0.11, 0.00). We found evidence that environmental phenols and parabens are associated with lower TSH and free T4 in pregnant women after controlling for related chemical exposures. Copyright © 2018 Elsevier Inc. All rights reserved.

Association of Intrauterine and Early-Life Exposures With Age at Menopause in the Sister Study

PubMed Central

Steiner, Anne Z.; D'Aloisio, Aimee A.; DeRoo, Lisa A.; Sandler, Dale P.; Baird, Donna D.

2010-01-01

Oocytes are formed in utero; menopause occurs when the oocyte pool is depleted. The authors hypothesized that early-life events could affect the number of a woman's oocytes and determine age at menopause. To test their hypothesis, the authors conducted a secondary analysis of baseline data from 22,165 participants in the Sister Study (2003–2007) who were aged 35–59 years at enrollment. To estimate the association between early-life events and age at natural menopause, the authors used Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals, adjusting for current age, race/ethnicity, education, childhood family income, and smoking history. Earlier menopause was associated with in-utero diethylstilbestrol exposure (hazard ratio (HR) = 1.45, 95% confidence interval (CI): 1.27, 1.65). Suggestive associations included maternal prepregnancy diabetes (HR = 1.33, 95% CI: 0.89, 1.98) and low birth weight (HR = 1.09, 95% CI: 0.99, 1.20). Having a mother aged 35 years or older at birth appeared to be associated with a later age at menopause (HR = 0.95, 95% CI: 0.89, 1.01). Birth order, in-utero smoke exposure, and having been breastfed were not related to age at menopause. In-utero and perinatal events may subsequently influence age at menopause. PMID:20534821

In utero and acute exposure to benzene: investigation of DNA double-strand breaks and DNA recombination in mice.

PubMed

Lau, Annette; Belanger, Christine Lea; Winn, Louise M

2009-05-31

Benzene, a ubiquitous pollutant, has been identified as a human leukemogen and early exposure to environmental carcinogens such as benzene has been linked to childhood leukemia. It is known that genotoxic agents can increase the frequency of DNA double-strand breaks (DSBs), which can initiate DNA recombinational repair mechanisms. In this study we investigated the induction of micronuclei, the formation of gamma-H2A.X as a marker of DNA DSBs, and the induction of somatic DNA recombination events in hematopoietic tissue from pKZ1 transgenic mice exposed acutely or in utero to benzene. Adult male C57Bl/6N mice were treated with a single i.p. injection of benzene, and timed-pregnant females pKZ1 were treated with daily i.p. injections of 200 mg/kg or 400 mg/kg benzene through gestational days 7-15. Acute exposure to 400 mg/kg benzene resulted in a statistically significant increase in the percentage of micronucleated cells in adult male bone marrow cells and in fetal liver and post-natal day 9 bone marrow cells of mice exposed in utero. Immunoblotting techniques did not detect benzene-induced increases in the formation of gamma-H2A.X in bone marrow cells of adult male mice and in maternal bone marrow, fetal liver, and post-natal bone marrow cells after specific time-point exposures. Finally, no recombination events were detected in adult pKZ1 mouse tissue; however, in post-natal day 9 pups in utero exposure to 400 mg/kg of benzene caused a trend towards increasing recombination frequency although this did not reach statistical significance. These results demonstrate that in utero exposure increases the frequency of micronuclei and DNA recombination events in hematopoietic tissue of fetal and post-natal mice and may be an initiating event in the etiology of childhood leukemias. Further investigations into different types of DNA damage and repair pathways are warranted to fully elucidate the role of genotoxic mechanisms in the etiology of benzene-induced childhood leukemias.

Manipulation of pre and postnatal androgen environments and anogenital distance in rats.

PubMed

Kita, Diogo H; Meyer, Katlyn B; Venturelli, Amanda C; Adams, Rafaella; Machado, Daria L B; Morais, Rosana N; Swan, Shanna H; Gennings, Chris; Martino-Andrade, Anderson J

2016-08-10

We examined the anogenital distance (AGD) plasticity in rats through the manipulation of the androgen environment in utero and during puberty. Dams were treated from gestation days 13-20 with vehicle, flutamide (20mg/kg/day), di-(2-ethylhexyl) phthalate (DEHP, 750mg/kg/day), or testosterone (1.0mg/kg/day). After weaning, male pups were randomly assigned to one of four postnatal groups, which received the same treatments given prenatally. Sixteen treatment groups were established based on the combination of pre- and postnatal exposures. The postnatal treatments were conducted from postnatal days 23-53. In utero flutamide and DEHP exposure significantly shortened male AGD, although this effect was more pronounced in flutamide-exposed rats. Postnatal flutamide, DEHP, and testosterone induced slight but significant reductions in male AGD. Our study indicates that AGD is a stable anatomical landmark that reflects the androgen action in utero, although it can also be slightly responsive to changes in the androgen environment following pubertal exposure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In utero exposure to the Korean War and its long-term effects on socioeconomic and health outcomes.

PubMed

Lee, Chulhee

2014-01-01

Prenatal exposure to the disruptions caused by the Korean War (1950-1953) negatively affected the individual socioeconomic and health outcomes at older ages. The educational attainment, labor market performance, and other socioeconomic outcomes of the subjects of the 1951 birth cohort, who were in utero during the worst time of the war, were significantly lower in 1990 and in 2000. The results of difference-in-difference estimations suggest that the magnitude of the negative cohort effect is significantly larger for individuals who were more seriously traumatized by the war. Whereas the 1950 male birth cohort exhibited significantly higher disability and mortality rates at older age, the health outcomes of females are unaffected by the war. Different aspects of human capital (e.g., health and cognitive skills) were impaired by in utero exposure to the war, depending on the stage of pregnancy when the negative shocks were experienced. Copyright © 2013 Elsevier B.V. All rights reserved.

In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver.

PubMed

Drake, Amanda J; O'Shaughnessy, Peter J; Bhattacharya, Siladitya; Monteiro, Ana; Kerrigan, David; Goetz, Sven; Raab, Andrea; Rhind, Stewart M; Sinclair, Kevin D; Meharg, Andrew A; Feldmann, Jörg; Fowler, Paul A

2015-01-29

Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown. In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses. In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1). Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.

In utero exposure to fine particulate matter results in an altered neuroimmune phenotype in adult mice.

PubMed

Kulas, Joshua A; Hettwer, Jordan V; Sohrabi, Mona; Melvin, Justine E; Manocha, Gunjan D; Puig, Kendra L; Gorr, Matthew W; Tanwar, Vineeta; McDonald, Michael P; Wold, Loren E; Combs, Colin K

2018-05-22

Environmental exposure to air pollution has been linked to a number of health problems including organ rejection, lung damage and inflammation. While the deleterious effects of air pollution in adult animals are well documented, the long-term consequences of particulate matter (PM) exposure during animal development are uncertain. In this study we tested the hypothesis that environmental exposure to PM 2.5 μm in diameter in utero promotes long term inflammation and neurodegeneration. We evaluated the behavior of PM exposed animals using several tests and observed deficits in spatial memory without robust changes in anxiety-like behavior. We then examined how this affects the brains of adult animals by examining proteins implicated in neurodegeneration, synapse formation and inflammation by western blot, ELISA and immunohistochemistry. These tests revealed significantly increased levels of COX2 protein in PM2.5 exposed animal brains in addition to changes in synaptophysin and Arg1 proteins. Exposure to PM2.5 also increased the immunoreactivity for GFAP, a marker of activated astrocytes. Cytokine concentrations in the brain and spleen were also altered by PM2.5 exposure. These findings indicate that in utero exposure to particulate matter has long term consequences which may affect the development of both the brain and the immune system in addition to promoting inflammatory change in adult animals. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model.

PubMed

Kaminen-Ahola, Nina; Ahola, Arttu; Maga, Murat; Mallitt, Kylie-Ann; Fahey, Paul; Cox, Timothy C; Whitelaw, Emma; Chong, Suyinn

2010-01-15

Recent studies have shown that exposure to some nutritional supplements and chemicals in utero can affect the epigenome of the developing mouse embryo, resulting in adult disease. Our hypothesis is that epigenetics is also involved in the gestational programming of adult phenotype by alcohol. We have developed a model of gestational ethanol exposure in the mouse based on maternal ad libitum ingestion of 10% (v/v) ethanol between gestational days 0.5-8.5 and observed changes in the expression of an epigenetically-sensitive allele, Agouti viable yellow (A(vy)), in the offspring. We found that exposure to ethanol increases the probability of transcriptional silencing at this locus, resulting in more mice with an agouti-colored coat. As expected, transcriptional silencing correlated with hypermethylation at A(vy). This demonstrates, for the first time, that ethanol can affect adult phenotype by altering the epigenotype of the early embryo. Interestingly, we also detected postnatal growth restriction and craniofacial dysmorphology reminiscent of fetal alcohol syndrome, in congenic a/a siblings of the A(vy) mice. These findings suggest that moderate ethanol exposure in utero is capable of inducing changes in the expression of genes other than A(vy), a conclusion supported by our genome-wide analysis of gene expression in these mice. In addition, offspring of female mice given free access to 10% (v/v) ethanol for four days per week for ten weeks prior to conception also showed increased transcriptional silencing of the A(vy) allele. Our work raises the possibility of a role for epigenetics in the etiology of fetal alcohol spectrum disorders, and it provides a mouse model that will be a useful resource in the continued efforts to understand the consequences of gestational alcohol exposure at the molecular level.

ATRAZINE INCREASES DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY TUMOR INCIDENCE IN LONG EVANS OFFSPRING EXPOSED IN UTERO

EPA Science Inventory

ATRAZINE INCREASES DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY TUMOR INCIDENCE IN LONG EVANS OFFSPRING EXPOSED IN UTERO.

SE Fenton and CC Davis

Reproductive Toxicology Division, NHEERL, ORD, USEPA, Durham, NC, USA

Recently, we found that ATR exposure during ma...

Health effects of inhaled gasoline engine emissions.

PubMed

McDonald, Jacob D; Reed, Matthew D; Campen, Matthew J; Barrett, Edward G; Seagrave, JeanClare; Mauderly, Joe L

2007-01-01

Despite their prevalence in the environment, and the myriad studies that have shown associations between morbidity or mortality with proximity to roadways (proxy for motor vehicle exposures), relatively little is known about the toxicity of gasoline engine emissions (GEE). We review the studies conducted on GEE to date, and summarize the findings from each of these studies. While there have been several studies, most of the studies were conducted prior to 1980 and thus were not conducted with contemporary engines, fuels, and driving cycles. In addition, many of the biological assays conducted during those studies did not include many of the assays that are conducted on contemporary inhalation exposures to air pollutants, including cardiovascular responses and others. None of the exposures from these earlier studies were characterized at the level of detail that would be considered adequate today. A recent GEE study was conducted as part of the National Environmental Respiratory Center (www.nercenter.org). In this study several in-use mid-mileage General Motors (Chevrolet S-10) vehicles were purchased and utilized for inhalation exposures. An exposure protocol was developed where engines were operated with a repeating California Unified Driving Cycle with one cold start per day. Two separate engines were used to provide two cold starts over a 6-h inhalation period. The exposure atmospheres were characterized in detail, including detailed chemical and physical analysis of the gas, vapor, and particle phase. Multiple rodent biological models were studied, including general toxicity and inflammation (e.g., serum chemistry, lung lavage cell counts/differentials, cytokine/chemokine analysis, histopathology), asthma (adult and in utero exposures with pulmonary function and biochemical analysis), cardiovascular effects (biochemical and electrocardiograph changes in susceptible rodent models), and susceptibility to infection (Pseudomonas bacteria challenge). GEE resulted in significant biological effects for upregulation of MIP-2, clearance of Pseudomonas bacteria, development of allergic response after in utero exposure, and cardiovascular indicators of vasoconstriction, oxidant stress, and damage.

Environmental toxicants: hidden players on the reproductive stage.

PubMed

Giudice, Linda C

2016-09-15

A growing body of evidence suggests that environmental contaminants, including natural gas, endocrine-disrupting chemicals, and air pollution, are posing major threats to human reproductive health. Many chemicals are in commonly used personal care products, linings of food containers, pesticides, and toys, as well as in discarded electronic waste, textile treatments, and indoor and outdoor air and soil. They travel across borders through trade, food, wind, and water. Reproductive and other health effects can be incurred by exposures in utero, in the neonatal or adolescent periods, or in adulthood and can have transgenerational effects. Most chemicals do not undergo the level of evaluation for harm that pharmaceuticals, e.g., do, and they are rarely seen or seriously considered as a danger to human health. Herein, the burden of exposures, challenges in assessing data and populations at risk, models for evaluating harm, and mechanisms of effects are briefly reviewed, ending with a call to action for reproductive health care professionals to advocate for further research, education, and chemical policy reform for the health of this and future generations. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life.

PubMed

Kaushal, Akhilesh; Zhang, Hongmei; Karmaus, Wilfried J J; Everson, Todd M; Marsit, Carmen J; Karagas, Margaret R; Tsai, Shih-Fen; Wen, Hui-Ju; Wang, Shu-Li

2017-05-30

In utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life. Genome-wide DNA methylation in cord blood from 64 subjects in the Taiwanese maternal infant and birth cohort was analyzed. Robust regressions were applied to assess the association of DNA methylation with in utero arsenic exposure. Multiple testing was adjusted by controlling false discovery rate (FDR) of 0.05. The DAVID bioinformatics tool was implemented for functional annotation analyses on the detected CpGs. The identified CpGs were further tested in an independent cohort. For the CpGs replicated in the independent cohort, linear mixed models were applied to assess the association of DNA methylation with low-density lipoprotein (LDL) at different ages (2, 5, 8, 11 and 14 years). In total, 579 out of 385,183 CpGs were identified after adjusting for multiple testing (FDR = 0.05), of which ~60% were positively associated with arsenic exposure. Functional annotation analysis on these CpGs detected 17 KEGG pathways (FDR = 0.05) including pathways for cardiovascular diseases (CVD) and diabetes mellitus. In the independent cohort, about 46% (252 out of 553 CpGs) of the identified CpGs showed associations consistent with those in the study cohort. In total, 11 CpGs replicated in the independent cohort were in the pathways related to CVD and diabetes mellitus. Via longitudinal analyses, we found at 5 out of the 11 CpGs methylation was associated with LDL over time and interactions between DNA methylation and time were observed at 4 of the 5 CpGs, cg25189764 (coeff = 0.157, p-value = 0.047), cg04986899 (coeff. For interaction [coeff.int] = 0.030, p-value = 0.024), cg04903360 (coeff.int = 0.026, p-value = 0.032), cg08198265 (coeff.int = -0.063, p-value = 0.0021), cg10473311 (coeff.int = -0.021, p-value = 0.027). In utero arsenic exposure was associated with cord blood DNA methylation at various CpGs. The identified CpGs may help determine pathological epigenetic mechanisms linked to in utero arsenic exposure. Five CpGs (cg25189764, cg04986899, cg04903360, cg08198265 and cg10473311) may serve as epigenetic markers for changes in LDL later in life.

Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants.

PubMed

Rice, Mabel L; Zeldow, Bret; Siberry, George K; Purswani, Murli; Malee, Kathleen; Hoffman, Howard J; Frederick, Toni; Buchanan, Ashley; Sirois, Patricia A; Allison, Susannah M; Williams, Paige L

2013-10-01

Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected, particularly for neurodevelopmental problems, such as language delays. We studied late language emergence (LLE) in HIV-exposed but uninfected children enrolled in a US-based prospective cohort study. LLE was defined as a caregiver-reported score ≤10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for 1-year olds and as ≥1 standard deviation below age-specific norms for the Ages and Stages Questionnaire for 2-year olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal and environmental characteristics. 1129 language assessments were conducted among 792 1- and 2-year-old children (50% male, 62% black and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of 1-year olds and 23% of 2-year olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed 1-year olds, increased odds of LLE was observed for those exposed to atazanavir (adjusted odds ratio = 1.83, 95% confidence interval: 1.10-3.04), particularly after the first trimester (adjusted odds ratio = 3.56, P = 0.001), compared with atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among 2-year olds. In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in 1-year-old infants with atazanavir exposure.

In utero exposure to valproic acid and autism--a current review of clinical and animal studies.

PubMed

Roullet, Florence I; Lai, Jonathan K Y; Foster, Jane A

2013-01-01

Valproic acid (VPA) is both an anti-convulsant and a mood stabilizer. Clinical studies over the past 40 years have shown that exposure to VPA in utero is associated with birth defects, cognitive deficits, and increased risk of autism. Two recent FDA warnings related to use of VPA in pregnancy emphasize the need to reevaluate its use clinically during child-bearing years. The emerging clinical evidence showing a link between VPA exposure and both cognitive function and risk of autism brings to the forefront the importance of understanding how VPA exposure influences neurodevelopment. In the past 10 years, animal studies have investigated anatomical, behavioral, molecular, and physiological outcomes related to in utero VPA exposure. Behavioral studies show that VPA exposure in both rats and mice leads to autistic-like behaviors in the offspring, including social behavior deficits, increased repetitive behaviors, and deficits in communication. Based on this work VPA maternal challenge in rodents has been proposed as an animal model to study autism. This model has both face and construct validity; however, like all animal models there are limitations to its translation to the clinical setting. Here we provide a review of clinical studies that examined pregnancy outcomes of VPA use as well as the related animal studies. Copyright © 2013 Elsevier Inc. All rights reserved.

Fetal Phthalate Screen: Assessment of Several Phthalate Esters (PE) on Fetal Rodent Testosterone (T) Production and Gene Expressionfollowing In Utero Exposure

EPA Science Inventory

PE are a large family of compounds used in a wide array of products from medical tubing to pharmaceuticals to cables. Studies have shown that in utero treatment with PE such as diethyl hexyl phthalate (DEHP) during the critical period of fetal reproductive development produced ma...

Fetal Phthalate Screen: Assessment of Several Phthalate Esters on Fetal Rodent Testosterone Production and Gene Expression Following In Utero Exposure

EPA Science Inventory

Phthalate esters(PE) are a large family of compounds used in a wide array of common products from medical tubing to pharmaceuticals to cables, and wall/floor coverings. Laboratory studies have demonstrated that in utero treatment with PE such as di-ethyl hexyl phthalate (DEHP) du...

A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of human immunodeficiency virus-infected mothers.

PubMed

Williams, Paige L; Seage, George R; Van Dyke, Russell B; Siberry, George K; Griner, Raymond; Tassiopoulos, Katherine; Yildirim, Cenk; Read, Jennifer S; Huo, Yanling; Hazra, Rohan; Jacobson, Denise L; Mofenson, Lynne M; Rich, Kenneth

2012-05-01

The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites between 2007 and 2011 that was designed to evaluate the safety of in utero antiretroviral drug exposure in children not infected with human immunodeficiency virus who were born to mothers who were infected. This ongoing study uses a "trigger-based" design; that is, initial assessments are conducted on all children, and only those meeting certain thresholds or "triggers" undergo more intensive evaluations to determine whether they have had an adverse event (AE). The authors present the estimated rates of AEs for each domain of interest in the Surveillance Monitoring of ART Toxicities Study. They also evaluated the efficiency of this trigger-based design for estimating AE rates and for testing associations between in utero exposures to antiretroviral drugs and AEs. The authors demonstrate that estimated AE rates from the trigger-based design are unbiased after correction for the sensitivity of the trigger for identifying AEs. Even without correcting for bias based on trigger sensitivity, the trigger approach is generally more efficient for estimating AE rates than is evaluating a random sample of the same size. Minor losses in efficiency when comparing AE rates between persons exposed and unexposed in utero to particular antiretroviral drugs or drug classes were observed under most scenarios.

Ultrasound-induced temperature increase in guinea-pig fetal brain in utero: third-trimester gestation.

PubMed

Horder, M M; Barnett, S B; Vella, G J; Edwards, M J; Wood, A K

1998-11-01

Temperature increase was measured at various depths in the brain of living fetal guinea pigs during in utero exposure to unscanned pulsed ultrasound at ISPTA 2.8 W/cm2. Mean temperature increases of 4.9 degrees C close to parietal bone and 1.2 degrees C in the midbrain were recorded after 2-min exposures. When exposures were repeated on the same sites in each fetus after death, the corresponding mean temperature increases were 4.9 degrees C and 1.3 degrees C, respectively. Cerebral blood perfusion had little cooling effect on ultrasound-induced heating in the guinea pig fetus of 57-61 days gestational age.

Revealing Behavioral Learning Deficit Phenotypes Subsequent to In Utero Exposure to Benzo(a)pyrene

PubMed Central

McCallister, Monique M.; Li, Zhu; Zhang, Tongwen; Ramesh, Aramandla; Clark, Ryan S.; Maguire, Mark; Hutsell, Blake; Newland, M. Christopher; Hood, Darryl B.

2016-01-01

To characterize behavioral deficits in pre-adolescent offspring exposed in utero to Benzo(a)pyrene [B(a)P], timed-pregnant Long Evans Hooded rats were treated with B(a)P (150, 300, 600, and 1200 µg/kg BW) or peanut oil (vehicle) on E14, 15, 16, and 17. Following birth, during the pre-weaning period, B(a)P metabolites were examined in plasma and whole brain or cerebral cortex from exposed and control offspring. Tissue concentrations of B(a)P metabolites were (1) dose-dependent and (2) followed a time-dependence for elimination with ∼60% reduction by PND5 in the 1200 µg/kg BW experimental group. Spatial discrimination-reversal learning was utilized to evaluate potential behavioral neurotoxicity in P40–P60 offspring. Late-adolescent offspring exposed in utero to 600 and 1200 µg/kg BW were indistinguishable from their control counterparts for ability to acquire an original discrimination (OD) and reach criterion. However, a dose-dependent effect of in utero B(a)P-exposure was evident upon a discrimination reversal as exposed offspring perseverated on the previously correct response. This newly characterized behavioral deficit phenotype for the first reversal was not apparent in either the (1) OD or (2) subsequent reversal sessions relative to the respective control offspring. Furthermore, the expression of activity related-cytoskeletal-associated protein (Arc), an experience-dependent cortical protein marker known to be up-regulated in response to acquisition of a novel behavior, was greater in B(a)P-exposed offspring included in the spatial discrimination cohort versus home cage controls. Collectively, these findings support the hypothesis that in utero exposure to B(a)P during critical windows of development representing peak periods of neurogenesis results in behavioral deficits in later life. PMID:26420751

In Utero Exposure to the Antiandrogen Di-(2-Ethylhexyl) Phthalate Decreases Adrenal Aldosterone Production in the Adult Rat1

PubMed Central

Martinez-Arguelles, Daniel B.; Guichard, Theodore; Culty, Martine; Zirkin, Barry R.; Papadopoulos, Vassilios

2011-01-01

We previously reported that in utero exposure of the male fetus to the plasticizer di-(2-ethylhexyl) phthalate (DEHP) resulted in decreased circulating levels of testosterone in the adult without affecting Leydig cell numbers, luteinizing hormone levels, or steroidogenic enzyme expression. Fetal exposure to DEHP resulted in reduced mineralocorticoid receptor (MR; NR3C2) expression in adult Leydig cells. In the present studies, treatment of pregnant Sprague-Dawley dams from Gestational Day 14 until birth with 20, 50, 100, 300, or 750 mg kg−1 day−1 of DEHP resulted in significant sex-specific decreases in serum aldosterone but not corticosterone levels at Postnatal Day 60 (PND60) but not at PND21. There was no effect on circulating levels of potassium, angiotensin II or adrenocorticotropin hormone (ACTH). However, there was reduced expression of AT receptor Agtr1a, Agtr1b, and Agtr2 mRNAs. The mRNA levels of proteins and enzymes implicated in aldosterone biosynthesis were not affected by in utero DEHP treatment except for Cyp11b2, which was decreased at high (≥500 mg kg−1 day−1) doses. The data presented herein, together with our previous observation that aldosterone stimulates testosterone production via an MR-mediated mechanism, suggest that in utero exposure to DEHP causes reduction in both adrenal aldosterone synthesis and MR expression in Leydig cells, leading to reduced testosterone production in the adult. Moreover, these results suggest the existence of a DEHP-sensitive adrenal-testis axis regulating androgen formation. PMID:21389346

Environmental Chemicals in an Urban Population of Pregnant Women and Their Newborns from San Francisco.

PubMed

Morello-Frosch, Rachel; Cushing, Lara J; Jesdale, Bill M; Schwartz, Jackie M; Guo, Weihong; Guo, Tan; Wang, Miaomiao; Harwani, Suhash; Petropoulou, Syrago-Styliani E; Duong, Wendy; Park, June-Soo; Petreas, Myrto; Gajek, Ryszard; Alvaran, Josephine; She, Jianwen; Dobraca, Dina; Das, Rupali; Woodruff, Tracey J

2016-11-15

Exposures to environmental pollutants in utero may increase the risk of adverse health effects. We measured the concentrations of 59 potentially harmful chemicals in 77 maternal and 65 paired umbilical cord blood samples collected in San Francisco during 2010-2011, including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), and perfluorinated compounds (PFCs) in serum and metals in whole blood. Consistent with previous studies, we found evidence that concentrations of mercury (Hg) and lower-brominated PBDEs were often higher in umbilical cord blood or serum than in maternal samples (median cord:maternal ratio > 1), while for most PFCs and lead (Pb), concentrations in cord blood or serum were generally equal to or lower than their maternal pair (median cord:maternal ratio ≤ 1). In contrast to the conclusions of a recent review, we found evidence that several PCBs and OCPs were also often higher in cord than maternal serum (median cord:maternal ratio > 1) when concentrations are assessed on a lipid-adjusted basis. Our findings suggest that for many chemicals, fetuses may experience higher exposures than their mothers and highlight the need to characterize potential health risks and inform policies aimed at reducing sources of exposure.

Neonatal episodic hypoglycemia: a finding of valproic acid withdrawal.

PubMed

Çoban, Dilek; Kurtoğlu, Selim; Akın, Mustafa Ali; Akçakuş, Mustafa; Güneş, Tamer

2010-01-01

The treatment of epilepsy during pregnancy is a worldwide problem. Drugs need to be used to control seizures in the mothers. In utero, exposure to valproic acid (VPA) and phenytoin (PH) may cause congenital malformations and also withdrawal symptoms such as irritability, jitteriness and symptoms of hypoglycemia. We present here a newborn with episodic hypoglycemia due to in utero exposure to VPA and PH. The mother was diagnosed as having complex partial epilepsy and was treated with PH (200 mg/day) and VPA (600 mg/day). The offspring developed jitteriness on the second day of life. The infant was hypoglycemic (32 mg/dl). These findings were accepted as withdrawal symptoms, since serum levels of VPA and PH were 37.8 μg/ml (50-100 μg/ml) and 6.37 μg/dl (10-20 μg/ml), respectively. Measurement of blood glucose is important and should be carefully monitored in infants exposed to antiepileptics in utero.

Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE).

PubMed

Lannerö, Eva; Wickman, Magnus; Pershagen, Goran; Nordvall, Lennart

2006-01-05

Exposure to cigarette smoking during foetal and early postnatal life may have implications for lung health. The aim of this study was to assess the possible effects of such exposure in utero on lower respiratory disease in children up to two years of age. A birth cohort of 4089 newborn infants was followed for two years using parental questionnaires. When the infant was two months old the parents completed a questionnaire on various lifestyle factors, including maternal smoking during pregnancy and after birth. At one and two years of age information was obtained by questionnaire on symptoms of allergic and respiratory diseases as well as on environmental exposures, particularly exposure to environmental tobacco smoke (ETS). Adjustments were made for potential confounders. When the mother had smoked during pregnancy but not after that, there was an increased risk of recurrent wheezing up to two years' age, ORadj = 2.2, (95% CI 1.3-3.6). The corresponding OR was 1.6, (95% CI 1.2-2.3) for reported exposure to ETS with or without maternal smoking in utero. Maternal smoking during pregnancy but no exposure to ETS also increased the risk of doctor's diagnosed asthma up to two years of age, ORadj = 2.1, (95% CI 1.2-3.7). Exposure to maternal cigarette smoking in utero is a risk factor for recurrent wheezing, as well as doctor's diagnosed asthma in children up to two years of age.

Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE)

PubMed Central

Lannerö, Eva; Wickman, Magnus; Pershagen, Goran; Nordvall, Lennart

2006-01-01

Background Exposure to cigarette smoking during foetal and early postnatal life may have implications for lung health. The aim of this study was to assess the possible effects of such exposure in utero on lower respiratory disease in children up to two years of age. Methods A birth cohort of 4089 newborn infants was followed for two years using parental questionnaires. When the infant was two months old the parents completed a questionnaire on various lifestyle factors, including maternal smoking during pregnancy and after birth. At one and two years of age information was obtained by questionnaire on symptoms of allergic and respiratory diseases as well as on environmental exposures, particularly exposure to environmental tobacco smoke (ETS). Adjustments were made for potential confounders. Results When the mother had smoked during pregnancy but not after that, there was an increased risk of recurrent wheezing up to two years' age, ORadj = 2.2, (95% CI 1.3 – 3.6). The corresponding OR was 1.6, (95% CI 1.2 – 2.3) for reported exposure to ETS with or without maternal smoking in utero. Maternal smoking during pregnancy but no exposure to ETS also increased the risk of doctor's diagnosed asthma up to two years of age, ORadj = 2.1, (95% CI 1.2 – 3.7). Conclusion Exposure to maternal cigarette smoking in utero is a risk factor for recurrent wheezing, as well as doctor's diagnosed asthma in children up to two yearsof age. PMID:16396689

In utero exposure to Onchocerca volvulus: relationship to subsequent infection intensity and cellular immune responsiveness.

PubMed Central

Elson, L H; Days, A; Calvopiña, M; Paredes, W; Araujo, E; Guderian, R H; Bradley, J E; Nutman, T B

1996-01-01

Afro-Ecuadorian individuals from an area where Onchocerca volvulus is hyperendemic have been monitored for infection over the past 16 years. To determine whether in utero exposure to O. volvulus biases a child's subsequent immune responses, children (9 to 16 years old) for whom the mother's infection status was known were chosen for study. Children of infected mothers (n = 19) had significantly higher levels of skin microfilariae than children of uninfected mothers (n = 13; P = 0.021). While the serum levels of O. volvulus-specific immunoglobulin G (IgG), IgG subclasses, and IgE showed no significant differences between the two groups of children, peripheral blood mononuclear cells of children of infected mothers produced higher levels of Th2-type cytokines to several parasite antigens and lower levels of Th1-type cytokines to nonparasite antigens than those of children of uninfected mothers. Thus, in utero exposure to O. volvulus has a long-term effect on the child's subsequent cellular immune response that may render the child more susceptible to O. volvulus infection postnatally. PMID:8945547

In Utero Fine Particle Air Pollution and Placental Expression of Genes in the Brain-Derived Neurotrophic Factor Signaling Pathway: An ENVIRONAGE Birth Cohort Study.

PubMed

Saenen, Nelly D; Plusquin, Michelle; Bijnens, Esmée; Janssen, Bram G; Gyselaers, Wilfried; Cox, Bianca; Fierens, Frans; Molenberghs, Geert; Penders, Joris; Vrijens, Karen; De Boever, Patrick; Nawrot, Tim S

2015-08-01

Developmental processes in the placenta and the fetal brain are shaped by the same biological signals. Recent evidence suggests that adaptive responses of the placenta to the maternal environment may influence central nervous system development. We studied the association between in utero exposure to fine particle air pollution with a diameter ≤ 2.5 μm (PM2.5) and placental expression of genes implicated in neural development. Expression of 10 target genes in the brain-derived neurotrophic factor (BDNF) signaling pathway were quantified in placental tissue of 90 mother-infant pairs from the ENVIRONAGE birth cohort using quantitative real-time polymerase chain reaction. Trimester-specific PM2.5 exposure levels were estimated for each mother's home address using a spatiotemporal model. Mixed-effects models were used to evaluate the association between the target genes and PM2.5 exposure measured in different time windows of pregnancy. A 5-μg/m3 increase in residential PM2.5 exposure during the first trimester of pregnancy was associated with a 15.9% decrease [95% confidence interval (CI): -28.7, -3.2%, p = 0.015] in expression of placental BDNF at birth. The corresponding estimate for synapsin 1 (SYN1) was a 24.3% decrease (95% CI: -42.8, -5.8%, p = 0.011). Placental expression of BDNF and SYN1, two genes implicated in normal neurodevelopmental trajectories, decreased with increasing in utero exposure to PM2.5. Future studies are needed to confirm our findings and evaluate the potential relevance of associations between PM2.5 and placental expression of BDNF and SYN1 on neurodevelopment. We provide the first molecular epidemiological evidence concerning associations between in utero fine particle air pollution exposure and the expression of genes that may influence neurodevelopmental processes.

DI(N-BUTYL) PHTHALATE AND DIETHYLHEXYL PHTHALATE IN COMBINATION ALTER SEXUAL DIFFERENTIATION IN A CUMULATIVE MANNER AS A RESULT OF DEPRESSED FETAL TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RATS

EPA Science Inventory

Plasticizers di(n-butyl) phthalate (DBP) and diehtylhexyl phthalate (DEHP) have similar modes of action: in utero exposure reduces testosterone (T) production in fetal male rats, inhibits reproductive tract differentiation, and induces reproductive organ malformations. In utero e...

Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate and diisononyl phthalate

EPA Science Inventory

Several phthalate esters have been linked to the Phthalate Syndrome, affecting male reproductive development when administered to pregnant rats during in utero sexual differentiation. The goal of the current study was to enhance understanding of this class of compounds in the Spr...

In utero treatment with the herbicide linuron produces male rat reproductive malformations similar to the phthalate esters but through a different mechanism of action.

EPA Science Inventory

Although linuron has been reported to act as an androgen receptor (AR) antagonist, the suite of malformations observed in male rat offspring after in utero exposure differs from that of other AR antagonists and more closely resembles that produced by phthalate esters (PE) such as...

Effect of in-utero diethylstilboestrol exposure on human oocyte quality and fertilization in a programme of in-vitro fertilization.

PubMed

Kerjean, A; Poirot, C; Epelboin, S; Jouannet, P

1999-06-01

Genital tract abnormalities and adverse pregnancy outcome are well known in women exposed in utero to diethylstilboestrol (DES). Data about adverse reproductive performance in women exposed to DES have been published, including controversial reports of menstrual dysfunction, poor responses after ovarian stimulation, oocyte maturation and fertilization abnormalities. We compared oocyte quality, in-vitro fertilization results and embryo quality for women exposed in utero to DES with a control group. Between 1989 and 1996, 56 DES-exposed women who had 125 in-vitro fertilization (IVF) attempts were retrospectively compared to a control group of 45 women with tubal disease, who underwent 73 IVF attempts. Couples suffering from male infertility were excluded. The parameters compared were oocyte quality (maturation abnormalities, immature oocyte, mature oocyte), fertilization and cleavage rate (per treated and metaphase II oocytes), and embryo quality (number and grade). We found no significant difference in oocyte maturational status, fertilization rates, cleavage rates, embryo quality and development between DES-exposed subjects and control subjects. These results suggest that in-utero exposure to DES has no significant influence on oocyte quality and fertilization ability as judged during IVF attempts.

Ambient and household air pollution: complex triggers of disease

PubMed Central

Farmer, Stephen A.; Nelin, Timothy D.; Falvo, Michael J.

2014-01-01

Concentrations of outdoor air pollution are on the rise, particularly due to rapid urbanization worldwide. Alternatively, poor ventilation, cigarette smoke, and other toxic chemicals contribute to rising concentrations of indoor air pollution. The World Health Organization recently reported that deaths attributable to indoor and outdoor air pollutant exposure are more than double what was originally documented. Epidemiological, clinical, and animal data have demonstrated a clear connection between rising concentrations of air pollution (both indoor and outdoor) and a host of adverse health effects. During the past five years, animal, clinical, and epidemiological studies have explored the adverse health effects associated with exposure to both indoor and outdoor air pollutants throughout the various stages of life. This review provides a summary of the detrimental effects of air pollution through examination of current animal, clinical, and epidemiological studies and exposure during three different periods: maternal (in utero), early life, and adulthood. Additionally, we recommend future lines of research while suggesting conceivable strategies to curb exposure to indoor and outdoor air pollutants. PMID:24929855

Aflatoxin exposure in utero causes growth faltering in Gambian infants.

PubMed

Turner, Paul C; Collinson, Andrew C; Cheung, Yin Bun; Gong, Yunyun; Hall, Andrew J; Prentice, Andrew M; Wild, Christopher P

2007-10-01

Growth faltering in West African children has previously been associated with dietary exposure to aflatoxins, particularly upon weaning. However, in animal studies in utero exposure to low levels of aflatoxin also results in growth faltering. This study investigated the effect of in utero aflatoxin exposure on infant growth in the first year of life in The Gambia. Height and weight were measured for 138 infants at birth and at regular monthly intervals for one year. Aflatoxin-albumin (AF-alb) adduct level was measured in maternal blood during pregnancy, in cord blood and in infants at age 16 weeks. The geometric mean AF-alb levels were 40.4 pg/mg (range 4.8-260.8 pg/mg), 10.1 pg/mg (range 5.0-189.6 pg/mg) and 8.7 pg/mg (range 5.0-30.2 pg/mg) in maternal, cord and infant blood, respectively. AF-alb in maternal blood was a strong predictor of both weight (P = 0.012) and height (P = 0.044) gain, with lower gain in those with higher exposure. A reduction of maternal AF-alb from 110 pg/mg to 10 pg/mg would lead to a 0.8 kg increase in weight and 2 cm increase in height within the first year of life. This study shows a strong effect of maternal aflatoxin exposure during pregnancy on growth in the first year of life and thus extends earlier observations of an association between aflatoxin exposure during infancy and growth faltering. The findings imply value in targeting intervention strategies at early life exposures.

Exposure to genocide and the risk of schizophrenia: a population-based study.

PubMed

Levine, S Z; Levav, I; Goldberg, Y; Pugachova, I; Becher, Y; Yoffe, R

2016-03-01

No evidence exists on the association between genocide and the incidence of schizophrenia. This study aims to identify critical periods of exposure to genocide on the risk of schizophrenia. This population-based study comprised of all subjects born in European nations where the Holocaust occurred from 1928 to 1945, who immigrated to Israel by 1965 and were indexed in the Population Register (N = 113 932). Subjects were followed for schizophrenia disorder in the National Psychiatric Case Registry from 1950 to 2014. The population was disaggregated to compare groups that immigrated before (indirect exposure: n = 8886, 7.8%) or after (direct exposure: n = 105 046, 92.2%) the Nazi or fascist era of persecutions began. The latter group was further disaggregated to examine likely initial prenatal or postnatal genocide exposures. Cox regression modelling was computed to compare the risk of schizophrenia between the groups, adjusting for confounders. The likely direct group was at a statistically (p < 0.05) greater risk of schizophrenia (hazard ratio = 1.27, 95% confidence interval 1.06-1.51) than the indirect group. Also, the likely combined in utero and postnatal, and late postnatal (over age 2 years) exposure subgroups were statistically at greater risk of schizophrenia than the indirect group (p < 0.05). The likely in utero only and early postnatal (up to age 2 years) exposure subgroups compared with the indirect exposure group did not significantly differ. These results were replicated across three sensitivity analyses. This study showed that genocide exposure elevated the risk of schizophrenia, and identified in utero and postnatal (combined) and late postnatal (age over 2 years) exposures as critical periods of risk.

Effects of in utero JP-8 jet fuel exposure on the immune systems of pregnant and newborn mice.

PubMed

Harris, D T; Sakiestewa, D; He, X; Titone, D; Witten, M

2007-10-01

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. In the present study, the effects of in-utero JP-8 jet fuel exposure in mice were examined to ascertain any potential effects of jet fuel exposure on female personnel and their offspring. Exposure by the aerosol route (at 1000 mg/m3 for 1 h/day; similar to exposures incurred by flight line personnel) commencing during the first (d7 to birth) or last (d15 to birth) trimester of pregnancy was analyzed. It was observed that even 6-8 weeks after the last jet fuel exposure that the immune system of the dams (mother of newborn mice) was affected (in accordance with previous reports on normal mice). That is, thymus organ weights and viable cell numbers were decreased, and immune function was depressed. A decrease in viable male offspring was found, notably more pronounced when exposure started during the first trimester of pregnancy. Regardless of when jet fuel exposure started, all newborn mice (at 6-8 weeks after birth) reported significant immunosuppression. That is, newborn pups displayed decreased immune organ weights, decreased viable immune cell numbers and suppressed immune function. When the data were analyzed in relation to the respective mothers of the pups the data were more pronounced. Although all jet fuel-exposed pups were immunosuppressed as compared with control pups, male offspring were more affected by jet fuel exposure than female pups. Furthermore, the immune function of the newborn mice was directly correlated to the immune function of their respective mothers. That is, mothers showing the lowest immune function after JP-8 exposure gave birth to pups displaying the greatest effects of jet fuel exposure on immune function. Mothers who showed the highest levels of immune function after in-utero JP-8 exposure gave birth to pups displaying levels of immune function similar to controls animals that had the lowest levels of immune function. These data indicated that a genetic component might be involved in determining immune responses after jet fuel exposure. Overall, the data showed that in-utero JP-8 jet fuel exposure had long-term detrimental effects on newborn mice, particularly on the viability and immune competence of male offspring.

Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial.

PubMed

Gibb, Diana M; Kizito, Hilda; Russell, Elizabeth C; Chidziva, Ennie; Zalwango, Eva; Nalumenya, Ruth; Spyer, Moira; Tumukunde, Dinah; Nathoo, Kusum; Munderi, Paula; Kyomugisha, Hope; Hakim, James; Grosskurth, Heiner; Gilks, Charles F; Walker, A Sarah; Musoke, Phillipa

2012-01-01

Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)-recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0-4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12-38) months. From mothers' ART, 62/9/111 infants had no/20%-89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75-212) days. Overall, 14 infants died at median (IQR) age 9 (3-23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. Overall 1-year 5% infant mortality was similar to the 2%-4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children. www.controlled-trials.com ISRCTN13968779

The Development of Cervical and Vaginal Adenosis as a Result of Diethylstilbestrol Exposure In Utero

PubMed Central

Laronda, Monica M.; Unno, Kenji; Butler, Lindsey M.; Kurita, Takeshi

2012-01-01

Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed with DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses its molecular pathogenesis. PMID:22682699

Effects of in utero and lactational exposure to triphenyltin chloride on pregnancy outcome and postnatal development in rat offspring.

PubMed

Grote, Konstanze; Hobler, Carolin; Andrade, Anderson J M; Grande, Simone Wichert; Gericke, Christine; Talsness, Chris E; Appel, Klaus E; Chahoud, Ibrahim

2007-09-05

The organotin compound (OTC) triphenyltin (TPT) is used extensively as a herbicide, pesticide and fungicide in agriculture as well as, together with tributyltin (TBT), in marine antifouling paints. We studied the effects of in utero exposure to 2 or 6 mg triphenyltinchloride (TPTCl)/kgb.w. on pregnancy outcome and postnatal development in rat offspring. Gravid Wistar rats were treated per gavage from gestational day 6 until the end of lactation. In the 6 mg TPTCl dose group gestational mortality in dams as well as an increased incidence of anticipated and delayed parturition was observed. Furthermore, treatment resulted in a significant increase in perinatal mortality, a decrease in lactational body weight gain as well as in delayed physical maturation of offspring. Similarily, exposure to 2mg TPTCl/kgb.w. resulted in a significant increase in perinatal mortality and in delayed eye opening. Lactational body weight gain and other landmarks of physical maturation were unaffected in the low dose group. We conclude, that in utero exposure to TPTCl at the described dose levels severely affected pregnancy outcome and perinatal survival of offspring. These results were unexpected, as in two earlier studies with pubertal rats TPTCl at the same dose levels no signs of general toxicity were observed.

Congenital anomalies in children exposed to antithyroid drugs in-utero: a meta-analysis of cohort studies.

PubMed

Li, Huixia; Zheng, Jianfei; Luo, Jiayou; Zeng, Rong; Feng, Na; Zhu, Na; Feng, Qi

2015-01-01

Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is commonly managed with antithyroid drugs (ATDs). However, previous studies about the effects of ATDs on congenital anomalies are controversial. Therefore, the present meta-analysis was performed to explore the risk of congenital anomalies in children exposed to ATDs in-utero. Embase, Pubmed, Web of Knowledge, and BIOSIS Citation Index were searched to find out studies about congenital anomalies in children exposed to ATDs in-utero reported up to May 2014. The references cited by the retrieved articles were also searched. The relative risks (RRs) and confidence intervals (CIs) for the individual studies were pooled by fixed effects models, and heterogeneity was analyzed by chi-square and I2 tests. Eight studies met the inclusion criteria. Exposure to propylthiouracil (PTU), methimazole/carbimazole (MMI/CMZ), and PTU & MMI/CMZ was investigated in 7, 7 and 2 studies, respectively. The pooled RR was 1.20 (95%CI: 1.02-1.42), 1.64 (95%CI: 1.39-1.92), and 1.83 (95%CI: 1.30-2.56) for congenital anomalies after exposure to PTU, MMI/CMZ, and PTU & MMI/CMZ, respectively. The meta-analysis suggests that exposure to ATDs in-utero increases the risk of congenital anomalies. The use of ATDs in pregnancy should be limited when possible. Further research is needed to delineate the exact teratogenic risk for particular congenital anomaly.

Congenital Anomalies in Children Exposed to Antithyroid Drugs In-Utero: A Meta-Analysis of Cohort Studies

PubMed Central

Luo, Jiayou; Zeng, Rong; Feng, Na; Zhu, Na; Feng, Qi

2015-01-01

Background Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is commonly managed with antithyroid drugs (ATDs). However, previous studies about the effects of ATDs on congenital anomalies are controversial. Therefore, the present meta-analysis was performed to explore the risk of congenital anomalies in children exposed to ATDs in-utero. Methods Embase, Pubmed, Web of Knowledge, and BIOSIS Citation Index were searched to find out studies about congenital anomalies in children exposed to ATDs in-utero reported up to May 2014. The references cited by the retrieved articles were also searched. The relative risks (RRs) and confidence intervals (CIs) for the individual studies were pooled by fixed effects models, and heterogeneity was analyzed by chi-square and I 2 tests. Results Eight studies met the inclusion criteria. Exposure to propylthiouracil (PTU), methimazole/carbimazole (MMI/CMZ), and PTU & MMI/CMZ was investigated in 7, 7 and 2 studies, respectively. The pooled RR was 1.20 (95%CI: 1.02-1.42), 1.64 (95%CI: 1.39-1.92), and 1.83 (95%CI: 1.30-2.56) for congenital anomalies after exposure to PTU, MMI/CMZ, and PTU & MMI/CMZ, respectively. Conclusions The meta-analysis suggests that exposure to ATDs in-utero increases the risk of congenital anomalies. The use of ATDs in pregnancy should be limited when possible. Further research is needed to delineate the exact teratogenic risk for particular congenital anomaly. PMID:25974033

A Trigger-based Design for Evaluating the Safety of In Utero Antiretroviral Exposure in Uninfected Children of Human Immunodeficiency Virus-Infected Mothers

PubMed Central

Williams, Paige L.; Seage, George R.; Van Dyke, Russell B.; Siberry, George K.; Griner, Raymond; Tassiopoulos, Katherine; Yildirim, Cenk; Read, Jennifer S.; Huo, Yanling; Hazra, Rohan; Jacobson, Denise L.; Mofenson, Lynne M.; Rich, Kenneth

2012-01-01

The Pediatric HIV/AIDS Cohort Study’s Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites between 2007 and 2011 that was designed to evaluate the safety of in utero antiretroviral drug exposure in children not infected with human immunodeficiency virus who were born to mothers who were infected. This ongoing study uses a “trigger-based” design; that is, initial assessments are conducted on all children, and only those meeting certain thresholds or “triggers” undergo more intensive evaluations to determine whether they have had an adverse event (AE). The authors present the estimated rates of AEs for each domain of interest in the Surveillance Monitoring of ART Toxicities Study. They also evaluated the efficiency of this trigger-based design for estimating AE rates and for testing associations between in utero exposures to antiretroviral drugs and AEs. The authors demonstrate that estimated AE rates from the trigger-based design are unbiased after correction for the sensitivity of the trigger for identifying AEs. Even without correcting for bias based on trigger sensitivity, the trigger approach is generally more efficient for estimating AE rates than is evaluating a random sample of the same size. Minor losses in efficiency when comparing AE rates between persons exposed and unexposed in utero to particular antiretroviral drugs or drug classes were observed under most scenarios. PMID:22491086

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

Philbrook, Nicola A.; Winn, Louise M., E-mail: winnl@queensu.ca; School of Environmental Studies, Queen's University, Kingston, ON K7L3N6

Exposure to the ubiquitous environmental pollutant benzene is positively correlated with leukemia in adults and may be associated with childhood leukemia following in utero exposure. While numerous studies implicate oxidative stress and DNA damage as playing a role in benzene-mediated carcinogenicity, emerging evidence suggests that alterations in epigenetic regulations may be involved. The present study aimed to determine whether DNA methylation and/or various histone modifications were altered following in utero benzene exposure in CD-1 mice. Global DNA methylation and promoter-specific methylation of the tumor suppressor gene, p15, were assessed. Additionally, levels of acetylated histones H3, H4, and H3K56, as wellmore » as methylated histones H3K9 and H3K27 were assessed by Western blotting. A significant decrease in global DNA methylation of maternal bone marrow was observed following benzene exposure; however no effect on global DNA methylation was detected in fetal livers. Additionally, no effect of benzene exposure was observed on p15 promoter methylation or any measured histone modifications in both maternal bone marrow and fetal livers. These results suggest that the methodology used in the present study did not reveal alterations in DNA methylation and histone modifications following in utero exposure to benzene; however further experimentation investigating these modifications at the whole genome/epigenome level, as well as at later stages of benzene-induced carcinogenesis, are warranted. - Highlights: • Benzene exposure in pregnant mice decreased global DNA methylation in maternal bone marrow. • Benzene exposure in pregnant mice had no effect on global DNA methylation in fetal livers. • No effect of benzene exposure was observed on p15 promoter methylation. • No effect of benzene on measured histone modifications in both maternal bone marrow and fetal livers was observed.« less

In utero exposure to dietheylhexyl phthalate differentially affects fetal testosterone and insl3 levels in the testes of male Sprague Dawley and Wistar rats: A dose response study

EPA Science Inventory

We previously reported that 750 mg/kg/day of diethylhexyl phthalate (DEHP) administered in utero during the period of sex differentiation resulted in a higher prevalence of gubernacular lesions in male Wistar offspring than in the male Sprague Dawley (SD) rat offspring, whereas D...

Balance ability in 7- and 10-year-old children: associations with prenatal lead and cadmium exposure and with blood lead levels in childhood in a prospective birth cohort study

PubMed Central

Taylor, Caroline M; Humphriss, Rachel; Hall, Amanda; Golding, Jean; Emond, Alan M

2015-01-01

Objectives Most studies reporting evidence of adverse effects of lead and cadmium on the ability to balance have been conducted in high-exposure groups or have included adults. The effects of prenatal exposure have not been well studied, nor have the effects in children been directly studied. The aim of the study was to identify the associations of lead (in utero and in childhood) and cadmium (in utero) exposure with the ability to balance in children aged 7 and 10 years. Design Prospective birth cohort study. Participants Maternal blood lead (n=4285) and cadmium (n=4286) levels were measured by inductively coupled plasma mass spectrometry in women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) during pregnancy. Child lead levels were measured in a subsample of 582 of ALSPAC children at age 30 months. Main outcome measures Children completed a heel-to-toe walking test at 7 years. At 10 years, the children underwent clinical tests of static and dynamic balance. Statistical analysis using SPSS V.19 included logistic regression modelling, comparing categories of ≥5 vs <5 µg/dL for lead, and ≥1 vs <1 µg/L for cadmium. Results Balance at age 7 years was not associated with elevated in utero lead or cadmium exposure (adjusted OR for balance dysfunction: Pb 1.01 (95% CI 0.95 to 1.01), n=1732; Cd 0.95 (0.77 to 1.20), n=1734), or with elevated child blood lead level at age 30 months (adjusted OR 0.98 (0.92 to 1.05), n=354). Similarly, neither measures of static nor dynamic balance at age 10 years were associated with in utero lead or cadmium exposure, or child lead level. Conclusions These findings do not provide any evidence of an association of prenatal exposure to lead or cadmium, or lead levels in childhood, on balance ability in children. Confirmation in other cohorts is needed. PMID:26719320

Off to a good start: the influence of pre- and periconceptional exposures, parental fertility, and nutrition on children's health.

PubMed

Chapin, Robert E; Robbins, Wendie A; Schieve, Laura A; Sweeney, Anne M; Tabacova, Sonia A; Tomashek, Kay M

2004-01-01

The scientific community is developing a compelling body of evidence that shows the importance of the in utero environment (including chemical and hormonal levels) to the ultimate health of the child and even of the aging adult. This article summarizes the evidence that shows this impact begins with conception. Only a full life-cycle evaluation will help us understand these impacts, and only such an understanding will produce logically prioritized mitigation strategies to address the greatest threats first. Clearly, the time for analysis begins when the next generation is but a twinkle in the eye.

Off to a good start: the influence of pre- and periconceptional exposures, parental fertility, and nutrition on children's health.

PubMed Central

Chapin, Robert E; Robbins, Wendie A; Schieve, Laura A; Sweeney, Anne M; Tabacova, Sonia A; Tomashek, Kay M

2004-01-01

The scientific community is developing a compelling body of evidence that shows the importance of the in utero environment (including chemical and hormonal levels) to the ultimate health of the child and even of the aging adult. This article summarizes the evidence that shows this impact begins with conception. Only a full life-cycle evaluation will help us understand these impacts, and only such an understanding will produce logically prioritized mitigation strategies to address the greatest threats first. Clearly, the time for analysis begins when the next generation is but a twinkle in the eye. PMID:14698934

Violence, selection and infant mortality in Congo.

PubMed

Dagnelie, Olivier; Luca, Giacomo Davide De; Maystadt, Jean-François

2018-05-01

This paper documents the effects of the recent civil war in the Democratic Republic of Congo on mortality both in utero and during the first year of life. It instruments for conflict intensity using a mineral price index, which exploits the exogenous variation in the potential value of mineral resources generated by changes in world mineral prices to predict the geographic distribution of the conflict. Using estimates of civil war exposure on mortality across male and female newborn to assess their relative health, it provides evidence of culling effect (in utero selection) as a consequence of in utero shocks. Copyright © 2018 Elsevier B.V. All rights reserved.

Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study

PubMed Central

Agerbo, Esben; Ingstrup, Katja G; Musliner, Katherine; Meltzer-Brody, Samantha; Bergink, Veerle; Munk-Olsen, Trine

2017-01-01

Objective To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders. Design Population based cohort study. Setting Danish national registers. Participants 905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk. Exposures for observational studies Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy). Main outcome measure First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models. Results Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group. Conclusions In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive. PMID:28877907

In Utero DDT and DDE Exposure and Obesity Status of 7-Year-Old Mexican-American Children in the CHAMACOS Cohort

PubMed Central

Schall, Raul Aguilar; Harley, Kim G.; Bradman, Asa; Barr, Dana; Eskenazi, Brenda

2013-01-01

Background: In utero exposure to endocrine disrupting compounds including dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) has been hypothesized to increase risk of obesity later in life. Objectives: The Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study is a longitudinal birth cohort of low-income Latinas living in a California agricultural community. We examined the relation of in utero DDT and DDE exposure to child obesity at 7 years of age. We also examined the trend with age (2, 3.5, 5, and 7 years) in the exposure–obesity relation. Methods: We included 270 children with o,p´-DDT, p,p´-DDT, and p,p´-DDE concentrations measured in maternal serum during pregnancy (nanograms per gram lipid) and complete 7-year follow-up data including weight (kilograms) and height (centimeters). Body mass index (BMI; kilograms per meter squared) was calculated and obesity was defined as ≥ 95th percentile on the sex-specific BMI-for-age Centers for Disease Control and Prevention 2000 growth charts. Results: At 7 years, 96 (35.6%) children were obese. A 10-fold increase in o,p´-DDT, p,p´-DDT, or p,p´-DDE, was nonsignificantly associated with increased odds (OR) of obesity [o,p´-DDT adjusted (adj-) OR = 1.17, 95% CI: 0.75, 1.82; p,p´-DDT adj-OR = 1.19, 95% CI: 0.81, 1.74; p,p´-DDE adj-OR = 1.22, 95% CI: 0.72, 2.06]. With increasing age at follow-up, we observed a significant trend toward a positive association between DDT and DDE exposure and odds of obesity. Conclusion: We did not find a significant positive relation between in utero DDT and DDE exposure and obesity status of 7-year-old children. However, given the observed trend with age, continued follow-up will be informative. PMID:23512307

Transforming growth factor- 1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma.

PubMed

Salam, Muhammad T; Gauderman, W James; McConnell, Rob; Lin, Pi-Chu; Gilliland, Frank D

2007-12-15

Transforming growth factor (TGF)-beta1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-beta1 gene expression. We hypothesized that the effects of functional TGF-beta1 variants on asthma occurrence vary by these exposures. We tested these hypotheses among 3,023 children who participated in the Children's Health Study. Tagging single-nucleotide polymorphisms rs4803457 C>T and C-509T (a functional promoter polymorphism) accounted for 94% of the haplotype diversity of the upstream region. Exposure to maternal smoking in utero was based on smoking by biological mother during pregnancy. Residential distance from nearest freeway was calculated based on residential address at study entry. Children with the -509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [CI], 1.11-2.95). This association varied marginally significantly by in utero exposure to maternal smoking. Compared with children with the -509CC/CT genotype with no in utero exposure to maternal smoking, those with the -509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% CI, 1.46-7.80; interaction, P = 0.11). The association between TGF-beta1 C-509T and lifetime asthma varied by residential proximity to freeways (interaction P = 0.02). Children with the -509TT genotype living within 500 m of a freeway had over three-fold increased lifetime asthma risk (95% CI, 1.29-7.44) compared with children with CC/CT genotype living > 1500 m from a freeway. Children with the TGF-beta1 -509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.

Primary non-clear-cell adenocarcinoma of the vagina in a diethylstilbestrol exposed woman.

PubMed

Patel, Samit A; Sunde, Jan

2014-04-01

A 54-year-old woman with a history of in-utero diethylstilbestrol (DES) exposure, who had a prior hysterectomy for symptomatic leiomyomata and dysmenorrhea, presented for vaginal bleeding. Vaginal biopsies showed a non-clear-cell adenocarcinoma, and the patient was subsequently treated with radiation therapy. We present a case of primary vaginal non-clear-cell adenocarcinoma in a patient with in-utero DES exposure. Continued monitoring of older DES-exposed women for vaginal lesions is warranted because of reported cases of non-clear-cell adenocarcinoma and persistent risk of clear cell adenocarcinoma. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

Prenatal ethanol exposure alters steroidogenic enzyme activity in newborn rat testes.

PubMed

Kelce, W R; Rudeen, P K; Ganjam, V K

1989-10-01

We have examined the in utero effects of ethanol exposure on testicular steroidogenesis in newborn male pups. Pregnant Sprague-Dawley rats were fed a liquid ethanol diet (35% ethanol-derived calories), a pair-fed isocaloric liquid diet, or a standard laboratory rat chow and water diet beginning on Day 12 of gestation and continuing through parturition. Although there were no significant differences in the enzymatic activity of 5-ene-3 beta-hydroxysteroid dehydrogenase/isomerase or C17,20-lyase, the enzymatic activity of 17 alpha-hydroxylase was significantly (p less than 0.01) reduced (i.e., approximately 36%) in the ethanol-exposed pups compared to those from the pair-fed and chow treatment groups. This lesion in testicular steroidogenic enzyme activity in newborn male pups exposed to alcohol in utero was transient as 17 alpha-hydroxylase activity from the ethanol-exposed animals returned to control levels by postnatal Day 20 and remained at control levels through adulthood (postnatal Day 60). These data suggest that the suppression of the perinatal testosterone surge in male rats exposed to alcohol in utero and the associated long term demasculinizing effects of prenatal ethanol exposure might be the result of reduced testicular steroidogenic enzyme activity in the perinatal animal.

Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl) phthalate.

PubMed

Barlow, Norman J; McIntyre, Barry S; Foster, Paul M D

2004-01-01

In utero exposure of male rats to the antiandrogen di(n-butyl) phthalate (DBP) leads to decreased anogenital distance (AGD) on postnatal day (PND) 1, increased areolae retention on PND 13, malformations in the male reproductive tract, and histologic testicular lesions including marked seminiferous epithelial degeneration and a low incidence of Leydig cell (LC) adenomas on PND 90. One objective of this study was to determine the incidence and persistence of decreased AGD, increased areolae retention, and LC adenomas in adult rats following in utero DBP exposure. A second objective was to determine whether AGD and areolae retention during the early postnatal period are associated with lesions in the male reproductive tract. Pregnant Crl:CD(SD)BR rats were gavaged with corn oil or DBP at 100 or 500 mg/kg/day, 10 dams per group. Three replicates of rats (n = 30 rats per replicate) were exposed from gestation day 12 to 21 and the male offspring allowed to mature to 6, 12, or 18 months of age. Gross malformations in the male reproductive tract and histologic lesions in the testes were similar to those previously described. However, testicular dysgenesis, a lesion of proliferating LCs and aberrant tubules that has not been previously described in DBP-exposed testes, was diagnosed. The incidence of this lesion was approximately 20% unilateral and 7-18% bilateral in the high-dose group and was similar among all ages examined, implicating a developmental alteration rather than an age-related change. AGD and areolae retention were found to be permanent changes following in utero exposure to 500 mg/kg/day of DBP. Decreased AGD was a sensitive predictor of lesions in the male reproductive tract, relatively small changes in AGD were associated with a significant incidence of male reproductive malformations. In utero DBP exposure induced proliferative developmental lesions, some of which would have been diagnosed as LC adenomas by the morphological criteria set forth by the Society of Toxicologic Pathology. However, these lesions were dissimilar to traditional LC adenomas as the LCs were poorly differentiated and the lesions contained aberrant seminiferous tubules. While the morphology and incidence of this DBP-induced testicular developmental lesion has been fully characterized by this study, the detailed pathogenesis warrants further investigation.

Incorporating children's toxicokinetics into a risk framework.

PubMed Central

Ginsberg, Gary; Slikker, William; Bruckner, James; Sonawane, Babasaheb

2004-01-01

Children's responses to environmental toxicants will be affected by the way in which their systems absorb, distribute, metabolize, and excrete chemicals. These toxicokinetic factors vary during development, from in utero where maternal and placental processes play a large role, to the neonate in which emerging metabolism and clearance pathways are key determinants. Toxicokinetic differences between neonates and adults lead to the potential for internal dosimetry differences and increased or decreased risk, depending on the mechanisms for toxicity and clearance of a given chemical. This article raises a number of questions that need to be addressed when conducting a toxicokinetic analysis of in utero or childhood exposures. These questions are organized into a proposed framework for conducting the assessment that involves problem formulation (identification of early life stage toxicokinetic factors and chemical-specific factors that may raise questions/concerns for children); data analysis (development of analytic approach, construction of child/adult or child/animal dosimetry comparisons); and risk characterization (evaluation of how children's toxicokinetic analysis can be used to decrease uncertainties in the risk assessment). The proposed approach provides a range of analytical options, from qualitative to quantitative, for assessing children's dosimetry. Further, it provides background information on a variety of toxicokinetic factors that can vary as a function of developmental stage. For example, the ontology of metabolizing systems is described via reference to pediatric studies involving therapeutic drugs and evidence from in vitro enzyme studies. This type of resource information is intended to help the assessor begin to address the issues raised in this paper. PMID:14754583

Biological Relevance of Key Events (KE) in utero in The Androgen Adverse Outcome Pathway Network (AOPn) to Adverse Effects in F1 Male Rats

EPA Science Inventory

We are conducting studies to evaluate the biological relevance of changes in KEs and molecular initiating events (MIE) in AOPs to determine if these can accurately predict of the dose levels of chemicals that disrupt the androgen signaling pathway in utero. Herein, we focus on ch...

Testicular steroidogenesis is not altered by 137 cesium Chernobyl fallout, following in utero or post-natal chronic exposure.

PubMed

Grignard, Elise; Guéguen, Yann; Grison, Stéphane; Dublineau, Isabelle; Gourmelon, Patrick; Souidi, Maâmar

2010-05-01

The testis is especially sensitive to pollutants, including radionuclides. Following the Chernobyl nuclear power plant accident, several of these radionuclides were emitted and spread in the environment. Subsequently, children presented some disruptions of the endocrine system. To determine whether these disruptions were due to 137 cesium ((137)Cs) exposure, the effects of chronic contamination with low doses of (137)Cs in utero or from birth on testicular steroidogenesis in rats were studied. Contamination was continued for 9 months. No modification was observed in circulating level of hormones (17beta-estradiol, testosterone, follicle-stimulating hormone, luteinizing hormone) following in utero or post-natal contamination. Expression of several genes involved in testicular steroidogenesis was affected (cyp19a1, fxr, sf-1), without modification of protein expression or activity. Our results suggest that growing organisms may be affected at the molecular level by (137)Cs contamination at this post-accidental dose. Copyright 2010 Académie des sciences. Published by Elsevier SAS. All rights reserved.

Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus.

PubMed

Ruchat, Stephanie-May; Hivert, Marie-France; Bouchard, Luigi

2013-10-01

It is now well accepted that offspring exposed to maternal undernutrition, obesity, or gestational diabetes mellitus have an increased risk for chronic diseases later in life, supporting the theory of the early origins of chronic diseases. However, the molecular mechanisms through which the exposure to an altered in utero environment translates into the development of chronic diseases are not yet well understood. Recently reported promising results help to resolve this issue. They suggest that epigenetic modifications are a potential mechanism for fetal metabolic programming. This review provides an overview of the relationship between the exposure to an altered intrauterine environment and fetal metabolic programming, focusing on gestational diabetes mellitus and epigenetic variations at adipokine candidate genes. © 2013 International Life Sciences Institute.

Prenatal stress and epigenetics.

PubMed

Cao-Lei, L; de Rooij, S R; King, S; Matthews, S G; Metz, G A S; Roseboom, T J; Szyf, M

2017-05-18

In utero exposure to environmental stress in both animals and humans could result in long-term epigenome alterations which further lead to consequences for adaptation and development in the offspring. Epigenetics, especially DNA methylation, is considered one of the most widely studied and well-characterized mechanisms involved in the long-lasting effects of in utero stress exposure. In this review, we outlined evidence from animal and human prenatal research supporting the view that prenatal stress could lead to lasting, broad and functionally organized signatures in DNA methylation which, in turn, could mediate exposure-phenotype associations. We also emphasized the advantage of using stressor from quasi-randomly assigned experiments. Furthermore, we discuss challenges that still need to be addressed in this field in the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

Long-run effects of gestation during the Dutch Hunger Winter famine on labor market and hospitalization outcomes.

PubMed

Scholte, Robert S; van den Berg, Gerard J; Lindeboom, Maarten

2015-01-01

The Dutch Hunger Winter (1944/45) is the most-studied famine in the literature on long-run effects of malnutrition in utero. Its temporal and spatial demarcations are clear, it was severe, it was not anticipated, and nutritional conditions in society were favorable and stable before and after the famine. This is the first study to analyze effects of in utero exposure on labor market outcomes and hospitalization late in life, and the first to use register data covering the full Dutch population to examine long-run effects of this famine. We provide results of famine exposure by sub-interval of gestation. We find a significantly negative effect of exposure during the first trimester of gestation on employment outcomes 53 or more years after birth. Hospitalization rates in the years before retirement are higher after middle or late gestational exposure. Copyright © 2014 Elsevier B.V. All rights reserved.

Calculating summary statistics for population chemical biomonitoring in women of childbearing age with adjustment for age-specific natality.

PubMed

Axelrad, Daniel A; Cohen, Jonathan

2011-01-01

The effects of chemical exposures during pregnancy on children's health have been an increasing focus of environmental health research in recent years, leading to greater interest in biomonitoring of chemicals in women of childbearing age in the general population. Measurements of mercury in blood from the National Health and Nutrition Examination Survey are frequently reported for "women of childbearing age," defined to be of ages 16-49 years. The intent is to represent prenatal chemical exposure, but blood mercury levels increase with age. Furthermore, women of different ages have different probabilities of giving birth. We evaluated options to address potential bias in biomonitoring summary statistics for women of childbearing age by accounting for age-specific probabilities of giving birth. We calculated median and 95th percentile levels of mercury, PCBs, and cotinine using these approaches: option 1: women aged 16-49 years without natality adjustment; option 2: women aged 16-39 years without natality adjustment; option 3: women aged 16-49 years, adjusted for natality by age; option 4: women aged 16-49 years, adjusted for natality by age and race/ethnicity. Among the three chemicals examined, the choice of option has the greatest impact on estimated levels of serum PCBs, which are strongly associated with age. Serum cotinine levels among Black non-Hispanic women of childbearing age are understated when age-specific natality is not considered. For characterizing in utero exposures, adjustment using age-specific natality provides a substantial improvement in estimation of biomonitoring summary statistics. Copyright © 2010 Elsevier Inc. All rights reserved.

TRANSGENERATIONAL (IN UTERO/LACTATIONAL) EXPOSURE PROTOCOL TO INVESTIGATE THE EFFECTS OF ENDOCRINE DISRUPTING COMPOUNDS (EDCS) IN RATS

EPA Science Inventory

This protocol is designed to evaluate the effects of Endocrine Disrupting Compounds (EDCs) through fetal (transplacental) and/or neonatal (via the dam's milk) exposure during the critical periods of reproductive organogenesis in the rat. Continued direct exposure to the F1 pups...

Fetal alcohol exposure and mammary tumorigenesis in offspring: role of the estrogen and insulin-like growth factor systems.

PubMed

Cohick, Wendie S; Crismale-Gann, Catina; Stires, Hillary; Katz, Tiffany A

2015-01-01

Fetal alcohol spectrum disorders affect a significant number of live births each year, indicating that alcohol consumption during pregnancy is an important public health issue. Environmental exposures and lifestyle choices during pregnancy may affect the offspring's risk of disease in adulthood, leading to the idea that a woman's risk of breast cancer may be pre-programmed prior to birth. Exposure of pregnant rats to alcohol increases tumorigenesis in the adult offspring in response to mammary carcinogens. The estrogen and insulin-like growth factor (IGF-I) axes occupy central roles in normal mammary gland development and breast cancer. 17-β estradiol (E2) and IGF-I synergize to regulate formation of terminal end buds and ductal elongation during pubertal development. The intracellular signaling pathways mediated by the estrogen and IGF-I receptors cross-talk at multiple levels through both genomic and non-genomic mechanisms. Several components of the E2 and IGF-I systems are altered in early development in rat offspring exposed to alcohol in utero, therefore, these changes may play a role in the enhanced susceptibility to mammary carcinogens observed in adulthood. Alcohol exposure in utero induces a number of epigenetic alterations in non-mammary tissues in the offspring and other adverse in utero exposures induce epigenetic modifications in the mammary gland. Future studies will determine if fetal alcohol exposure can induce epigenetic modifications in genes that regulate E2/IGF action at key phases of mammary development, ultimately leading to changes in susceptibility to carcinogens.

In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism.

PubMed

Radford, Elizabeth J; Ito, Mitsuteru; Shi, Hui; Corish, Jennifer A; Yamazawa, Kazuki; Isganaitis, Elvira; Seisenberger, Stefanie; Hore, Timothy A; Reik, Wolf; Erkek, Serap; Peters, Antoine H F M; Patti, Mary-Elizabeth; Ferguson-Smith, Anne C

2014-08-15

Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. Copyright © 2014, American Association for the Advancement of Science.

Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate.

PubMed

Hokanson, R; Fudge, R; Chowdhary, R; Busbee, D

2007-09-01

Gene expression is altered in mammalian cells (MCF-7 cells), by exposure to a variety of chemicals that mimic steroid hormones or interact with endocrine receptors or their co-factors. Among those populations chronically exposed to these endocrine disruptive chemicals are persons, and their families, who are employed in agriculture or horticulture, or who use agricultural/horticultural chemicals. Among the chemicals most commonly used, both commercially and in the home, is the herbicide glyphosate. Although glyphosate is commonly considered to be relatively non-toxic, we utilized in vitro DNA microarray analysis of this chemical to evaluate its capacity to alter the expression of a variety of genes in human cells. We selected a group of genes, determined by DNA microarray analysis to be dysregulated, and used quantitative real-time PCR to corroborate their altered states of expression. We discussed the reported function of those genes, with emphasis on altered physiological states that are capable of initiating adverse health effects that might be anticipated if gene expression were significantly altered in either adults or embryos exposed in utero.

Relation between in Utero Arsenic Exposure and Birth Outcomes in a Cohort of Mothers and Their Newborns from New Hampshire

PubMed Central

Gilbert-Diamond, Diane; Emond, Jennifer A.; Baker, Emily R.; Korrick, Susan A.; Karagas, Margaret R.

2016-01-01

Background: Studies suggest that arsenic exposure influences birth outcomes; however, findings are mixed. Objective: We assessed in utero arsenic exposure in relation to birth outcomes and whether maternal prepregnancy weight and infant sex modified the associations. Methods: Among 706 mother–infant pairs exposed to low levels of arsenic through drinking water and diet, we assessed in utero arsenic exposure using maternal second-trimester urinary arsenic, maternal prepregnancy weight through self-report, and birth outcomes from medical records. Results: Median (interquartile range) of total urinary arsenic [tAs; inorganic arsenic (iAs) + monomethylarsonic acid (MMA) + dimethylarsinic acid (DMA)] was 3.4 μg/L (1.7–6.0). In adjusted linear models, each doubling of tAs was associated with a 0.10-cm decrease (95% CI: –0.19, –0.01) in head circumference. Results were similar for MMA and DMA. Ln(tAs) and ln(DMA) were positively associated with birth length in infant males only; among males, each doubling of tAs was associated with a 0.28-cm increase (95% CI: 0.09, 0.46) in birth length (pinteraction = 0.04). Results were similar for DMA. Additionally, arsenic exposure was inversely related to ponderal index, and associations differed by maternal weight. Each ln(tAs) doubling of tAs was associated with a 0.55-kg/m3 lower (95% CI: –0.82, –0.28, p < 0.001) ponderal index for infants of overweight/obese, but not normal-weight, mothers (pinteraction < 0.01). Finally, there was a significant interaction between maternal weight status, infant sex, and arsenic exposure on birth weight (pinteraction = 0.03). In girls born of overweight/obese mothers, each doubling of tAs was associated with a 62.9-g decrease (95% CI: –111.6, –14.2) in birth weight, though the association was null in the other strata. Conclusions: Low-level arsenic exposure may affect fetal growth, and the associations may be modified by maternal weight status and infant sex. Citation: Gilbert-Diamond D, Emond JA, Baker ER, Korrick SA, Karagas MR. 2016. Relation between in utero arsenic exposure and birth outcomes in a cohort of mothers and their newborns from New Hampshire. Environ Health Perspect 124:1299–1307; http://dx.doi.org/10.1289/ehp.1510065 PMID:26955061

Relation between in Utero Arsenic Exposure and Birth Outcomes in a Cohort of Mothers and Their Newborns from New Hampshire.

PubMed

Gilbert-Diamond, Diane; Emond, Jennifer A; Baker, Emily R; Korrick, Susan A; Karagas, Margaret R

2016-08-01

Studies suggest that arsenic exposure influences birth outcomes; however, findings are mixed. We assessed in utero arsenic exposure in relation to birth outcomes and whether maternal prepregnancy weight and infant sex modified the associations. Among 706 mother-infant pairs exposed to low levels of arsenic through drinking water and diet, we assessed in utero arsenic exposure using maternal second-trimester urinary arsenic, maternal prepregnancy weight through self-report, and birth outcomes from medical records. Median (interquartile range) of total urinary arsenic [tAs; inorganic arsenic (iAs) + monomethylarsonic acid (MMA) + dimethylarsinic acid (DMA)] was 3.4 μg/L (1.7-6.0). In adjusted linear models, each doubling of tAs was associated with a 0.10-cm decrease (95% CI: -0.19, -0.01) in head circumference. Results were similar for MMA and DMA. Ln(tAs) and ln(DMA) were positively associated with birth length in infant males only; among males, each doubling of tAs was associated with a 0.28-cm increase (95% CI: 0.09, 0.46) in birth length (pinteraction = 0.04). Results were similar for DMA. Additionally, arsenic exposure was inversely related to ponderal index, and associations differed by maternal weight. Each ln(tAs) doubling of tAs was associated with a 0.55-kg/m3 lower (95% CI: -0.82, -0.28, p < 0.001) ponderal index for infants of overweight/obese, but not normal-weight, mothers (pinteraction < 0.01). Finally, there was a significant interaction between maternal weight status, infant sex, and arsenic exposure on birth weight (pinteraction = 0.03). In girls born of overweight/obese mothers, each doubling of tAs was associated with a 62.9-g decrease (95% CI: -111.6, -14.2) in birth weight, though the association was null in the other strata. Low-level arsenic exposure may affect fetal growth, and the associations may be modified by maternal weight status and infant sex. Gilbert-Diamond D, Emond JA, Baker ER, Korrick SA, Karagas MR. 2016. Relation between in utero arsenic exposure and birth outcomes in a cohort of mothers and their newborns from New Hampshire. Environ Health Perspect 124:1299-1307; http://dx.doi.org/10.1289/ehp.1510065.

Beta-2 receptor agonist exposure in the uterus associated with subsequent risk of childhood asthma.

PubMed

Ogawa, Kohei; Tanaka, Satomi; Limin, Yang; Arata, Naoko; Sago, Haruhiko; Yamamoto-Hanada, Kiwako; Narita, Masami; Ohya, Yukihiro

2017-12-01

Although the beta-2 receptor agonist (B2RA) is occasionally prescribed in the prenatal period for women with preterm labor, few studies have referred to the long-term effects of intrauterine exposure to B2RA on fetus. We examined the association between intrauterine exposure to B2RA and asthma in the offspring. We obtained data from a hospital-based birth cohort study conducted in Tokyo, Japan. The outcomes of interest were three indicators, consisting of current wheeze, current asthma, and ever asthma at 5 years of age, based on the International Study of Asthma and Allergies in Childhood questionnaire. Logistic regression analysis was used to evaluate the association between intrauterine B2RA exposure and outcomes. To evaluate dose-dependent risk, we categorized children into three groups according to both the cumulative dose and duration (days) and conducted trend analysis. Of 1158 children, 94 (8.1%) were exposed to B2RA in utero, and 191 (16.5%), 111 (9.6%), and 168 (14.5%) children experienced current wheeze, current asthma, and ever asthma, respectively. After adjusting for confounders, we found an increased risk of current asthma caused by B2RA exposure with an adjusted odds ratio of 2.04 (95% confidence interval: 1.02-4.05). Trend analysis showed that B2RA exposure in utero was associated with a dose-dependent increased risk of current asthma in terms of both cumulative dose and duration (P values for trend were .015 and .017, respectively). These results were similar to those for other outcome measures. Exposure to B2RA in utero could be a risk for childhood asthma. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

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

Farzan, Shohreh F.; Karagas, Margaret R.; Section of Biostatistics and Epidemiology, Department of Community and Family Medicine and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756

Background: There is a growing body of evidence that prenatal and early childhood exposure to arsenic from drinking water can have serious long-term health implications. Objectives: Our goal was to understand the potential long-term health and disease risks associated with in utero and early life exposure to arsenic, as well as to examine parallels between findings from epidemiological studies with those from experimental animal models. Methods: We examined the current literature and identified relevant studies through PubMed by using combinations of the search terms “arsenic”, “in utero”, “transplacental”, “prenatal” and “fetal”. Discussion: Ecological studies have indicated associations between in uteromore » and/or early life exposure to arsenic at high levels and increases in mortality from cancer, cardiovascular disease and respiratory disease. Additional data from epidemiologic studies suggest intermediate effects in early life that are related to risk of these and other outcomes in adulthood. Experimental animal studies largely support studies in humans, with strong evidence of transplacental carcinogenesis, atherosclerosis and respiratory disease, as well as insight into potential underlying mechanisms of arsenic's health effects. Conclusions: As millions worldwide are exposed to arsenic and evidence continues to support a role for in utero arsenic exposure in the development of a range of later life diseases, there is a need for more prospective studies examining arsenic's relation to early indicators of disease and at lower exposure levels. - Highlights: • We review in utero and early-life As exposure impacts on lifelong disease risks. • Evidence indicates that early-life As increases risks of lung disease, cancer and CVD. • Animal work largely parallels human studies and may lead to new research directions. • Prospective studies and individual exposure assessments with biomarkers are needed. • Assessing intermediary endpoints may aid early intervention and establish causality.« less

Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review.

PubMed

Giulivo, Monica; Lopez de Alda, Miren; Capri, Ettore; Barceló, Damià

2016-11-01

Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

PRESENTED AT THE TRIANGLE CONSORTIUM FOR REPRODUCTIVE BIOLOGY MEETING ON 2/11/06: DI(N-BUTYL) PHTHALATE AND DIETHYLHEXYL PHTHALATE IN COMBINATION ALTER SEXUAL DIFFERENTIATION IN A CUMULATIVE MANNER AS A RESULT OF DEPRESSED FETAL TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RATS

EPA Science Inventory

Plasticizers di(n-butyl) phthalate (DBP) and diehtylhexyl phthalate (DEHP) have similar modes of action: in utero exposure reduces testosterone (T) production in fetal male rats, inhibits reproductive tract differentiation, and induces reproductive organ malformations. In utero e...

Health effects of prenatal radiation exposure.

PubMed

Williams, Pamela M; Fletcher, Stacy

2010-09-01

Pregnant women are at risk of exposure to nonionizing and ionizing radiation resulting from necessary medical procedures, workplace exposure, and diagnostic or therapeutic interventions before the pregnancy is known. Nonionizing radiation includes microwave, ultrasound, radio frequency, and electromagnetic waves. In utero exposure to nonionizing radiation is not associated with significant risks; therefore, ultrasonography is safe to perform during pregnancy. Ionizing radiation includes particles and electromagnetic radiation (e.g., gamma rays, x-rays). In utero exposure to ionizing radiation can be teratogenic, carcinogenic, or mutagenic. The effects are directly related to the level of exposure and stage of fetal development. The fetus is most susceptible to radiation during organogenesis (two to seven weeks after conception) and in the early fetal period (eight to 15 weeks after conception). Noncancer health effects have not been detected at any stage of gestation after exposure to ionizing radiation of less than 0.05 Gy (5 rad). Spontaneous abortion, growth restriction, and mental retardation may occur at higher exposure levels. The risk of cancer is increased regardless of the dose. When an exposure to ionizing radiation occurs, the total fetal radiation dose should be estimated and the mother counseled about the potential risks so that she can make informed decisions about her pregnancy management.

Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: the NewGeneris cohort.

PubMed

Merlo, Domenico Franco; Agramunt, Silvia; Anna, Lívia; Besselink, Harrie; Botsivali, Maria; Brady, Nigel J; Ceppi, Marcello; Chatzi, Leda; Chen, Bowang; Decordier, Ilse; Farmer, Peter B; Fleming, Sarah; Fontana, Vincenzo; Försti, Asta; Fthenou, Eleni; Gallo, Fabio; Georgiadis, Panagiotis; Gmuender, Hans; Godschalk, Roger W; Granum, Berit; Hardie, Laura J; Hemminki, Kari; Hochstenbach, Kevin; Knudsen, Lisbeth E; Kogevinas, Manolis; Kovács, Katalin; Kyrtopoulos, Soterios A; Løvik, Martinus; Nielsen, Jeanette K; Nygaard, Unni Cecilie; Pedersen, Marie; Rydberg, Per; Schoket, Bernadette; Segerbäck, Dan; Singh, Rajinder; Sunyer, Jordi; Törnqvist, Margareta; van Loveren, Henk; van Schooten, Frederik J; Vande Loock, Kim; von Stedingk, Hans; Wright, John; Kleinjans, Jos C; Kirsch-Volders, Micheline; van Delft, Joost H M

2014-02-01

Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development. We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN. We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.

Clear cell adenocarcinoma of cervix in 1-year-old girl without in utero exposure to diethylstilbestrol: an uncommon tumour at an uncommon age and site.

PubMed

Arora, Aditi; Rastogi, Anurag; Neyaz, Azfar; Husain, Nuzhat

2017-03-16

Adenocarcinoma of cervix constitutes about 10-15% cases of carcinoma cervix. Clear cell variant is even a rarer variant of adenocarcinoma. It rarely occurs in the paediatric age group and a known risk factor is in utero exposure to diethylstilbestrol (DES). We report here a case of primary cervical tumour in a 1-year-old girl, which was initially suspected to be an embryonal rhabdomyosarcoma botryoides. Histopathology with immunohistochemical analysis revealed clear cell adenocarcinoma. There was no maternal history of DES intake during pregnancy. We discuss the histopathological characteristics and clinical course of this unusual tumour. 2017 BMJ Publishing Group Ltd.

In utero exposure to dioxins and dioxin-like compounds and anogenital distance in newborns and infants.

PubMed

Vafeiadi, Marina; Agramunt, Silvia; Papadopoulou, Eleni; Besselink, Harrie; Mathianaki, Kleopatra; Karakosta, Polyxeni; Spanaki, Ariana; Koutis, Antonis; Chatzi, Leda; Vrijheid, Martine; Kogevinas, Manolis

2013-01-01

Anogenital distance in animals is used as a measure of fetal androgen action. Prenatal exposure to dioxins and dioxin-like compounds in rodents causes reproductive changes in male offspring and decreases anogenital distance. We assessed whether in utero exposure to dioxins and dioxin-like compounds adversely influences anogenital distance in newborns and young children (median age, 16 months; range, 1-31 months). We measured anogenital distance among participants of the "Rhea" mother-child cohort study in Crete and the Hospital del Mar (HMAR) cohort in Barcelona. Anogenital distance (AGD; anus to upper penis), anoscrotal distance (ASD; anus to scrotum), and penis width (PW) were measured in 119 newborn and 239 young boys; anoclitoral (ACD; anus to clitoris) and anofourchetal distance (AFD; anus to fourchette) were measured in 118 newborn and 223 young girls. We estimated plasma dioxin-like activity in maternal blood samples collected at delivery with the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX®) bioassay. Anogenital distances were sexually dimorphic, being longer in males than females. Plasma dioxin-like activity was negatively associated with AGD in male newborns. The estimated change in AGD per 10 pg CALUX®-toxic equivalent/g lipid increase was -0.44 mm (95% CI: -0.80, -0.08) after adjusting for confounders. Negative but smaller and nonsignificant associations were observed for AGD in young boys. No associations were found in girls. Male infants may be susceptible to endocrine-disrupting effects of dioxins. Our findings are consistent with the experimental animal evidence used by the Food and Agriculture Organization/World Health Organization to set recommendations for human dioxin intake.

In Utero Exposure to Dioxins and Dioxin-like Compounds and Anogenital Distance in Newborns and Infants

PubMed Central

Vafeiadi, Marina; Agramunt, Silvia; Papadopoulou, Eleni; Besselink, Harrie; Mathianaki, Kleopatra; Karakosta, Polyxeni; Spanaki, Ariana; Koutis, Antonis; Chatzi, Leda; Vrijheid, Martine

2012-01-01

Background: Anogenital distance in animals is used as a measure of fetal androgen action. Prenatal exposure to dioxins and dioxin-like compounds in rodents causes reproductive changes in male offspring and decreases anogenital distance. Objective: We assessed whether in utero exposure to dioxins and dioxin-like compounds adversely influences anogenital distance in newborns and young children (median age, 16 months; range, 1–31 months). Methods: We measured anogenital distance among participants of the “Rhea” mother–child cohort study in Crete and the Hospital del Mar (HMAR) cohort in Barcelona. Anogenital distance (AGD; anus to upper penis), anoscrotal distance (ASD; anus to scrotum), and penis width (PW) were measured in 119 newborn and 239 young boys; anoclitoral (ACD; anus to clitoris) and anofourchetal distance (AFD; anus to fourchette) were measured in 118 newborn and 223 young girls. We estimated plasma dioxin-like activity in maternal blood samples collected at delivery with the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX®) bioassay. Results: Anogenital distances were sexually dimorphic, being longer in males than females. Plasma dioxin-like activity was negatively associated with AGD in male newborns. The estimated change in AGD per 10 pg CALUX®–toxic equivalent/g lipid increase was –0.44 mm (95% CI: –0.80, –0.08) after adjusting for confounders. Negative but smaller and nonsignificant associations were observed for AGD in young boys. No associations were found in girls. Conclusions: Male infants may be susceptible to endocrine-disrupting effects of dioxins. Our findings are consistent with the experimental animal evidence used by the Food and Agriculture Organization/World Health Organization to set recommendations for human dioxin intake. PMID:23171674

Prenatal exposure to methanol as a dopamine system sensitization model in C57BL/6J mice

PubMed Central

Mackey, Veronica R.; Muthian, Gladson; Smith, Marquitta; King, Jennifer; Charlton, Clivel G.

2012-01-01

Aims In this study, the effects of prenatal exposure to methanol (MeOH) on the nigrostriatal dopamine (NSDA) system were examined to determine if the interaction could sensitize this system, and serve as an underpinning for Parkinson's disease (PD) like changes that occur later in life. Methanol was studied because its toxicity resembles the symptoms of PD and the symptoms are relieved by l-dopa meaning that MeOH targets the NSDA system. Since fermentation and wood combustion are major sources for MeOH, the incidence of human encounters with MeOH is high. As a superior solvent and the precursor for formaldehyde, MeOH has a powerful and sometimes, irreversible impact on chemical processes, such as cross-linking proteins and nucleic acids. It may cause subthreshold changes that sensitizes the NSDA system to PD, that occur during aging. Main methods To study the prenatal effects of MeOH, pregnant C57BL/6J mice were administered 40 mg/kg MeOH by oral gavage during gestation days 8–12, twice daily. Twelve weeks after birth, behavior impairments were recorded. The striatum was dissected for the determination of tyrosine hydroxylase (TH), l-aromatic amino acid decarboxylase (LAAD), α-synuclein and levels of dopamine (DA) and its metabolites. Key findings MeOH reduced striatal TH and LAAD protein by 47% and 57% respectively and DA by 32%. Significance The results mean that in utero exposure to toxins similar to MeOH could sensitize the striatal system to changes that cause PD. This study may help identify strategies to block this type of in utero toxicity. PMID:23000099

Risk Factors in Early Child Development: Is Prenatal Cocaine/Polydrug Exposure a Key Variable?

ERIC Educational Resources Information Center

Phelps, Leadelle; Wallace, Nancy Virginia; Bontrager, Annie

1997-01-01

Assessed the effect of cocaine/polydrug in utero exposure on early childhood development while controlling for covariant factors. Analysis of two matched samples of preschoolers (20 with drug exposure and 20 without) revealed that both groups scored approximately one standard deviation below the expected mean in social skills, auditory…

The Molecular Epidemiology of Chronic Aflatoxin Driven Impaired Child Growth

PubMed Central

Turner, Paul Craig

2013-01-01

Aflatoxins are toxic secondary fungal metabolites that contaminate dietary staples in tropical regions; chronic high levels of exposure are common for many of the poorest populations. Observations in animals indicate that growth and/or food utilization are adversely affected by aflatoxins. This review highlights the development of validated exposure biomarkers and their use here to assess the role of aflatoxins in early life growth retardation. Aflatoxin exposure occurs in utero and continues in early infancy as weaning foods are introduced. Using aflatoxin-albumin exposure biomarkers, five major studies clearly demonstrate strong dose response relationships between exposure in utero and/or early infancy and growth retardation, identified by reduced birth weight and/or low HAZ and WAZ scores. The epidemiological studies include cross-sectional and longitudinal surveys, though aflatoxin reduction intervention studies are now required to further support these data and guide sustainable options to reduce the burden of exposure. The use of aflatoxin exposure biomarkers was essential in understanding the observational data reviewed and will likely be a critical monitor of the effectiveness of interventions to restrict aflatoxin exposure. Given that an estimated 4.5 billion individuals live in regions at risk of dietary contamination the public health concern cannot be over stated. PMID:24455429

In utero exposure to iodine-131 from Chernobyl fallout and anthropometric characteristics in adolescence.

PubMed

Neta, Gila; Hatch, Maureen; Kitahara, Cari M; Ostroumova, Evgenia; Bolshova, Elena V; Tereschenko, Valery P; Tronko, Mykola D; Brenner, Alina V

2014-03-01

Prenatal exposure to external radiation has been linked to growth retardation among atomic bomb survivors in adolescence. It is unclear from previous studies whether in utero exposure to internal radiation such as iodine-131 (I-131), which concentrates in the thyroid gland, has an effect on physical growth. We examined the associations between estimated thyroid gland dose from prenatal exposure to I-131 and self-reported height and weight in a cohort of 2,460 individuals exposed to radioactive fallout from the 1986 Chernobyl nuclear accident [mean I-131 dose = 72 (mGy)] and screened for thyroid diseases in adolescence. Using multivariable linear regression models, we estimated the mean differences in height, weight and body mass index (BMI) per unit increase in dose (100 mGy) in models adjusted for gender, age at examination, type of residence (rural/urban) and presence of thyroid disease diagnosed at screening. All of the adjustment factors as well as the trimester of exposure were evaluated as potential modifiers of the dose response. Overall, no significant dose response was found for height (P = 0.29), weight (P = 0.14) or BMI (P = 0.16). We found significant modification of the dose response for weight and BMI by presence/absence of thyroid disease (P = 0.02 and P = 0.03, respectively), but not for other factors. In individuals without thyroid disease (n = 1,856), there was a weak, significant association between I-131 thyroid dose and higher weight (210 g per 100 mGy, P = 0.02) or BMI (70 g/m² per 100 mGy, P = 0.02) that depended on individuals (n = 52) exposed to ≥500 mGy. In individuals with thyroid disease (n = 579, 67.4% with simple diffuse goiter) no significant association with I-131 for weight (P = 0.14) or BMI (P = 0.14) was found. These results do not support the hypothesis that in utero exposure to I-131 at levels experienced by a majority of study subjects may be associated with meaningful differences in adolescent anthropometry. However, additional studies are needed to clarify whether in utero exposure to I-131 at levels > = 500 mGy may be associated with increases in weight/BMI and to evaluate the confounding or modifying role of thyroid disease, past iodine deficiency, maternal and prenatal/postnatal factors.

In Utero Exposure to Iodine-131 from Chernobyl Fallout and Anthropometric Characteristics in Adolescence

PubMed Central

Neta, Gila; Hatch, Maureen; Kitahara, Cari M.; Ostroumova, Evgenia; Bolshova, Elena V.; Tereschenko, Valery P.; Tronko, Mykola D.; Brenner, Alina V.

2014-01-01

Prenatal exposure to external radiation has been linked to growth retardation among atomic bomb survivors in adolescence. It is unclear from previous studies whether in utero exposure to internal radiation such as iodine-131 (I-131), which concentrates in the thyroid gland, has an effect on physical growth. We examined the associations between estimated thyroid gland dose from prenatal exposure to I-131 and self-reported height and weight in a cohort of 2,460 individuals exposed to radioactive fallout from the 1986 Chernobyl nuclear accident [mean I-131 dose = 72 (mGy)] and screened for thyroid diseases in adolescence. Using multivariable linear regression models, we estimated the mean differences in height, weight and body mass index (BMI) per unit increase in dose (100 mGy) in models adjusted for gender, age at examination, type of residence (rural/urban) and presence of thyroid disease diagnosed at screening. All of the adjustment factors as well as the trimester of exposure were evaluated as potential modifiers of the dose response. Overall, no significant dose response was found for height (P = 0.29), weight (P = 0.14) or BMI (P = 0.16). We found significant modification of the dose response for weight and BMI by presence/absence of thyroid disease (P = 0.02 and P = 0.03, respectively), but not for other factors. In individuals without thyroid disease (n = 1,856), there was a weak, significant association between I-131 thyroid dose and higher weight (210 g per 100 mGy, P = 0.02) or BMI (70 g/m2 per 100 mGy, P = 0.02) that depended on individuals (n = 52) exposed to ≥500 mGy. In individuals with thyroid disease (n = 579, 67.4% with simple diffuse goiter) no significant association with I-131 for weight (P = 0.14) or BMI (P = 0.14) was found. These results do not support the hypothesis that in utero exposure to I-131 at levels experienced by a majority of study subjects may be associated with meaningful differences in adolescent anthropometry. However, additional studies are needed to clarify whether in utero exposure to I-131 at levels > = 500 mGy may be associated with increases in weight/BMI and to evaluate the confounding or modifying role of thyroid disease, past iodine deficiency, maternal and prenatal/postnatal factors. PMID:24611659

Air pollution-induced placental epigenetic alterations in early life: a candidate miRNA approach

PubMed Central

Tsamou, Maria; Vrijens, Karen; Madhloum, Narjes; Lefebvre, Wouter; Vanpoucke, Charlotte; Nawrot, Tim S

2018-01-01

ABSTRACT Particulate matter (PM) exposure during in utero life may entail adverse health outcomes in later-life. Air pollution's adverse effects are known to alter gene expression profiles, which can be regulated by microRNAs (miRNAs). We investigate the potential influence of air pollution exposure in prenatal life on placental miRNA expression. Within the framework of the ENVIRONAGE birth cohort, we measured the expression of six candidate miRNAs in placental tissue from 210 mother-newborn pairs by qRT-PCR. Trimester-specific PM2.5 exposure levels were estimated for each mother's home address using a spatiotemporal model. Multiple regression models were used to study miRNA expression and in utero exposure to PM2.5 over various time windows during pregnancy. The placental expression of miR-21 (−33.7%, 95% CI: −53.2 to −6.2, P = 0.022), miR-146a (−30.9%, 95% CI: −48.0 to −8.1, P = 0.012) and miR-222 (−25.4%, 95% CI: −43.0 to −2.4, P = 0.034) was inversely associated with PM2.5 exposure during the 2nd trimester of pregnancy, while placental expression of miR-20a and miR-21 was positively associated with 1st trimester exposure. Tumor suppressor phosphatase and tensin homolog (PTEN) was identified as a common target of the miRNAs significantly associated with PM exposure. Placental PTEN expression was strongly and positively associated (+59.6% per 5 µg/m³ increment, 95% CI: 26.9 to 100.7, P < 0.0001) with 3rd trimester PM2.5 exposure. Further research is required to establish the role these early miRNA and mRNA expression changes might play in PM-induced health effects. We provide molecular evidence showing that in utero PM2.5 exposure affects miRNAs expression as well as its downstream target PTEN. PMID:27104955

Brain heparan sulphate proteoglycans are altered in developing foetus when exposed to in-utero hyperglycaemia.

PubMed

Sandeep, M S; Nandini, C D

2017-08-01

In-utero exposure of foetus to hyperglycaemic condition affects the growth and development of the organism. The brain is one of the first organs that start to develop during embryonic period and glycosaminoglycans (GAGs) and proteoglycans (PGs) are one of the key molecules involved in its development. But studies on the effect of hyperglycaemic conditions on brain GAGs/PGs are few and far between. We, therefore, looked into the changes in brain GAGs and PGs at various developmental stages of pre- and post-natal rats from non-diabetic and diabetic mothers as well as in adult rats induced with diabetes using a diabetogenic agent, Streptozotocin. Increased expression of GAGs especially that of heparan sulphate class in various developmental stages were observed in the brain as a result of in-utero hyperglycaemic condition but not in that of adult rats. Changes in disaccharides of heparan sulphate (HS) were observed in various developmental stages. Furthermore, various HSPGs namely, syndecans-1 and -3 and glypican-1 were overexpressed in offspring from diabetic mother. However, in adult diabetic rats, only glypican-1 was overexpressed. The offsprings from diabetic mothers became hyperphagic at the end of 8 weeks after birth which can have implications in the long run. Our results highlight the likely impact of the in-utero exposure of foetus to hyperglycaemic condition on brain GAGs/PGs compared to diabetic adult rats.

Does acute maternal stress in pregnancy affect infant health outcomes? Examination of a large cohort of infants born after the terrorist attacks of September 11, 2001.

PubMed

Endara, Skye M; Ryan, Margaret A K; Sevick, Carter J; Conlin, Ava Marie S; Macera, Caroline A; Smith, Tyler C

2009-07-20

Infants in utero during the terrorist attacks of September 11, 2001 may have been negatively affected by maternal stress. Studies to date have produced contradictory results. Data for this retrospective cohort study were obtained from the Department of Defense Birth and Infant Health Registry and included up to 164,743 infants born to active-duty military families. Infants were considered exposed if they were in utero on September 11, 2001, while the referent group included infants gestating in the same period in the preceding and following year (2000 and 2002). We investigated the association of this acute stress during pregnancy with the infant health outcomes of male:female sex ratio, birth defects, preterm birth, and growth deficiencies in utero and in infancy. No difference in sex ratio was observed between infants in utero in the first trimester of pregnancy on September 11, 2001 and infants in the referent population. Examination of the relationship between first-trimester exposure and birth defects also revealed no significant associations. In adjusted multivariable models, neither preterm birth nor growth deficiencies were significantly associated with the maternal exposure to the stress of September 11 during pregnancy. The findings from this large population-based study suggest that women who were pregnant during the terrorist attacks of September 11, 2001 had no increased risk of adverse infant health outcomes.

Maternal and cord blood vitamin D status and childhood infection and allergic disease: a systematic review

PubMed Central

Fried, David A.; Rhyu, Jane; Odato, Karen; Blunt, Heather; Karagas, Margaret R.

2016-01-01

Context: It is unclear how in utero vitamin D deficiency affects the extraskeletal health of children, despite the known risks for adverse pregnancy/birth outcomes. Objective: This systematic review seeks to assess the effect of in utero vitamin D exposure on childhood allergy and infection outcomes using the PRISMA guidelines. Data Sources: MEDLINE, Cochrane Library, and Web of Science databases were searched. Study Selection: Literature published through April 2015 was searched for studies reporting on the association between maternal pregnancy or cord blood vitamin D status and childhood allergy and infection. Data Extraction: Of 4175 articles identified, 43 studies met the inclusion criteria. They examined a wide variety of outcomes, using many different vitamin D cutoff values in their analyses. Data Synthesis: For most outcomes, results were inconsistent, although there appeared to be a protective effect between higher in utero vitamin D status and childhood lower respiratory tract infection (5 of 10 studies). Conclusions: More research is needed on childhood allergy and infection outcomes, and future studies should standardize outcome reporting, especially with regard to cutoff values for vitamin D concentrations. Evidence of a protective association between in utero vitamin D exposure and lower respiratory tract infection was found, while the other outcomes were either understudied or showed inconsistent results. PROSPERO registration no. CRD42013006156. PMID:27083486

Urinary 3-phenoxybenzoic acid (3-PBA) levels among pregnant women in Mexico City: Distribution and relationships with child neurodevelopment

PubMed Central

Watkins, Deborah J.; Fortenberry, Gamola Z.; Sánchez, Brisa N.; Barr, Dana Boyd; Panuwet, Parinya; Schnaas, Lourdes; Osorio-Valencia, Erika; Solano-González, Maritsa; Ettinger, Adrienne S.; Hernández-Ávila, Mauricio; Hu, Howard; Téllez-Rojo, Martha María; Meeker, John D.

2016-01-01

Background In recent years, pyrethroid pesticide use has increased in Mexico, the United States, and elsewhere, resulting in extensive human exposure. There is growing concern that pregnant women may be a particularly vulnerable population, as in utero fetal exposure during critical periods of development could adversely affect long-term neurobehavioral function. Methods We measured maternal urinary 3-phenoxybenzoic acid (3-PBA) concentrations during the third trimester of pregnancy as a measure of in utero pyrethroid exposure to the fetus among participants in an established Mexico City birth cohort (n=187). In a subset of mothers, we measured 3-PBA during the first, second, and third trimester (n=21) to assess variability across pregnancy. We examined associations between third trimester 3-PBA concentrations and children’s scores on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) from the Bayley Scales for Infant Development (BSID-IIS) at 24 and 36 months of age. Results 3-PBA was detected in 46% of all urine samples, with similar detection rates and geometric mean concentrations across pregnancy among the 21 participants who provided repeat samples. Participants in the medium and high 3-PBA categories (≥LOD) had lower MDI scores at 24 months compared to those in the low 3-PBA category (

The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic

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

Tsang, Verne; Fry, Rebecca C.; Niculescu, Mihai D.

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never beenmore » thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. Highlights: ► We used transplacental CD1 mice model for inorganic arsenic (iAs) carcinogenesis. ► We examined the effects of gestational iAs and high folate exposure on DNA methylation. ► iAs–folate interaction resulted in low fetal weights and changes in DNA methylation. ► Epigenetically altered genes were associated with cancer and neurodevelopment. ► We showed that in utero iAs–folate interaction negatively affects fetal development.« less

In-utero exposure to DDT and cognitive development among infants and school-aged children

PubMed Central

Jusko, Todd A.; Klebanoff, Mark A.; Brock, John W.; Longnecker, Matthew P.

2012-01-01

Background Dichlorodiphenyltrichloroethane (DDT) continues to be used for control of infectious diseases in several countries. In-utero exposure to DDT and dichlorodiphenyldichloroethylene (DDE) has been associated with developmental and cognitive impairment among children. We examined this association in an historical cohort in which the level of exposure was greater than in previous studies. Methods The association of in-utero DDT and DDE exposure with infant and child neurodevelopment was examined in approximately 1100 subjects in the Collaborative Perinatal Project, a prospective birth cohort enrolling pregnant women from 12 study centers in the U.S. from 1959 to 1965. Maternal DDT and DDE concentrations were measured in archived serum specimens. Infant mental and motor development was assessed at age 8 months using the Bayley Scales of Infant Development, and child cognitive development was assessed at age 7 years using the Wechsler Intelligence Scale for Children. Results Although levels of both DDT and DDE were relatively high in this population (median DDT concentration, 8.9 µg/L; DDE, 24.5 µg/L), neither was related to Mental or Psychomotor Development scores on the Bayley Scales or to Full-Scale IQ at 7 years of age. Categorical analyses showed no evidence of dose-response for either maternal DDT or DDE, and estimates of the association between continuous measures of exposure and neurodevelopment were indistinguishable from 0. Conclusions Adverse associations were not observed between maternal serum DDT and DDE concentrations and offspring neurodevelopment at 8 months or 7 years of age in this cohort. PMID:22766752

Differential neurotoxic effects of in utero and lactational exposure to hydroxylated polychlorinated biphenyl (OH-PCB 106) on spontaneous locomotor activity and motor coordination in young adult male mice.

PubMed

Haijima, Asahi; Lesmana, Ronny; Shimokawa, Noriaki; Amano, Izuki; Takatsuru, Yusuke; Koibuchi, Noriyuki

2017-01-01

We investigated whether in utero or lactational exposure to 4-hydroxy-2',3,3',4',5'-pentachlorobiphenyl (OH-PCB 106) affects spontaneous locomotor activity and motor coordination in young adult male mice. For in utero exposure, pregnant C57BL/6J mice received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from gestational day 10 to 18. For lactational exposure, the different groups of dams received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from postpartum day 3 to 13. At 6-7 weeks of age, the spontaneous locomotor activities of male offspring were evaluated for a 24-hr continuous session in a home cage and in an open field for 30-min. Motor coordination function on an accelerating rotarod was also measured. Mice exposed prenatally to OH-PCB 106 showed increased spontaneous locomotor activities during the dark phase in the home cage and during the first 10-min in the open field compared with control mice. Mice exposed lactationally to OH-PCB 106, however, did not show a time-dependent decrease in locomotor activity in the open field. Instead, their locomotor activity increased significantly during the second 10-min block. In addition, mice exposed lactationally to OH-PCB 106 displayed impairments in motor coordination in the rotarod test. These results suggest that perinatal exposure to OH-PCB 106 affects motor behaviors in young adult male mice. Depending on the period of exposure, OH-PCB 106 may have different effects on neurobehavioral development.

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

PubMed

Comish, Paul B; Drumond, Ana Luiza; Kinnell, Hazel L; Anderson, Richard A; Matin, Angabin; Meistrich, Marvin L; Shetty, Gunapala

2014-01-01

Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

Fetal Cyclophosphamide Exposure Induces Testicular Cancer and Reduced Spermatogenesis and Ovarian Follicle Numbers in Mice

PubMed Central

Comish, Paul B.; Drumond, Ana Luiza; Kinnell, Hazel L.; Anderson, Richard A.; Matin, Angabin; Meistrich, Marvin L.; Shetty, Gunapala

2014-01-01

Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼70% of control and induced atrophic seminiferous tubules in ∼30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan. PMID:24691397

Increased Risk of Severe Infant Anemia Following Exposure to Maternal HAART, Botswana

PubMed Central

Dryden-Peterson, Scott; Shapiro, Roger L.; Hughes, Michael D.; Powis, Kathleen; Ogwu, Anthony; Moffat, Claire; Moyo, Sikhulile; Makhema, Joseph; Essex, Max; Lockman, Shahin

2011-01-01

Background Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission (MTCT), but may increase the risk for infant anemia. Methods The incidence of first severe anemia (Grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana MTCT prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding and 1 month of postnatal zidovudine (HAART-BF); infants exposed to maternal zidovudine (ZDV) in utero, 6 months of postnatal ZDV, and breastfeeding (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). Results A total of 1719 infants were analyzed— 691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P<0.001) and 2.5% of ZDV-FF infants (P<0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. Conclusions Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study. Trial Registration ClinicalTrials.gov identifiers: NCT00197587 and NCT00270296. PMID:21266910

Epigenetic Perspective on the Developmental Effects of Bisphenol A

PubMed Central

Kundakovic, Marija; Champagne, Frances A.

2013-01-01

Bisphenol A (BPA) is an estrogenic environmental toxin widely used in the production of plastics and ubiquitous human exposure to this chemical has been proposed to be a potential risk to public health. Animal studies suggest that in utero and early postnatal exposure to this compound may produce a broad range of adverse effects, including impaired brain development, sexual differentiation, behavior, and immune function, which could extend to future generations. Molecular mechanisms that underlie the long-lasting effects of BPA continue to be elucidated, and likely involve disruption of epigenetic programming of gene expression during development. Several studies have provided evidence that maternal exposure to BPA results in postnatal changes in DNA methylation status and altered expression of specific genes in offspring. However, further studies are needed to extend these initial findings to other genes in different tissues, and to examine the correlations between BPA-induced epigenetic alterations, changes in gene expression, and various phenotypic outcomes. It will be also important to explore whether the epigenetic effects of BPA are related to its estrogenic activity, and to determine which downstream effector proteins could mediate changes in DNA methylation. In this review, we will highlight research indicating a consequence of prenatal BPA exposure for brain, behavior, and immune outcomes and discuss evidence for the role of epigenetic pathways in shaping these developmental effects. Based on this evidence, we will suggest future directions in the study of BPA-induced epigenetic effects and discuss the transgenerational implications of exposure to endocrine disrupting chemicals. PMID:21333735

Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities.

PubMed

Gill, W B; Schumacher, G F; Bibbo, M; Straus, F H; Schoenberg, H W

1979-07-01

Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls. Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent). Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism. Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent. Although none of our Diekmann's lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid. A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.

Adverse health outcomes in women exposed in utero to diethylstilbestrol.

PubMed

Hoover, Robert N; Hyer, Marianne; Pfeiffer, Ruth M; Adam, Ervin; Bond, Brian; Cheville, Andrea L; Colton, Theodore; Hartge, Patricia; Hatch, Elizabeth E; Herbst, Arthur L; Karlan, Beth Y; Kaufman, Raymond; Noller, Kenneth L; Palmer, Julie R; Robboy, Stanley J; Saal, Robert C; Strohsnitter, William; Titus-Ernstoff, Linda; Troisi, Rebecca

2011-10-06

Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

Combined Exposure to Anti-Androgens Exacerbates Disruption of Sexual Differentiation in the Rat

PubMed Central

Hass, Ulla; Scholze, Martin; Christiansen, Sofie; Dalgaard, Majken; Vinggaard, Anne Marie; Axelstad, Marta; Metzdorff, Stine Broeng; Kortenkamp, Andreas

2007-01-01

Objective The aim of this study was to assess whether the joint effects of three androgen receptor antagonists (vinclozolin, flutamide, procymidone) on male sexual differentiation after in utero and postnatal exposures can be predicted based on dose–response data of the individual chemicals. Methods Test chemicals and mixtures were administered by gavage to time-mated nulliparous, young adult Wistar rats from gestational day 7 to the day before expected birth, and from postnatal days 1–16. Changes in anogenital distance (AGD) and nipple retention (NR) in male offspring rats were chosen as end points for extensive dose–response studies. Vinclozolin, flutamide, and procymidone were combined at a mixture ratio proportional to their individual potencies for causing retention of six nipples in male offspring. Results With AGD as the end point, the joint effects of the three anti-androgens were essentially dose additive. The observed responses for NR were slightly higher than those expected on the basis of dose addition. A combination of doses of each chemical, which on its own did not produce statistically significant AGD alterations, induced half-maximal mixture effects. At individual doses associated with only modest effects on NR, the mixture induced NR approaching female values in the males. Conclusions Effects of a mixture of similarly acting anti-androgens can be predicted fairly accurately on the basis of the potency of the individual mixture components by using the dose addition concept. Exposure to anti-androgens, which individually appears to exert only small effects, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals. PMID:18174960

Predicting Later-Life Outcomes of Early-Life Exposures

EPA Science Inventory

Background: In utero exposure of the fetus to a stressor can lead to disease in later life. Epigenetic mechanisms are likely mediators of later-life expression of early-life events.Objectives: We examined the current state of understanding of later-life diseases resulting from ea...

Di-isoheptyl Phthalate (DIHP) in utero exposure reduces testicular testosterone (T) production in fetal Sprague Dawley (SD) rats

EPA Science Inventory

Exposure to DIHP, a commercial phthalate ester plasticizer used in flooring manufacturing, during the fetal period of sexual differentiation disrupts male reproductive development resulting in reproductive malformations and reduced androgen-dependent reproductive tissue weights i...

Phthalate-induced toxicity: Identifying the vulnerable pathways during sexual differentiation in the male rat

EPA Science Inventory

Human exposures to phthalate ester plasticizer compounds are widespread. Studies in rodents have demonstrated that in utero exposure to various phthalates throughout sexual differentiation (GD14-18) results in decreased fetal testicular androgen production, and ultimately leads t...

Arsenic Metabolism and Distribution in Developing Organisms

EPA Science Inventory

A growing body of evidence suggests that exposure to inorganic arsenic during early life has long term adverse effects. The extent of exposure to inorganic arsenic and its methylated metabolites in utero is determined not only by the rates of formation and transfer of arsenicals...

Disclosing in utero HIV/ARV exposure to the HIV-exposed uninfected adolescent: is it necessary?

PubMed Central

Jao, Jennifer; Hazra, Rohan; Mellins, Claude A; Remien, Robert H; Abrams, Elaine J

2016-01-01

Introduction The tremendous success of antiretroviral therapy has resulted in a diminishing population of perinatally HIV-infected children on the one hand and a mounting number of HIV-exposed uninfected (HEU) children on the other. As the oldest of these HEU children are reaching adolescence, questions have emerged surrounding the implications of HEU status disclosure to these adolescents. This article outlines the arguments for and against disclosure of a child's HEU status. Discussion Disclosure of a child's HEU status, by definition, requires disclosure of maternal HIV status. It is necessary to weigh the benefits and harms which could occur with disclosure in each of the following domains: psychosocial impact, long-term physical health of the HEU individual and the public health impact. Does disclosure improve or worsen the psychological health of the HEU individual and extended family unit? Do present data on the long-term safety of in utero HIV/ARV exposure reveal potential health risks which merit disclosure to the HEU adolescent? What research and public health programmes or systems need to be in place to afford monitoring of HEU individuals and which, if any, of these require disclosure? Conclusions At present, it is not clear that there is sufficient evidence on whether long-term adverse effects are associated with in utero HIV/ARV exposures, making it difficult to mandate universal disclosure. However, as more countries adopt electronic medical record systems, the HEU status of an individual should be an important piece of the health record which follows the infant not only through childhood and adolescence but also adulthood. Clinicians and researchers should continue to approach the dialogue around mother–child disclosure with sensitivity and a cogent consideration of the evolving risks and benefits as new information becomes available while also working to maintain documentation of an individual's perinatal HIV/ARV exposures as a vital part of his/her medical records. As more long-term adult safety data on in utero HIV/ARV exposures become available these decisions may become clearer, but at this time, they remain complex and multi-faceted. PMID:27741954

In utero and lactational exposure to BDE-47 promotes obesity development in mouse offspring fed a high-fat diet: impaired lipid metabolism and intestinal dysbiosis.

PubMed

Wang, Dezhen; Yan, Jin; Teng, Miaomiao; Yan, Sen; Zhou, Zhiqiang; Zhu, Wentao

2018-05-01

In this study, we investigated the effects of in utero and lactational exposure to BDE-47 on the progression of obesity and metabolic dysfunction in a diet-induced obesity model. Pregnant ICR mice were treated via oral gavage with low doses of BDE-47 (0, 0.002, and 0.2 mg/kg body weight) from gestational day 6 to postnatal day 21. After weaning, male offspring were fed an AIN93-based normal diet (ND) or high-fat diet (HFD: 60% calories from fat) for 14 weeks. We examined body weight, liver weight, histopathology, blood biochemistry, gene expression, and serum metabolic changes. A combination of 16S rRNA gene sequencing and 1 H NMR-based metabolomics was conducted to examine the effects of BDE-47 on the gut microbiome. Results showed that in utero and lactational exposure to BDE-47 caused a worsening of HFD-induced obesity, hepatic steatosis, and injury; impaired glucose homeostasis and metabolic dysfunction, and mRNA levels of genes involved in lipid metabolism were significantly altered in the BDE-47-treated HFD group. The gut microbiome were perturbed by BDE-47, causing diversity reduction, compositional alteration, and metabolic changes. These changes were more pronounced for BDE-47-treated HFD mice. All these results indicate that early life exposure to low doses of BDE-47 can promote obesity and the development of metabolic dysfunction.

Gestational Atrazine Exposure: Effects on Male Reproductive Development and Metabolite Distribution in the Dam, Fetus, and Neonate

EPA Science Inventory

Few studies have investigated the long-term effects of atrazine (ATR)following in utero exposure. We evaluated the effects of gestational exposure of Sprague Dawley dams to ATR (0, 1, 5.20, or 100 mg/Kg-d) on the reproductive development of male offspring. We also quantified the...

Household Financial Distress and Initial Endowments: Evidence from the 2008 Financial Crisis.

PubMed

Olafsson, Arna

2016-11-01

This paper studies in utero exposure to the 2008 financial crisis. Exploiting the sudden and unexpected collapse of the Icelandic economy, I find that first-trimester exposure to the crisis led to a sizable and significant reduction in birth weight, increased the probability of a low birth weight ( < 2500 g), and decreased the probability of a high birth weight ( > 4000 g). I also find evidence that the collapse reduced the sex ratio, indicating selection in utero due to maternal prenatal stress exposure. My results imply large welfare losses from financial distress that have hitherto been ignored - because children with worse health at birth can expect substantially lower lifetime earnings - and suggest that economic hardships may in general exacerbate income inequalities in the long run as low-income households are typically more exposed to financial distress. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Keap1-Nrf2 regulated redox signaling in utero: Priming of disease susceptibility in offspring.

PubMed

Chapple, Sarah J; Puszyk, William M; Mann, Giovanni E

2015-11-01

Intrauterine exposure to gestational diabetes, pre-eclampsia or intrauterine growth restriction alters the redox status of the developing fetus. Such pregnancy-related diseases in most cases do not have a readily identifiable genetic cause, and epigenetic 'priming' mechanisms in utero may predispose both mother and child to later-life onset of cardiovascular and metabolic diseases. The concept of 'fetal programing' or 'developmental priming' and its association with an increased risk of disease in childhood or adulthood has been reviewed extensively. This review focuses on adaptive changes in the in utero redox environment during normal pregnancy and the consequences of alterations in redox control associated with pregnancies characterized by oxidative stress. We evaluate the evidence that the Keap1-Nrf2 pathway is important for protecting the fetus against adverse conditions in utero and may itself be subject to epigenetic priming, potentially contributing to an increased risk of vascular disease and insulin resistance in later life. Copyright © 2015 Elsevier Inc. All rights reserved.

Association between fetal exposure to phthalate endocrine disruptor and genome-wide DNA methylation at birth.

PubMed

Chen, Chung-Hsing; Jiang, Shih Sheng; Chang, I-Shou; Wen, Hui-Ju; Sun, Chien-Wen; Wang, Shu-Li

2018-04-01

Phthalic acid esters are ubiquitous and antiandrogenic, and may cause systemic effects in humans, particularly with in utero exposure. Epigenetic modification, such as DNA methylation, has been hypothesized to be an important mechanism that mediates certain biological processes and pathogenic effects of in utero phthalate exposure. The aim of this study was to examine the association between genome-wide DNA methylation at birth and prenatal exposure to phthalate. We studied 64 infant-mother pairs included in TMICS (Taiwan Maternal and Infant Cohort Study), a long-term follow-up birth cohort from the general population. DNA methylation levels at more than 450,000 CpG sites were measured in cord blood samples using Illumina Infinium HumanMethylation450 BeadChips. The concentrations of three metabolites of di-(2-ethylhexyl) phthalate (DEHP) were measured using liquid chromatography tandem-mass spectrometry (LC-MS/MS) in urine samples collected from the pregnant women during 28-36 weeks gestation. We identified 25 CpG sites whose methylation levels in cord blood were significantly correlated with prenatal DEHP exposure using a false discovery rate (FDR) of 5% (q-value < 0.05). Via gene-set enrichment analysis (GSEA), we also found that there was significant enrichment of genes involved in the androgen response, estrogen response, and spermatogenesis within those genes showing DNA methylation changes in response to exposure. Specifically, PA2G4, HMGCR, and XRCC6 genes were involved in genes in response to androgen. Phthalate exposure in utero may cause significant alterations in the DNA methylation in cord blood. These changes in DNA methylation might serve as biomarkers of maternal exposure to phthalate in infancy and potential candidates for studying mechanisms via which phthalate may impact on health in later life. Future investigations are warranted. Copyright © 2018 Elsevier Inc. All rights reserved.

Validation of an automated counting procedure for phthalate-induced testicular multinucleated germ cells

EPA Science Inventory

In utero exposure to certain phthalate esters results in testicular toxicity, characterized at the tissue level by induction of multinucleated germ cells (MNGs) in rat, mouse, and human fetal testis. Phthalate exposures also result in a decrease in testicular testosterone in rats...

76 FR 22045 - Fluopicolide; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-20

... increased quantitative susceptibility of rat or rabbit fetuses to in utero or postnatal exposure to... is identified as docket ID number EPA-HQ-OPP-2006-0481. A quantitative reassessment of the BAM risk... fluopicolide and separately, its metabolite, BAM in food as follows: i. Acute exposure. Quantitative acute...

Precocious glucocorticoid exposure reduces skeletal muscle satellite cells in the fetal rat

USDA-ARS?s Scientific Manuscript database

Perinatal skeletal muscle growth rates are a function of protein and myonuclear accretion. Precocious exposure of the fetus to glucocorticoids (GLC) in utero impairs muscle growth. Reduced muscle protein synthesis rates contribute to this response, but the consequences for myonuclear hyperplasia are...

Effects of arsenic exposure on DNA methylation in cord blood samples from newborn babies and in a human lymphoblast cell line

PubMed Central

2012-01-01

Background Accumulating evidence indicates that in utero exposure to arsenic is associated with congenital defects and long-term disease consequences including cancers. Recent studies suggest that arsenic carcinogenesis results from epigenetic changes, particularly in DNA methylation. This study aimed to investigate DNA methylation changes as a result of arsenic exposure in utero and in vitro. Methods For the exposure in utero study, a total of seventy-one newborns (fifty-five arsenic-exposed and sixteen unexposed newborns) were recruited. Arsenic concentrations in the drinking water were measured, and exposure in newborns was assessed by measurement of arsenic concentrations in cord blood, nails and hair by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). In the in vitro study, human lymphoblasts were treated with arsenite at 0-100 μM for two, four and eight hours (short-term) and at 0, 0.5 and 1.0 μM for eight-weeks period (long-term). DNA methylation was analyzed in cord blood lymphocytes and lymphoblasts treated with arsenite in vitro. Global DNA methylation was determined as LINE-1 methylation using combined bisulfite restriction analysis (COBRA) and total 5-methyldeoxycytidine (5MedC) content which was determined by HPLC-MS/MS. Methylation of p53 was determined at the promoter region using methylation-specific restriction endonuclease digestion with MspI and HpaII. Results Results showed that arsenic-exposed newborns had significantly higher levels of arsenic in cord blood, fingernails, toenails and hair than those of the unexposed subjects and a slight increase in promoter methylation of p53 in cord blood lymphocytes which significantly correlated with arsenic accumulation in nails (p < 0.05) was observed, while LINE-1 methylation was unchanged. Short-term in vitro arsenite treatment in lymphoblastoid cells clearly demonstrated a significant global hypomethylation, determined as reduction in LINE-1 methylation and total 5-MedC content, and p53 hypermethylation (p < 0.05). However, a slight LINE-1 hypomethylation and transient p53 promoter hypermethylation were observed following long-term in vitro treatment. Conclusions This study provides an important finding that in utero arsenic exposure affects DNA methylation, particularly at the p53 promoter region, which may be linked to the mechanism of arsenic carcinogenesis and the observed increased incidence of cancer later in life. PMID:22551203

Differential expression of the phthalate syndrome in male Sprague-Dawley and Wistar rats after in utero DEHP exposure

EPA Science Inventory

Exposure to phthalate esters during sexual differentiation disrupts testosterone and insulin-like three hormones resulting in malformations of androgen- and insulin-like three-dependent tissues. The current study was designed to test the hypothesis that gubernacular lesions would...

Comparison of ex vivo DSP and in vitro MBP Exposures on Fetal Testis Testosterone Production

EPA Science Inventory

In utero exposure to di‐butyl phthalate (DBP) during sex differentiation reduces androgen production and produces a characteristic profile of gene expression changes in the fetal testis. The DPB metabolite mono‐butyl phthalate (MBP) is hypothesized to produce these changes by ...

In utero glucocorticoid (GLC) exposure reduces fetal skeletal muscle growth in rats

USDA-ARS?s Scientific Manuscript database

Maternal undernutrition and stress expose the fetus to above normal levels of GLC and predispose to intrauterine growth restriction. The aim of this study was to determine if fetal GLC exposure impairs skeletal muscle growth independently of maternal undernutrition. Three groups (n=7/group) of timed...

In utero exposure to lipopolysaccharide alters the postnatal acute phase response in beef heifers

USDA-ARS?s Scientific Manuscript database

This study was designed to determine the potential effect of prenatal lipopolysaccharide (LPS) exposure on the postnatal acute phase response (APR) to an LPS challenge in heifers. Pregnant crossbred cows (n = 50) were separated into prenatal immune stimulation (PIS; n = 25; administered 0.1 microgr...

75 FR 80346 - Flutolanil; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-22

... turnip greens. The Interregional Research Project Number 4 requested these tolerances under the Federal... the Interregional Research Project No. 4 (IR-4), 500 College Road East, Suite 201W, Princeton, NJ... susceptibility of rat or rabbit fetuses to in utero exposure or rat pups to pre- and post-natal exposure to...

Opiate and Cocaine Exposed Newborns: Growth Outcomes.

ERIC Educational Resources Information Center

Butz, Arlene M.; Kaufmann, Walter E.; Royall, Richard; Kolodner, Ken; Pulsifer, Margaret B.; Lears, Mary Kathleen; Henderson, Robin; Belcher, Harolyn; Sellers, Sherri; Wilson, Modena

1999-01-01

Examines growth parameters at birth in 204 infants born to mothers who used cocaine and/or opiates during pregnancy. Outcome measures included birth weight, length, and head circumference. Study provides support that in utero cocaine exposure may confer more risk for somatic growth retardation at birth than opiate exposure. (Author/GCP)

Longitudinal Effects of Embryonic Exposure to Cocaine on Morphology, Cardiovascular Physiology, and Behavior in Zebrafish.

PubMed

Mersereau, Eric J; Boyle, Cody A; Poitra, Shelby; Espinoza, Ana; Seiler, Joclyn; Longie, Robert; Delvo, Lisa; Szarkowski, Megan; Maliske, Joshua; Chalmers, Sarah; Darland, Diane C; Darland, Tristan

2016-05-31

A sizeable portion of the societal drain from cocaine abuse results from the complications of in utero drug exposure. Because of challenges in using humans and mammalian model organisms as test subjects, much debate remains about the impact of in utero cocaine exposure. Zebrafish offer a number of advantages as a model in longitudinal toxicology studies and are quite sensitive physiologically and behaviorally to cocaine. In this study, we have used zebrafish to model the effects of embryonic pre-exposure to cocaine on development and on subsequent cardiovascular physiology and cocaine-induced conditioned place preference (CPP) in longitudinal adults. Larval fish showed a progressive decrease in telencephalic size with increased doses of cocaine. These treated larvae also showed a dose dependent response in heart rate that persisted 24 h after drug cessation. Embryonic cocaine exposure had little effect on overall health of longitudinal adults, but subtle changes in cardiovascular physiology were seen including decreased sensitivity to isoproterenol and increased sensitivity to cocaine. These longitudinal adult fish also showed an embryonic dose-dependent change in CPP behavior, suggesting an increased sensitivity. These studies clearly show that pre-exposure during embryonic development affects subsequent cocaine sensitivity in longitudinal adults.

Does acute maternal stress in pregnancy affect infant health outcomes? Examination of a large cohort of infants born after the terrorist attacks of September 11, 2001

PubMed Central

Endara, Skye M; Ryan, Margaret AK; Sevick, Carter J; Conlin, Ava Marie S; Macera, Caroline A; Smith, Tyler C

2009-01-01

Background Infants in utero during the terrorist attacks of September 11, 2001 may have been negatively affected by maternal stress. Studies to date have produced contradictory results. Methods Data for this retrospective cohort study were obtained from the Department of Defense Birth and Infant Health Registry and included up to 164,743 infants born to active-duty military families. Infants were considered exposed if they were in utero on September 11, 2001, while the referent group included infants gestating in the same period in the preceding and following year (2000 and 2002). We investigated the association of this acute stress during pregnancy with the infant health outcomes of male:female sex ratio, birth defects, preterm birth, and growth deficiencies in utero and in infancy. Results No difference in sex ratio was observed between infants in utero in the first trimester of pregnancy on September 11, 2001 and infants in the referent population. Examination of the relationship between first-trimester exposure and birth defects also revealed no significant associations. In adjusted multivariable models, neither preterm birth nor growth deficiencies were significantly associated with the maternal exposure to the stress of September 11 during pregnancy. Conclusion The findings from this large population-based study suggest that women who were pregnant during the terrorist attacks of September 11, 2001 had no increased risk of adverse infant health outcomes. PMID:19619310

Limits of fetal thyroid risk from radioiodine exposure

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

Lloyd, R.D.; Tripp, D.A.; Kerber, R.A.

1996-04-01

An incident in which a young women became pregnant soon after being treated with 444 MBq {sup 131}I for Graves disease prompted us to search local records for the occurrence of thyroid abnormalities among people exposed in utero to fallout radioiodine. The data base from the Utah Fallout Study indicated that there had been 480 cohort subjects for whom dose to thyroid from fallout radioiodine had been calculated and who could have received any thyroid dose before birth (2473 subjects had been re-examined in 1985-86 of the 4818 examined in 1965-70). Of these 480 subjects in this category, 403 ofmore » them could be located in the 1980`s and were examined for abnormalities. Although nodules, thyroiditis, hypothyroidism and goiter were seen among the 375 persons with in utero thyroid doses from fallout radioiodine below 0.42 Gy, no thyroid abnormalities of any kind occurred in the 4 persons with in utero thyroid doses of 0.5 to 2.6 Gy. In addition, no neoplasia was found in any of the 403 subjects examined about 3 decades after in utero fallout exposure. These limited data do not indicate that the fetal thyroid is more sensitive than the postnatal thyroid by more than about a factor of about 4 when thyroid dose is considered and by not much more than unity when the comparison is based on dose equivalent (x-ray vs. radioiodine). 21 refs., 1 tab.« less

Alcohol-Induced Developmental Origins of Adult-Onset Diseases

PubMed Central

Lunde, Emilie R.; Washburn, Shannon E.; Golding, Michael C.; Bake, Shameena; Miranda, Rajesh C.; Ramadoss, Jayanth

2016-01-01

Fetal alcohol exposure may impair growth, development, and function of multiple organ systems, and is encompassed by the term Fetal Alcohol Spectrum Disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker’s hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult-development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psycho-behavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult-onset of neuro-behavioral deficits, cardiovascular disease, endocrine dysfunction, nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation is a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter-relation are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD. PMID:27254466

Alcohol-Induced Developmental Origins of Adult-Onset Diseases.

PubMed

Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C; Bake, Shameena; Miranda, Rajesh C; Ramadoss, Jayanth

2016-07-01

Fetal alcohol exposure may impair growth, development, and function of multiple organ systems and is encompassed by the term fetal alcohol spectrum disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker's hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psychobehavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult onset of neurobehavioral deficits, cardiovascular disease, endocrine dysfunction, and nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation are a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose, and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter relation, are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD. Copyright © 2016 by the Research Society on Alcoholism.

Pregnancy exposures and risk of childhood asthma admission in a population birth cohort.

PubMed

Algert, Charles S; Bowen, Jennifer R; Lain, Samantha L; Allen, Hugh D; Vivian-Taylor, Josephine M; Roberts, Christine L

2011-12-01

There is increasing interest in the potential for in utero exposures to affect the risk of asthma. We used population data to explore the associations between perinatal conditions and the risk of hospital admission with asthma between the 2nd and 5th birthday. The study population was 240,511 singleton infants born during 2001-2003. Birth records and longitudinally linked hospital admissions were used to identify asthma admissions and to model potential risk factors. A total of 7245 children (3.0%) had one or more childhood admissions with asthma. In utero infectious exposures associated with childhood asthma were maternal antenatal admission with a urinary tract infection (UTI) [adjusted odds ratio (aOR) = 1.49, 95% confidence interval (1.23-1.79)] and pre-term pre-labor rupture of membranes (PROM) [aOR = 1.23 (1.04-1.45)]. There was no evidence that gestational age at time of first antenatal UTI admission (<28, ≥ 28 wks) affected the risk of asthma (homogeneity test p = 0.6). Pre-term birth was a risk factor for asthma admission, with the risk decreasing by 5.3% with each extra week of gestation. Autumn and winter conceptions were associated with an increased risk of childhood asthma admission: winter aOR = 1.15 (1.08-1.23), autumn aOR = 1.09 (1.02-1.16). As in utero exposure to both UTI and PROM carry an increased risk of childhood asthma admission, this suggests that the immune system response generally is the relevant factor rather than a specific organism. The season-associated risk is consistent with early pregnancy exposures such as the winter flu season or low vitamin D. © 2011 John Wiley & Sons A/S.

Preliminary analysis of in utero low-level arsenic exposure and fetal growth using biometric measurements extracted from fetal ultrasound reports.

PubMed

Davis, Matthew A; Higgins, John; Li, Zhigang; Gilbert-Diamond, Diane; Baker, Emily R; Das, Amar; Karagas, Margaret R

2015-03-30

Early life exposure to arsenic is associated with decreased birth weight in highly exposed populations but little is known about effects of low-level arsenic exposure on growth in utero. Using a sample of 272 pregnancies from New Hampshire we obtained biometric measurements directly from fetal ultrasound reports commonly found in electronic medical records. We used information extraction methods to develop and validate an automated approach for mining biometric measurements from the text of clinical reports. As a preliminary analysis, we examined associations between in utero low-level arsenic exposure (as measured by maternal urinary arsenic concentration) and fetal growth measures (converted to Z-scores based on reference populations for estimated fetal weight, head, and other body measures) at approximately 18 weeks of gestation. In a preliminary cross-sectional analysis of 223 out of 272 pregnancies, maternal urinary arsenic concentration (excluding arsenobetaine) was associated with a reduction in head circumference Z-score (Spearman correlation coefficient, rs = -0.08, p-value = 0.21) and a stronger association was observed among female fetuses at approximately 18 weeks of gestation (rs = - 0.21, p-value < 0.05). Although, associations were attenuated in adjusted analyses - among female fetuses a 1 μg/L increase in maternal urinary arsenic concentration was associated with a decrease of 0.047 (95% CI: -0.115, 0.021) in head circumference and 0.072 (95% CI: -0.151, 0.007) decrease in biparietal head diameter Z-score. Our study demonstrates that useful data can be extracted directly from electronic medical records for epidemiologic research. We also found evidence that exposure to low-level arsenic may be associated with reduced head circumference in a sex dependent manner that warrants further investigation.

Arsenic

MedlinePlus

... its development. Arsenic is also associated with adverse pregnancy outcomes and infant mortality, with impacts on child health (1) , and exposure in utero and in early childhood has been linked to increases in mortality ...

Cumulative effects of in utero administration of mixtures of "antiandrogens" on male rat reproductive development

EPA Science Inventory

Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act requires the USEPA to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies to provide a fra...

CUMULATIVE EFFECTS OF IN UTERO ADMINISTRATION OF A MIXTURE OF SEVEN ANTIANDROGENS ON MALE RAT REPRODUCTIVE DEVELOPMENT

EPA Science Inventory

Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 FQPA requires the USEPA to consider cumulative risk from chemicals that act via a common mechanism of action. To this end, we are conducting studies with mixtures to provide a framework fo...

In utero exposure to low doses of bisphenol A lead to long-term deleterious effects in the vagina.

PubMed

Schönfelder, G; Flick, B; Mayr, E; Talsness, C; Paul, M; Chahoud, I

2002-01-01

The origins of the "endocrine disrupter hypothesis" may be traced to reports on adolescent daughters born to women who had taken the highly potent synthetic estrogen, diethylstilbestrol, while pregnant, and who developed a rare form of vaginal cancer and adenocarcinoma. Bisphenol A (BPA) is an estrogenic chemical that is highly employed in the manufacture of a wide range of consumer products. Some observational studies have suggested that the amounts of BPA to which we are exposed could alter the reproductive organs of developing rodents. We examined the influence of BPA at low doses to address the questions of (a) whether in utero exposure affects the vagina of the offspring and (b) which mechanisms cause the toxic effects. Gravid Sprague-Dawley dams were administered either 0.1 (low dose) or 50 mg/kg per day BPA, the no observed effect level, or 0.2 mg/kg per day 17 alpha-ethinyl estradiol by gavage. Striking morphological changes were observed in the vagina of postpubertal offspring leading us to examine vaginal estrogen receptor (ER) expression because BPA binds to the ER alpha, which is important for growth of the vaginal epithelium. We show that the full-length ER alpha is not expressed during estrus in the vagina of female offspring exposed to either dose of BPA when compared to the control group, whereas ER alpha expression does not differ from the control group during the diestrus stage. ER alpha downregulation seems to be responsible for the observed altered vaginal morphology.

In Utero Exposure to Low Doses of Bisphenol A Lead to Long-term Deleterious Effects in the Vagina1

PubMed Central

Schönfelder, G; Flick, B; Mayr, E; Talsness, C; Paul, M; Chahoud, I

2002-01-01

Abstract The origins of the “endocrine disrupter hypothesis” may be traced to reports on adolescent daughters born to women who had taken the highly potent synthetic estrogen, diethylstilbestrol, while pregnant, and who developed a rare form of vaginal cancer and adenocarcinoma. Bisphenol A (BPA) is an estrogenic chemical that is highly employed in the manufacture of a wide range of consumer products. Some observational studies have suggested that the amounts of BPA to which we are exposed could alter the reproductive organs of developing rodents. We examined the influence of BPA at low doses to address the questions of (a) whether in utero exposure affects the vagina of the offspring and (b) which mechanisms cause the toxic effects. Gravid Sprague-Dawley dams were administered either 0.1 (low dose) or 50 mg/kg per day BPA, the no observed effect level, or 0.2 mg/kg per day 17α-ethinyl estradiol by gavage. Striking morphological changes were observed in the vagina of postpubertal offspring leading us to examine vaginal estrogen receptor (ER) expression because BPA binds to the ERα, which is important for growth of the vaginal epithelium. We show that the full -length ERα is not expressed during estrus in the vagina of female offspring exposed to either dose of BPA when compared to the control group, whereas ERα expression does not differ from the control group during the diestrus stage. ERα downregulation seems to be responsible for the observed altered vaginal morphology. PMID:11896564

Maternal factors associated with offspring polycystic ovarian syndrome.

PubMed

Steiner, Anne Z

2018-04-19

In this Swedish national registry-based cohort study Valgeirsdottir et al. sought to determine the association between 1) in-utero exposures and 2) birth indices and the subsequent development of polycystic ovarian syndrome (PCOS) after age 15. To do this, they selected 681,123 girls, whose birth was recorded in the Swedish birth registry between 1982 and 1995. They followed the girls in the Swedish Patient Registry until 2010 for a diagnosis of PCOS using International Classification of Diseases (ICD) codes. The authors found that in-utero exposure to maternal obesity and smoking, but not maternal pre-eclampsia or gestational diabetes, increased the risk of PCOS as an adolescent or young adult. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The rate of X-ray-induced DNA double-strand break repair in the embryonic mouse brain is unaffected by exposure to 50 Hz magnetic fields.

PubMed

Woodbine, Lisa; Haines, Jackie; Coster, Margaret; Barazzuol, Lara; Ainsbury, Elizabeth; Sienkiewicz, Zenon; Jeggo, Penny

2015-06-01

Following in utero exposure to low dose radiation (10-200 mGy), we recently observed a linear induction of DNA double-strand breaks (DSB) and activation of apoptosis in the embryonic neuronal stem/progenitor cell compartment. No significant induction of DSB or apoptosis was observed following exposure to magnetic fields (MF). In the present study, we exploited this in vivo system to examine whether exposure to MF before and after exposure to 100 mGy X-rays impacts upon DSB repair rates. 53BP1 foci were quantified following combined exposure to radiation and MF in the embryonic neuronal stem/progenitor cell compartment. Embryos were exposed in utero to 50 Hz MF at 300 μT for 3 h before and up to 9 h after exposure to 100 mGy X-rays. Controls included embryos exposed to MF or X-rays alone plus sham exposures. Exposure to MF before and after 100 mGy X-rays did not impact upon the rate of DSB repair in the embryonic neuronal stem cell compartment compared to repair rates following radiation exposure alone. We conclude that in this sensitive system MF do not exert any significant level of DNA damage and do not impede the repair of X-ray induced damage.

In utero and early childhood exposure to arsenic decreases lung function in children

PubMed Central

Recio-Vega, Rogelio; Gonzalez-Cortes, Tania; Olivas-Calderon, Edgar; Lantz, R. Clark; Gandolfi, A. Jay; Gonzalez-De Alba, Cesar

2016-01-01

Background The lung is a target organ for adverse health outcomes following exposure to arsenic. Several studies have reported a high prevalence of respiratory symptoms and diseases in subjects highly exposed to arsenic through drinking water, however, most studies to date has been performed in exposed adults, with little information on respiratory effects in children. The objective of the study was to evaluate the association between urinary levels of arsenic and its metabolites with lung function in children exposed in utero and in early childhood to high arsenic levels through drinking water. Methods A total of 358 healthy children were included in our study. Individual exposure was assessed based on urinary concentration of inorganic arsenic. Lung function was assessed by spirometry. Results Participants were exposed since pregnancy until early childhood to an average water As concentration of 152.13 μg/L. The mean urinary arsenic level registered in the studied subjects was 141.2 μg/L and only 16.7% had a urinary concentration below the national concern level. Forced vital capacity was significantly decreased in the studied population and it was negatively associated with the percent of inorganic arsenic. More than 57% of the subjects had a restrictive spirometric pattern. The urinary As level was higher in those children with restrictive lung patterns when compared with the levels registered in subjects with normal spirometric patterns. Conclusion Exposure to arsenic through drinking water during in utero and early life was associated with a decrease in FVC and with a restrictive spirometric pattern in the children evaluated. PMID:25131850

In utero and early childhood exposure to arsenic decreases lung function in children.

PubMed

Recio-Vega, Rogelio; Gonzalez-Cortes, Tania; Olivas-Calderon, Edgar; Lantz, R Clark; Gandolfi, A Jay; Gonzalez-De Alba, Cesar

2015-04-01

The lung is a target organ for adverse health outcomes following exposure to As. Several studies have reported a high prevalence of respiratory symptoms and diseases in subjects highly exposed to As through drinking water; however, most studies to date has been performed in exposed adults, with little information on respiratory effects in children. The objective of the study was to evaluate the association between urinary levels of As and its metabolites with lung function in children exposed in utero and in early childhood to high As levels through drinking water. A total of 358 healthy children were included in our study. Individual exposure was assessed based on urinary concentration of inorganic As. Lung function was assessed by spirometry. Participants were exposed since pregnancy until early childhood to an average water As concentration of 152.13 µg l⁻¹. The mean urinary As level registered in the studied subjects was 141.2 µg l⁻¹ and only 16.7% had a urinary concentration below the national concern level. Forced vital capacity was significantly decreased in the studied population and it was negatively associated with the percentage of inorganic As. More than 57% of the subjects had a restrictive spirometric pattern. The urinary As level was higher in those children with restrictive lung patterns when compared with the levels registered in subjects with normal spirometric patterns. Exposure to As through drinking water during in utero and early life was associated with a decrease in forced vital capacity and with a restrictive spirometric pattern in the children evaluated. Copyright © 2014 John Wiley & Sons, Ltd.

In utero azathioprine exposure and increased utilization of special educational services in children born to mothers with systemic lupus erythematosus

PubMed Central

Marder, Wendy; Ganser, Martha A; Romero, Vivian; Hyzy, Margaret A; Gordon, Caroline; McCune, WJ; Somers, Emily C

2012-01-01

Objective Azathioprine (AZA) is recognized among immunosuppressive medications as relatively safe during pregnancy for women with systemic lupus erythematosus (SLE) requiring aggressive treatment. This pilot study aimed to determine whether SLE therapy during pregnancy was associated with developmental delays in offspring. Methods This cohort study included SLE patients with at least one live birth post-diagnosis. Medical histories were obtained via interviews and chart review. Multiple logistic regression was used to examine associations between SLE therapy during pregnancy and maternal report of special educational (SE) requirements (as proxy for developmental delays) among offspring. Propensity scoring (incorporating corticosteroid use, lupus flare, and lupus nephritis) was used to account for disease severity. Results Of 60 eligible offspring from 38 mothers, 15 required SE services, the most common indication for which was speech delay. 7 of the 13 (54%) children with in utero AZA exposure utilized SE services versus 8 of 47 (17%) non-exposed (p<0.05). After adjustment for pregnancy duration, small for gestational age, propensity score, maternal education and antiphospholipid antibody syndrome, AZA was significantly associated with SE utilization occurring from age 2 onward (OR 6.6, 95% CI 1.0, 43.3), and bordered significance for utilization at any age or age <2 years. Conclusions AZA exposure during SLE pregnancy was independently associated with increased SE utilization in offspring, after controlling for confounders. Further research is indicated to fully characterize developmental outcomes among offspring with in utero AZA exposure. Vigilance and early interventions for suspected developmental delays among exposed offspring may be warranted. PMID:23139238

Sexually dimorphic effects of ancestral exposure to vinclozolin on stress reactivity in rats.

PubMed

Gillette, Ross; Miller-Crews, Isaac; Nilsson, Eric E; Skinner, Michael K; Gore, Andrea C; Crews, David

2014-10-01

How an individual responds to the environment depends upon both personal life history as well as inherited genetic and epigenetic factors from ancestors. Using a 2-hit, 3 generations apart model, we tested how F3 descendants of rats given in utero exposure to the environmental endocrine-disrupting chemical (EDC) vinclozolin reacted to stress during adolescence in their own lives, focusing on sexually dimorphic phenotypic outcomes. In adulthood, male and female F3 vinclozolin- or vehicle-lineage rats, stressed or nonstressed, were behaviorally characterized on a battery of tests and then euthanized. Serum was used for hormone assays, and brains were used for quantitative PCR and transcriptome analyses. Results showed that the effects of ancestral exposure to vinclozolin converged with stress experienced during adolescence in a sexually dimorphic manner. Debilitating effects were seen at all levels of the phenotype, including physiology, behavior, brain metabolism, gene expression, and genome-wide transcriptome modifications in specific brain nuclei. Additionally, females were significantly more vulnerable than males to transgenerational effects of vinclozolin on anxiety but not sociality tests. This fundamental transformation occurs in a manner not predicted by the ancestral exposure or the proximate effects of stress during adolescence, an interaction we refer to as synchronicity.

Xenotransplantation as a model for human testicular development.

PubMed

Hutka, Marsida; Smith, Lee B; Mitchell, Rod T

The developing male reproductive system may be sensitive to disruption by a wide range of exogenous 'endocrine disruptors'. In-utero exposure to environmental chemicals and pharmaceuticals have been hypothesized to have an impact in the increasing incidence of male reproductive disorders. The vulnerability to adverse effects as a consequence of such exposures is elevated during a specific 'window of susceptibility' in fetal life referred to as the masculinisation programing window (MPW). Exposures that occur during prepuberty, such as chemotherapy treatment for cancer during childhood, may also affect future fertility. Much of our current knowledge about fetal and early postnatal human testicular development derives from studies conducted in animal models predictive for humans. Therefore, over recent years, testicular transplantation has been employed as a 'direct' approach to understand the development of human fetal and prepubertal testis in health and disease. In this review we describe the potential use of human testis xenotransplantation to study testicular development and its application for (i) assessing the effects of environmental exposures in humans, and (ii) establishing fertility preservation options for prepubertal boys with cancer. Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Exposure to lipopolysaccharide in utero alters the postnatal metabolic response in heifers

USDA-ARS?s Scientific Manuscript database

This study was designed to determine the effect of prenatal lipopolysaccharide (LPS) exposure on the postnatal metabolic response to an LPS challenge in beef heifers. Pregnant crossbred cows (n = 50) were assigned to a prenatal immune stimulation (PIS; n = 25; administered 0.1 micrograms/kg BW LPS s...

In utero glucocorticoid exposure reduced fetal skeletal muscle mass in rats independent of effects on maternal nutrition

USDA-ARS?s Scientific Manuscript database

Maternal stress and undernutrition can occur together and expose the fetus to high glucocorticoid (GLC) levels during this vulnerable period. To determine the consequences of GLC exposure on fetal skeletal muscle independently of maternal food intake, groups of timed-pregnant Sprague-Dawley rats (n ...

Methamphetamine Exposure: A Rural Early Intervention Challenge

ERIC Educational Resources Information Center

Lester, Barry M.; Arria, Amelia M.; Derauf, Christian; Grant, Penny; LaGasse, Linda; Newman, Elana; Shah, Rizwan Z.; Stewart, Sara; Wouldes, Trecia

2006-01-01

In the Infant Development, Environment and Lifestyle (IDEAL) Study of methamphetamine (MA) effects on children, the authors screened approximately 27,000 newborn infants for MA exposure, and from that pool derived a sample of in utero MA-exposed children as well as a comparison group matched for other drug use and other factors. IDEAL measures…

Intervention for Individuals with Fetal Alcohol Spectrum Disorders: Treatment Approaches and Case Management

ERIC Educational Resources Information Center

Paley, Blair; O'Connor, Mary J.

2009-01-01

Exposure to alcohol in utero is considered to be the leading cause of developmental disabilities of known etiology. The most severe consequence of such exposure, fetal alcohol syndrome (FAS), is characterized by a distinct constellation of characteristic facial anomalies, growth retardation, and central nervous system (CNS) dysfunction. Some…

Effects of prenatal diesel exhaust inhalation on pulmonary inflammation and development of specific immune responses

EPA Science Inventory

There is increasing evidence that exposure to air pollutants during pregnancy can result in a number of deleterious effects including low birth weight and the incidence of allergic asthma. To investigate the in utero effects of DE exposure, timed pregnant BALB/c mice were exposed...

The Effect of In Utero Diesel Exhaust (DE) Exposure on Development of Allergic Inflammation in Offspring

EPA Science Inventory

Recent studies have shown that pre-term birth weights and the incidence of asthma are increased in children born from mothers who live close to heavily trafficked roads and highways. In this study we examined the effect of inhalation DE exposure by pregnant mice on the subsequen...

The grass isn't always greener: The effects of cannabis on embryological development.

PubMed

Friedrich, Joseph; Khatib, Dara; Parsa, Keon; Santopietro, Ariana; Gallicano, G Ian

2016-09-29

With the increasing publicity of marijuana due to recent legislation, it is pertinent that the effects of fetal exposure to the drug are assessed. While in utero cannabis exposure has been associated with early pregnancy failure, birth defects and developmental delay, the mechanisms of such outcomes are largely unexplained. Furthermore, the use of cannabinoids in cancer treatment via growth inhibition and apoptosis may indicate how cannabis exposure likely harms a growing fetus. Cannabinoid signaling is required for proper pre-implantation development, embryo transport to the uterus, and uterine receptivity during implantation. In post-implantation development, cannabinoid signaling functions in a multitude of pathways, including, but not limited to, folic acid, VEGF, PCNA, MAPK/ERK, and BDNF. Disrupting the normal activity of these pathways can significantly alter many vital in utero processes, including angiogenesis, cellular replication, tissue differentiation, and neural cognitive development. This paper aims to demonstrate the effects of cannabis exposure on a developing embryo in order to provide a molecular explanation for the adverse outcomes associated with cannabis use during pregnancy.

Level of In Utero Cocaine Exposure and Neonatal Ultrasound Findings

PubMed Central

Frank, Deborah A.; McCarten, Kathleen M.; Robson, Caroline D.; Mirochnick, Mark; Cabral, Howard; Park, Henry; Zuckerman, Barry

2008-01-01

Objective To assess whether there is an association between the level of in utero cocaine exposure and findings on neonatal cranial ultrasound, controlling for potentially confounding variables. Study Design In a prospective longitudinal study, three cocaine exposure groups were defined by maternal report and infant meconium assay: unexposed, heavier cocaine exposure (>75th percentile self-reported days of use or of meconium benzoylecogonine concentration) or lighter cocaine exposure (all others). Neonatal ultrasounds from 241 well, term infants were read by a single radiologist who was masked to the exposure group. Results Infants with lighter cocaine exposure did not differ from the unexposed infants on any ultrasound findings. After controlling for infant gender, gestational age, and birth weight z scores and for maternal parity, blood pressure in labor, ethnicity, and use of cigarettes, alcohol, and marijuana during pregnancy, the more heavily cocaine-exposed infants were more likely than the unexposed infants to show subependymal hemorrhage in the caudothalamic groove (covariate adjusted odds ratio: 3.88; 95% confidence interval: 1.45, 10.35). Conclusions This is the first study to demonstrate that ultrasound findings suggestive of vascular injury to the neonatal central nervous system are related to the level of prenatal cocaine exposure. Inconsistency in previous research in identifying an association between prenatal cocaine exposure and neonatal cranial ultrasound findings may reflect failure to consider dose effects. PMID:10545554

In utero undernourishment perturbs the adult sperm methylome and is linked to metabolic disease transmission

PubMed Central

Radford, Elizabeth J.; Corish, Jennifer A.; Seisenberger, Stefanie; Hore, Timothy A.; Reik, Wolf; Erkek, Serap; Peters, Antoine H. F. M.; Patti, Mary-Elizabeth; Ferguson-Smith, Anne C.

2015-01-01

Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance but mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, potentially impacting F2 development. Importantly, differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. PMID:25011554

Disruption of Skin Stem Cell Homeostasis following Transplacental Arsenicosis; Alleviation by Combined Intake of Selenium and Curcumin.

PubMed

Poojan, Shiv; Kumar, Sushil; Verma, Vikas; Dhasmana, Anupam; Lohani, Mohtashim; Verma, Mukesh K

2015-01-01

Of late, a consirable interest has grown in literature on early development of arsenicosis and untimely death in humans after exposure to iAs in drinking water in utero or during the childhood. The mechanism of this kind of intrauterine arsenic poisoning is not known; however it is often suggested to involve stem cells. We looked into this possibility by investigating in mice the influence of chronic in utero exposure to arsenical drinking water preliminarily on multipotent adult stem cell and progenitor cell counts at the beginning of neonatal age. We found that repeated intake of 42.5 or 85 ppm iAs in drinking water by pregnant BALB/c mice substantially changed the counts of EpASCs, the progenitor cells, and the differentiated cells in epidermis of their zero day old neonates. EpASCs counts decreased considerably and the differentiated/apoptosed cell counts increased extensively whereas the counts of progenitor cell displayed a biphasic effect. The observed trend of response was dose-dependent and statistically significant. These observations signified a disruption in stem cell homeostasis. The disorder was in parallel with changes in expression of biomarkers of stem cell and progenitor (TA) cell besides changes in expression of pro-inflammatory and antioxidant molecules namely Nrf2, NFkB, TNF-α, and GSH. The biological monitoring of exposure to iAs and the ensuing transplacental toxicity was verifiable correspondingly by the increase in iAs burden in hair, kidney, skin, liver of nulliparous female mice and the onset of chromosomal aberrations in neonate bone marrow cells. The combined intake of selenite and curcumin in utero was found to prevent the disruption of homeostasis and associated biochemical changes to a great extent. The mechanism of prevention seemed possibly to involve (a) curcumin and Keap-1 interaction, (b) consequent escalated de novo GSH biosynthesis, and (c) the resultant toxicant disposition. These observations are important with respect to the development of vulnerability to arsenicosis and other morbidities later in life after repeated in utero or postnatal exposure to iAs in drinking water that may occur speculatively through impairment of adult stem cell dependent innate tissue repair mechanism.

Disruption of Skin Stem Cell Homeostasis following Transplacental Arsenicosis; Alleviation by Combined Intake of Selenium and Curcumin

PubMed Central

Poojan, Shiv; Kumar, Sushil; Verma, Vikas; Dhasmana, Anupam; Lohani, Mohtashim; Verma, Mukesh K.

2015-01-01

Of late, a consirable interest has grown in literature on early development of arsenicosis and untimely death in humans after exposure to iAs in drinking water in utero or during the childhood. The mechanism of this kind of intrauterine arsenic poisoning is not known; however it is often suggested to involve stem cells. We looked into this possibility by investigating in mice the influence of chronic in utero exposure to arsenical drinking water preliminarily on multipotent adult stem cell and progenitor cell counts at the beginning of neonatal age. We found that repeated intake of 42.5 or 85ppm iAs in drinking water by pregnant BALB/c mice substantially changed the counts of EpASCs, the progenitor cells, and the differentiated cells in epidermis of their zero day old neonates. EpASCs counts decreased considerably and the differentiated / apoptosed cell counts increased extensively whereas the counts of progenitor cell displayed a biphasic effect. The observed trend of response was dose-dependent and statistically significant. These observations signified a disruption in stem cell homeostasis. The disorder was in parallel with changes in expression of biomarkers of stem cell and progenitor (TA) cell besides changes in expression of pro-inflammatory and antioxidant molecules namely Nrf2, NFkB, TNF-α, and GSH. The biological monitoring of exposure to iAs and the ensuing transplacental toxicity was verifiable correspondingly by the increase in iAs burden in hair, kidney, skin, liver of nulliparous female mice and the onset of chromosomal aberrations in neonate bone marrow cells. The combined intake of selenite and curcumin in utero was found to prevent the disruption of homeostasis and associated biochemical changes to a great extent. The mechanism of prevention seemed possibly to involve (a) curcumin and Keap-1 interaction, (b) consequent escalated de novo GSH biosynthesis, and (c) the resultant toxicant disposition. These observations are important with respect to the development of vulnerability to arsenicosis and other morbidities later in life after repeated in utero or postnatal exposure to iAs in drinking water that may occur speculatively through impairment of adult stem cell dependent innate tissue repair mechanism. PMID:26624291

The perils of climate change: In utero exposure to temperature variability and birth outcomes in the Andean region.

PubMed

Molina, Oswaldo; Saldarriaga, Victor

2017-02-01

The discussion on the effects of climate change on human activity has primarily focused on how increasing temperature levels can impair human health. However, less attention has been paid to the effect of increased climate variability on health. We investigate how in utero exposure to temperature variability, measured as the fluctuations relative to the historical local temperature mean, affects birth outcomes in the Andean region. Our results suggest that exposure to a temperate one standard deviation relative to the municipality's long-term temperature mean during pregnancy reduces birth weight by 20g. and increases the probability a child is born with low birth weight by a 0.7 percentage point. We also explore potential channels driving our results and find some evidence that increased temperature variability can lead to a decrease in health care and increased food insecurity during pregnancy. Copyright © 2016 Elsevier B.V. All rights reserved.

Caffeine in the milk prevents respiratory disorders caused by in utero caffeine exposure in rats.

PubMed

Bodineau, Laurence; Saadani-Makki, Fadoua; Jullien, Hugues; Frugière, Alain

2006-01-25

Consequences of postnatal caffeine exposure by the milk on ponto-medullary respiratory disturbances observed following an in utero caffeine exposure were analysed. Ponto-medullary-spinal cord preparations from newborn rats exposed to caffeine during gestation but not after the birth display an increase in respiratory frequency and an exaggeration of the hypoxic respiratory depression compared to not treated preparations. These data suggest that tachypneic and apneic episodes encountered in human newborns whose mother consumed caffeine during pregnancy are due in large part to central effect of caffeine at the ponto-medullary level. Both baseline respiratory frequency increase and emphasis of hypoxic respiratory depression are not encountered if rat dams consumed caffeine during nursing. Our hypothesis is that newborn rats exposed to caffeine during gestation but not after the birth would be in withdrawal situation whereas, when caffeine is present in drinking fluid of lactating dams, it goes down the milk and is able to prevent ponto-medullary respiratory disturbances.

Anogenital distance of women in relation to their mother's gynaecological characteristics before or during pregnancy.

PubMed

Mira-Escolano, María-Pilar; Mendiola, Jaime; Mínguez-Alarcón, Lidia; Roca, Manuela; Cutillas-Tolín, Ana; López-Espín, José J; Torres-Cantero, Alberto M

2014-02-01

Animal models suggest that anogenital distance (AGD) at birth reflects androgen concentrations during in-utero development and predicts adult AGD. Several human observational studies show an association between menstrual cycle irregularities and a hyperandrogenic environment and that may result in a potential alteration of the female reproductive tract during in-utero development. This study examined associations between AGD of young women and their mother's gynaecological characteristics before or during pregnancy. This is cross-sectional study of 100 college-age volunteers in southern Spain. Physical and gynaecological examinations were conducted on the young women and they and their mothers completed epidemiological questionnaires on lifestyles and gynaecological history. Linear regression analysis was used to examine the association between AGD measurements (anus-fourchette (AGDAF) and anus-clitoris (AGDAC)) of women and their mother's gynaecological characteristics. Longer AGDAF was associated with the presence of mother's menstrual cycle irregularities before pregnancy (P=0.03). Longer female AGD has been related to excess androgen exposure in utero in toxicological studies. The current findings may be consistent with studies in which an association between menstrual cycle irregularities and an hyperandrogenic environment has been reported, which therefore may result in a potential modification of the female offspring's reproductive tract during in-utero development, including AGD. Rodent models suggest that perineal length at birth reflects male hormone concentrations (androgens) during in-utero development and predicts adult perineal length. Several human studies show a relationship between menstrual cycle irregularities and an excessive androgen environment. We hypothesize that androgen excess may result in a potential alteration of the female reproductive tract during in-utero development. Our aim was to examine associations between perineal length of young women and their mother's gynaecological characteristics before or during pregnancy. This is a study of 100 college-age volunteers in Southern Spain. Physical and gynaecological examinations were conducted on the young women and they and their mothers completed epidemiological questionnaires on lifestyles and gynaecological history. We used multivariate analyses to assess the association between perineal length of women and their mother's gynaecological characteristics. Longer perineal length was associated with the presence of mother's menstrual cycle irregularities before pregnancy. Longer female perineal length has been related to excess androgen exposure in utero in rodent studies. Our findings may be consistent with previous studies in which an association between menstrual cycle irregularities and an excess of androgen has been reported, which therefore may result in a potential modification of the female offspring's reproductive tract during in-utero development, including perineal length. Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

The Epigenetic Effects of a High Prenatal Folate Intake in Male Mouse Fetuses Exposed In Utero to Arsenic

PubMed Central

Tsang, Verne; Fry, Rebecca C.; Niculescu, Mihai D.; Rager, Julia E.; Saunders, Jesse; Paul, David S.; Zeisel, Steven H.; Waalkes, Michael P.; Stýblo, Miroslav; Drobná, Zuzana

2012-01-01

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. PMID:22959928

Safety of in utero and neonatal antiretroviral exposure: cognitive and academic outcomes in HIV-exposed, uninfected children 5-13 years of age.

PubMed

Nozyce, Molly L; Huo, Yanling; Williams, Paige L; Kapetanovic, Suad; Hazra, Rohan; Nichols, Sharon; Hunter, Scott; Smith, Renee; Seage, George R; Sirois, Patricia A

2014-11-01

Long-term effects of in utero and neonatal antiretroviral (ARV) exposure on cognitive and academic development in HIV-exposed, uninfected school-age children are unknown. HIV-exposed, uninfected children, ages 5-13 years, in Pediatric HIV/AIDS Cohort Study Surveillance Monitoring for Antiretroviral Treatment Toxicities, a US-based multisite cohort study, completed age-appropriate Wechsler intelligence and academic scales (WPPSI-III, WASI, WIAT-II-A). Associations between cognitive and academic outcomes and in utero ARV exposure by regimen, class and individual ARVs were evaluated, adjusting for potential confounders. Children completing WPPSI-IIIs (n = 350) were 49% male, 74% Black, 25% Hispanic; WASI (n = 337) and WIAT-II-A (n = 415) cohorts were similar. The percentage exposed to combination ARV (cARV) was 84% (WPPSI-III), 64% (WASI) and 67% (WIAT-II-A). Among ARV-exposed children, there were no significant associations between any ARV regimen or class and any cognitive or academic outcome. In addition, in both unadjusted models and after adjustment for caregiver IQ, sociodemographic factors and maternal health and substance use during pregnancy, no individual ARV drug was associated with significantly lower cognitive or academic scores. Factors typically associated with lower cognitive and academic scores in the general population, such as prematurity, small for gestational age, maternal alcohol use and lower maternal cognitive status, were also associated with lower scores in this study. Overall, the safety of prenatal and neonatal ARV use was supported.

Language Outcomes at 12 Years for Children Exposed Prenatally to Cocaine

ERIC Educational Resources Information Center

Lewis, Barbara A.; Minnes, Sonia; Short, Elizabeth J.; Min, Meeyoung O.; Wu, Miaoping; Lang, Adelaide; Weishampel, Paul; Singer, Lynn T.

2013-01-01

Purpose: In this study, the authors aimed to examine the long-term effects of prenatal cocaine exposure (PCE) on the language development of 12-year-old children using a prospective design, controlling for confounding prenatal drug exposure and environmental factors. Method: Children who were exposed to cocaine in utero (PCE; "n" = 183)…

COMPARING IMMUNOTOXICITY IN RATS AFTER IN UTERO VERSUS AN ADULT EXPOSURE: IS DEVELOPMENTAL EXPOSURE MORE SENSITIVE?

EPA Science Inventory

Using a known immunosuppresant, dexamethasone (DEX), pregnant Sprague Dawley (SD) rats were given subcutaneous (s.c.) injections of DEX (0.0, 0.0375, 0.075, 0.15, 0.3 mg/kg) during gestation days 6 to 21. Both male and female offspring were tested for immune dysfunction. In a ...

Periventricular leukomalacia and prenatal methamphetamine exposure: a case report.

PubMed

Murphy, Cary R; Bell, Edward F; Sato, Yutaka; Klein, Jonathan M

2007-02-01

Periventricular leukomalacia (PVL) is a complication of prematurity that carries a high risk of long-term neurologic morbidity. We report the first case, to our knowledge, of unexpected PVL associated with in utero methamphetamine exposure in a 30-week gestation premature infant with a benign hospital course, who subsequently developed cerebral palsy by 24 months of life.

Defining the Borders of Dose Addition: Mixture Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dibutyl phthalate on Male Rat Reproductive Tract Development

EPA Science Inventory

In utero exposure to either dibutyl phthalate (DBP) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disrupts male rat reproductive tract differentiation. However, they act via different modes of toxicity and induce distinct postnatal phenotypes. DBP exposure decreases anogenital di...

Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

PubMed Central

Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

2014-01-01

Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

In Utero Exposure to Antiretroviral Drugs: Effect on Birth Weight and Growth Among HIV-Exposed Uninfected Children in Brazil

PubMed Central

Hofer, Cristina Barroso; Keiser, Olivia; Zwahlen, Marcel; Lustosa, Carla Sepulveda; CisneFrota, Ana Cristina; de Oliveira, Ricardo Hugo; Abreu, Thalita F; Carvalho, Alice Weber; Araujo, Lucia Evangelista; Egger, Matthias

2015-01-01

Context There are concerns about the effects of in utero exposure to antiretroviral drugs (ARVs) on the development of HIV exposed but uninfected (HEU) children. Objectives To evaluate whether in utero exposure to ARVs is associated with lower birth weight/height and reduced growth during the first two years of life. Design Cohort study of HEU infants. Setting Tertiary children's hospital in Rio de Janeiro, Brazil. Study population HEU infants born 1996-2010. Main outcome measures Weight measured by mechanical scale, height measured by measuring board. Z-scores for weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) were calculated. We modeled trajectories by mixed-effects models and adjusted for mother's age, CD4 cell count, viral load, year of birth and family income. Results A total of 588 HEU infants were included of whom 155 (26%) were not exposed to ARVs, 114 (19%) were exposed early (first trimester) and 319 (54%) later. WAZ were lower among infants exposed early compared to infants exposed later: adjusted differences were −0.52 (95% CI −0.99 to −0.04, P=0.02) at birth and −0.22 (95% CI −0.47 to 0.04, P=0.10) during follow-up. LAZ were lower during follow-up: −0.35 (95% CI −0.63 to −0.08, P=0.01). There were no differences in WLZ scores. Z-scores of infants exposed late during pregnancy were similar to unexposed infants. Conclusions In HEU children early exposure to ARVs was associated with lower WAZ at birth and lower LAZ up to 2 years of life. Growth of HEU children needs to be monitored closely. PMID:26741583

Safety of MR Imaging at 1.5 T in Fetuses: A Retrospective Case-Control Study of Birth Weights and the Effects of Acoustic Noise.

PubMed

Strizek, Brigitte; Jani, Jacques C; Mucyo, Eugène; De Keyzer, Frederik; Pauwels, Inge; Ziane, Samir; Mansbach, Anne-Laure; Deltenre, Paul; Cos, Teresa; Cannie, Mieke M

2015-05-01

To evaluate the effects of exposure to routine magnetic resonance (MR) imaging at 1.5 T during pregnancy on fetal growth and neonatal hearing function in relation to the dose and timing of in utero exposure in a group of newborns at low risk for congenital hearing impairment or deafness. This retrospective case-control study was approved by the local ethics committee, and written informed consent was waived. Between January 2008 and December 2012, a group of 751 neonates exposed to MR imaging in utero and a group of control subjects comprising 10 042 nonexposed neonates, both groups with no risk factors for hearing impairment at birth, were included. Neonatal hearing screening was performed by means of otoacoustic emission testing and auditory brain stem response according to national guidelines, and the prevalence of hearing impairment in the two groups was compared by using a noninferiority test with Wilson score confidence intervals. The effect of MR exposure on birth weight percentile was examined between the singleton neonates in the exposed group and a randomly chosen subset of 1805 singleton newborns of the nonexposed group by performing an analysis of variance. The rate of hearing impairment or deafness was found to be 0% (0 of 751) in the neonates in the exposed group and was not inferior to that in the nonexposed group (34 of 10 042 [0.34%], P < .05). There was no between-group difference in birth weight percentiles (50.6% for exposed vs 48.4% for nonexposed; P = .22). This study showed no adverse effects of exposure to 1.5-T MR imaging in utero on neonatal hearing function or birth weight percentiles. (©) RSNA, 2015.

In Utero Exposure to Toxic Air Pollutants and Risk of Childhood Autism

PubMed Central

von Ehrenstein, Ondine S; Aralis, Hilary; Cockburn, Myles; Ritz, Beate

2015-01-01

Background Genetic and environmental factors are believed to contribute to the development of autism, but relatively few studies have considered potential environmental risks. Here we examine risks for autism in children related to in utero exposure to monitored ambient air toxics from urban emissions. Methods Among the cohort of children born in Los Angeles County, California 1995–2006, those whose mothers resided during pregnancy in a 5km buffer around air-toxics monitoring stations were included (n=148,722). To identify autism cases in this cohort, birth records were linked to records of children diagnosed with primary autistic disorder at the California Department of Developmental Services between 1998 and 2009 (n=768). We calculated monthly average exposures during pregnancy for 24 air toxics selected based on suspected or known neurotoxicity or neurodevelopmental toxicity. Factor analysis helped us identify the correlational structure among air toxics, and we estimated odds ratios (ORs) for autism from logistic regression analyses. Results Autism risks were increased per interquartile-range increase in average concentrations during pregnancy of several correlated toxics mostly loading on one factor, including 1,3-butadiene (OR=1.59 [95% confidence interval=1.18–2.15]), meta/para-xylene (1.51 [1.26–182]), other aromatic solvents, lead (1.49 [1.23–1.81]), perchloroethylene (1.40 [1.09–1.80]), and formaldehyde (1.34 [1.17–1.52]), adjusting for maternal age, race/ethnicity, nativity, education, insurance type, maternal birth place, parity, child sex, and birth year. Conclusions Risks for autism in children may increase following in utero exposure to ambient air toxics from urban traffic and industry emissions, as measured by community-based air -monitoring stations. PMID:25051312

Developmental Effects of Prenatal Exposure to Bisphenol A on the Uterus of Rat Offspring1

PubMed Central

Schönfelder, Gilbert; Friedrich, Karin; Paul, Martin; Chahoud, Ibrahim

2004-01-01

Abstract Exposure to estrogenic compounds during critical periods of fetal development could result in adverse effects on the development of reproductive organs that are not apparent until later in life. Bisphenol A (BPA), which is employed in the manufacture of a wide range of consumer products, is a prime candidate for endocrine disruption. We examined BPA to address the question of whether in utero exposure affects the uterus of the offspring and studied the expression and distribution of the estrogen receptors alpha (ERα) and beta (ERβ), because estrogens influence the development, growth, and function of the uterus through both receptors. Gravid Sprague-Dawley dams were administered by gavage either 0.1 or 50 mg/kg per day BPA or 0.2 mg/kg per day 17α-ethinyl estradiol (EE2) as reference dose on gestation days 6 through 21. Female offspring were killed in estrus. Uterine morphologic changes as well as ERα and ERβ distribution and expression were measured by immunohistochemistry and Western blot analysis. Striking morphologic changes were observed in the uterine epithelium of postpubertal offspring during estrus of the in utero BPA-treated animals (the thickness of the total epithelium was significantly reduced). ERα expression was increased in the 50-mg BPA and EE2-treated group. In contrast, we observed significantly decreased ERβ expression in all BPA- and EE2-treated animals when compared with the control. In summary, these results clearly indicate that in utero exposure of rats to BPA promotes uterine disruption in offspring. We hypothesize that the uterine disruption could possibly be provoked by a dysregulation of Erα and ERβ. PMID:15548368

Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure.

PubMed

Liu, Jie; Xie, Yaxiong; Ducharme, Danica M K; Shen, Jun; Diwan, Bhalchandra A; Merrick, B Alex; Grissom, Sherry F; Tucker, Charles J; Paules, Richard S; Tennant, Raymond; Waalkes, Michael P

2006-03-01

Our previous work has shown that exposure to inorganic arsenic in utero produces hepatocellular carcinoma (HCC) in adult male mice. To explore further the molecular mechanisms of transplacental arsenic hepatocarcinogenesis, we conducted a second arsenic transplacental carcinogenesis study and used a genomewide microarray to profile arsenic-induced aberrant gene expression more extensively. Briefly, pregnant C3H mice were given drinking water containing 85 ppm arsenic as sodium arsenite or unaltered water from days 8 to 18 of gestation. The incidence of HCC in adult male offspring was increased 4-fold and tumor multiplicity 3-fold after transplacental arsenic exposure. Samples of normal liver and liver tumors were taken at autopsy for genomic analysis. Arsenic exposure in utero resulted in significant alterations (p < 0.001) in the expression of 2,010 genes in arsenic-exposed liver samples and in the expression of 2,540 genes in arsenic-induced HCC. Ingenuity Pathway Analysis revealed that significant alterations in gene expression occurred in a number of biological networks, and Myc plays a critical role in one of the primary networks. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis of selected genes/proteins showed > 90% concordance. Arsenic-altered gene expression included activation of oncogenes and HCC biomarkers, and increased expression of cell proliferation-related genes, stress proteins, and insulin-like growth factors and genes involved in cell-cell communications. Liver feminization was evidenced by increased expression of estrogen-linked genes and altered expression of genes that encode gender-related metabolic enzymes. These novel findings are in agreement with the biology and histology of arsenic-induced HCC, thereby indicating that multiple genetic events are associated with transplacental arsenic hepatocarcinogenesis.

In utero exposure to venlafaxine, a serotonin-norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat.

PubMed

Laurent, Laetitia; Huang, Chunwei; Ernest, Sheila R; Berard, Anick; Vaillancourt, Cathy; Hales, Barbara F

2016-12-01

Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat. Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression. Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT 2B /Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts. In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044-1055, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

In utero and postnatal exposure to a phytoestrogen-enriched diet increases parameters of acute inflammation in a rat model of TNBS-induced colitis.

PubMed

Seibel, Jan; Molzberger, Almut F; Hertrampf, Torsten; Laudenbach-Leschowski, Ute; Degen, Gisela H; Diel, Patrick

2008-12-01

Inflammatory bowel disease (IBD) is very common in Europe and USA. Its incidence in East Asia has been traditionally low, albeit the risk of IBD increases in Asian immigrants adopting western lifestyles, suggesting a strong role of environmental/dietary factors in IBD. A lifelong exposure to phytoestrogen-rich diets has been associated with a decreased risk of developing breast cancer and might also be protective against IBD. We studied the influence of in utero and postnatal exposure to a phytoestrogen (PE)-rich diet on acute inflammation in an animal model of TNBS-induced colitis. Wistar rats were exposed in utero and postnatally to high (genistein: 240 microg/g feed; daidzein: 232 microg/g feed) or very low levels (genistein and daidzein <10 microg/g feed) of phytoestrogen isoflavones fed to pregnant dams with the diet and throughout nursing. After weaning, the offspring had free access to these diets. At the age of 11 weeks, colitis was induced with an enema of TNBS. After 3 days, animals were sacrificed and tissues were collected for histological evaluation and analysis of molecular markers of inflammation. Animals kept on a PE-rich diet (PRD) had higher colon weights than animals on low PE-levels (PDD), suggesting enhanced acute inflammation by phytoestrogens. This result was supported by histological findings and by analysis of myeloperoxidase activity. Interestingly, relative mRNA and protein expression of cyclooxygenase-2 (COX-2) were modulated in rats on PRD, providing evidence that COX-2, the inducible isoform of the enzyme, is involved in the management of colonic inflammation. Our results suggest that early-in-life exposure to PE might not protect against the development of IBD but enhances the extent of acute inflammation.

Maternal Methadone Dose, Placental Methadone Concentrations, and Neonatal Outcomes

PubMed Central

de Castro, Ana; Jones, Hendreé E.; Johnson, Rolley E.; Gray, Teresa R.; Shakleya, Diaa M.; Huestis, Marilyn A.

2015-01-01

BACKGROUND Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadone-maintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs. METHODS We calculated the correlations of placental methadone and EDDP concentrations and their correlations with maternal methadone doses and neonatal outcomes. Cocaine- and opiate-positive placenta results were compared with the results for meconium samples and for urine samples collected throughout gestation. RESULTS Positive correlations were found between placental methadone and EDDP concentrations (r = 0.685), and between methadone concentration and methadone dose at delivery (r = 0.542), mean daily dose (r = 0.554), mean third-trimester dose (r = 0.591), and cumulative daily dose (r = 0.639). The EDDP/methadone concentration ratio was negatively correlated with cumulative daily dose (r = 0.541) and positively correlated with peak neonatal abstinence syndrome (NAS) score (r = 0.513). Placental EDDP concentration was negatively correlated with newborn head circumference (r = 0.579). Cocaine and opiate use was detected in far fewer placenta samples than in thrice-weekly urine and meconium samples, a result suggesting a short detection window for placenta. CONCLUSIONS Quantitative methadone and EDDP measurement may predict NAS severity. The placenta reflects in utero drug exposure for a shorter time than meconium but may be useful when meconium is unavailable or if documentation of recent exposure is needed. PMID:21245372

In utero exposure to toxic air pollutants and risk of childhood autism.

PubMed

von Ehrenstein, Ondine S; Aralis, Hilary; Cockburn, Myles; Ritz, Beate

2014-11-01

Genetic and environmental factors are believed to contribute to the development of autism, but relatively few studies have considered potential environmental risks. Here, we examine risks for autism in children related to in utero exposure to monitored ambient air toxics from urban emissions. Among the cohort of children born in Los Angeles County, California, 1995-2006, those whose mothers resided during pregnancy in a 5-km buffer around air toxics monitoring stations were included (n = 148,722). To identify autism cases in this cohort, birth records were linked to records of children diagnosed with primary autistic disorder at the California Department of Developmental Services between 1998 and 2009 (n = 768). We calculated monthly average exposures during pregnancy for 24 air toxics selected based on suspected or known neurotoxicity or neurodevelopmental toxicity. Factor analysis helped us identify the correlational structure among air toxics, and we estimated odds ratios (ORs) for autism from logistic regression analyses. Autism risks were increased per interquartile range increase in average concentrations during pregnancy of several correlated toxics mostly loading on 1 factor, including 1,3-butadiene (OR = 1.59 [95% confidence interval = 1.18-2.15]), meta/para-xylene (1.51 [1.26-1.82]), other aromatic solvents, lead (1.49 [1.23-1.81]), perchloroethylene (1.40 [1.09-1.80]), and formaldehyde (1.34 [1.17-1.52]), adjusting for maternal age, race/ethnicity, nativity, education, insurance type, parity, child sex, and birth year. Risks for autism in children may increase following in utero exposure to ambient air toxics from urban traffic and industry emissions, as measured by community-based air-monitoring stations.

Marijuana, Spice ‘herbal high’, and early neural development: implications for rescheduling and legalization

PubMed Central

Psychoyos, Delphine; Vinod, K. Yaragudri

2014-01-01

Marijuana is the most widely used illicit drug by pregnant women in the world. In utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), a major psychoactive component of marijuana, is associated with an increased risk for anencephaly and neurobehavioural deficiencies in the offspring, including attention deficit hyperactivity disorder (ADHD), learning disabilities, and memory impairment. Recent studies demonstrate that the developing central nervous system (CNS) is susceptible to the effects of Δ9-THC and other cannabimimetics, including the psychoactive ingredients of the branded product ‘Spice’ branded products. These exocannabinoids interfere with the function of an endocannabinoid (eCB) system, present in the developing CNS from E12.5 (week 5 of gestation in humans), and required for proliferation, migration, and differentiation of neurons. Until recently, it was not known whether the eCB system is also present in the developing CNS during the initial stages of its ontogeny, i.e. from E7.0 onwards (week 2 of gestation in humans), and if so, whether this system is also susceptible to the action of exocannabinoids. Here, we review current data, in which the presence of an eCB system during the initial stage of development of the CNS is demonstrated. Furthermore, we focus on recent advances on the effect of canabimimetics on early gestation. The relevance of these findings and potential adverse developmental consequences of in utero exposure to ‘high potency’ marijuana, Spice branded products and/or cannabinoid research chemicals during this period is discussed. Finally, we address the implication of these findings in terms of the potential dangers of synthetic cannabinoid use during pregnancy, and the ongoing debate over legalization of marijuana. PMID:22887867

Analgesic use in pregnancy and male reproductive development

PubMed Central

Hurtado-Gonzalez, Pablo; Mitchell, Rod T.

2017-01-01

Purpose of review Male reproductive disorders are common and increasing in incidence in many countries. Environmental factors (including pharmaceuticals) have been implicated in the development of these disorders. This review aims to summarise the emerging epidemiological and experimental evidence for a potential role of in-utero exposure to analgesics in the development of male reproductive disorders. Recent findings A number of epidemiological studies have demonstrated an association between in-utero exposure to analgesics and the development of cryptorchidism, although these findings are not consistent across all studies. Where present, these associations primarily relate to exposure during the second trimester of pregnancy. In-vivo and in-vitro experimental studies have demonstrated variable effects of exposure to analgesics on Leydig cell function in the fetal testis of rodents, particularly in terms of testosterone production. These effects frequently involve exposures that are in excess of those to which humans are exposed. Investigation of the effects of analgesics on human fetal testis have also demonstrated effects on Leydig cell function. Variation in species, model system, dosage and timing of exposure is likely to contribute to differences in the findings between studies. Summary There is increasing evidence for analgesic effects on the developing testis that have the potential to impair reproductive function. However, the importance of these findings in relation to human-relevant exposures and the risk of male reproductive disorders remains unclear. PMID:28277341

Neonatal outcomes following exposure in utero to fallout from Chernobyl.

PubMed

Hatch, Maureen; Little, Mark P; Brenner, Alina V; Cahoon, Elizabeth K; Tereshchenko, Valery; Chaikovska, Ludmyla; Pasteur, Igor; Likhtarov, Ilya; Bouville, Andre; Shpak, Victor; Bolshova, Olena; Zamotayeva, Galyna; Grantz, Katherine; Sun, Liping; Mabuchi, Kiyohiko; Albert, Paul; Tronko, Mykola

2017-12-01

Iodine 131 (I-131), the principal component of nuclear fallout from the Chernobyl accident, concentrates in the thyroid gland and may pose risks to fetal development. To evaluate this, neonatal outcomes following the accident in April of 1986 were investigated in a cohort of 2582 in utero-exposed individuals from northern Ukraine for whom estimates of fetal thyroid I-131 dose were available. We carried out a retrospective review of cohort members' prenatal, delivery and newborn records. The relationships of dose with neonatal anthropometrics and gestational length were modeled via linear regression with adjustment for potentially confounding variables. We found similar, statistically significant dose-dependent reductions in both head circumference (-1.0 cm/Gy, P = 0.005) and chest circumference (-0.9 cm/Gy, P = 0.023), as well as a similar but non-significant reduction in neonatal length (-0.6 cm/Gy, P = 0.169). Gestational length was significantly increased with increasing fetal dose (0.5 wks/Gy, P = 0.007). There was no significant (P > 0.1) effect of fetal dose on birth weight. The observed associations of radioiodine exposure with decreased head and chest circumference are consistent with those observed in the Japanese in utero-exposed atomic bomb survivors.

The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice

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

Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei, E-mail: hongfeixia@yahoo.com.cn

Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity.more » Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. -- Highlights: ► DES induced adipocyte differentiation in a dose-dependent manner in 3T3-L1 cells. ► DES activated adipogenic critical regulators and markers in vitro and in vivo. ► Perinatal exposure to DES led to the obese phenotype in female offspring. ► DES might be a potential chemical stressor for obesity and obesity-related disorders.« less

Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators

PubMed Central

Padmanabhan, Vasantha; Sarma, Hiren N.; Savabieasfahani, Mozhgan; Steckler, Teresa L.; Veiga-Lopez, Almudena

2014-01-01

The inappropriate programming of developing organ systems by exposure to excess native or environmental steroids, particularly the contamination of our environment and our food sources with synthetic endocrine disrupting chemicals that can interact with steroid receptors, is a major concern. Studies with native steroids have found that in utero exposure of sheep to excess testosterone, an estrogen precursor, results in low birth weight offspring and leads to an array of adult reproductive / metabolic deficits manifested as cycle defects, functional hyperandrogenism, neuroendocrine / ovarian defects, insulin resistance, and hypertension. Furthermore, the severity of reproductive dysfunction is amplified by excess postnatal weight gain. The constellation of adult reproductive and metabolic dysfunction in prenatal testosterone-treated sheep is similar to features seen in women with polycystic ovary syndrome. Prenatal dihydrotestosterone treatment failed to result in similar phenotype suggesting that many effects of prenatal testosterone excess are likely facilitated via aromatization to estradiol. Similarly, exposure to environmental steroid imposters such as bisphenol A (BPA) and methoxychlor (MXC) from days 30-90 of gestation had long-term but differential effects. Exposure of sheep to BPA, which resulted in maternal levels of 30-50 ng/ml BPA, culminated in low birth-weight offspring. These female offspring were hypergonadotropic during early postnatal life and characterized by severely dampened preovulatory LH surges. Prenatal MXC-treated females had normal birth weight and manifested delayed but normal amplitude LH surges. Importantly, the effects of BPA were evident at levels, which approximated twice the highest levels found in human maternal circulation of industrialized nations. These findings provide evidence in support of developmental origin of adult reproductive and metabolic diseases and highlight the risk posed by exposure to environmental endocrine disrupting chemicals. PMID:20070410

Repeated in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure affects male gonads in offspring, leading to sex ratio changes in F{sub 2} progeny

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

Ikeda, Masahiko; Tamura, Masashi; Yamashita, Junko

2005-08-15

The effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the reproductive system of male rat offspring (F{sub 1}) and the sex ratio of the subsequent generation (F{sub 2}) were examined. Female Holtzman rats were gavaged with an initial loading dose of 400 ng/kg TCDD prior to mating, followed by weekly maintenance doses of 80 ng/kg during mating, pregnancy, and the lactation period. Maternal exposure to TCDD had no significant effects on fetus/pup (F{sub 1}) mortality, litter size, or sex ratio on gestation day (GD) 20 or postnatal day (PND) 2. The TCDD concentration in maternal livers and adipose tissuemore » on GD20 was 1.21 and 1.81 ng/kg, respectively, and decreased at weaning to 0.72 in the liver and 0.84 in the adipose tissue. In contrast, the TCDD concentration in pup livers was 1.32 ng/kg on PND2 and increased to 1.80 ng/kg at weaning. Ventral prostate weight of male offspring was significantly decreased by TCDD exposure on PND28 and 120 compared with that of controls. Weight of the testes, cauda epididymides, and seminal vesicle, and sperm number in the cauda epididymis were not changed by TCDD exposure at PND120. TCDD- or vehicle-exposed male offspring were mated with unexposed females. The sex ratio (percentage of male pups) of F{sub 2} offspring was significantly reduced in the TCDD-exposed group compared with controls. These results suggest that in utero and lactational TCDD exposures affect the development of male gonads in offspring (F{sub 1}), leading to changes in the sex ratio of the subsequent generation (F{sub 2})« less

Antiretroviral Treatment in HIV-1-Positive Mothers: Neurological Implications in Virus-Free Children

PubMed Central

Coelho, Antonio Victor Campos; Tricarico, Paola Maura; Celsi, Fulvio; Crovella, Sergio

2017-01-01

Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity. This review aims at discussing the possible neurological impairment of children exposed to ART in utero, focusing attention on the drugs commonly used for HIV-1 MTCT prevention, clinical reports of ART neurotoxicity in children born to HIV-1-positive mothers, and neurologic effects of protease inhibitors (PIs), especially ritonavir-“boosted” lopinavir (LPV/r) in cell and animal central nervous system models evaluating the potential neurotoxic effect of ART. Finally, we present the findings of a meta-analysis to assess the effects on the neurodevelopment of children exposed to ART in utero. PMID:28212307

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

Adams, W.H.; Harper, J.A.; Rittmaster, R.S.

This report updates, for 1980 through 1982, the results of continuing medical surveillance of a Marshallese population accidentally exposed to radioactive fallout in March 1954. The originally exposed Marshallese population comprised 64 persons on Rongelap Atoll who each received, on the average, an estimated 190 rads of absorbed external gamma radiation, 18 on Ailingnae Atoll who received 110 rads, and 159 on Utirik who received 11 rads. There were, in addition, 3 persons in utero on Rongelap, 1 person in utero on Ailingnae, and 8 persons in utero on Utirik who are considered exposed. The recipients of primary medical caremore » include exposed and comparison populations as well as a rather large number of additional beneficiaries who are seen on a humanitarian basis of practical need and resource availability. In recent years, about 1400 people have been seen annually. This report, however, deals with four clearly defined groups: the remaining individuals who were exposed to radioactive fallout on Rongelap, Ailingnae, and Utirik in 1954 (including those in utero), and a comparison population of individuals from Rongelap who were unexposed. The number of persons now in each exposure category are 51, 12, 116, and 137, respectively. 100 references, 4 figures, 5 tables. (ACR)« less

PPAR involvement in PFAA developmental toxicity

EPA Science Inventory

Perfluoroalkyl acids (PFAAs) are found in the environment and in serum of wildlife and humans. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctane sulfonate (PFOS) are developmentally toxic in rodents. The effects of in utero exposure include increas...

CUMULATIVE EFFECTS OF IN UTERO ADMINISTRATION OF MIXTURES OF "ANTIANDROGENS" ON MALE RAT REPRODUCTIVIE DEVELOPMENT.

EPA Science Inventory

Although risk assessments are typically conducted on a chemical-bychemical

basis, the 1996 Food Quality Protection Act Law requires the USEPA to

consider cumulative risk of chemicals that act via a common mode/mechanism of

action. To this end, we are conducti...

Trained immunity in newborn infants of HBV-infected mothers

PubMed Central

Hong, Michelle; Sandalova, Elena; Low, Diana; Gehring, Adam J.; Fieni, Stefania; Amadei, Barbara; Urbani, Simonetta; Chong, Yap-Seng; Guccione, Ernesto; Bertoletti, Antonio

2015-01-01

The newborn immune system is characterized by an impaired Th1-associated immune response. Hepatitis B virus (HBV) transmitted from infected mothers to newborns is thought to exploit the newborns’ immune system immaturity by inducing a state of immune tolerance that facilitates HBV persistence. Contrary to this hypothesis, we demonstrate here that HBV exposure in utero triggers a state of trained immunity, characterized by innate immune cell maturation and Th1 development, which in turn enhances the ability of cord blood immune cells to respond to bacterial infection in vitro. These training effects are associated with an alteration of the cytokine environment characterized by low IL-10 and, in most cases, high IL-12p40 and IFN-α2. Our data uncover a potentially symbiotic relationship between HBV and its natural host, and highlight the plasticity of the fetal immune system following viral exposure in utero. PMID:25807344

Cannabinoid receptor 1 signaling in embryo neurodevelopment

PubMed Central

Psychoyos, Delphine; Vinod, K. Yaragudri; Cao, Jin; Hyson, Richard L.; Wlodarczyk, Bogdan; He, Weimin; Cooper, Thomas B.; Hungund, Basalingappa L.; Finnell, Richard H.

2014-01-01

In utero exposure to THC, the psychoactive component of marijuana, is associated with an increased risk for neurodevelopmental defects in the offspring by interfering with the functioning of the endocannabinoid (eCB) system. At the present time it is not clearly known whether the eCB system is present prior to neurogenesis. Using an array of biochemical techniques we analyzed the levels of CB1 receptors, eCBs (AEA and 2-AG), and the enzymes (NAPE-PLD, DAGLα, DAGLβ MAGL and FAAH) involved in the metabolism of the eCBs in chick and mouse models during development. The findings demonstrate the presence of eCB system in early embryo, prior to neurogenesis. The eCB system might play a critical role in early embryogenesis and there might be adverse developmental consequences of in utero exposure to marijuana and other drugs of abuse during this period. PMID:22311661

Early-life conditions and child development: Evidence from a violent conflict.

PubMed

Duque, Valentina

2017-12-01

This paper investigates how the exposure to violent conflicts in utero and in early and late childhood affect human capital formation. I focus on a wide range of child development outcomes, including novel cognitive and non-cognitive indicators. Using monthly and municipality-level variation in the timing and severity of massacres in Colombia from 1999 to 2007, I show that children exposed to terrorist attacks in utero and in childhood achieve lower height-for-age (0.09 SD) and cognitive outcomes (PPVT falls by 0.18SD and math reasoning and general knowledge fall by 0.16SD), and that these results are robust to controlling for mother fixed-effects. The timing of these exposures matters and differs by type of skill. In terms of parental investments, I find some evidence that parents reinforce the negative effects of violence by increasing their frequency of physical aggression.

Lessons from the polybrominated diphenyl ethers (PBDEs): precautionary principle, primary prevention, and the value of community-based body-burden monitoring using breast milk.

PubMed

Hooper, Kim; She, Jianwen

2003-01-01

Levels of chemicals in humans (body burdens) are useful indicators of environmental quality and of community health. Chemical body burdens are easily monitored using breast milk samples collected from first-time mothers (primiparae) with infants 2-8 weeks of age. Currently, there is no body-burden monitoring program using breast milk in the United States, although ad hoc systems operate successfully in several European countries. In this article we describe the value of such monitoring and important considerations of how it might be accomplished, drawing from our experiences with pilot monitoring projects. Breast milk has several advantages as a sampling matrix: It is simple and noninvasive, with samples collected by the mother. It monitors body burdens in reproductive-age women and it estimates in utero and nursing-infant exposures, all important to community health. Time-trend data from breast milk monitoring serve as a warning system that identifies chemicals whose body burdens and human exposures are increasing. Time trends also serve as a report card on how well past regulatory actions have reduced environmental chemical exposures. Body-burden monitoring using breast milk should include educational programs that encourage breast-feeding. Finally, and most important, clean breast milk matters to people and leads to primary prevention--the limiting of chemical exposures. We illustrate these advantages with polybrominated diphenyl ethers (PBDEs), a formerly obscure group of brominated flame retardants that rose to prominence and were regulated in Sweden when residue levels were found to be rapidly increasing in breast milk. A community-based body-burden monitoring program using breast milk could be set up in the United States in collaboration with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). WIC has a large number of lactating first-time mothers: It has 6,000 clinics nationwide and serves almost half (47%) the infants born in the United States. Educational programs (e.g., those run by WIC) are needed that encourage breast-feeding, especially in lower-income communities where breast-feeding rates are low and where breast-feeding may help protect the infant from the effects of environmental chemical exposures. Education is also needed about reducing chemical body burdens. A body-burden monitoring program would provide valuable data on time trends, background levels, and community hot spots in need of mitigation and follow-up health studies; develop analytic methods for new chemicals of concern; and archive breast milk samples for future analyses of other agents.

In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: Effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology

USDA-ARS?s Scientific Manuscript database

The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure wo...

High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring

USDA-ARS?s Scientific Manuscript database

The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosi...

Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation

EPA Science Inventory

The postnatal effects of in utero exposure to perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestation day (GD) 2 to GD 21; pregnant CD-1 mice were treated ...

Current Evidence for Developmental, Structural, and Functional Brain Defects following Prenatal Radiation Exposure

PubMed Central

Verreet, Tine; Quintens, Roel; Baatout, Sarah; Benotmane, Mohammed A.

2016-01-01

Ionizing radiation is omnipresent. We are continuously exposed to natural (e.g., radon and cosmic) and man-made radiation sources, including those from industry but especially from the medical sector. The increasing use of medical radiation modalities, in particular those employing low-dose radiation such as CT scans, raises concerns regarding the effects of cumulative exposure doses and the inappropriate utilization of these imaging techniques. One of the major goals in the radioprotection field is to better understand the potential health risk posed to the unborn child after radiation exposure to the pregnant mother, of which the first convincing evidence came from epidemiological studies on in utero exposed atomic bomb survivors. In the following years, animal models have proven to be an essential tool to further characterize brain developmental defects and consequent functional deficits. However, the identification of a possible dose threshold is far from complete and a sound link between early defects and persistent anomalies has not yet been established. This review provides an overview of the current knowledge on brain developmental and persistent defects resulting from in utero radiation exposure and addresses the many questions that still remain to be answered. PMID:27382490

Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population in five European countries.

PubMed

Jensen, Tina Kold; Jørgensen, Niels; Punab, Margus; Haugen, Trine B; Suominen, Jyrki; Zilaitiene, Birute; Horte, Antero; Andersen, Anne-Grethe; Carlsen, Elisabeth; Magnus, Øystein; Matulevicius, Valentinas; Nermoen, Ingrid; Vierula, Matti; Keiding, Niels; Toppari, Jorma; Skakkebaek, Niels E

2004-01-01

Between 1996 and 1999, the authors invited all young men from five European countries who were undergoing compulsory medical examination for possible military service to participate in a study on male reproductive health. The participation rate was 19% in two cities in Denmark (n = 889), 17% in Oslo, Norway (n = 221), 13% in Turku, Finland (n = 313), 14% in Kaunas, Lithuania (n = 157), and 19% in Tartu, Estonia (n = 190). Each man provided a semen sample, was examined by a physician, and, in collaboration with his mother, completed a questionnaire about general and reproductive health, current smoking habits, and exposure to smoking in utero. After adjustment for confounding factors, men exposed to smoking in utero had a reduction in sperm concentration of 20.1% (95% confidence interval (CI): 6.8, 33.5) and a reduction in total sperm count of 24.5% (95% CI: 9.5, 39.5) in comparison with unexposed men. Percentages of motile and morphologically normal sperm cells were 1.85 (95% CI: 0.46, 3.23) and 0.64 (95% CI: -0.02, 1.30) percentage points lower, respectively, among men exposed in utero, and exposed men had a 1.15-ml (95% CI: 0.66, 1.64) smaller testis size. The associations were present when data from the study centers were analyzed separately (though not in Lithuania, where only 1% of mothers smoked during pregnancy), although the strength of the association varied. Maternal smoking may have long-term implications for the reproductive health of the offspring. This is another good reason to advise pregnant women to avoid smoking.

Early life exposure to ambient air pollution and childhood asthma in China.

PubMed

Deng, Qihong; Lu, Chan; Norbäck, Dan; Bornehag, Carl-Gustaf; Zhang, Yinping; Liu, Weiwei; Yuan, Hong; Sundell, Jan

2015-11-01

Early life is suggested to be a critical time in determining subsequent asthma development, but the extent to which the effect of early-life exposure to ambient air pollution on childhood asthma is unclear. We investigated doctor-diagnosed asthma in preschool children due to exposure to ambient air pollution in utero and during the first year of life. In total 2490 children aged 3-6 years participated in a questionnaire study regarding doctor-diagnosed asthma between September 2011 and January 2012 in China. Children's exposure to critical air pollutants, sulfur dioxide (SO2) as proxy of industrial air pollution, nitrogen dioxide (NO2) as proxy of traffic pollution, and particulate matter≤10µm in diameter (PM10) as a mixture, was estimated from the concentrations measured at the ambient air quality monitoring stations by using an inverse distance weighted (IDW) method. Logistic regression analysis was employed to determine the relationship between early-life exposure and childhood asthma in terms of odds ratio (OR) and 95% confidence interval (CI). Association between early-life exposure to air pollutants and childhood asthma was observed. SO2 and NO2 had significant associations with adjusted OR (95% CI) of 1.45 (1.02-2.07) and 1.74 (1.15-2.62) in utero and 1.62 (1.01-2.60) and 1.90 (1.20-3.00) during the first year for per 50 µg/m(3) and 15 µg/m(3) increase respectively. Exposure to the combined high level of SO2 and NO2 in China significantly elevated the asthmatic risk with adjusted OR (95% CI) of 1.76 (1.18-2.64) in utero and 1.85 (1.22-2.79) during the first year compared to the low level exposure. The associations were higher for males and the younger children aged 3-4 than females and the older children aged 5-6. Early-life exposure to ambient air pollution is associated with childhood asthma during which the level and source of air pollution play important roles. The high level and nature of combined industrial and traffic air pollution in China may contribute to the recent rapid increase of childhood asthma. Copyright © 2015 Elsevier Inc. All rights reserved.

Sexually Dimorphic Effects of Ancestral Exposure to Vinclozolin on Stress Reactivity in Rats

PubMed Central

Gillette, Ross; Miller-Crews, Isaac; Nilsson, Eric E.; Skinner, Michael K.; Gore, Andrea C.

2014-01-01

How an individual responds to the environment depends upon both personal life history as well as inherited genetic and epigenetic factors from ancestors. Using a 2-hit, 3 generations apart model, we tested how F3 descendants of rats given in utero exposure to the environmental endocrine-disrupting chemical (EDC) vinclozolin reacted to stress during adolescence in their own lives, focusing on sexually dimorphic phenotypic outcomes. In adulthood, male and female F3 vinclozolin- or vehicle-lineage rats, stressed or nonstressed, were behaviorally characterized on a battery of tests and then euthanized. Serum was used for hormone assays, and brains were used for quantitative PCR and transcriptome analyses. Results showed that the effects of ancestral exposure to vinclozolin converged with stress experienced during adolescence in a sexually dimorphic manner. Debilitating effects were seen at all levels of the phenotype, including physiology, behavior, brain metabolism, gene expression, and genome-wide transcriptome modifications in specific brain nuclei. Additionally, females were significantly more vulnerable than males to transgenerational effects of vinclozolin on anxiety but not sociality tests. This fundamental transformation occurs in a manner not predicted by the ancestral exposure or the proximate effects of stress during adolescence, an interaction we refer to as synchronicity. PMID:25051444

Fetal programming and environmental exposures ...

EPA Pesticide Factsheets

Fetal programming is an enormously complex process that relies on numerous environmental inputs from uterine tissue, the placenta, the maternal blood supply, and other sources. Recent evidence has made clear that the process is not based entirely on genetics, but rather on a delicate series of interactions between genes and the environment. It is likely that epigenctic (“above the genome”) changes are responsible for modifying gene expression in the developing fetus, and these modifications can have long-lasting health impacts. Determining which epigenetic regulators are most vital in embryonic development will improve pregnancy outcomes and our ability to treat and prevent disorders that emerge later in life. “Fetal Programming and Environmental Exposures: Implications for Prenatal Care and Preterm Birth’ began with a keynote address by Frederick vom Saal, who explained that low-level exposure to endocrine disrupting chemicals (EDCs) perturbs hormone systems in utero and can have negative effects on fetal development. vom Saal presented data on the LOC bisphenol A (BPA), an estrogen-mimicking compound found in many plastics. He suggested that low-dose exposure to LOCs can alter the development process and enhance chances of acquiring adult diseases, such as breastcancer, diabetes, and even developmental disorders such as attention deficit disorder (ADHD).’ Fetal programming is an enormously complex process that relies on numerous environmental inputs

Japanese Legacy Cohorts: The Life Span Study Atomic Bomb Survivor Cohort and Survivors' Offspring.

PubMed

Ozasa, Kotaro; Grant, Eric J; Kodama, Kazunori

2018-04-05

Cohorts of atomic bomb survivors-including those exposed in utero-and children conceived after parental exposure were established to investigate late health effects of atomic bomb radiation and its transgenerational effects by the Atomic Bomb Casualty Commission (ABCC) in the 1950s. ABCC was reorganized to the Radiation Effects Research Foundation (RERF) in 1975, and all work has been continued at RERF. The Life Span Study, the cohort of survivors, consists of about 120,000 subjects and has been followed since 1950. Cohorts of in utero survivors and the survivors' children include about 3,600 and 77,000 subjects, respectively, and have been followed since 1945. Atomic bomb radiation dose was estimated for each subject based on location at the time of the bombing and shielding conditions from exposure, which were obtained through enormous efforts of investigators and cooperation of subjects. Outcomes include vital status, cause of death, and cancer incidence. In addition, sub-cohorts of these three cohorts were constructed to examine clinical features of late health effects, and the subjects have been invited to periodic health examinations at clinics of ABCC and RERF. They were also asked to donate biosamples for biomedical investigations. Epidemiological studies have observed increased radiation risks for malignant diseases among survivors, including those exposed in utero, and possible risks for some non-cancer diseases. In children of survivors, no increased risks due to parental exposure to radiation have been observed for malignancies or other diseases, but investigations are continuing, as these cohorts are still relatively young.

In utero exposure to 25-hydroxyvitamin D and risk of childhood asthma, wheeze, and respiratory tract infections: A meta-analysis of birth cohort studies.

PubMed

Feng, Haixia; Xun, Pengcheng; Pike, Katharine; Wills, Andrew K; Chawes, Bo L; Bisgaard, Hans; Cai, Wei; Wan, Yanping; He, Ka

2017-05-01

Studies of the associations between in utero 25-hydroxyvitamin D (25[OH]D) exposure and risk of childhood asthma, wheeze, and respiratory tract infections are inconsistent and inconclusive. We sought to assess associations between 25(OH)D levels in cord blood or maternal venous blood and risk of offspring's asthma, wheeze, and respiratory tract infections. Data were derived from PubMed, Embase, Google Scholar, references from relevant articles, and de novo results from published studies until December 2015. A random-effects meta-analysis was conducted among 16 birth cohort studies. Comparing the highest with the lowest category of 25(OH)D levels, the pooled odds ratios were 0.84 (95% CI, 0.70-1.01; P = .064) for asthma, 0.77 (95% CI, 0.58-1.03; P = .083) for wheeze, and 0.85 (95% CI, 0.66-1.09; P = .187) for respiratory tract infections. The observed inverse association for wheeze was more pronounced and became statistically significant in the studies that measured 25(OH)D levels in cord blood (0.43; 95% CI, 0.29-0.62; P < .001). Accumulated evidence generated from this meta-analysis suggests that increased in utero exposure to 25(OH)D is inversely associated with the risk of asthma and wheeze during childhood. These findings are in keeping with the results of 2 recently published randomized clinical trials of vitamin D supplementation during pregnancy. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Ureaplasma parvum undergoes selection in utero resulting in genetically diverse isolates colonizing the chorioamnion of fetal sheep.

PubMed

Dando, Samantha J; Nitsos, Ilias; Polglase, Graeme R; Newnham, John P; Jobe, Alan H; Knox, Christine L

2014-02-01

Ureaplasmas are the microorganisms most frequently isolated from the amniotic fluid of pregnant women and can cause chronic intrauterine infections. These tiny bacteria are thought to undergo rapid evolution and exhibit a hypermutatable phenotype; however, little is known about how ureaplasmas respond to selective pressures in utero. Using an ovine model of chronic intraamniotic infection, we investigated if exposure of ureaplasmas to subinhibitory concentrations of erythromycin could induce phenotypic or genetic indicators of macrolide resistance. At 55 days gestation, 12 pregnant ewes received an intraamniotic injection of a nonclonal, clinical Ureaplasma parvum strain followed by (i) erythromycin treatment (intramuscularly, 30 mg/kg/day, n = 6) or (ii) saline (intramuscularly, n = 6) at 100 days gestation. Fetuses were then delivered surgically at 125 days gestation. Despite injecting the same inoculum into all the ewes, significant differences between amniotic fluid and chorioamnion ureaplasmas were detected following chronic intraamniotic infection. Numerous polymorphisms were observed in domain V of the 23S rRNA gene of ureaplasmas isolated from the chorioamnion (but not the amniotic fluid), resulting in a mosaiclike sequence. Chorioamnion isolates also harbored the macrolide resistance genes erm(B) and msr(D) and were associated with variable roxithromycin minimum inhibitory concentrations. Remarkably, this variability occurred independently of exposure of ureaplasmas to erythromycin, suggesting that low-level erythromycin exposure does not induce ureaplasmal macrolide resistance in utero. Rather, the significant differences observed between amniotic fluid and chorioamnion ureaplasmas suggest that different anatomical sites may select for ureaplasma subtypes within nonclonal, clinical strains. This may have implications for the treatment of intrauterine ureaplasma infections.

In utero and early-life exposure of rats to a Wi-Fi signal: screening of immune markers in sera and gestational outcome.

PubMed

Aït-Aïssa, Saliha; Billaudel, Bernard; Poulletier de Gannes, Florence; Ruffié, Gilles; Duleu, Sébastien; Hurtier, Annabelle; Haro, Emmanuelle; Taxile, Murielle; Athané, Axel; Geffard, Michel; Wu, Tongning; Wiart, Joe; Bodet, Dominique; Veyret, Bernard; Lagroye, Isabelle

2012-07-01

An experimental approach was used to assess immunological biomarkers in the sera of young rats exposed in utero and postnatal to non-ionizing radiofrequency fields. Pregnant rats were exposed free-running, 2 h/day and 5 days/week to a 2.45 GHz Wi-Fi signal in a reverberation chamber at whole-body specific absorption rates (SAR) of 0, 0.08, 0.4, and 4 W/kg (with 10, 10, 12, and 9 rats, respectively), while cage control rats were kept in the animal facility (11 rats). Dams were exposed from days 6 to 21 of gestation and then three newborns per litter were further exposed from birth to day 35 postnatal. On day 35 after birth, all pups were sacrificed and sera collected. The screening of sera for antibodies directed against 15 different antigens related to damage and/or pathological markers was conducted using enzyme-linked immunosorbent assay (ELISA). No change in humoral response of young pups was observed, regardless of the types of biomarker and SAR levels. This study also provided some data on gestational outcome following in utero exposure to Wi-Fi signals. Mass evaluation of dams and pups and the number of pups per litter was monitored, and the genital tracts of young rats were observed for abnormalities by measuring anogenital distance. Under these experimental conditions, our observations suggest a lack of adverse effects of Wi-Fi exposure on delivery and general condition of the animals. Copyright © 2012 Wiley Periodicals, Inc.

Fetal exposure to teratogens: evidence of genes involved in autism.

PubMed

Dufour-Rainfray, Diane; Vourc'h, Patrick; Tourlet, Sébastien; Guilloteau, Denis; Chalon, Sylvie; Andres, Christian R

2011-04-01

Environmental challenges during the prenatal period can result in behavioral abnormalities and cognitive deficits that appear later in life such as autism. Prenatal exposure to valproic acid, ethanol, thalidomide and misoprostol has been shown to be associated with an increased incidence of autism. In addition, rodents exposed in utero to some of these drugs show autism-like abnormalities, including brain changes and lifelong behavior dysfunction. Our aim is to summarize current understanding of the relationship between in utero exposure to these drugs and autism in humans and in autism-like animal model phenotypes. It also highlights the importance of these models to understanding the neurobiology of autism, particularly in the identification of susceptibility genes. These drugs are able to modulate the expression of many genes involved in processes such as proliferation, apoptosis, neuronal differentiation and migration, synaptogenesis and synaptic activity. It seems essential to focus research on genes expressed during early neurodevelopment which may be the target of mutations or affected by drugs such as those included in this review. Copyright © 2011. Published by Elsevier Ltd.

Digit-Length Ratios (2D:4D) as a Phenotypic Indicator of in Utero Androgen Exposure is Not Prognostic for Androgenic Alopecia: a Descriptive-Analytic Study of 1200 Iranian Men.

PubMed

Feily, Amir; Hosseinpoor, Masoomeh; Bakhti, Ali; Nekuyi, Mohamad; Sobhanian, Saeed; Fathinezhad, Zahra; Sahraei, Reza; Ramirez-Fort, Marigdalia K

2016-06-15

The etiology of androgenic alopecia (AGA) involves several factors, including genetics, androgens, age and nutrition. Digit-length ratio of the index and ring finger (2D:4D) is an indicator of prenatal exposure to sex hormones. There is a paucity of studies that systemically review the possible positive predictive value of 2D:4D in the development of AGA. We performed a single-site, descriptive-analytical study among a racially homogeneous population. Our results revealed that no significant association was determined between right 2D:4D and AGA severity within our entire population (P=0.384, r=0.025), however a positive correlation coefficient was identified in subjects above the age of 40. Based on the receiver operating characteristic curve analysis, 2D:4D does not predict the development of AGA. AGA is truly a multifactorial disease. Further, our findings suggest that increased in utero exposure to androgens as a fetus does not predispose men to develop AGA.

Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential?

PubMed

McCorry, D; Bromley, R

2015-05-01

A clinical scenario of a young female on 800 mg of sodium valproate (VPA) who has recently failed lamotrigine (LTG) and levetiracetam (LEV) and who is currently planning a pregnancy is presented. Currently available data pertaining to the longer-term development of children exposed to antiepileptic drugs (AEDs) are reviewed along with considerations around the methodology and interpretation of such research. There is an accumulation of data highlighting significant risks associated with prenatal exposed to VPA, with the level of risk being mediated by dose. The majority of published evidence does not find a significant risk associated with carbamazepine (CBZ) exposure in utero for global cognitive abilities however the evidence for more specific cognitive skills are unclear. Limited data indicate that LTG may be a preferred treatment to VPA in terms of foetal outcome but further evidence is required. Too little data pertaining to LEV exposure is available and a lack of evidence regarding risk of this and other new AEDs should not be interpreted as evidence of safety. Copyright © 2015. Published by Elsevier Ltd.

ARSENIC - SUSCEPTIBILITY & IN UTERO EFFECTS

EPA Science Inventory

Exposure to inorganic arsenic remains a serious public health problem at many locations worldwide. If has often been noted that prevalences of signs and symptoms of chronic arsenic poisoning differ among various populations. For example, skin lesions or peripheral vascular dis...

Developmental origins of non-communicable disease: Implications for research and public health

PubMed Central

2012-01-01

This White Paper highlights the developmental period as a plastic phase, which allows the organism to adapt to changes in the environment to maintain or improve reproductive capability in part through sustained health. Plasticity is more prominent prenatally and during early postnatal life, i.e., during the time of cell differentiation and specific tissue formation. These developmental periods are highly sensitive to environmental factors, such as nutrients, environmental chemicals, drugs, infections and other stressors. Nutrient and toxicant effects share many of the same characteristics and reflect two sides of the same coin. In both cases, alterations in physiological functions can be induced and may lead to the development of non-communicable conditions. Many of the major diseases – and dysfunctions – that have increased substantially in prevalence over the last 40 years seem to be related in part to developmental factors associated with either nutritional imbalance or exposures to environmental chemicals. The Developmental Origins of Health and Disease (DOHaD) concept provides significant insight into new strategies for research and disease prevention and is sufficiently robust and repeatable across species, including humans, to require a policy and public health response. This White Paper therefore concludes that, as early development (in utero and during the first years of postnatal life) is particularly sensitive to developmental disruption by nutritional factors or environmental chemical exposures, with potentially adverse consequences for health later in life, both research and disease prevention strategies should focus more on these vulnerable life stages. PMID:22715989

Effects of prenatal exposure to diesel exhaust particles on postnatal development, behavior, genotoxicity and inflammation in mice

PubMed Central

Hougaard, Karin S; Jensen, Keld A; Nordly, Pernille; Taxvig, Camilla; Vogel, Ulla; Saber, Anne T; Wallin, Håkan

2008-01-01

Background Results from epidemiological studies indicate that particulate air pollution constitutes a hazard for human health. Recent studies suggest that diesel exhaust possesses endocrine activity and therefore may affect reproductive outcome. This study in mice aimed to investigate whether exposure to diesel exhaust particles (DEP; NIST 2975) would affect gestation, postnatal development, activity, learning and memory, and biomarkers of transplacental toxicity. Pregnant mice (C57BL/6; BomTac) were exposed to 19 mg/m3 DEP (~1·106 particles/cm3; mass median diameter ≅ 240 nm) on gestational days 9–19, for 1 h/day. Results Gestational parameters were similar in control and diesel groups. Shortly after birth, body weights of DEP offspring were slightly lower than in controls. This difference increased during lactation, so by weaning the DEP exposed offspring weighed significantly less than the control progeny. Only slight effects of exposure were observed on cognitive function in female DEP offspring and on biomarkers of exposure to particles or genotoxic substances. Conclusion In utero exposure to DEP decreased weight gain during lactation. Cognitive function and levels of biomarkers of exposure to particles or to genotoxic substances were generally similar in exposed and control offspring. The particle size and chemical composition of the DEP and differences in exposure methods (fresh, whole exhaust versus aged, resuspended DEP) may play a significant role on the biological effects observed in this compared to other studies. PMID:18331653

In utero exposure to levetiracetam vs valproate: development and language at 3 years of age.

PubMed

Shallcross, R; Bromley, R L; Cheyne, C P; García-Fiñana, M; Irwin, B; Morrow, J; Baker, G A

2014-01-21

To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] -24.5 to -7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI -11.0 to -1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI -14.7 to -4.4, p < 0.001). The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women's preferred choice of antiepileptic drug.

[Structural and functional status of the hypophyseal-thyroid system in prenatally irradiated children].

PubMed

Makiienko, T S; Pavliuk, V P; Pavliuk, I V; Mosiienko, A P

2001-01-01

In order to evaluate the morphologic-and-functional state of the hypophysis-thyroid system long after the Chernobyl accident we examined 1491 children from the northern territories of the Zhitomir region. Of these, 261 had not been in utero exposed to radioiodine, 1230 pediatric subjects proved to be postconception-exposed. In utero radioiodine has not been found to affect the thyroid size in any noticeable way. The degree of structural-and-functional indices for the thyreostat system in prenatally irradiated children depends on the stage of the thyroid development just when there happened to be an exposure to radioiodine.

Exposure to hazardous substances and male reproductive health: a research framework.

PubMed Central

Moline, J M; Golden, A L; Bar-Chama, N; Smith, E; Rauch, M E; Chapin, R E; Perreault, S D; Schrader, S M; Suk, W A; Landrigan, P J

2000-01-01

The discovery in the mid-1970s that occupational exposures to pesticides could diminish or destroy the fertility of workers sparked concern about the effects of hazardous substances on male reproductive health. More recently, there is evidence that sperm quantity and quality may have declined worldwide, that the incidence of testicular cancer has progressively increased in many countries, and that other disorders of the male reproductive tract such as hypospadias and cryptorchidism may have also increased. There is growing concern that occupational factors and environmental chemical exposures, including in utero and childhood exposures to compounds with estrogenic activity, may be correlated with these observed changes in male reproductive health and fertility. We review the evidence and methodologies that have contributed to our current understanding of environmental effects on male reproductive health and fertility and discuss the methodologic issues which confront investigators in this area. One of the greatest challenges confronting researchers in this area is assessing and comparing results from existing studies. We elaborate recommendations for future research. Researchers in the field of male reproductive health should continue working to prioritize hazardous substances; elucidate the magnitude of male reproductive health effects, particularly in the areas of testicular cancer, hypospadias, and cryptorchidism; develop biomarkers of exposure to reproductive toxins and of reproductive health effects for research and clinical use; foster collaborative interdisciplinary research; and recognize the importance of standardized laboratory methods and sample archiving. PMID:11017884

CUMULATIVE REPRODUCTIVE EFFECTS OF IN UTERO ADMINISTRATION OF A MIXTURE OF TEN “ANTIANDROGENS” IN MALE SD RATS: SYNERGY OR ADDITIVITY?

EPA Science Inventory

In 1996, the USEPA was charged under FQPA to consider the cumulative effects of chemicals in their risk assessments. We are conducting studies to provide a framework for assessing the cumulative effects of antiandrogens. In the current study, ten “antiandrogenic” chemicals were a...

In utero and childhood DDT, DDE, PBDE and PCBs exposure and sex hormones in adolescent boys: The CHAMACOS study.

PubMed

Eskenazi, Brenda; Rauch, Stephen A; Tenerelli, Rachel; Huen, Karen; Holland, Nina T; Lustig, Robert H; Kogut, Katherine; Bradman, Asa; Sjödin, Andreas; Harley, Kim G

2017-04-01

Dichlorodiphenyltrichloroethane (DDT), polybrominated diphenyl ether (PBDE) flame retardants, and polychlorinated biphenyls (PCBs) are believed to be endocrine-disrupting chemicals (EDCs) in humans and animals. The purpose of this study is to examine the relationship of in utero and childhood exposure to these purported EDCs and reproductive hormones in adolescent boys who participated in CHAMACOS, an ongoing birth cohort in California's Salinas Valley. We measured o,p'- and p,p'-DDT, p,p'-DDE, PBDEs and PCBs in serum collected from mothers during pregnancy or at delivery and from their sons at 9 years. We measured concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone (T) from 234 of their sons at 12 years. In adjusted models, we found that a 10-fold increase in maternal prenatal serum concentrations of BDE-153 was associated with a 22.2% increase (95% CI: 1.0, 47.9) in FSH, a 96.6% increase (95% CI: 35.7, 184.7) in LH, and a 92.4% increase (95% CI: 20.9, 206.2) increase in T. Similarly, BDE-100 concentrations were associated with increases in boys' LH levels. A 10-fold increase in total prenatal ΣPCBs was associated with a 64.5% increase (95% CI: 8.6, 149.0) in FSH, primarily driven by non- dioxin-like congeners. Boys' hormone levels were only marginally associated with prenatal DDT or DDE in primary models, but when boys' Tanner stage at age 12 was added to models, prenatal maternal DDT levels were associated with decreases in LH (adjusted percent change per 10-fold increase=-18.5%, 95% CI: -29.8, -5.4) and T (percent change=-18.2%, 95% CI: -30.2, -4.2) and DDE with LH (percent change=-18.3%, 95% CI: -32.9, -0.6). Exposures measured in the children's serum at 9 years also showed associations between BDE-153 and ΣPCBs. However, there is evidence that these associations appear to be mediated by child BMI. This study suggests associations on male hormones of 12year old boys related to exposure to certain EDC exposure prenatally. The implications on future reproductive function in puberty and adulthood should be determined. Copyright © 2016 Elsevier GmbH. All rights reserved.

In utero and childhood DDT, DDE, PBDE and PCBs exposure and sex hormones in adolescent boys: The CHAMACOS study

PubMed Central

Eskenazi, Brenda; Rauch, Stephen A.; Tenerelli, Rachel; Huen, Karen; Holland, Nina T.; Lustig, Robert H.; Kogut, Katherine; Bradman, Asa; Sjodin, Andreas; Harley, Kim G.

2016-01-01

Dichlorodiphenyltrichloroethane (DDT), polybrominated diphenyl ether (PBDE) flame retardants, and polychlorinated biphenyls (PCBs) are believed to be endocrine-disrupting chemicals (EDCs) in humans and animals. The purpose of this study is to examine the relationship of in utero and childhood exposure to these purported EDCs and reproductive hormones in adolescent boys who participated in CHAMACOS, an ongoing birth cohort in California’s Salinas Valley. We measured o,p′- and p,p′-DDT, p,p′- DDE, PBDEs and PCBs in serum collected from mothers during pregnancy or at delivery and from their sons at 9 years. We measured concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone (T) from 234 of their sons at 12 years. In adjusted models, we found that a 10-fold increase in maternal prenatal serum concentrations of BDE-153 was associated with a 22.2% increase (95% CI: 1.0, 47.9) in FSH, a 96.6% increase (95% CI: 35.7, 184.7) in LH, and a 92.4% increase (95% CI: 20.9, 206.2) increase in T. Similarly, BDE-100 concentrations were associated with increases in boys’ LH levels. A 10-fold increase in total prenatal ΣPCBs was associated with a 64.5% increase (95% CI: 8.6, 149.0) in FSH, primarily driven by non-dioxin-like congeners. Boys’ hormone levels were only marginally associated with prenatal DDT or DDE in primary models, but when boys’ Tanner stage at age 12 was added to models, prenatal maternal DDT levels were associated with decreases in LH (adjusted percent change per 10-fold increase = −18.5%, 95% CI: −29.8, −5.4) and T (percent change = −18.2%, 95% CI: −30.2, −4.2) and DDE with LH (percent change = −18.3%, 95% CI: −32.9, −0.6). Exposures measured in the children’s serum at 9 years also showed associations between BDE-153 and ΣPCBs. However, there is evidence that these associations appear to be mediated by child BMI. This study suggests associations on male hormones of 12 year old boys related to exposure to certain EDC exposure prenatally. The implications on future reproductive function in puberty and adulthood should be determined. PMID:27876543

A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice.

PubMed

Demars, Fanny; Clark, Kristen; Wyeth, Megan S; Abrams, Emily; Buckmaster, Paul S

2018-05-01

Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long-term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study's in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2 to 6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1-11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive-control pilocarpine-treated mice, but seizure duration was similar. None of the mice treated in utero with vehicle or DA displayed hilar neuron loss or intense mossy fiber sprouting, a form of aberrant synaptic reorganization that develops in patients with temporal lobe epilepsy and in pilocarpine-treated mice. FVB mice that developed epilepsy (vehicle- and DA-treated) displayed mild mossy fiber sprouting. Results of this study suggest that a single subconvulsive dose of DA at mid-gestation does not cause temporal lobe epilepsy in mice. Copyright © 2018 Elsevier B.V. All rights reserved.

REPRODUCTIVE TOXICITY OF PHTHALATE ESTERS

EPA Science Inventory

Phthalate esters display several modes of toxicity in mammalian species. In the rat, in utero exposure at relatively low dosage levels disrupts development of the reproductive system of the male rat by altering fetal testis hormone production. This presentation is a review of t...

76 FR 7712 - Clothianidin; Time-Limited Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-11

... registration of this seed treatment. Valent has requested an experimental use permit and this tolerance to... evidence of increased quantitative or qualitative susceptibility of rat or rabbit fetuses following in utero exposure to clothianidin in developmental studies; however, increased quantitative susceptibility...

Lipidomic fatty acid profile and global gene expression pattern in mammary gland of rats that were exposed to lard-based high fat diet during fetal and lactation periods associated to breast cancer risk in adulthood.

PubMed

Andrade, Fábia de Oliveira; de Assis, Sonia; Jin, Lu; Fontelles, Camile Castilho; Barbisan, Luís Fernando; Purgatto, Eduardo; Hilakivi-Clarke, Leena; Ong, Thomas Prates

2015-09-05

The persistent effects of animal fat consumption during pregnancy and nursing on the programming of breast cancer risk among female offspring were studied here. We have previously found that female offspring of rat dams that consumed a lard-based high-fat (HF) diet (60% fat-derived energy) during pregnancy, or during pregnancy and lactation, were at a reduced risk of developing mammary cancer. To better understand the unexpected protective effects of early life lard exposure, we have applied lipidomics and nutrigenomics approaches to investigate the fatty acid profile and global gene expression patterns in the mammary tissue of the female offspring. Consumption of this HF diet during gestation had few effects on the mammary tissue fatty acids profile of young adult offspring, while exposure from gestation throughout nursing promoted significant alterations in the fatty acids profile. Major differences were related to decreases in saturated fatty acids (SFA) and increases in omega-6 polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and conjugated linolenic acid (CLA) concentrations. In addition several differences in gene expression patterns by microarray analysis between the control and in utero or in utero and during lactation HF exposed offspring were identified. Differential dependency network (DDN) analysis indicated that many of the genes exhibited unique connections to other genes only in the HF offspring. These unique connections included Hrh1-Ythdf1 and Repin1-Elavl2 in the in utero HF offspring, and Rnf213-Htr3b and Klf5-Chrna4 in the in utero and lactation HF offspring, compared with the control offspring. We conclude that an exposure to a lard-based HF diet during early life changes the fatty acid profile and transcriptional network in mammary gland in young adult rats, and these changes appear to be consistent with reduced mammary cancer risk observed in our previous study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pre- and post-natal exposure to antibiotics and the development of eczema, recurrent wheezing and atopic sensitization in children up to the age of 4 years.

PubMed

Dom, S; Droste, J H J; Sariachvili, M A; Hagendorens, M M; Oostveen, E; Bridts, C H; Stevens, W J; Wieringa, M H; Weyler, J J

2010-09-01

Little data are available on the relationship between indirect antibiotic exposure of the child in utero or during lactation and allergic diseases. On the other hand, several studies have been conducted on the association with direct post-natal antibiotic exposure, but the results are conflicting. The aim of this study was to investigate pre- and post-natal antibiotic exposure and the subsequent development of eczema, recurrent wheeze and atopic sensitization in children up to the age of 4 years. We conducted an aetiologic study in 773 children based on a prospective birth cohort project in which environmental and health information were collected using questionnaires. Antibiotic exposure was assessed as maternal antibiotic intake during pregnancy and during lactation and as medication intake of the child. The chronology of exposures and outcomes was taken into account during the data processing. At the age of 1 and 4 years, a blood sample was taken for the quantification of specific IgE. Prenatal antibiotic exposure was significantly positively associated with eczema, whereas no association was found with recurrent wheeze and atopic sensitization. We found a positive, although statistically not significant, association between antibiotic exposure through breastfeeding and recurrent wheeze. Neither eczema nor atopic sensitization was significantly associated with antibiotic exposure through breastfeeding. Finally, we observed a negative association between the use of antibiotics in the first year of life and eczema and atopic sensitization, and also between antibiotic use after the first year of life and recurrent wheeze, eczema and atopic sensitization. Indirect exposure to antibiotics (in utero and during lactation) increases the risk for allergic symptoms in children, while direct exposure to antibiotics appears to be protective. The biological mechanisms underlying these findings still need to be elucidated.

Classification of phthalates based on an in vitro neurosphere assay using rat mesencephalic neural stem cells.

PubMed

Ishido, Masami; Suzuki, Junko

2014-02-01

Exposure to environmental neurotoxic chemicals both in utero and during the early postnatal period can cause neurodevelopmental disorders. To evaluate the disruption of neurodevelopmental programming, we previously established an in vitro neurosphere assay system using rat mesencephalic neural stem cells that can be used to evaluate. Here, we extended the assay system to examine the neurodevelopmental toxicity of the endocrine disruptors butyl benzyl phthalate, di-n-butyl phthalate, dicyclohexyl phthalate, diethyl phthalate, di(2-ethyl hexyl) phthalate, di-n-pentyl phthalate, and dihexyl phthalate at a range of concentrations (0-100 μM). All phthalates tested inhibited cell migration with a linear or non-linear range of concentrations when comparing migration distance to the logarithm of the phthalate concentrations. On the other hand, some, but not all, phthalates decreased the number of proliferating cells. Apoptotic cells were not observed upon phthalate exposure under any of the conditions tested, whereas the dopaminergic toxin rotenone induced significant apoptosis. Thus, we were able to classify phthalate toxicity based on cell migration and cell proliferation using the in vitro neurosphere assay.

Perfluoroctane sulfonate-induced changes in fetal rat liver gene expression

EPA Science Inventory

In utero exposure of rats to perfluorooctane sulfonate (PFOS, C8F17SO3), a widely disseminated product of the surfactant and coating industries, is associated with residual hepatoxic complications in the surviving offspring. This hepatocellular hypertrophy resembles that observe...

75 FR 6576 - Acetamiprid; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-10

.... Interregional Research Project Number 4 (IR-4) requested these tolerances under the Federal Food, Drug, and... is a non- competitive inhibitor. Furthermore, even if future research shows that neonicotinoids share... of quantitative or qualitative susceptibility of rat or rabbit fetuses following in utero exposure to...

Blood metal levels and third trimester maternal plasma matrix metalloproteinases (MMPs).

PubMed

Au, Felicia; Bielecki, Agnieszka; Blais, Erica; Fisher, Mandy; Cakmak, Sabit; Basak, Ajoy; Gomes, James; Arbuckle, Tye E; Fraser, William D; Vincent, Renaud; Kumarathasan, Prem

2016-09-01

While it is known that in utero exposure to environmental toxicants, namely heavy metals, can adversely affect the neonate, there remains a significant paucity of information on maternal biological changes specific to metal exposures during pregnancy. This study aims at identifying associations between maternal metal exposures and matrix metalloproteinases (MMPs) that are known to be engaged in pregnancy process. Third trimester maternal plasma (n = 1533) from a pregnancy cohort (Maternal-Infant Research on Environmental Chemicals Study, MIREC) were analyzed for MMP-1,-2,-7,-9 and -10 by affinity-based multiplex protein array analyses. Maternal metal concentrations (mercury, cadmium, lead, arsenic and manganese) in 1st and 3rd trimesters exhibited strong correlations (p < 0.05). Multivariate regression models were used to estimate odds ratio (OR) for the association between metal concentrations in quartiles and high (90%) and low (10%) maternal MMP levels. Significant (p < 0.05) metal exposure-related effects were observed with the different MMP isoform responses. MMP profiles were specific to the trimester at which the maternal blood metals were analyzed. Our findings suggest that the profiles of these MMP isoforms vary with the type of metal exposure, blood metal concentrations and the trimester at which metal levels were determined. These new findings on maternal metal-MMP relationships can guide future explorations on toxicity mechanisms relevant to metal exposure-mediated adverse birth outcomes. Copyright © 2016. Published by Elsevier Ltd.

Interhemispheric Functional Brain Connectivity in Neonates with Prenatal Alcohol Exposure: Preliminary Findings.

PubMed

Donald, Kirsten A; Ipser, Jonathan C; Howells, Fleur M; Roos, Annerine; Fouche, Jean-Paul; Riley, Edward P; Koen, Nastassja; Woods, Roger P; Biswal, Bharat; Zar, Heather J; Narr, Katherine L; Stein, Dan J

2016-01-01

Children exposed to alcohol in utero demonstrate reduced white matter microstructural integrity. While early evidence suggests altered functional brain connectivity in the lateralization of motor networks in school-age children with prenatal alcohol exposure (PAE), the specific effects of alcohol exposure on the establishment of intrinsic connectivity in early infancy have not been explored. Sixty subjects received functional imaging at 2 to 4 weeks of age for 6 to 8 minutes during quiet natural sleep. Thirteen alcohol-exposed (PAE) and 14 age-matched control (CTRL) participants with usable data were included in a multivariate model of connectivity between sensorimotor intrinsic functional connectivity networks. Seed-based analyses of group differences in interhemispheric connectivity of intrinsic motor networks were also conducted. The Dubowitz neurological assessment was performed at the imaging visit. Alcohol exposure was associated with significant increases in connectivity between somatosensory, motor networks, brainstem/thalamic, and striatal intrinsic networks. Reductions in interhemispheric connectivity of motor and somatosensory networks did not reach significance. Although results are preliminary, findings suggest PAE may disrupt the temporal coherence in blood oxygenation utilization in intrinsic networks underlying motor performance in newborn infants. Studies that employ longitudinal designs to investigate the effects of in utero alcohol exposure on the evolving resting-state networks will be key in establishing the distribution and timing of connectivity disturbances already described in older children. Copyright © 2016 by the Research Society on Alcoholism.

Hyperparasitaemia during clinical malaria episodes in infants aged 0-24 months and its association with in utero exposure to Plasmodium falciparum.

PubMed

Sylvester, Boniphace; Gasarasi, Dinah B; Aboud, Said; Tarimo, Donath; Massawe, Siriel; Mpembeni, Rose; Swedberg, Gote

2018-04-04

Existing information has shown that infants who are prenatally exposed to P. falciparum are susceptible to subsequent malaria infections. However, the effect of prenatal exposure to P. falciparum on parasite density during clinical malaria episodes has not been fully elucidated. This study is a component of a prospective cohort study for which initial results have been published. This component was designed to determine the effect of prenatal exposure to P. falciparum on parasite density during clinical malaria episodes in the first 24 months of life. A total of 215 infants were involved and monitored for clinical malaria episodes defined by fever (≥ 37 °C) and parasitaemia. The geometric mean parasite counts between exposed and unexposed infants were compared using independent samples t test. The effect of in utero exposure to P. falciparum on parasite density was assessed using binary logistic regression. The geometric mean parasite count per µl of blood during clinical malaria episodes in exposed infants was 24,889 (95% CI 18,286-31,490) while in unexposed infants it was 14,035 (95% CI 12,111-15,960), P < 0.05. Prenatal exposure to P. falciparum was associated with hyperparasitaemia during clinical malaria episodes (OR 7.04, 95% CI 2.31-21.74), while other factors were not significantly associated (P > 0.05).

In utero exposure to female hormones and germ cell tumors in children.

PubMed

Shankar, Sadhna; Davies, Stella; Giller, Roger; Krailo, Mark; Davis, Mary; Gardner, Kathleen; Cai, Hui; Robison, Leslie; Shu, Xiao-Ou

2006-03-01

Maternal exposure to exogenous female hormones during pregnancy has been implicated as a risk factor for malignant germ cell tumors (GCTs) in the offspring in some epidemiologic studies of testicular and ovarian carcinoma in adults. From 1996 to 2002, 278 children younger than 15 years of age with malignant GCTs and 423 healthy controls, frequency-matched for geographic location, age, and sex were enrolled in a case-control study to investigate whether in utero exposure to female hormones is associated with the risk of malignant GCT in children. Cases were recruited from 84 institutions in the U.S. and controls were enrolled through random digit dialing. Information was obtained through telephone interview with the biological mothers of the subjects and through blinded review of the mothers' medical records. Neither self-reported (odds ratio [OR] = 1.15; 95% confidence interval [CI], 0.63, 2.12) nor medical chart based (OR = 1.14; 95% CI, 0.75, 1.73) maternal exposure to exogenous female hormones was related to malignant GCT risk. Pregnancy-related conditions that may have altered serum levels of circulating female hormones were also unrelated to the risk of GCT in the offspring. This study failed to provide strong evidence to support the hypothesis that maternal exposure to exogenous female hormones during pregnancy increases the risk of GCT in the offspring.

Effects of maternal and early tobacco exposure on the development of asthma and airway hyperreactivity.

PubMed

Lødrup Carlsen, K C; Carlsen, K H

2001-04-01

In 1999 a comprehensive review was published in Thorax that evaluated the role of exposure to tobacco smoke products (TSPs) in respiratory disease. The present review addresses papers published within the past 12 months on the effects of TSPs on childhood asthma and atopic disease, along with a few reports on possible mechanisms by which TSPs exert their adverse effects. Most of the observational studies published during the past year support the conclusion that both in-utero and, to some degree, passive (environmental) tobacco smoke (ETS) exposure adversely affect pulmonary function, and predispose to asthma symptoms and possibly bronchial hyperresponsiveness in childhood, but play little or no role in atopy development. However, in TSP-induced pulmonary disease, a mechanism of upregulation of pulmonary neuroendocrine cells has been hypothesized. An interventional study clearly demonstrated a need for a total (instead of partial) ban on indoor smoking in the homes of children with asthma in order to achieve significant reductions in levels of urinary cotinine. Because there is a large body of evidence for adverse effects of in-utero TSP as well as ETS exposure on respiratory health in children, we are in dire need of studies to elucidate when TSP exposure causes most damage, the mechanisms that underlie this damage, and how we can prevent unnecessary harm to the respiratory system in the vulnerable child.

In utero cortisol and testosterone exposure and fear reactivity in infancy.

PubMed

Bergman, Kristin; Glover, Vivette; Sarkar, Pampa; Abbott, Dave H; O'Connor, Thomas G

2010-03-01

Fetal programming is emerging as a major conceptual model for understanding developmental origins of health and disease, including behavioral outcomes. As part of a larger study of prenatal stress and child development, we examined the association between prenatal hormone exposure and fear reactivity, a temperament dimension that is a predictor of long-term behavioral adjustment. Amniotic fluid was collected from a sample of women undergoing clinically indicated amniocentesis for later analysis of cortisol and testosterone. Children with normal birth outcomes were recalled for follow-up assessment at 17 months, at which time we administered an observational assessment of temperament (lab-TAB; n=108). Information on pregnancy and obstetric outcome was included as covariates. Results indicated that there was a significant association between prenatal testosterone and observed fear reactivity in boys (r(53)=0.34, p=0.01); no significant effect was found in girls (r(54)=-0.07, ns); the effect remained when obstetric, psychosocial, and parental anxiety were controlled for. There was not a significant association between fetal cortisol exposure and fear reactivity. The prediction from in utero testosterone exposure to fear reactivity in boys extends prior research on prenatal testosterone and may represent an association with a general predisposition to greater arousal and reactivity. Copyright 2010 Elsevier Inc. All rights reserved.

In utero cortisol and testosterone exposure and fear reactivity in infancy

PubMed Central

Bergman, Kristin; Glover, Vivette; Sarkar, Pampa; Abbott, Dave; O'Connor, Thomas G

2010-01-01

Fetal programming is emerging as a major conceptual model for understanding developmental origins of health and disease, including behavioral outcomes. As part of a larger study of prenatal stress and child development, we examined the association between prenatal hormone exposure and fear reactivity, a temperament dimension that is a predictor of long-term behavioral adjustment. Amniotic fluid was collected from a sample of women undergoing clinically indicated amniocentesis for later analysis of cortisol and testosterone. Children with normal birth outcomes were recalled for follow-up assessment at 17 months, at which time we administered an observational assessment of temperament (lab-TAB; n=108). Information on pregnancy and obstetric outcome was included as covariates. Results indicated that there was a significant association between prenatal testosterone and observed fear reactivity in boys (r(53)=0.34, p=0.01); no significant effect was found in girls (r(54)=-.07, ns); the effect remained when obstetric, psychosocial, and parental anxiety were controlled for. There was not a significant association between fetal cortisol exposure and fear reactivity. The prediction from in utero testosterone exposure to fear reactivity in boys extends prior research on prenatal testosterone, and may represent an association with a general predisposition to greater arousal and reactivity. PMID:20060000

Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats

PubMed Central

Ehrlich, David E.; Neigh, Gretchen N.; Bourke, Chase H.; Nemeth, Christina L.; Hazra, Rimi; Ryan, Steven J.; Rowson, Sydney; Jairam, Nesha; Sholar, Courtney; Rainnie, Donald G.; Stowe, Zachary N.; Owens, Michael J.

2015-01-01

Depression during pregnancy has been linked to in utero stress and is associated with long-lasting symptoms in offspring, including anxiety, helplessness, attentional deficits, and social withdrawal. Depression is diagnosed in 10-20% of expectant mothers, but the impact of antidepressant treatment on offspring development is not well documented, particularly for females. Here, we used a prenatal stress model of maternal depression to test the hypothesis that in utero antidepressant treatment could mitigate the effects of prenatal stress. We also investigated the effects of prenatal stress and antidepressant treatment on gene expression related to GABAergic and serotonergic neurotransmission in the amygdala, which may underlie behavioral effects of prenatal stress. Nulliparous female rats were implanted with osmotic minipumps delivering clinically-relevant concentrations of escitalopram and mated. Pregnant dams were exposed to 12 days of mixed-modality stressors, and offspring were behaviorally assessed in adolescence (postnatal day 28) and adulthood (beyond day 90) to determine the extent of behavioral change. We found that in utero stress exposure, regardless of escitalopram treatment, increased anxiety-like behavior in adolescent females and profoundly influenced amygdala expression of the chloride transporters KCC2 and NKCC1, which regulate GABAergic function. In contrast, prenatal escitalopram exposure alone elevated amygdala expression of 5-HT1A receptors. In adulthood, anxiety-like behavior returned to baseline and gene expression effects in the amygdala abated, whereas deficits emerged in novel object recognition for rats exposed to stress during gestation. These findings suggest prenatal stress causes age-dependent deficits in anxiety-like behavior and amygdala function in female offspring, regardless of antidepressant exposure. PMID:26032436

PON1 and Neurodevelopment in Children from the CHAMACOS Study Exposed to Organophosphate Pesticides in Utero

PubMed Central

Eskenazi, Brenda; Huen, Karen; Marks, Amy; Harley, Kim G.; Bradman, Asa; Barr, Dana Boyd; Holland, Nina

2010-01-01

Background Paraoxonase 1 (PON1) detoxifies oxon derivatives of some organophosphate (OP) pesticides, and its genetic polymorphisms influence enzyme activity and quantity. We previously reported that maternal urinary concentrations of dialkyl phosphate (DAP) metabolites, a marker of OP pesticide exposure, were related to poorer mental development and maternally reported symptoms consistent with pervasive developmental disorder (PDD) in 2-year-olds participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. Objective We determined whether PON1 genotypes and enzyme measurements were associated with child neurobehavioral development and whether PON1 modified the association of in utero exposure to OPs (as assessed by maternal DAPs) and neurobehavior. Methods We measured DAP concentrations in maternal urine during pregnancy, PON1192 and PON1−108 genotypes in mothers and children, and arylesterase (ARYase) and paraoxonase (POase) in maternal, cord, and 2-year-olds’ blood. We assessed 353 2-year-olds on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development and queried their mothers on the Child Behavior Checklist to obtain a score for PDD. Results Children with the PON1−108T allele had poorer MDI scores and somewhat poorer PDI scores. Children were less likely to display PDD when they or their mothers had higher ARYase activity and when their mothers had higher POase activity. The association between DAPs and MDI scores was strongest in children with PON1−108T allele, but this and other interactions between DAPs and PON1 polymorphisms or enzymes were not significant. Conclusion PON1 was associated with child neurobehavioral development, but additional research is needed to confirm whether it modifies the relation with in utero OP exposure. PMID:21126941

Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

PubMed Central

Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

2015-01-01

The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr -/- and in utero TCDD-exposed Ahr +/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr -/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

Antidepressant use during pregnancy and childhood cancer in the offspring.

PubMed

Momen, Natalie C; Munk-Olsen, Trine; Li, Jiong; Ingstrup, Katja G; Olsen, Jørn; Bergink, Veerle; Liu, Xiaoqin

2018-01-01

Antidepressant use during pregnancy has been increasing in recent years. We evaluated whether in utero exposure to antidepressants increased the risk of childhood cancer. This population-based cohort study using national registers in Denmark comprised 915 128 liveborn singletons during 1998-2012. We categorised children into three mutually exclusive exposure groups according to maternal redemption of an antidepressant prescription from 2 years before pregnancy until delivery of the index child: Unexposed (N = 863 033), prior user (use before but not during pregnancy) (N = 30 607), and use during pregnancy (N = 21 488). The children were followed from birth until first diagnosis of cancer, death, emigration, or December 31, 2012, whichever came first. The children were followed maximum 14.9 years and contributed to 6.9 × 10 6 person-years at risk. We estimated hazard ratios (HRs) of cancer using Cox regression with 95% confidence intervals (CIs). In total, 1298 (0.1%) children were diagnosed with cancer. Antidepressant use during pregnancy was not associated with a significantly increased risk of childhood cancer in general; the HR was 1.03 (95% CI, 0.63-1.68), compared to children born by mothers who discontinued antidepressant use prior to pregnancy. The association between in utero exposure to antidepressants and childhood cancer did not depend on type or duration of antidepressant use. There was no strong evidence indicating a higher risk of leukaemia or nervous system tumours among children exposed to antidepressants in utero. Antidepressant use during pregnancy was not significantly associated with childhood cancer in general nor with leukaemia or nervous system tumours in specific. Copyright © 2017 John Wiley & Sons, Ltd.

In utero exposure to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) did not increase body weight or intestinal tumorigenesis in multiple intestinal neoplasia (Min/+) mice.

PubMed

Ngo, Ha Thi; Hetland, Ragna Bogen; Sabaredzovic, Azemira; Haug, Line Småstuen; Steffensen, Inger-Lise

2014-07-01

We examined whether perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) had obesogenic effects and if they increased spontaneous intestinal tumorigenesis in the mouse model C57BL/6J-Min/+ (multiple intestinal neoplasia) after in utero exposure. The dams were exposed to PFOA or PFOS (0.01, 0.1 or 3.0mg/kg bw/day) by po gavage on GD1-17. The Min/+ and wild-type offspring were terminated at week 11 for examination of intestinal tumorigenesis or at week 20 for obesogenic effect, respectively. Body weights of the dams and pups were recorded throughout life. Food intake was determined at week 6 and 10. Blood glucose (non-fasted) was measured at week 6 and 11. No obesogenic effect of PFOA or PFOS was observed up to 20 weeks of age. PFOA or PFOS did not increase the incidence or number of tumors in the small intestine or colon of the Min/+ mice or affect their location along the intestines. Feed intake was not affected. There were some indications of toxicity of PFOA, but not of PFOS. There was lower survival of pups after 3.0mg/kg PFOA, lower body weight in pups after 3.0 and possibly 0.1mg/kg PFOA, and increased relative liver weight after 0.01 and possibly 0.1mg/kg PFOA. Plasma glucose was lower after 0.01 and 0.1mg/kg PFOA. In conclusion, exposure to PFOA and PFOS in utero with the doses used did not have obesogenic effect on either Min/+ or wild-type mice, at least not up to 11 or 20 weeks of age, nor increased intestinal tumorigenesis in Min/+ mice. Copyright © 2014 Elsevier Inc. All rights reserved.

Maternal exposure to ambient air pollution and fetal growth in North-East Scotland: A population-based study using routine ultrasound scans.

PubMed

Clemens, Tom; Turner, Steve; Dibben, Chris

2017-10-01

Maternal ambient air pollution exposure is associated with reduced birthweight. Few studies have examined the effect on growth in utero and none have examined the effect of exposure to particulates less than 2.5µm (PM 2.5 ) and possible effect modification by smoking status. Examine the effect of maternal exposure to ambient concentrations of PM 10 , PM 2.5 and nitrogen dioxide (NO 2 ) for in utero fetal growth, size at birth and effect modification by smoking status. Administratively acquired second and third trimester fetal measurements (bi-parietal diameter, femur length and abdominal circumference), birth outcomes (weight, crown heel length and occipito-frontal circumference) and maternal details were obtained from routine fetal ultrasound scans and maternity records (period 1994-2009). These were modelled against residential annual pollution concentrations (calendar year mean) adjusting for covariates and stratifying by smoking status. In the whole sample (n=13,775 pregnancies), exposure to PM 10 , PM 2.5 and NO 2 was associated with reductions in measurements at birth and biparietal diameter from late second trimester onwards. Among mothers who did not smoke at all during pregnancy (n=11,075), associations between biparietal diameter and pollution exposure remained significant but were insignificant among those who did smoke (n=2700). Femur length and abdominal circumference were not significantly associated with pollution exposure. Fetal growth is strongly associated with particulates exposure from later in second trimester onwards but the effect appears to be subsumed by smoking. Typical ambient exposures in this study were relatively low compared to other studies and given these results, it may be necessary to consider reducing recommended "safe" ambient air exposures. Copyright © 2017. Published by Elsevier Ltd.

Detection of in utero cannabis exposure by umbilical cord analysis.

PubMed

Kim, Jiyoung; de Castro, Ana; Lendoiro, Elena; Cruz-Landeira, Angelines; López-Rivadulla, Manuel; Concheiro, Marta

2018-04-01

According to the 2014 National Survey on Drug Use and Health, 5.3% of pregnant women smoked marijuana in the past month. This prevalence is expected to increase as a growing number of states and countries are now considering legalization. Although the umbilical cord is becoming a useful objective tool to detect in utero drug exposure, currently data about analytical methods and its utility to detect cannabis exposure are scarce. The objective of this work was to develop a method for the determination of Δ 9 -tetrahydrocannabinol (THC), 11-hydroxyTHC (THC-OH), 11-nor-9-carboxy-THC (THCCOOH), 8-β-11-dihydroxyTHC (THC-diOH), THC and THCCOOH glucuronides, and cannabidiol (CBD) in the umbilical cord by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with dual ionization source. Umbilical cord samples (0.5 g) were homogenized in methanol and extracted by solid-phase extraction. Reversed-phase chromatographic separation was performed in 14 minutes, and 2 transitions per analyte were monitored in multiple reaction monitoring mode. Method validation included linearity (1-10 to 20-200 ng/g), precision (4.1%-23.4%), accuracy (87.5%-111.4%), matrix effect (-54.8% to -5.8%), extraction efficiency (25%-45.6%), limits of detection and quantification (1-10 ng/g), and endogenous (n = 5) or exogenous interferences (not detected). The method was applied to 13 authentic samples from cannabis-exposed newborns, which meconium samples had tested positive for cannabis. Twelve cord specimens tested positive for THCCOOH-glucuronide (1.6-19.1 ng/g). We developed and validated a specific and sensitive method for the simultaneous determination of THC, its metabolites, including THC and THCCOOH glucuronides, and CBD in umbilical cord samples by LC-MS/MS. The analysis of authentic samples showed the usefulness of umbilical cord to detect cannabis in utero exposure. Copyright © 2017 John Wiley & Sons, Ltd.

Perinatal Exposure to Perfluorooctane Sulfonate Affects Glucose Metabolism in Adult Offspring

PubMed Central

Wan, Hin T.; Zhao, Yin G.; Leung, Pik Y.; Wong, Chris K. C.

2014-01-01

Perfluoroalkyl acids (PFAAs) are globally present in the environment and are widely distributed in human populations and wildlife. The chemicals are ubiquitous in human body fluids and have a long serum elimination half-life. The notorious member of PFAAs, perfluorooctane sulfonate (PFOS) is prioritized as a global concerning chemical at the Stockholm Convention in 2009, due to its harmful effects in mammals and aquatic organisms. PFOS is known to affect lipid metabolism in adults and was found to be able to cross human placenta. However the effects of in utero exposure to the susceptibility of metabolic disorders in offspring have not yet been elucidated. In this study, pregnant CD-1 mice (F0) were fed with 0, 0.3 or 3 mg PFOS/kg body weight/day in corn oil by oral gavage daily throughout gestational and lactation periods. We investigated the immediate effects of perinatal exposure to PFOS on glucose metabolism in both maternal and offspring after weaning (PND 21). To determine if the perinatal exposure predisposes the risk for metabolic disorder to the offspring, weaned animals without further PFOS exposure, were fed with either standard or high-fat diet until PND 63. Fasting glucose and insulin levels were measured while HOMA-IR index and glucose AUCs were reported. Our data illustrated the first time the effects of the environmental equivalent dose of PFOS exposure on the disturbance of glucose metabolism in F1 pups and F1 adults at PND 21 and 63, respectively. Although the biological effects of PFOS on the elevated levels of fasting serum glucose and insulin levels were observed in both pups and adults of F1, the phenotypes of insulin resistance and glucose intolerance were only evident in the F1 adults. The effects were exacerbated under HFD, highlighting the synergistic action at postnatal growth on the development of metabolic disorders. PMID:24498028

Postnatal development and behavior effects of in-utero exposure of rats to radiofrequency waves emitted from conventional WiFi devices.

PubMed

Othman, Haifa; Ammari, Mohamed; Rtibi, Kaïs; Bensaid, Noura; Sakly, Mohsen; Abdelmelek, Hafedh

2017-06-01

The present work investigated the effects of prenatal exposure to radiofrequency waves of conventional WiFi devices on postnatal development and behavior of rat offspring. Ten Wistar albino pregnant rats were randomly assigned to two groups (n=5). The experimental group was exposed to a 2.45GHz WiFi signal for 2h a day throughout gestation period. Control females were subjected to the same conditions as treated group without applying WiFi radiations. After delivery, the offspring was tested for physical and neurodevelopment during its 17 postnatal days (PND), then for anxiety (PND 28) and motricity (PND 40-43), as well as for cerebral oxidative stress response and cholinesterase activity in brain and serum (PND 28 and 43). Our main results showed that the in-utero WiFi exposure impaired offspring neurodevelopment during the first seventeen postnatal days without altering emotional and motor behavior at adult age. Besides, prenatal WiFi exposure induced cerebral oxidative stress imbalance (increase in malondialdehyde level (MDA) and hydrogen peroxide (H 2 O 2 ) levels and decrease in catalase (CAT) and superoxide dismutase (SOD) activities) at 28 but not 43days old, also the exposure affected acethylcolinesterase activity at both cerebral and seric levels. Thus, the current study revealed that maternal exposure to WiFi radiofrequencies led to various adverse neurological effects in the offspring by affecting neurodevelopment, cerebral stress equilibrium and cholinesterase activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Neonate exposure to thimerosal mercury from hepatitis B vaccines.

PubMed

Dórea, José G; Marques, Rejane C; Brandão, Katiane G

2009-08-01

Infant exposure to ethylmercury (EtHg) has not only increased but is starting earlier as a result of the current immunization schedule that uses thimerosal-containing vaccines (TCVs). Although vaccination schedule varies considerably between countries, infants in less-developed countries continue to be exposed to EtHg derived from more affordable TCVs. We studied the exposure of newborns to EtHg from hepatitis B vaccines; hospital records (21,685) were summarized for the years 2001 to 2005 regarding date of birth, vaccination date, and birth weight. Most of the vaccinations occurred in the first 24 hours postdelivery; over the 5 years, there was an increase in vaccinations within hours of birth (same day), from 7.4% (2001) to 87.8% (2005). Nearly 94.6% of infants are now being vaccinated within the first 24 hours. Range of mercury exposure spread from 4.2 to 21.1 microg mercury/kg body weight for those receiving TCVs with the highest thimerosal concentration; these exposure levels are conservative for 2% of children receiving vaccines within 2 to 3 postnatal days, when they are still going through physiological postnatal weight loss. Because of the particular timing (transitioning from in utero to ex utero metabolism) and specific aspects of exposure (i.e., parenteral mode, bypassing gastroenteric barriers) and dose (related to vaccine manufacturer and with variation in birth weight), this study reveals critical issues that can modulate toxicokinetics and toxicodynamics of organomercurials in neonates.

Labor market effects of intrauterine exposure to nutritional deficiency: Evidence from administrative data on Muslim immigrants in Denmark.

PubMed

Schultz-Nielsen, Marie Louise; Tekin, Erdal; Greve, Jane

2016-05-01

This paper examines whether nutritional disruptions experienced during the stage of fetal development impair an individual's labor market productivity later in life. We consider intrauterine exposure to the month of Ramadan as a natural experiment that might cause shocks to the inflow of nutrients essential for fetal development. Specifically, we use administrative data from Denmark to investigate the impact of exposure to Ramadan in utero on labor market outcomes of adult Muslim males, including employment status, annual salary, hourly wage rate, and hours of work. Our findings indicate that potential exposure to nutritional disruptions during a critical stage of fetal development is likely to have scarring effects on the fetus expressed as poor labor market outcomes later in life. Specifically, exposure to Ramadan around the 7th month of gestation results in a lower likelihood of employment and, to a lesser extent, a lower salary, and reduced labor supply. For example, the 7th month intrauterine exposure to Ramadan is associated with a 2.6 percentage points reduction in the likelihood of employment among Muslim males. We do not find an impact on the wage rate. Finally, we also document suggestive evidence that these results may partially be driven by increased disability and to a lesser extent by poor educational attainment among those who were exposed to Ramadan during this particular period in utero. Copyright © 2016 Elsevier B.V. All rights reserved.

Correlations between Prenatal Exposure to Perfluorinated Chemicals and Reduced Fetal Growth

PubMed Central

Washino, Noriaki; Saijo, Yasuaki; Sasaki, Seiko; Kato, Shizue; Ban, Susumu; Konishi, Kanae; Ito, Rie; Nakata, Ayako; Iwasaki, Yusuke; Saito, Koichi; Nakazawa, Hiroyuki; Kishi, Reiko

2009-01-01

Background Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are man-made, ubiquitous, and persistent contaminants in the environment, wildlife, and humans. Although recent studies have shown that these chemicals interfere with fetal growth in humans, the results are inconsistent. Objectives Our goal was to investigate the correlation between relatively low levels of PFOS and PFOA in maternal serum and birth weight and birth size. Methods We conducted a hospital-based prospective cohort study between July 2002 and October 2005 in Sapporo, Japan. A total of 428 women and their infants were involved in the study. We obtained characteristics of the mothers and infants from self-administered questionnaire surveys and from medical records. We analyzed maternal serum samples for PFOS and PFOA by liquid chromatography–tandem mass spectrometry (LC/MS/MS). Results After adjusting for confounding factors, PFOS levels negatively correlated with birth weight [per log10 unit: β = −148.8 g; 95% confidence interval (CI), −297.0 to −0.5 g]. In addition, analyses stratified by sex revealed that PFOS levels negatively correlated with birth weight only in female infants (per log10 unit: β = −269.4 g; 95% CI, −465.7 to −73.0 g). However, we observed no correlation between PFOA levels and birth weight. Conclusion Our results indicate that in utero exposure to relatively low levels of PFOS was negatively correlated with birth weight. PMID:19440508

In utero exposure to persistent organic pollutants in relation to testicular cancer risk.

PubMed

Hardell, Lennart; Bavel, Bert; Lindström, Gunilla; Eriksson, Mikael; Carlberg, Michael

2006-02-01

Testicular cancer is the most common tumour type in young men. In Sweden the annual age-adjusted incidence increased significantly by 2.4% during the time period 1984-1993 and during 1994-2003 by 1.4%. Exposure to endocrine disrupting chemicals during the foetal period has been postulated to be a risk factor. In this investigation we studied the concentrations of chlorinated biphenyls (PCBs), p,p'-dichlorodiphenyl-dichloroethylene (pp'-DDE), hexachlorobenzene (HCB), chlordanes and polybrominated diphenylethers (PBDEs) in 58 cases with testicular cancer and 61 age-matched controls. Furthermore, case and control mothers were also asked to participate and 44 case mothers and 45 control mothers agreed. No significant differences were found between cases and controls. Case mothers had in general higher concentrations of these chemicals. For the sum of PCBs an odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.4-10 was calculated using the median concentration for the controls as cut-off value. For HCB OR = 4.4, CI = 1.7-12 and for PBDE OR = 2.5, 95% CI = 1.02-6.0 were obtained, whereas OR was not significantly increased for pp'-DDE and sum of chlordanes. The cases were born during a period with high concentrations of persistent organic pollutants (POPs) in humans. The decline of the increasing incidence of testicular cancer during recent years may reflect decreasing body burden of certain POPs since the 1980s.

ALTERED MAMMARY GLAND DEVELOPMENT IN MALE RATS EXPOSED TO GENISTEIN AND METHOXYCHLOR

EPA Science Inventory

Genistein is a prevalent phytoestrogen whose presence in human and animal foods may affect biological actions of synthetic endocrine active compounds. We have previously reported that in utero and lactational exposure to genistein and the endocrine active pesticide methoxychlor c...

77 FR 48907 - Fludioxonil; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-15

... permanent and time-limited tolerances. Interregional Research Project Number 4 (IR-4) and Syngenta Crop... pelvis in the presence of maternal toxicity. There was no quantitative or qualitative evidence of increased susceptibility to rats and rabbits following in utero exposure. There was also no quantitative or...

77 FR 12207 - Pyroxasulfone; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-29

... and post- natal toxicity database for pyroxasulfone includes developmental toxicity studies in rats... study and developmental toxicity study in rabbits following in utero or post-natal exposure to... reliability as well as the relationship of the results of the studies to human risk. EPA has also considered...

PRENATAL AND POSTNATAL EFFECTS IN RATS OF PERFLUORONONANOIC ACID EXPOSURE IN UTERO

EPA Science Inventory

In recent years, our understanding of the developmental toxicity of perfluoroalkyl acids (PFAAs) has focused on the C8 compounds. Ubiquitous environmental contaminants, PFAA’s are utilized as surfactants in a variety of industrial applications. Although several PFAAs have been ex...

Perinatal substance use, residential instability, and negative behavioral outcomes among adolescents: Lessons from the maternal lifestyle study.

PubMed

Cotton, Brandi P; Lohman, Matthew C; Brooks, Jessica M; LaGasse, Linda L

2017-08-01

Both housing instability and prenatal substance use are known risk factors for behavioral problems among adolescents. The purpose of this study was to investigate the association between residential instability (residential mobility and homelessness) and delinquent behaviors among adolescents enrolled in the maternal lifestyle study (MLS), a 16-year research study that explored short-term and long-term effects of in-utero exposure to cocaine and/or opiates (N = 736). Logistic regression was used to measure the association between housing problems with youth crimes, school delinquency, and substance use at 11, 15, and 16 years of age. Both high-frequency residential mobility and homelessness were associated with deviant behaviors across the entire sample of children born with in-utero cocaine/opiate exposure and those without. Psychiatric nursing care of youth should include a comprehensive assessment of residential instability to identify risk and target potential interventions. © 2018 Wiley Periodicals, Inc.

Neurodevelopmental disorders in children born to mothers with systemic lupus erythematosus.

PubMed

Vinet, É; Pineau, C A; Clarke, A E; Fombonne, É; Platt, R W; Bernatsky, S

2014-10-01

Children born to women with systemic lupus erythematosus seem to have a potentially increased risk of neurodevelopmental disorders compared to children born to healthy women. Recent experimental data suggest in utero exposure to maternal antibodies and cytokines as important risk factors for neurodevelopmental disorders. Interestingly, women with systemic lupus erythematosus display high levels of autoantibodies and cytokines, which have been shown, in animal models, to alter fetal brain development and induce behavioral anomalies in offspring. Furthermore, subjects with systemic lupus erythematosus and neurodevelopmental disorders share a common genetic predisposition, which could impair the fetal immune response to in utero immunologic insults. Moreover, systemic lupus erythematosus pregnancies are at increased risk of adverse obstetrical outcomes and medication exposures, which have been implicated as potential risk factors for neurodevelopmental disorders. In this article, we review the current state of knowledge on neurodevelopmental disorders and their potential determinants in systemic lupus erythematosus offspring. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Effects of addictive substances during pregnancy and infancy and their analysis in biological materials.

PubMed

Płotka, Justyna; Narkowicz, Sylwia; Polkowska, Zaneta; Biziuk, Marek; Namieśnik, Jacek

2014-01-01

The use of addictive substances during pregnancy is a serious social problem, not only because of effects on the health of the woman and child, but also because drug or alcohol dependency detracts from child care and enhances the prospect of child neglect and family breakdown. Developing additive substance abuse treatment programs for pregnant women is socially important and can help ensure the health of babies, prevent subsequent developmental and behavioral problems (i.e., from intake of alcohol or other additive substances such as methamphetamine, cocaine,or heroine) and can reduce addiction costs to society. Because women of childbearing age often abuse controlled substances during their pregnancy, it is important to undertake biomonitoring of these substances in biological samples taken from the pregnant or nursing mother (e.g., blood, urine,hair, breast milk, sweat, oral fluids, etc.), from the fetus and newborn (e.g., meconium,cord blood, neonatal hair and urine) and from both the mother and fetus (i.e.,amniotic fluids and placenta). The choice of specimens to be analyzed is determined by many factors; however, the most important is knowledge of the chemical and physical characteristics of a substance and the route of it administration. Maternal and neonatal biological materials reflect exposures that occur over a specific time period, and each of these biological specimens has different advantages and disadvantages,in terms of accuracy, time window of exposure and cost/benefit ratio.Sampling the placenta may be the most important biomonitoring choice for assessing in utero exposure to addictive substances. The use of the placenta in scientific research causes a minimum of ethical problems, partly because its sampling is noninvasive, causes no harm to mother or child, and partly because, in any case,placentas are discarded and incinerated after birth. Such samples, when properly analyzed, may provide key essential information about fetal exposure to toxic substances, and may provide the groundwork for protecting the fetus or newborn and the mother from further damage.Several sensitive and specific bioanalytical methods are commonly utilized to accurately measure for drug biomarkers of in utero drug exposure. Moreover, several immunoassay methods are used to rapidly screen for drugs in many biological specimen types. However, results from immunoassays should be carefully interpreted,and should be confirmed by more specific and sensitive chromatographic methods, such as GC-MS or LC-MS. Although techniques for analysis of addictive substances are still being developed or are being refined, current methods are efficient and sensitive and provide valuable information on human exposures to addictive substances and their metabolites.

Neurodevelopment of children exposed in utero to treatment of maternal malignancy

PubMed Central

Nulman, I; Laslo, D; Fried, S; Uleryk, E; Lishner, M; Koren, G

2001-01-01

Cancer is the second most common cause of death during the reproductive years, complicating approximately 1/1000 pregnancies. The occurrence of cancer during gestation is likely to increase as a result of a woman's tendency to delay childbearing. Improved diagnostic techniques for malignancies increases detection of cancer during pregnancy. Malignant conditions during gestation are believed to be associated with an increase in poor perinatal and fetal outcomes that are often due to maternal treatment. Physicians should weigh the benefits of treatment against the risks of fetal exposure. To date, most reports have focused on morphologic observations made very close to the time of delivery with little data collected on children's long-term neurodevelopment following in utero exposure to malignancy and treatment. Because the brain differentiates throughout pregnancy and in early postnatal life, damage may occur even after first trimester exposure. The possible delayed effects of treatment on a child's neurological, intellectual and behavioural functioning have never been systematically evaluated. The goal of this report was to summarize all related issues into one review to facilitate both practitioners' and patients' access to known data on fetal risks and safety. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11742476

Gestational Exposure to Bisphenol A Produces Transgenerational Changes in Behaviors and Gene Expression

PubMed Central

Wolstenholme, Jennifer T.; Edwards, Michelle; Shetty, Savera R. J.; Gatewood, Jessica D.; Taylor, Julia A.; Connelly, Jessica J.

2012-01-01

Bisphenol A (BPA) is a plasticizer and an endocrine-disrupting chemical. It is present in a variety of products used daily including food containers, paper, and dental sealants and is now widely detected in human urine and blood. Exposure to BPA during development may affect brain organization and behavior, perhaps as a consequence of its actions as a steroid hormone agonist/antagonist and/or an epigenetic modifier. Here we show that BPA produces transgenerational alterations in genes and behavior. Female mice received phytoestrogen-free chow with or without BPA before mating and throughout gestation. Plasma levels of BPA in supplemented dams were in a range similar to those measured in humans. Juveniles in the first generation exposed to BPA in utero displayed fewer social interactions as compared with control mice, whereas in later generations (F2 and F4), the effect of BPA was to increase these social interactions. Brains from embryos (embryonic d 18.5) exposed to BPA had lower gene transcript levels for several estrogen receptors, oxytocin, and vasopressin as compared with controls; decreased vasopressin mRNA persisted into the F4 generation, at which time oxytocin was also reduced but only in males. Thus, exposure to a low dose of BPA, only during gestation, has immediate and long-lasting, transgenerational effects on mRNA in brain and social behaviors. Heritable effects of an endocrine-disrupting chemical have implications for complex neurological diseases and highlight the importance of considering gene-environment interactions in the etiology of complex disease. PMID:22707478

Early postnatal exposure to cigarette smoke impairs the antigen-specific T-cell responses in the spleen.

PubMed

Singh, Shashi P; Razani-Boroujerdi, Seddigheh; Pena-Philippides, Juan C; Langley, Raymond J; Mishra, Neerad C; Sopori, Mohan L

2006-12-15

Annually, approximately two million babies are exposed to cigarette smoke in utero and postnatally through cigarette smoking of their mothers. Exposure to mainstream cigarette smoke is known to impair both innate and adaptive immunities, and it has been hypothesized that the effects of in utero exposure to cigarette smoke on children's health might primarily stem from the adverse effects of cigarette smoke on the immune system. To simulate the environment that babies from smoking mothers encounter, we examined the effects of prenatal mainstream and postnatal sidestream cigarette smoke on spleen cell responses. Results show that postnatal exposure of newborn Balb/c mouse pups to sidestream cigarette smoke through the first 6 weeks of life strongly suppresses the antibody response of spleen cells to the T-cell-dependent antigen, sheep red blood cells. The reduction in the antibody response seen within 6 weeks of postnatal smoke exposure is much quicker than the published data on the time 25 weeks) required to establish reproducible immunosuppression in adult rats and mice. Moreover, the immunosuppression is not associated with significant changes in T-cell numbers or subset distribution. While the postnatal exposure to cigarette smoke did not affect the mitogenic response of T and B cells, the exposure inhibited the T cell receptor-mediated rise in the intracellular calcium concentration. These results suggest that the early postnatal period is highly sensitive to the immunosuppressive effects of environmental tobacco smoke, and the effects are causally associated with impaired antigen-mediated signaling in T cells.

Effect of in utero wi-fi exposure on the pre- and postnatal development of rats.

PubMed

Poulletier de Gannes, Florence; Haro, Emmanuelle; Hurtier, Annabelle; Taxile, Murielle; Athane, Axel; Ait-Aissa, Saliha; Masuda, Hiroshi; Percherncier, Yann; Ruffié, Gilles; Billaudel, Bernard; Dufour, Philippe; Veyret, Bernard; Lagroye, Isabelle

2012-04-01

The increase in exposure to the Wireless Fidelity (Wi-Fi) wireless communication signal has raised public health concerns especially for young people. Animal studies looking at the effects of early life and prenatal exposure to this source of electromagnetic fields, in the radiofrequency (RF) range, on development and behavior have been considered as high priority research needs by the World Health Organization. For the first time, our study assessed the effects of in utero exposure to a 2450 MHz Wi-Fi signal (2 hr/day, 6 days/week for 18 days) on pregnant rats and their pups. Three levels in terms of whole-body specific absorption rate were used: 0.08, 0.4, and 4 W/kg. The prenatal study on fetuses delivered by caesarean (P20) concerned five females/group. The dams and their offspring were observed for 28 days after delivery (15 females/group). For all test conditions, no abnormalities were noted in the pregnant rats and no significant signs of toxicity were observed in the pre- and postnatal development of the pups, even at the highest level of 4 W/kg. In the present study, no teratogenic effect of repeated exposures to the Wi-Fi wireless communication signal was demonstrated even at the highest level of 4 W/kg. The results from this screening study aimed at investigating Wi-Fi effects, strengthen the previous conclusions that teratology and development studies have not detected any noxious effects of exposures to mobile telephony-related RF fields at exposure levels below standard limits. © 2012 Wiley Periodicals, Inc.

Prenatal dioxin exposure and neurocognitive development in Hong Kong 11-year-old children.

PubMed

Hui, Lai Ling; Lam, Hugh Simon; Lau, Esther Yuet Ying; Nelson, Edmund Anthony Severn; Wong, Tze Wai; Fielding, Richard

2016-10-01

In utero exposure to dioxins and related compounds have been associated with adverse neurocognitive development in infants. It is unclear whether neurodevelopmental deficits persist to childhood. We assessed the association of prenatal dioxin exposure with neurocognitive function in 11-year-old children, and to test whether the association is modified by duration of breastfeeding. In this prospective study of 161 children born in Hong Kong in 2002, prenatal dioxin exposure was proxied by the dioxin toxicity equivalence (TEQ) in breast milk collected during the early postnatal period as determined by the Chemical-Activated LUciferase gene eXpression (CALUX) bioassay. We used multivariate linear regression analyses to assess the association of prenatal dioxin exposure with the performance on the Wechsler Intelligence Scale for Children-IV, Hong Kong, the Hong Kong List Learning Test, the Tests for Everyday Attention for Children and the Grooved Pegboard Test, adjusting for child's sex, mother's place of birth, mother's habitual seafood consumption, mother's age at delivery and socioeconomic position. Measures of neurocognitive and intellectual function, including full-scale IQ, fine motor coordination, verbal and non-verbal reasoning, learning ability and attention at 11 years old did not show significant variations with prenatal dioxin exposures (proxied by CALUX-TEQ total dioxin load in early breast milk). None of these associations varied by breastfeeding duration or sex. Neurocongitive function, as measured with psychological tests, in 11-year-old children was not associated with prenatal dioxin exposure to background levels of dioxins in the 2000s in Hong Kong. Copyright © 2016 Elsevier Inc. All rights reserved.

Developmental Exposure to Mild Variable Stress: Adult ...

EPA Pesticide Factsheets

In utero exposure to mild variable stress has been reported to influence learning and memory formation in offspring. Our research aims to examine whether nonchemical environmental stressors will exacerbate effects to chemical exposure. This study utilized a varying stress paradigm to simulate human psychosocial stress incurred during and after pregnancy to identify phenotypic learning changes in adult offspring that are potential stress markers. We additionally wanted to compare these behavioral outcomes to rat performance induced by perinatal exposure to manganese (Mn), a neurotoxic environmental element, at 2 or 5 g/l in drinking water throughout gestation and lactation. Pregnant Long Evans rats were exposed to an unpredictable series of mild stressful events which had previously been shown to increase maternal corticosterone levels. Nonchemical stressors were presented from GD 13 through GD 21 and included varying noise, light, housing, and confinement during both sleep and wake cycles. A subgroup of offspring was also exposed to periods of maternal separation. Starting at PND 97 offspring were trained with a trace fear conditioning protocol whereby rats were exposed to a compound cue (light and tone) followed by 30 seconds (trace period) and a mild foot shock (1mA, 0.5 seconds). Five paired training sessions occurred on the first day. The following day, context and cue learning were assessed by measuring motor activity. Preliminary data suggests adu

In utero and lactational exposure to low-doses of the pyrethroid insecticide cypermethrin leads to neurodevelopmental defects in male mice—An ethological and transcriptomic study

PubMed Central

Herzine, Ameziane; Perche, Olivier; Richard, Olivier; Montecot-Dubourg, Céline; Menuet, Arnaud; Mazaud-Guittot, Séverine; Lesné, Laurianne; Jegou, Bernard; Mortaud, Stéphane

2017-01-01

Accumulating evidence suggests that developmental exposure to environmental chemicals may modify the course of brain development, ultimately leading to neuropsychiatric / neurodegenerative disorders later in life. In the present study, we assessed the impact of one of the most frequently used pesticides in both residential and agricultural applications − the synthetic pyrethroid cypermethrin (CYP) − on developmental neurotoxicity (DNT). Female mice were perinatally exposed to low doses of CYP (5 and 20 mg/kg body weight) from gestation to postnatal day 15. Behavioral analyses were performed during the offspring’s early life and during adulthood. Postnatal analyses revealed that perinatal exposure to CYP disturbed motor development without modifying sensory and communicative skills. We found that later in life, CYP-exposed offspring expressed maladaptive behaviors in response to highly challenging tasks and abnormal sociability. Transcriptomic analyses performed in the offspring’s brain at the end of the exposure, highlighted mitochondrial dysfunction as a relevant pathomechanism underlying CYP-induced DNT. Interestingly, several genes involved in proteostasis maintenance were also shown to be dysregulated suggesting that alterations in biogenesis, folding, trafficking and degradation of proteins may significantly contribute to CYP-related DNT. From a regulatory perspective, this study highlights that behavioral and transcriptomic analyses are complementary tools providing useful direction for better DNT characterization, and as such, should be used together more systematically. PMID:29020013

Di(n)butyl phthalate reduces testicular weight, testosterone and associated gene expression in fetal Harlan Sprague Dawley rats.

EPA Science Inventory

Certain phthalate esters (PE) cause reproductive malformations in male rats when exposure occurs during sexual differentiation in utero. Reductions in fetal testosterone levels are causally linked to the induction of these malformations. While reproductive development studies on ...

MEASUREMENT OF PHTHALATE LEVELS IN HUMAN MILK IN THE US EPA MAMA STUDY

EPA Science Inventory

Phthalates are plasticizers used to impart flexibility in products including PVC, plastic toys, and medical devices. These products are widely used by the general population. Phthalates act as anti-androgens and in utero or perinatal exposure in laboratory animal models leads to ...

76 FR 53641 - Tetraconazole; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-29

... fuzzy kiwifruit, subgroup 13-07F. The Interregional Research Project Number 4 (IR-4) requested these... Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters, 500 College Road East, Suite 201 W... studies showed no increased quantitative susceptibility of the fetus to tetraconazole exposure in utero...

Cocaine-Induced Neurodevelopmental Deficits and Underlying Mechanisms

PubMed Central

Martin, Melissa M.; Graham, Devon L.; McCarthy, Deirdre M.; Bhide, Pradeep G.; Stanwood, Gregg D.

2017-01-01

Exposure to drugs early in life has complex and long-lasting implications for brain structure and function. This review summarizes work to date on the immediate and long-term effects of prenatal exposure to cocaine. In utero cocaine exposure produces disruptions in brain monoamines, particularly dopamine, during sensitive periods of brain development, and leads to permanent changes in specific brain circuits, molecules, and behavior. Here, we integrate clinical studies and significance with mechanistic preclinical studies, to define our current knowledge base and identify gaps for future investigation. PMID:27345015

RETINAL VASCULAR PATHOLOGY RISK DEVELOPMENT IN THE IRRADIATED AT DIFFERENT AGES AS A RESULT OF CHERNOBYL NPP ACCIDENT.

PubMed

Fedirko, P A; Babenko, T F; Dorichevska, R Yu; Garkava, N A

2015-12-01

To assess the relationship between the age at which a person undergoes radiation exposure and risk of developing eye lesions (case study of the retinal angiopathy prevalence). The object of the study was the state of the retinal vessels in 2,531 persons (1,948 evacuated from the city of Pripyat under the age of 20 and 583 exposed to radiation in utero as a result of the Chernobyl NPP disaster. The results of standardized ophthalmic examination conducted from 1993 to 2000 within the framework of Clinical and epidemiological registry are used for the analysis. The evacuees were subdivided into different age groups of the exposed to radiation. The cohort of control group formed corresponding age groups of the unirradiated control. Statistical analysis of the survey results was carried out using the free trial version of «Open Epi 2.2.1» software package. The results obtained revealed a significant prevalence of retinal vessels pathology in all groups. The difference in angiopathy prevalence in exposed in utero persons was significant compared to age-control. The prevalence of retinal vascular pathology was also significantly higher in all groups of evacuees. Angiopathy prevalence was higher in the group exposed in utero and at the age of 8-12 years, and in the group of people who were exposed at the age of 4-7 years, the risk of angiopathy was lower. It is proved that the occurrence of distant radiation effects mainly depends on the age at which a person has undergone irradiation. It should be noted that all the other conditions were approximately the same. If working conditions of the persons who were exposed in utero or were aged 8 to 20 years when the Chernobyl disaster happened are connected with occupational radiation exposure it is necessary to take additional preventive measures. P. А. Fedirko, T. F. Babenko, R. Yu. Dorichevska, N. А. Garkava.

Transgenerational Inheritance of Increased Fat Depot Size, Stem Cell Reprogramming, and Hepatic Steatosis Elicited by Prenatal Exposure to the Obesogen Tributyltin in Mice

PubMed Central

Chamorro-García, Raquel; Sahu, Margaret; Abbey, Rachelle J.; Laude, Jhyme; Pham, Nhieu

2013-01-01

Background: We have previously shown that exposure to tributyltin (TBT) modulates critical steps of adipogenesis through RXR/PPARγ and that prenatal TBT exposure predisposes multipotent mesenchymal stem cells (MSCs) to become adipocytes by epigenetic imprinting into the memory of the MSC compartment. Objective: We tested whether the effects of prenatal TBT exposure were heritable in F2 and F3 generations. Methods: We exposed C57BL/6J female mice (F0) to DMSO vehicle, the pharmaceutical obesogen rosiglitazone (ROSI), or TBT (5.42, 54.2, or 542 nM) throughout pregnancy via the drinking water. F1 offspring were bred to yield F2, and F2 mice were bred to produce F3. F1 animals were exposed in utero and F2 mice were potentially exposed as germ cells in the F1, but F3 animals were never exposed to the chemicals. We analyzed the effects of these exposures on fat depot weights, adipocyte number, adipocyte size, MSC programming, hepatic lipid accumulation, and hepatic gene expression in all three generations. Discussion: Prenatal TBT exposure increased most white adipose tissue (WAT) depot weights, adipocyte size, and adipocyte number, and reprogrammed MSCs toward the adipocyte lineage at the expense of bone in all three generations. Prenatal TBT exposure led to hepatic lipid accumulation and up-regulated hepatic expression of genes involved in lipid storage/transport, lipogenesis, and lipolysis in all three subsequent generations. Conclusions: Prenatal TBT exposure produced transgenerational effects on fat depots and induced a phenotype resembling nonalcoholic fatty liver disease through at least the F3 generation. These results show that early-life obesogen exposure can have lasting effects. PMID:23322813

Pregnancy-associated malaria and malaria in infants: an old problem with present consequences.

PubMed

Moya-Alvarez, Violeta; Abellana, Rosa; Cot, Michel

2014-07-11

Albeit pregnancy-associated malaria (PAM) poses a potential risk for over 125 million women each year, an accurate review assessing the impact on malaria in infants has yet to be conducted. In addition to an effect on low birth weight (LBW) and prematurity, PAM determines foetal exposure to Plasmodium falciparum in utero and is correlated to congenital malaria and early development of clinical episodes during infancy. This interaction plausibly results from an ongoing immune tolerance process to antigens in utero, however, a complete explanation of this immune process remains a question for further research, as does the precise role of protective maternal antibodies. Preventive interventions against PAM modify foetal exposure to P. falciparum in utero, and have thus an effect on perinatal malaria outcomes. Effective intermittent preventive treatment in pregnancy (IPTp) diminishes placental malaria (PM) and its subsequent malaria-associated morbidity. However, emerging resistance to sulphadoxine-pyrimethamine (SP) is currently hindering the efficacy of IPTp regimes and the efficacy of alternative strategies, such as intermittent screening and treatment (IST), has not been accurately evaluated in different transmission settings. Due to the increased risk of clinical malaria for offspring of malaria infected mothers, PAM preventive interventions should ideally start during the preconceptual period. Innovative research examining the effect of PAM on the neurocognitive development of the infant, as well as examining the potential influence of HLA-G polymorphisms on malaria symptoms, is urged to contribute to a better understanding of PAM and infant health.

Long-term effects of prenatal x-ray of human females. II. Growth and development.

PubMed

Meyer, M B; Tonascia, J

1981-09-01

Experimental studies and studies of survivors of in-utero exposure to atomic bomb blasts have shown significant stunting of growth and mental retardation following these exposures. Central nervous system damage following very low doses of x-ray at around the time of birth has also been observed in experimental animals. This long term follow-up studies of 1458 human females exposed in utero to diagnostic x-rays and of 1458 matched unexposed controls studied in Baltimore, Maryland, included measurements of height, weight and school achievement. Women who had been exposed to x-rays in utero were significantly shorter in their mid-twenties than were their matched, unexposed controls, even after adjustment for other social and economic factors. However, additional follow-up revealed that mothers of exposed women were also shorter than the control mothers. Short stature appeared to be a selective factor for x-ray during pregnancy (mostly pelvimetry, 1947-1952). Mothers' and daughters' heights were similarly correctly among exposed and control mother-daughter pairs, suggesting that the height differences between exposed daughters and their controls were due to these selective factor rather than to any direct effect of radiation on growth. Exposed women reported poorer school achievement than control women. However, except for a higher proportion of exposed women leaving school because of pregnancy, these measurements were no longer significantly different when rates were simultaneously adjusted for socioeconomic differences between exposed and control women.

Hydraulic fracturing and infant health: New evidence from Pennsylvania.

PubMed

Currie, Janet; Greenstone, Michael; Meckel, Katherine

2017-12-01

The development of hydraulic fracturing ("fracking") is considered the biggest change to the global energy production system in the last half-century. However, several communities have banned fracking because of unresolved concerns about the impact of this process on human health. To evaluate the potential health impacts of fracking, we analyzed records of more than 1.1 million births in Pennsylvania from 2004 to 2013, comparing infants born to mothers living at different distances from active fracking sites and those born both before and after fracking was initiated at each site. We adjusted for fixed maternal determinants of infant health by comparing siblings who were and were not exposed to fracking sites in utero. We found evidence for negative health effects of in utero exposure to fracking sites within 3 km of a mother's residence, with the largest health impacts seen for in utero exposure within 1 km of fracking sites. Negative health impacts include a greater incidence of low-birth weight babies as well as significant declines in average birth weight and in several other measures of infant health. There is little evidence for health effects at distances beyond 3 km, suggesting that health impacts of fracking are highly local. Informal estimates suggest that about 29,000 of the nearly 4 million annual U.S. births occur within 1 km of an active fracking site and that these births therefore may be at higher risk of poor birth outcomes.

Hydraulic fracturing and infant health: New evidence from Pennsylvania

PubMed Central

Currie, Janet; Greenstone, Michael; Meckel, Katherine

2017-01-01

The development of hydraulic fracturing (“fracking”) is considered the biggest change to the global energy production system in the last half-century. However, several communities have banned fracking because of unresolved concerns about the impact of this process on human health. To evaluate the potential health impacts of fracking, we analyzed records of more than 1.1 million births in Pennsylvania from 2004 to 2013, comparing infants born to mothers living at different distances from active fracking sites and those born both before and after fracking was initiated at each site. We adjusted for fixed maternal determinants of infant health by comparing siblings who were and were not exposed to fracking sites in utero. We found evidence for negative health effects of in utero exposure to fracking sites within 3 km of a mother’s residence, with the largest health impacts seen for in utero exposure within 1 km of fracking sites. Negative health impacts include a greater incidence of low–birth weight babies as well as significant declines in average birth weight and in several other measures of infant health. There is little evidence for health effects at distances beyond 3 km, suggesting that health impacts of fracking are highly local. Informal estimates suggest that about 29,000 of the nearly 4 million annual U.S. births occur within 1 km of an active fracking site and that these births therefore may be at higher risk of poor birth outcomes. PMID:29242825

Substance use during pregnancy and postnatal outcomes.

PubMed

Irner, Tina Birk; Teasdale, Thomas William; Nielsen, Tine; Vedal, Sissel; Olofsson, May

2012-01-01

Substance exposure in utero has been associated with physical birth defects and increased risk of regulatory and neuropsychological difficulties. The aims of this study were to describe women who use substances and are in treatment with respect to the type and number of substances used during pregnancy, as well as their background, and to examine the effect substance use has on gestational age, birth weight, and the development of neonatal abstinence syndrome at birth. A sample of 161 pregnant women and their 163 newborn children were included. The results indicate that the children whose mothers continued to use substances throughout their pregnancies were born at a lower gestational age (Chi-Square = 15.1(2), P < .01); children exposed to poly-substances in utero were more affected than those exposed to only alcohol and those with no substance exposure. The same children were more vulnerable to the development of neonatal abstinence syndrome at birth (Chi-Square = 51.7(2), P < .001). Newborns who were exposed primarily to alcohol in utero were at a significant risk of being born with low birth weight (Chi-Square = 8.8(2), P < .05) compared with those exposed to other types of substances. More than 50% of the mothers ceased using any substances (with the exception of tobacco) by birth, indicating that the treatment program did have an interventional effect on the mothers. The mothers' ability to either cease or decrease the use of substances during pregnancy appears to have direct positive effect on their newborns.

DES daughters in France: experts' points of view on the various genital, uterine and obstetric pathologies, and in utero DES exposure.

PubMed

Clement, R; Guilbaud, E; Barrios, L; Rougé-Maillart, C; Jousset, N; Rodat, O

2014-10-01

Compensation of diethylstilbestrol exposure depends on the judicial system. In France, girls having been exposed to diethylstilbestrol are currently being compensated, and each exposure victim is being evaluated. Fifty-nine expert evaluations were studied to determine the causal relation between exposure to diethylstilbestrol and the pathologies attributable to diethylstilbestrol. The following were taken into consideration: age at the first signs of the pathology; age of the sufferer at the time of evaluation; the pathologies grouped into five categories: fertility disorders - cancers - mishaps during pregnancy - psychosomatic complaints - pathologies of "3rd generation DES victims"; submission of proof of DES exposure; the degree of causality determined (direct, indirect, ruled out). 61% of the cases related to fertility disorders, 28.8% to cancer pathologies (clear-cell adenocarcinoma), 18.6% to mishaps during pregnancy, 8.5% to disorders resulting from preterm delivery, and 3.4% to psychosomatic disorders. Some cases involved a combination of two types of complaints. Indirect causality was determined in 47.1% of the cases involving primary sterility, in 66.7% involving secondary sterility, and in 5 out of 6 cases of total sterility. There is direct causality between in utero diethylstilbestrol exposure and vaginal or cervical clear cell adenocarcinoma. Causality is indirect in the case of disorders linked to prematurity in third generation victims. Causality was determined by the experts on the basis of scientific criteria which attribute the presenting pathologies to diethylstilbestrol exposure. When other risk factors come into play, or when exposure is indirect (third generation), this causality is diminished. © IMechE 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Birth defects among children born to HIV-infected women: Pediatric AIDS Clinical Trials Protocols 219 and 219C

PubMed Central

Brogly, Susan B.; Abzug, Mark J.; Watts, D. Heather; Cunningham, Coleen K.; Williams, Paige L.; Oleske, James; Conway, Daniel; Sperling, Rhoda S.; Spiegel, Hans; Van Dyke, Russell B.

2010-01-01

Background Some studies have detected associations between in utero antiretroviral therapy (ARV) exposure and birth defects but evidence is inconclusive. Methods 2,202 HIV-exposed children enrolled in the Pediatric AIDS Clinical Trials Group 219 and 219C protocols before one year of age were included. Birth defects were classified using the Metropolitan Atlanta Congenital Defects Program (MACDP) coding. Logistic regression models were used to evaluate associations between first trimester in utero ARV exposure and birth defects. Results 117 live-born children had birth defects for a prevalence of 5.3% (95% CI: 4.4, 6.3). Prevalence did not differ by HIV infection status or overall ARV exposure; rates were 4.8% (95% CI: 3.7, 6.1) and 5.8% (95% CI: 4.2, 7.8) in children without and with first trimester ARV exposure, respectively. The defect rate was higher among children with first trimester efavirenz exposure (5/32, 15.6%) versus children without first trimester efavirenz exposure [adjusted odds ratio (aOR)=4.31 (95% CI: 1.56, 11.86)]. Protective effects of first trimester zidovudine exposure on musculoskeletal defects were detected [aOR=0.24 (95% CI: 0.08, 0.69)], while a higher risk of heart defects was found [aOR=2.04 (95% CI: 1.03, 4.05)]. Conclusion The prevalence of birth defects was higher in this cohort of HIV-exposed children than in other pediatric cohorts. There was no association with overall ARV exposure, but there were some associations with specific agents including efavirenz. Additional studies are needed to rule out confounding and to evaluate newer ARV agents. PMID:20539252

Phthalate Esters and Reproductive Toxicity** Presentation requested by State of Mass Use Reductions Committee-TURI

EPA Science Inventory

Phthalate esters and reproductive toxicity the presentation described the uses of phthalates, the toxicity to mammals with a focus on reproductive toxicity and the potency of these chemicals to disrupt mammalian reproductive development in utero

PERFLUOROOCTANOIC ACID AND PERFLUORONONANOIC ACID IN FETAL AND NEONATAL MICE FOLLOWING IN UTERO EXPOSURE TO 8-2 FLUOROTELOMER ALCOHOL

EPA Science Inventory

8-2 fluorotelomer alcohol (FTOH) and its metabolites, perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA), are developmental toxicants, but metabolism and distribution during pregnancy is not known. To examine this, timed-pregnant mice received a single gavage dose (...

40 CFR 799.9380 - TSCA reproduction and fertility effects.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA reproduction and fertility effects...-generation reproduction testing and is designed to provide general information concerning the effects of a... subsequent tests. Additionally, since the study design includes in utero as well as postnatal exposure, this...

IN UTERO ENVIRONMENTAL EXPOSURES IN THE NATIONAL CHILDREN'S STUDY - MEASUREMENT STRATEGIES

EPA Science Inventory

The National Children¿s Study (NCS) is a longitudinal cohort study which is designed to follow a nationally representative sample of American children from prior to conception or early pregnancy until age 21 years. The Children's Health Act of 2000 directs a consortium of United...

ATRAZINE DISPOSITION IN PREGNANT AND LACTATING LONG-EVANS RATS

EPA Science Inventory

Atrazine (ATR) is a widely used herbicide shown to delay early mammary development in female offspring of gestationally exposed rats. The effects of ATR can be induced by in utero exposure and/or suckling from a dam exposed during late pregnancy, but ATR is reported to have a hal...

Can In Utero Exposures Program an Increased Risk for Diseases Later in Life?

EPA Science Inventory

In the early 1990's, David Barker and his colleagues studied the relationship between the incidence of coronary heart disease and birth weight in a population of adult men and women in Hertfordshire, England. They found an inverse correlation between the incidence of coronary hea...

IN UTERO EXPOSURE TO THE FUNGICIDE PROCYMIDONE AND DIBUTYL PHTHALATE PRODUCE DOSE ADDITIVE DISRUPTIONS OF MALE RAT SEXUAL DIFFERENTIATION

EPA Science Inventory

Procymidone (PRO) and dibutyl phthalate (DBP) alter male rat sexual differentiation by disrupting the androgen-signaling pathway via distinctly different cellular mechanisms of toxicity. DBP inhibits fetal Leydig cell androgen production whereas PRO binds AR and blocks androgen a...

Mechanisms of perfluoroalkyl acid (PFAA) toxicity: Involvement of peroxisome proliferator activator receptor alpha (PPAR) molecular signals.

EPA Science Inventory

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of environmentally persistent perfluorinated compounds and are found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in rats and mice. Exposure in utero reduces...

Prenatal zinc supplementation of zinc-adequate rats adversely affects immunity in offspring

USDA-ARS?s Scientific Manuscript database

We previously showed that zinc (Zn) supplementation of Zn-adequate dams induced immunosuppressive effects that persist in the offspring after weaning. We investigated whether the immunosuppressive effects were due to in utero exposure and/or mediated via milk using a cross-fostering design. Pregnant...

Induction of homologous recombination following in utero exposure to DNA-damaging agents.

PubMed

Karia, Bijal; Martinez, Jo Ann; Bishop, Alexander J R

2013-11-01

Much of our understanding of homologous recombination, as well as the development of the working models for these processes, has been derived from extensive work in model organisms, such as yeast and fruit flies, and mammalian systems by studying the repair of induced double strand breaks or repair following exposure to genotoxic agents in vitro. We therefore set out to expand this in vitro work to ask whether DNA-damaging agents with varying modes of action could induce somatic change in an in vivo mouse model of homologous recombination. We exposed pregnant dams to DNA-damaging agents, conferring a variety of lesions at a specific time in embryo development. To monitor homologous recombination frequency, we used the well-established retinal pigment epithelium pink-eyed unstable assay. Homologous recombination resulting in the deletion of a duplicated 70 kb fragment in the coding region of the Oca2 gene renders this gene functional and can be visualized as a pigmented eyespot in the retinal pigment epithelium. We observed an increased frequency of pigmented eyespots in resultant litters following exposure to cisplatin, methyl methanesulfonate, ethyl methanesulfonate, 3-aminobenzamide, bleomycin, and etoposide with a contrasting decrease in the frequency of detectable reversion events following camptothecin and hydroxyurea exposure. The somatic genomic rearrangements that result from such a wide variety of differently acting damaging agents implies long-term potential effects from even short-term in utero exposures. Copyright © 2013 Elsevier B.V. All rights reserved.

Sex dimorphic behaviors as markers of neuroendocrine disruption by environmental chemicals: the case of chlorpyrifos.

PubMed

Venerosi, A; Ricceri, L; Tait, S; Calamandrei, G

2012-12-01

The complexity of the neuroendocrine level of investigation requires the assessment of behavioral patterns that extend beyond the reproductive functions, which are age- and sex-specific in rodents, described by defined clusters of behavioral items regulated by genetic, hormonal, and epigenetic factors. The study of social behavior in laboratory rodents reveals sex-dimorphic effects of environmental chemicals that may be undetected either by a traditional neurotoxicological approach or referring to the classical definition of endocrine disrupting chemicals. Here we review data on the neurobehavioral effects of developmental exposure to the non-persistent organophosphorus insecticide chlorpyrifos, whose neurotoxic activity at low doses is currently a matter of concern for children's health. In mice exposed to chlorpyrifos in utero and/or in early development social/emotional responses are differently affected in the two sexes in parallel with sex-dependent interference on hypothalamic neuroendocrine pathways regulating social behaviors (vasopressin, oxytocin, and steroid regulated systems). Through the analysis of complex sex-dimorphic behavioral patterns we show that neurotoxic and endocrine disrupting activities of CPF overlap. This widely diffused organophosphorus pesticide might thus be considered as a neuroendocrine disruptor possibly representing a risk factor for sex-biased neurodevelopmental disorders in children. Copyright © 2012 Elsevier Inc. All rights reserved.

In utero heat stress increases postnatal core body temperature in pigs.

PubMed

Johnson, J S; Sanz Fernandez, M V; Seibert, J T; Ross, J W; Lucy, M C; Safranski, T J; Elsasser, T H; Kahl, S; Rhoads, R P; Baumgard, L H

2015-09-01

In utero heat stress (IUHS) negatively impacts postnatal development, but how it alters future body temperature parameters and energetic metabolism is not well understood. Future body temperature indices and bioenergetic markers were characterized in pigs from differing in utero thermal environments during postnatal thermoneutral (TN) and cyclical heat stress (HS) exposure. First-parity pregnant gilts ( = 13) were exposed to 1 of 4 ambient temperature (T) treatments (HS [cyclic 28°C to 34°C] or TN [cyclic 18°C to 22°C]) applied for the entire gestation (HSHS, TNTN), HS for the first half of gestation (HSTN), or HS for the second half of gestation (TNHS). Twenty-four offspring (23.1 ± 1.2 kg BW; = 6 HSHS, = 6 TNTN, = 6 HSTN, = 6 TNHS) were housed in TN (21.7°C ± 0.7°C) conditions and then exposed to 2 separate but similar HS periods (HS1 = 6 d; HS2 = 6 d; cycling 28°C to 36°C). Core body temperature (T) was assessed every 15 min with implanted temperature recorders. Regardless of in utero treatment, T increased during both HS periods ( = 0.01; 0.58°C). During TN, HS1, and HS2, all IUHS pigs combined had increased T ( = 0.01; 0.36°C, 0.20°C, and 0.16°C, respectively) compared to TNTN controls. Although unaffected by in utero environment, the total plasma thyroxine to triiodothyronine ratio was reduced ( = 0.01) during HS1 and HS2 (39% and 29%, respectively) compared with TN. In summary, pigs from IUHS maintained an increased T compared with TNTN controls regardless of external T, and this thermal differential may have practical implications to developmental biology and animal bioenergetics.

Flor-Essence® herbal tonic does not inhibit estrogen receptor negative mammary tumor development in a transgenic mouse model

PubMed Central

Bennett, L. Michelle; Montgomery, Jennifer L.; Collins, N. Keith; Steinberg, Seth M.; Kulp, Kristen S.

2012-01-01

Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. In this study four experimental groups of female MMTV-Neu mice were left untreated or treated with 3% Flor-Essence® in utero, from birth until 5 weeks of age, or throughout their lifetime. Palpable mammary tumor incidence and body weight was determined weekly for each group. The mice were sacrificed at 28 weeks of age and mammary tumors were enumerated to determine average tumor incidence and multiplicity for each group. Female mice exposed to Flor-Essence® herbal tonic in utero weighed significantly more than the control group (p < 0.001). The average tumor incidence and tumor multiplicity in the experimental mice treated with Flor-Essence® herbal tonic did not differ from the control animals. Flor-Essence® does not inhibit mammary tumor incidence or mammary tumor multiplicity in MMTV-Neu transgenic mice. Flor-Essence® exposure in utero causes increased body weight in experimental animals. This conclusion challenges widely available anecdotal information as well as the hopes of the consumer that this product will inhibit or suppress tumor development. Lay Abstract Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts often used by women with breast cancer in hopes that it will help cure disease or prevent recurrence. There is currently very little scientific data to support or refute its self-administration. We tested whether Flor-Essence® would influence tumor development in the mammary glands of a mouse model of Her2/neu breast cancer. The tonic was given at different life stages to determine if timing of the exposure influenced the response to treatment. This report shows that Flor-Essence® did not inhibit mammary tumor development in the treated mice challenging anecdotal information, as well as the hopes of the consumer, that this product will inhibit or suppress tumor development. This report also shows that Flor-Essence® exposure in utero causes increased body weight in experimental animals. PMID:22754942

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

PubMed

Bonde, Jens Peter; Flachs, Esben Meulengracht; Rimborg, Susie; Glazer, Clara Helene; Giwercman, Aleksander; Ramlau-Hansen, Cecilia Høst; Hougaard, Karin Sørig; Høyer, Birgit Bjerre; Hærvig, Katia Keglberg; Petersen, Sesilje Bondo; Rylander, Lars; Specht, Ina Olmer; Toft, Gunnar; Bräuner, Elvira Vaclavik

2016-12-01

More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Challenges in vaccinating infants born to mothers taking immunoglobulin biologicals during pregnancy.

PubMed

Ling, Juejing; Koren, Gideon

2016-01-01

While immunoglobulin biologicals are increasingly used during pregnancy, there have been concerns on the immune function and vaccination of infants born to mothers taking immunoglobulin biologicals. In addition to the detection of biologicals in cord blood, cases of severe neonatal neutropenia and fatal dissemination of Bacillus Calmette-Guérin (BCG) have been reported. With increasing number of infants exposed to immunoglobulin biologicals in utero, there is a need to address the challenges in vaccinating these infants. This review summarizes the available evidence to discuss the issues of immunoglobulin biological exposure in utero, neonatal immune function, long-term immune development, and the challenges and strategies of vaccinating newborns and infants who were born to mothers taking biologicals during pregnancy.

Striatal but not frontal cortical up-regulation of the epidermal growth factor receptor in rats exposed to immune activation in utero and cannabinoid treatment in adolescence.

PubMed

Idrizi, Rejhan; Malcolm, Peter; Weickert, Cynthia Shannon; Zavitsanou, Katerina; Suresh Sundram

2016-06-30

In utero maternal immune activation (MIA) and cannabinoid exposure during adolescence constitute environmental risk factors for schizophrenia. We investigated these risk factors alone and in combination ("two-hit") on epidermal growth factor receptor (EGFR) and neuregulin-1 receptor (ErbB4) levels in the rat brain. EGFR but not ErbB4 receptor protein levels were significantly increased in the nucleus accumbens and striatum of "two-hit" rats only, with no changes seen at the mRNA level. These findings support region specific EGF-system dysregulation as a plausible mechanism in this animal model of schizophrenia pathogenesis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

Badham, Helen J.; Winn, Louise M., E-mail: winnl@queensu.c; School of Environmental Studies, Queen's University, Kingston, Ontario, K7L 3N6

Benzene is a ubiquitous occupational and environmental toxicant. Exposures to benzene both prenatally and during adulthood are associated with the development of disorders such as aplastic anemia and leukemia. Mechanisms of benzene toxicity are unknown; however, generation of reactive oxygen species (ROS) by benzene metabolites may play a role. Little is known regarding the effects of benzene metabolites on erythropoiesis. Therefore, to determine the effects of in utero exposure to benzene on the growth and differentiation of fetal erythroid progenitor cells (CFU-E), pregnant CD-1 mice were exposed to benzene and CFU-E numbers were assessed in fetal liver (hematopoietic) tissue. Inmore » addition, to determine the effect of benzene metabolite-induced ROS generation on erythropoiesis, HD3 chicken erythroblast cells were exposed to benzene, phenol, or hydroquinone followed by stimulation of erythrocyte differentiation. Our results show that in utero exposure to benzene caused significant alterations in female offspring CFU-E numbers. In addition, exposure to hydroquinone, but not benzene or phenol, significantly reduced the percentage of differentiated HD3 cells, which was associated with an increase in ROS. Pretreatment of HD3 cells with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) prevented hydroquinone-induced inhibition of erythropoiesis, supporting the hypothesis that ROS generation is involved in the development of benzene erythrotoxicity. In conclusion, this study provided evidence that ROS generated as a result of benzene metabolism may significantly alter erythroid differentiation, potentially leading to the development of Blood Disorders.« less

Effects of low-dose drinking water arsenic on mouse fetal and postnatal growth and development.

PubMed

Kozul-Horvath, Courtney D; Zandbergen, Fokko; Jackson, Brian P; Enelow, Richard I; Hamilton, Joshua W

2012-01-01

Arsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level). C57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and health of the dams were assessed by a variety of measurements. Birth outcomes including litter weight, number of pups, and gestational length were unaffected. However, exposure during the in utero and postnatal period resulted in significant growth deficits in the offspring after birth, which was principally a result of decreased nutrients in the dam's breast milk. Cross-fostering of the pups reversed the growth deficit. Arsenic exposed dams displayed altered liver and breast milk triglyceride levels and serum profiles during pregnancy and lactation. The growth deficits in the F1 offspring resolved following separation from the dam and cessation of exposure in male mice, but did not resolve in female mice up to six weeks of age. Exposure to As at the current U.S. drinking water standard during critical windows of development induces a number of adverse health outcomes for both the dam and offspring. Such effects may contribute to the increased disease risks observed in human populations.

Epidemiological research on radiation-induced cancer in atomic bomb survivors

PubMed Central

Ozasa, Kotaro

2016-01-01

The late effects of exposure to atomic bomb radiation on cancer occurrence have been evaluated by epidemiological studies on three cohorts: a cohort of atomic bomb survivors (Life Span Study; LSS), survivors exposed in utero, and children of atomic bomb survivors (F1). The risk of leukemia among the survivors increased remarkably in the early period after the bombings, especially among children. Increased risks of solid cancers have been evident since around 10 years after the bombings and are still present today. The LSS has clarified the dose–response relationships of radiation exposure and risk of various cancers, taking into account important risk modifiers such as sex, age at exposure, and attained age. Confounding by conventional risk factors including lifestyle differences is not considered substantial because people were non-selectively exposed to the atomic bomb radiation. Uncertainty in risk estimates at low-dose levels is thought to be derived from various sources, including different estimates of risk at background levels, uncertainty in dose estimates, residual confounding and interaction, strong risk factors, and exposure to residual radiation and/or medical radiation. The risk of cancer in subjects exposed in utero is similar to that in LSS subjects who were exposed in childhood. Regarding hereditary effects of radiation exposure, no increased risk of cancers associated with parental exposure to radiation have been observed in the F1 cohort to date. In addition to biological and pathogenetic interpretations of the present results, epidemiological investigations using advanced technology should be used to further analyze these cohorts. PMID:26976124

Role of Light in Breast Cancer

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

Stevens, Richard G.; Anderson, Larry E.; Michael F. Holick

1999-06-14

There is a prima facie reason for studying possible biological effects of light-at-night (LAN) in the laboratory and human health effects in the population at large: LAN from the use of electricity represent exposures in the human environment not previously encountered in human evolution. These LAN exposures are pervasive in industrialized societies, and any adverse health effects from them could result in considerable consequences for the population. In particular, exposures of pregnant women to LAN that might result in increased estrogen exposure in utero to their child may lead to increased tissue mass and increased lifetime risk of breast cancermore » of the child.« less

Neonatal Neurobehavioral and Neuroanatomic Correlates of Prenatal Cocaine Exposure

PubMed Central

FRANK, DEBORAH A.; AUGUSTYN, MARILYN; ZUCKERMAN, BARRY S.

2008-01-01

Complex methodologic challenges face researchers studying the effects of prenatal cocaine exposure on infant outcome. These include unavoidable imprecision in ascertaining the gestational timing and dose of cocaine to which the fetus was exposed and difficulties in identifying and quantifying the confounding, mediating, and moderating variables. Review of research on neonatal behavioral and cranial ultrasound findings following in utero cocaine exposure is used to illustrate these issues. We conclude that there are measurable but not dramatic dose-related effects of prenatal cocaine exposure on infant central nervous system structure and function. The effects of dose of prenatal cocaine exposure on later child development remain to be determined. Such research would be facilitated by a scientific consensus delineating relative doses of prenatal cocaine exposure. PMID:9668396

Impacts of in utero and early infant taste experiences on later taste acceptance: a systematic review.

PubMed

Nehring, Ina; Kostka, Tanja; von Kries, Rüdiger; Rehfuess, Eva A

2015-06-01

Dietary behavior exerts a critical influence on health and is the outcome of a broad range of interacting factors, including food and taste acceptance. These may be programmed in utero and during early infancy. We examined the hypothesis that fetuses and infants exposed to sweet, salty, sour, bitter, umami, or specific tastes show greater acceptance of that same taste later in life. We conducted a systematic review of the literature, using comprehensive searches and following established procedures for screening, data extraction, and quality appraisal. We used harvest plots to synthesize the evidence graphically. Twenty studies comprising 38 subgroups that differed by taste, age, medium, and duration of exposure were included. Exposure to bitter and specific tastes increased the acceptance of these tastes. Studies on sweet and salty tastes showed equivocal results. Studies on sour tastes were sparse. Our systematic review clearly shows programming of the acceptance of bitter and specific tastes. For other tastes the results were either equivocal or confined to a few number of studies that precluded us from drawing conclusions. Further research should examine the association of salty and sour taste exposures on later preferences of these tastes. Long-term studies and randomized clinical trials on each type of taste are needed. © 2015 American Society for Nutrition.

Cognitive outcome in adolescents and young adults after repeat courses of antenatal corticosteroids.

PubMed

Stålnacke, Johanna; Diaz Heijtz, Rochellys; Norberg, Hanna; Norman, Mikael; Smedler, Ann-Charlotte; Forssberg, Hans

2013-08-01

To investigate whether repeat courses of antenatal corticosteroids have long-term effects on cognitive and psychological functioning. In a prospective cohort study, 58 adolescents and young adults (36 males) who had been exposed to 2-9 weekly courses of betamethasone in utero were assessed with neuropsychological tests and behavior self-reports. Unexposed subjects (n = 44, 25 males) matched for age, sex, and gestational age at birth served as a comparison group. In addition, individuals exposed in utero to a single course (n = 25, 14 males) were included for dose-response analysis. Group differences were investigated using multilevel linear modeling. Mean scores obtained in 2 measures of attention and speed were significantly lower in subjects exposed to 2 or more antenatal corticosteroids courses (Symbol Search, P = .009; Digit Span Forward, P = .02), but these were not dose-dependent. Exposure to repeat courses of antenatal corticosteroids was not associated with general deficits in higher cognitive functions, self-reported attention, adaptability, or overall psychological function. Although this study indicates that repeat exposure to antenatal corticosteroids may have an impact on aspects of executive functioning, it does not provide support for the prevailing concern that such fetal exposure will have a major adverse impact on cognitive functions and psychological health later in life. Copyright © 2013 Mosby, Inc. All rights reserved.

Effects of gestational exposure to PFOA on PPAR protein and mRNA expression in vital organs of fetal and postnatal mice

EPA Science Inventory

Perfluorooctanoic acid (PFOA) is developmentally toxic, causing in utero and neonatal mortality, and altering development and growth in mice. PFOA activates peroxisome proliferator-activated receptor (PPAR)a and PPARa signaling is required for toxicity. This study examines the ex...

In Utero Exposure to Selective Serotonin Reuptake Inhibitors and Risk for Autism Spectrum Disorder

ERIC Educational Resources Information Center

Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor; Yudell, Michael; Mortensen, Erik L.; Newschaffer, Craig J.

2014-01-01

We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status. There…

Dose additive effects of simvastatin and dipentyl phthalate on testosterone production in the fetal testis: A cummulative risk perspective

EPA Science Inventory

Sex differentiation of the mammalian reproductive tract is a highly regulated process that is driven, in part, by fetal testosterone (T) production. In utero exposure to phthalate esters (PE) during sex differentiation can cause reproductive tract malformations in rats. PE alter ...

Simvastatin and dipentyl phthalate lower testosterone production and exhibit dose additive effects on the fetal testis via distinct mechanistic pathways

EPA Science Inventory

Sex differentiation of the mammalian reproductive tract is a highly regulated process that is driven, in part, by fetal testosterone (T) production. In utero exposure to phthalate esters (PE) during sex differentiation can result in reproductive tract malformations in rats. PE al...

A New Neurobehavioral Model of Autism in Mice: Pre-and Postnatal Exposure to Sodium Valproate

ERIC Educational Resources Information Center

Wagner, George C.; Reuhl, Kenneth R.; Cheh, Michelle; McRae, Paulette; Halladay, Alycia K.

2006-01-01

Autism symptoms, including impairments in language development, social interactions, and motor skills, have been difficult to model in rodents. Since children exposed in utero to sodium valproate (VPA) demonstrate behavioral and neuroanatomical abnormalities similar to those seen in autism, the neurodevelopmental effects of this antiepileptic…

In utero exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of mitochondrial dynamics in rat placenta and offspring

USDA-ARS?s Scientific Manuscript database

The proportion of obese women who become pregnant continues to rise. Compelling evidence suggests the intrauterine environment is an important determinant of offspring health. Maternal obesity and unhealthy diets are shown to promote metabolic programming in the offspring. Mitochondria are matern...

Intergenerational response to the endocrine disruptor vinclozolin is influenced by maternal genotype and crossing scheme.

PubMed

Pietryk, Edward W; Clement, Kiristin; Elnagheeb, Marwa; Kuster, Ryan; Kilpatrick, Kayla; Love, Michael I; Ideraabdullah, Folami Y

2018-03-10

In utero exposure to vinclozolin (VIN), an antiandrogenic fungicide, is linked to multigenerational phenotypic and epigenetic effects. Mechanisms remain unclear. We assessed the role of antiandrogenic activity and DNA sequence context by comparing effects of VIN vs. M2 (metabolite with greater antiandrogenic activity) and wild-type C57BL/6 (B6) mice vs. mice carrying mutations at the previously reported VIN-responsive H19/Igf2 locus. First generation offspring from VIN-treated 8nrCG mutant dams exhibited increased body weight and decreased sperm ICR methylation. Second generation pups sired by affected males exhibited decreased neonatal body weight but only when dam was unexposed. Offspring from M2 treatments, B6 dams, 8nrCG sires or additional mutant lines were not similarly affected. Therefore, pup response to VIN over two generations detected here was an 8nrCG-specific maternal effect, independent of antiandrogenic activity. These findings demonstrate that maternal effects and crossing scheme play a major role in multigenerational response to in utero exposures. Copyright © 2018 Elsevier Inc. All rights reserved.

In utero oxcarbazepine and a withdrawal syndrome, anomalies, and hyponatremia.

PubMed

Rolnitsky, Asaph; Merlob, Paul; Klinger, Gil

2013-06-01

Oxcarbazepine is an antiepileptic agent that has been used during pregnancy, although its safety during pregnancy has not been sufficiently established. This article presents an infant born with renal and cardiac malformations who developed a withdrawal syndrome and hyponatremia following in utero exposure to oxcarbazepine. The infant was born at 35 weeks' gestation by urgent cesarean section to a mother in status epilepticus who had been treated with oxcarbazepine throughout her pregnancy. Evaluation for congenital anomalies identified mild aortic stenosis, a bicuspid aortic valve, patent foramen ovale, patent ductus arteriosus, and severe left hydronephrosis due to left ureteropelvic junction stenosis. On the third day of life the infant developed clinical signs of a withdrawal syndrome, which peaked on day 7 and resolved by day 12. Transient hyponatremia resolved by day 8 of life. Follow-up showed normal development at 15 months. The association of a withdrawal syndrome with oxcarbazepine exposure has not been previously reported. The hyponatremia is consistent with adult reports. The possible association of oxcarbazepine with renal and cardiac malformations requires further confirmation. Copyright © 2013 Elsevier Inc. All rights reserved.

Pregnancy hormone concentrations across ethnic groups: implications for later cancer risk.

PubMed

Potischman, Nancy; Troisi, Rebecca; Thadhani, Ravi; Hoover, Robert N; Dodd, Kevin; Davis, William W; Sluss, Patrick M; Hsieh, Chung-Cheng; Ballard-Barbash, Rachel

2005-06-01

A variety of in utero factors have been associated with risk of adult cancers, particularly birth weight, toxemia, and gestational age. These factors are thought to reflect hormonal exposures during pregnancy. We hypothesized that the prenatal hormonal milieu may explain part of the variation in cancer rates across ethnic groups, for example, the higher incidence of breast cancer in the Caucasian compared with Hispanic women and the higher incidence of prostate and lower incidence of testicular cancers among African-Americans compared with Caucasians. We measured hormones in early pregnancy blood samples from three ethnic groups in a health care plan in Boston, MA. Mean levels of androstenedione, testosterone, estrone, and prolactin were significantly lower in Caucasian women compared with Hispanic women. Although not statistically significant, estradiol levels were lower in Caucasian compared with Hispanic or African-American women. Concentrations of androstenedione, testosterone, and progesterone were notably higher in African-American compared with Caucasian or Hispanic women. These data are consistent with hypotheses that in utero hormonal exposures may explain some of the ethnic group differences in cancer risk.

Relationship between season of birth, temperature exposure, and later life wellbeing.

PubMed

Isen, Adam; Rossin-Slater, Maya; Walker, Reed

2017-12-19

We study how exposure to extreme temperatures in early periods of child development is related to adult economic outcomes measured 30 y later. Our analysis uses administrative earnings records for over 12 million individuals born in the United States between 1969 and 1977, linked to fine-scale, daily weather data and location and date of birth. We calculate the length of time each individual is exposed to different temperatures in utero and in early childhood, and we estimate flexible regression models that allow for nonlinearities in the relationship between temperature and long-run outcomes. We find that an extra day with mean temperatures above 32 °C in utero and in the first year after birth is associated with a 0.1% reduction in adult annual earnings at age 30. Temperature sensitivity is evident in multiple periods of early development, ranging from the first trimester of gestation to age 6-12 mo. We observe that household air-conditioning adoption, which increased dramatically over the time period studied, mitigates nearly all of the estimated temperature sensitivity.

Health effects in women exposed to low levels of ionizing radiation

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

Fabrikant, J.I.

1982-06-01

There are three delayed health effects of radiation which appear at the present time to have importance to women in radiation protection. These are: (1) the probability of cancer-induction at low doses and low-dose rates; (2) the consideration of those cancers in women, notably the breast and the thyroid, attributable to radiation exposure; and (3) the probability of induction of developmental abnormalities in the newborn following low-dose exposure in utero. The bases for the concern over these effects are discussed. (ACR)

GenX (FRD-902, ammonium (2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate) Does Not Display Estrogenic, (anti)androgenic or Glucocorticoid-like Activity In Vitro Whereas In Utero Exposure Induces Dose-related Maternal And Fetal Rat Liver PPAR Pathway Gene Expression Without Affecting Fetal Testis Testosterone Production.

EPA Science Inventory

GenX (CAS 13252-13-6) is an unregulated, persistent contaminant that has been found in both the Cape Fear River and in Wilmington NC drinking water. Concerns exist about the potential health effects of GenX exposure because it is not removed using traditional water treatment met...

Effects of in Utero Exposure of C57BL/6J Mice to 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Epidermal Permeability Barrier Development and Function

PubMed Central

Muenyi, Clarisse S.; Carrion, Sandra Leon; Jones, Lynn A.; Kennedy, Lawrence H.; Slominski, Andrzej T.

2014-01-01

Background: Development of the epidermal permeability barrier (EPB) is essential for neonatal life. Defects in this barrier are found in many skin diseases such as atopic dermatitis. Objective: We investigated the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the development and function of the EPB. Methods: Timed-pregnant C57BL/6J mice were gavaged with corn oil or TCDD (10 μg/kg body weight) on gestation day 12. Embryos were harvested on embryonic day (E) 15, E16, E17, and postnatal day (PND) 1. Results: A skin permeability assay showed that TCDD accelerated the development of the EPB, beginning at E15. This was accompanied by a significant decrease in transepidermal water loss (TEWL), enhanced stratification, and formation of the stratum corneum (SC). The levels of several ceramides were significantly increased at E15 and E16. PND1 histology revealed TCDD-induced acanthosis and epidermal hyperkeratosis. This was accompanied by disrupted epidermal tight junction (TJ) function, with increased dye leakage at the terminal claudin-1–staining TJs of the stratum granulosum. Because the animals did not have enhanced rates of TEWL, a commonly observed phenotype in animals with TJ defects, we performed tape-stripping. Removal of most of the SC resulted in a significant increase in TEWL in TCDD-exposed PND1 pups compared with their control group. Conclusions: These findings demonstrate that in utero exposure to TCDD accelerates the formation of an abnormal EPB with leaky TJs, warranting further study of environmental exposures, epithelial TJ integrity, and atopic disease. Citation: Muenyi CS, Leon Carrion S, Jones LA, Kennedy LH, Slominski AT, Sutter CH, Sutter TR. 2014. Effects of in utero exposure of C57BL/6J mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin on epidermal permeability barrier development and function. Environ Health Perspect 122:1052–1058; http://dx.doi.org/10.1289/ehp.1308045 PMID:24904982

Oxidative DNA damage and repair in children exposed to low levels of arsenic in utero and during early childhood: Application of salivary and urinary biomarkers

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

Hinhumpatch, Pantip; Navasumrit, Panida; Chulabhorn Graduate Institute, Laksi, Bangkok

The present study aimed to assess arsenic exposure and its effect on oxidative DNA damage and repair in young children exposed in utero and continued to live in arsenic-contaminated areas. To address the need for biological specimens that can be acquired with minimal discomfort to children, we used non-invasive urinary and salivary-based assays for assessing arsenic exposure and early biological effects that have potentially serious health implications. Levels of arsenic in nails showed the greatest magnitude of difference between exposed and control groups, followed by arsenic concentrations in saliva and urine. Arsenic levels in saliva showed significant positive correlations withmore » other biomarkers of arsenic exposure, including arsenic accumulation in nails (r = 0.56, P < 0.001) and arsenic concentration in urine (r = 0.50, P < 0.05). Exposed children had a significant reduction in arsenic methylation capacity indicated by decreased primary methylation index and secondary methylation index in both urine and saliva samples. Levels of salivary 8-OHdG in exposed children were significantly higher (∼ 4-fold, P < 0.01), whereas levels of urinary 8-OHdG excretion and salivary hOGG1 expression were significantly lower in exposed children (∼ 3-fold, P < 0.05), suggesting a defect in hOGG1 that resulted in ineffective cleavage of 8-OHdG. Multiple regression analysis results showed that levels of inorganic arsenic (iAs) in saliva and urine had a significant positive association with salivary 8-OHdG and a significant negative association with salivary hOGG1 expression. - Highlights: • The effects of arsenic exposure in utero and through early childhood were studied. • Arsenic-exposed children had a reduction in arsenic methylation capacity. • Exposed children had more DNA damage, observed as elevated salivary 8-OHdG. • Lower salivary hOGG1 in exposed children indicated impairment of 8-OHdG repair. • Salivary and urinary 8-OHdG levels were discordant.« less

Pregnancy outcome, thyroid dysfunction and fetal goitre after in utero exposure to propylthiouracil: a controlled cohort study

PubMed Central

Rosenfeld, Hila; Ornoy, Asher; Shechtman, Svetlana; Diav-Citrin, Orna

2009-01-01

AIMS Propylthiouracil (PTU) is presently considered to be the treatment of choice for hyperthyroidism in pregnancy. It is known to cross the human placenta, and therefore may affect the fetus. The major aims of this study were to evaluate the rate of major anomalies and to report the rate of fetal goitre, accompanied by hypothyroidism, in fetuses/ newborns of mothers after in utero exposure to PTU. METHODS Prospective observational controlled cohort study of PTU-exposed pregnancies of women counselled by the Israeli Teratology Information Service between the years 1994 and 2004 compared with women exposed to nonteratogens. RESULTS We followed up 115 PTU-exposed pregnancies and 1141 controls. The rate of major anomalies was comparable between the groups [PTU 1/80 (1.3%), control 34/1066 (3.2%), P= 0.507]. Hypothyroidism was found in 9.5% of fetuses/neonates (56.8% of whom with goitre). Hyperthyroidism, possibly resulting from maternal disease, was found in 10.3%. Goitres prenatally diagnosed by ultrasound were successfully treated in utero by maternal dose adjustment. In most cases neonatal thyroid functions normalized during the first month of life without any treatment. Median neonatal birth weight was lower [PTU 3145 g (2655–3537) vs. control 3300 g (2968–3600), P= 0.018]. CONCLUSIONS PTU does not seem to be a major human teratogen. However, it could cause fetal/neonatal hypothyroidism with or without goitre. Fetal thyroid size monitoring and neonatal thyroid function tests are important for appropriate prevention and treatment. PMID:19843064

Transplacental Arsenic Carcinogenesis in Mice

PubMed Central

Waalkes, Michael P.; Liu, Jie; Diwan, Bhalchandra A.

2007-01-01

Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from day 8 to 18 of gestation, and the offspring were observed for up to two years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and investigating a potential transplacental component of the human carcinogenic response to arsenic should be a research priority. PMID:17306315

Association between maternal urinary arsenic species and infant cord blood leptin levels in a New Hampshire Pregnancy Cohort.

PubMed

Gossai, Anala; Lesseur, Corina; Farzan, Shohreh; Marsit, Carmen; Karagas, Margaret R; Gilbert-Diamond, Diane

2015-01-01

Leptin is an important pleiotropic hormone involved in the regulation of nutrient intake and energy expenditure, and is known to influence body weight in infants and adults. High maternal levels of arsenic have been associated with reduced infant birth weight, but the mechanism of action is not yet understood. This study aimed to investigate the association between in utero arsenic exposure and infant cord blood leptin concentrations within 156 mother-infant pairs from the New Hampshire Birth Cohort Study (NHBCS) who were exposed to low to moderate levels of arsenic through well water and diet. In utero arsenic exposure was obtained from maternal second trimester urinary arsenic concentration, and plasma leptin levels were assessed through immunoassay. Results indicate that urinary arsenic species concentrations were predictive of infant cord blood leptin levels following adjustment for creatinine, infant birth weight for gestational age percentile, infant sex, maternal pregnancy-related weight gain, and maternal education level amongst 149 white mother-infant pairs in multivariate linear regression models. A doubling or 100% increase in total urinary arsenic concentration (iAs+MMA+DMA) was associated with a 10.3% (95% CI: 0.8-20.7%) increase in cord blood leptin levels. A 100% increase in either monomethylarsonic acid (MMA) or dimethylarsinic acid (DMA) was also associated with an 8.3% (95% CI: -1.0-18.6%) and 10.3% (95% CI: 1.2-20.2%) increase in cord blood leptin levels, respectively. The association between inorganic arsenic (iAs) and cord blood leptin was of similar magnitude and direction as other arsenic species (a 100% increase in iAs was associated with a 6.5% (95% CI: -3.4-17.5%) increase in cord blood leptin levels), albeit not significant. These results suggest in utero exposure to low levels of arsenic influences cord blood leptin concentration and presents a potential mechanism by which arsenic may impact early childhood growth. Copyright © 2014 Elsevier Inc. All rights reserved.

Infant mortality, season of birth and the health of older Puerto Rican adults

PubMed Central

McEniry, Mary

2010-01-01

The increasing prevalence of heart disease and diabetes among aging populations in low and middle income countries leads to questions regarding the degree to which endogenous early life exposures (exposures in utero) are important determinants of these health conditions. We devised a test using infant mortality (IMR) to verify if season of birth is a good indicator of early life (in utero) conditions that precipitate adult onset of disease. We linked annual infant mortality (IMR) at the municipality (municipio) level from the late 1920s-early 1940s with individual birth year and place using a representative sample of older Puerto Rican adults (n=1447) from the Puerto Rican Elderly: Health Conditions (PREHCO) study. We then estimated the effects of season of birth on adult heart disease and diabetes for all respondents and then for respondents according to whether they were born when IMR was lower or higher, controlling for age, gender, obesity, respondent’s educational level, adult behavior (smoking and exercise) and other early life exposures (childhood health, knee height and childhood socioeconomic status (SES)). The pattern of effects suggests that season of birth reflects endogenous causes: (1) odds of heart disease and diabetes were strong and significant for those born during the lean season in years when IMR was lower; (2) effects remained consistent even after controlling for other childhood conditions and adult behavior; but (3) no seasonality effects on adult health for adults born when IMR was higher. We conclude that in this population of older Puerto Rican adults there is continued support that the timing of adverse endogenous (in utero) conditions such as poor nutrition and infectious diseases may be associated with adult heart disease and diabetes. It will be important to test the validity of these findings in other similar populations in the developing world. PMID:20980087

Consequences of in utero exposure to Zika virus in offspring of AG129 mice.

PubMed

Julander, Justin G; Siddharthan, Venkatraman; Park, Albert H; Preston, Elizabeth; Mathur, Pranav; Bertolio, Michael; Wang, Hong; Zukor, Katherine; Van Wettere, Arnaud J; Sinex, Donal G; Morrey, John D

2018-06-20

Zika virus (ZIKV) can cause various diseases in offspring after congenital infection. The purpose of this study was to identify disease phenotypes in pups exposed to ZIKV in utero. Female interferon-α/β, -γ receptor knockout mice (AG129) were infected intraperitoneally with ZIKV 7.5 days' post coitus (dpc). Viral RNA, antigen and infectious virus were detected in some, but not all, maternal and fetal tissues at various times during gestation. Fetuses of infected dams had significant intrauterine growth restriction (IUGR), which was more pronounced as females neared parturition. Pups born to infected dams were significantly smaller and had significantly shortened skull lengths, as determined by measurement with a caliper and by micro-CT analysis, as compared with age-matched controls. Growth rates of exposed pups after birth, however, was similar to sham-exposed offspring. Viral RNA was detected in pups of infected dams after birth. A lower survival rate was observed in neonates exposed to ZIKV in utero. A mortality rate of over 50%, attributed to consequences of ZIKV infection, occurred after birth in pups born to infected dams. A transient hearing loss was observed in some animals exposed to virus in utero. No motor deficits or cognitive deficits were detected using running wheel or viral paresis scoring assays. Abnormalities in offspring included smaller size, shorter skull length and increased neonatal mortality, while the only functional deficit we could detect was a low incidence of transient hearing loss.

Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research.

PubMed

Pelkonen, Olavi; Terron, Andrea; Hernandez, Antonio F; Menendez, Pablo; Bennekou, Susanne Hougaard

2017-08-01

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease-secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide-and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.

Postnatal effects of dipentyl phthalate on male reproductive development

EPA Science Inventory

We conducted several in utero, ex vivo and in vitro studies to characterize the relative potencies of a series of phthalates on fetal rat testis testosterone production and gene expression. Dipentyl phthalate (DPeP) was the most potent of the active chemicals in its effect on fet...

Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes.

PubMed

Coppola, Danielle; Russo, Leo J; Kwarta, Robert F; Varughese, Ruana; Schmider, Juergen

2007-01-01

A significant number of women of childbearing age have schizophrenia or other psychoses. This means that there is a considerable risk of in utero exposure to risperidone due to maternal use. To determine whether in utero exposure to the atypical antipsychotic risperidone is associated with poor pregnancy and fetal/neonatal outcomes. A search of the Benefit Risk Management Worldwide Safety database, using a selection of preferred terms from the Medical Dictionary of Regulatory Activities, was performed to identify all cases of pregnancy or fetal/neonatal outcomes reported in association with risperidone treatment from its first market launch (international birth date, 1 June 1993) to 31 December 2004. The main measures were the patterns and reporting rates of pregnancy (stillbirth and spontaneous and induced abortion) and fetal/neonatal outcomes (congenital abnormalities, perinatal syndromes and withdrawal symptoms) for women administered risperidone during pregnancy. Overall, 713 pregnancies were identified in women who were receiving risperidone. Data were considered prospective in 516 of these, and retrospective in the remaining 197 cases. The majority of the known adverse pregnancy and fetal/neonatal outcomes were retrospectively reported. Of the 68 prospectively reported pregnancies with a known outcome, organ malformations and spontaneous abortions occurred 3.8% and 16.9% (when the 15 induced abortions were excluded from the denominator, as they were predominantly undertaken for nonmedical reasons), respectively, a finding consistent with background rates of the general population. There were 12 retrospectively reported pregnancies involving major organ malformations, the most frequently reported of which affected the heart, brain, lip and/or palate. There were 37 retrospectively reported pregnancies involving perinatal syndromes, of which 21 cases involved behavioural or motor disorders. In particular, there was a cluster of cases reporting tremor, jitteriness, irritability, feeding problems and somnolence, which may represent a withdrawal-emergent syndrome. This comprehensive review of the Benefit Risk Management Worldwide Safety database for case reports of risperidone exposure during pregnancy represents the largest ever published dataset documenting pregnancy outcomes for women taking the atypical antipsychotic risperidone. It indicates that in utero exposure to risperidone does not appear to increase the risk of spontaneous abortions, structural malformations and fetal teratogenic risk above that of the general population. Self-limited extrapyramidal effects in neonates were observed after maternal exposure to risperidone during the third trimester of pregnancy. Risperidone should only be used during pregnancy if the benefits outweigh the potential risks.

Effects of Continuous Gamma-Ray Exposure In Utero in B6C3F1 Mice on Gestation Day 18 and at 10 Weeks of Age.

PubMed

Gulay, K C M; Tanaka, I B; Komura, J; Tanaka, S

2018-04-01

Pregnant C57BL/6JJcl mice were exposed to γ rays at low dose rate (20 mGy/day, LDR) or medium dose rate (200 and 400 mGy/day, MDR) from gestation day (GD) 0-18 to total accumulated doses of 360, 3,600 and 7,200 mGy, respectively. An additional group of pregnant mice were acutely exposed to 2 Gy at high dose rate (HDR) of 0.77 Gy/min on GD 11. In experiment 1, fetuses collected via cesarean section on GD 18 were examined for external and skeletal abnormalities. While the results of LDR exposure (20 mGy/day) did not significantly differ from the nonirradiated controls in all parameters examined, MDR (200 and 400 mGy/day) and acute HDR (2 Gy) exposure caused growth retardation and significantly increased incidence of unossified bones. Increased incidence of external abnormalities was observed only in the acute HDR group. In experiment 2, the dams were allowed to give birth and the pups were clinically monitored and weighed periodically until 10 weeks of age when they were sacrificed and subjected to pathological examination. Pups exposed at MDRs of 200 and 400 mGy/dayand at acute HDR of 0.77 Gy/min had lower bodyweights from weaning (3 weeks) to 10 weeks of age except for females exposed to 400 mGy/day MDR. None of the pups exposed to an acute 2 Gy dose on GD 11 survived to 10 weeks of age. Histopathological changes were not significantly different between the nonirradiated control and the 20 mGy/day LDR groups. However, at both MDR exposures of 200 and 400 mGy/day. gonadal (testes and ovary) hypoplasia/atrophy was observed in all the 10-week-old pups. Our results show that in utero LDR exposure to 20 mGy/day for the entire gestation period did not cause any significant effect in pups when compared to the nonirradiated controls up to 10 weeks of age. However, pups exposed in utero to MDRs showed dose-related growth retardation with delayed ossifications (400 mGy/day) and gonadal hypoplasia/atrophy. These findings suggest that increased post-implantation loss in dams exposed at MDR is due to early embryonic deaths resulting in early resorption.

Cancer risk in men exposed in utero to diethylstilbestrol.

PubMed

Strohsnitter, W C; Noller, K L; Hoover, R N; Robboy, S J; Palmer, J R; Titus-Ernstoff, L; Kaufman, R H; Adam, E; Herbst, A L; Hatch, E E

2001-04-04

An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

Are endocrine disrupting compounds environmental risk factors for autism spectrum disorder?

PubMed

Moosa, Amer; Shu, Henry; Sarachana, Tewarit; Hu, Valerie W

2018-05-01

Recent research on the etiology of autism spectrum disorder (ASD) has shifted in part from a singular focus on genetic causes to the involvement of environmental factors and their gene interactions. This shift in focus is a result of the rapidly increasing prevalence of ASD coupled with the incomplete penetrance of this disorder in monozygotic twins. One such area of environmentally focused research is the association of exposures to endocrine disrupting compounds (EDCs) with elevated risk for ASD. EDCs are exogenous chemicals that can alter endogenous hormone activity and homeostasis, thus potentially disrupting the action of sex and other natural hormones at all stages of human development. Inasmuch as sex hormones play a fundamental role in brain development and sexual differentiation, exposure to EDCs in utero during critical stages of development can have lasting neurological and other physiological influences on the developing fetus and, ultimately, the child as well as adult. This review will focus on the possible contributions of EDCs to autism risk and pathogenesis by first discussing the influence of endogenous sex hormones on the autistic phenotype, followed by a review of documented human exposures to EDCs and associations with behaviors relevant to ASD. Mechanistic links between EDC exposures and aberrant neurodevelopment and behaviors are then considered, with emphasis on EDC-induced transcriptional profiles derived from animal and cellular studies. Finally, this review will discuss possible mechanisms through which EDC exposure can lead to persistent changes in gene expression and phenotype, which may in turn contribute to transgenerational inheritance of ASD. Copyright © 2017 Elsevier Inc. All rights reserved.

Time-activity patterns of pregnant women and changes during the course of pregnancy.

PubMed

Nethery, Elizabeth; Brauer, Michael; Janssen, Patti

2009-03-01

Numerous studies suggest that in utero exposures to environmental contaminants are associated with fetal development, congenital anomalies, learning difficulties or other health impacts later in life. Although location and time-activity data have been used to model exposure to specific contaminants in epidemiological studies, little information is available about time-activity patterns of pregnant women. We measured changes in location-based activity patterns over the course of pregnancy (48-h periods, during two or three trimesters) using a self-reported time-activity log among a nonrandom sample of pregnant women (n=62). We assessed the influence of demographics and personal factors on changes in activity over pregnancy using mixed effects regression models. Increasing weeks of pregnancy was a significant predictor for increased time spent at home (1 h/day increase for each trimester of pregnancy), after adjusting for income (2.6 more h/day at home in lowest income group), work status (3.5 more h/day at home for nonworkers) and other children in the family (1.5 more h/day at home with other children). No other measured activities (time outdoors, time in transit modalities or time in other indoor locations) were related to weeks of pregnancy. As our results indicate that pregnant women tend to spend more time at home during the latter stages of pregnancy, future exposure and epidemiological research should consider the potential increase in home-based exposures (i.e., indoor air pollution or chemicals in the home) late in pregnancy, and increased confidence in exposure proxies based on home locations or characteristics during the same period.

Prenatal Nitrate Exposure and Childhood Asthma. Influence of Maternal Prenatal Stress and Fetal Sex.

PubMed

Bose, Sonali; Chiu, Yueh-Hsiu Mathilda; Hsu, Hsiao-Hsien Leon; Di, Qian; Rosa, Maria José; Lee, Alison; Kloog, Itai; Wilson, Ander; Schwartz, Joel; Wright, Robert O; Cohen, Sheldon; Coull, Brent A; Wright, Rosalind J

2017-12-01

Impact of ambient pollution upon children's asthma may differ by sex, and exposure dose and timing. Psychosocial stress can also modify pollutant effects. These associations have not been examined for in utero ambient nitrate exposure. We implemented Bayesian-distributed lag interaction models to identify sensitive prenatal windows for the influence of nitrate (NO 3 - ) on child asthma, accounting for effect modification by sex and stress. Analyses included 752 mother-child dyads. Daily ambient NO 3 - exposure during pregnancy was derived using a hybrid chemical transport (Geos-Chem)/land-use regression model and natural log transformed. Prenatal maternal stress was indexed by a negative life events score (high [>2] vs. low [≤2]). The outcome was clinician-diagnosed asthma by age 6 years. Most mothers were Hispanic (54%) or black (29%), had a high school education or less (66%), never smoked (80%), and reported low prenatal stress (58%); 15% of children developed asthma. BDILMs adjusted for maternal age, race, education, prepregnancy obesity, atopy, and smoking status identified two sensitive windows (7-19 and 33-40 wk gestation), during which increased NO 3 - was associated with greater odds of asthma, specifically among boys born to mothers reporting high prenatal stress. Cumulative effects of NO 3 - across pregnancy were also significant in this subgroup (odds ratio = 2.64, 95% confidence interval = 1.27-5.39; per interquartile range increase in ln NO 3 - ). Prenatal NO 3 - exposure during distinct sensitive windows was associated with incident asthma in boys concurrently exposed to high prenatal stress.

Epidemiological research on radiation-induced cancer in atomic bomb survivors.

PubMed

Ozasa, Kotaro

2016-08-01

The late effects of exposure to atomic bomb radiation on cancer occurrence have been evaluated by epidemiological studies on three cohorts: a cohort of atomic bomb survivors (Life Span Study; LSS), survivors exposed IN UTERO : , and children of atomic bomb survivors (F1). The risk of leukemia among the survivors increased remarkably in the early period after the bombings, especially among children. Increased risks of solid cancers have been evident since around 10 years after the bombings and are still present today. The LSS has clarified the dose-response relationships of radiation exposure and risk of various cancers, taking into account important risk modifiers such as sex, age at exposure, and attained age. Confounding by conventional risk factors including lifestyle differences is not considered substantial because people were non-selectively exposed to the atomic bomb radiation. Uncertainty in risk estimates at low-dose levels is thought to be derived from various sources, including different estimates of risk at background levels, uncertainty in dose estimates, residual confounding and interaction, strong risk factors, and exposure to residual radiation and/or medical radiation. The risk of cancer in subjects exposed IN UTERO : is similar to that in LSS subjects who were exposed in childhood. Regarding hereditary effects of radiation exposure, no increased risk of cancers associated with parental exposure to radiation have been observed in the F1 cohort to date. In addition to biological and pathogenetic interpretations of the present results, epidemiological investigations using advanced technology should be used to further analyze these cohorts. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Maternal phthalate exposure during pregnancy is associated with DNA methylation of LINE-1 and Alu repetitive elements in Mexican-American children

PubMed Central

Huen, Karen; Calafat, Antonia M.; Bradman, Asa; Yousefi, Paul; Eskenazi, Brenda; Holland, Nina

2016-01-01

Phthalates are frequently used in personal care products and plasticizers and phthalate exposure is ubiquitous in the US population. Exposure to phthalates during critical periods in utero has been associated with a variety of adverse health outcomes but the biological mechanisms linking these exposures with disease are not well characterized. In this study, we examined the relationship of in utero phthalate exposure with repetitive element DNA methylation, an epigenetic marker of genome instability, in children from the longitudinal birth cohort CHAMACOS. Methylation of Alu and long interspersed nucleotide elements (LINE-1) was determined using pyrosequencing of bisulfite-treated DNA isolated from whole blood samples collected from newborns and 9 year old children (n=355). Concentrations of eleven phthalate metabolites were measured in urine collected from pregnant mothers at 13 and 26 weeks gestation. We found a consistent inverse association between prenatal concentrations of monoethyl phthalate, the most frequently detected urinary metabolite, with cord blood methylation of Alu repeats (β(95%CI):−0.14(−0.28,0.00) and −0.16(−0.31,−0.02)) for early and late pregnancy, respectively, and a similar but weaker association with LINE-1 methylation. Additionally, increases in urinary concentrations of di-(2-ethylhexyl) phthalate metabolites during late pregnancy were associated with lower levels of methylation of Alu repeats in 9 year old blood (significant p-values ranged from 0.003 to 0.03). Our findings suggest that prenatal exposure to some phthalates may influence differences in repetitive element methylation, highlighting epigenetics as a plausible biological mechanism through which phthalates may affect health. PMID:27019040

Maternal And Neonatal Plasma MicroRNA Biomarkers For Fetal Alcohol Exposure In An Ovine Model

PubMed Central

Balaraman, Sridevi; Lunde, E. Raine; Sawant, Onkar; Cudd, Timothy A.; Washburn, Shannon E.; Miranda, Rajesh C.

2014-01-01

Background Plasma or circulating miRNAs (cirmiRNAs) have potential diagnostic value as biomarkers for a range of diseases. Based on observations that ethanol altered intracellular miRNAs during development, we tested the hypothesis that plasma miRNAs were biomarkers for maternal alcohol exposure, and for past in utero exposure, in the neonate. Methods Pregnant sheep were exposed to a binge model of ethanol consumption resulting in an average peak blood alcohol content of 243 mg/dl, for a three-trimester equivalent period from gestational day (GD) 4 to GD 132. MiRNA profiles were assessed by quantitative PCR analysis in plasma, erythrocyte and leukocytes obtained from non-pregnant ewes, and plasma from pregnant ewes 24 hours following the last binge ethanol episode, and from newborn lambs, at birth on ~GD 147. Results Pregnant ewe and newborn lamb cirmiRNA profiles were similar to each other and different from non-pregnant female plasma, erythrocyte or leukocyte miRNAs. Significant changes in cirmiRNA profiles were observed in the ethanol-exposed ewe, and at birth, in the in utero, ethanol-exposed lamb. CirmiRNAs including miR-9, -15b, -19b and -20a were sensitive and specific measures of ethanol exposure in both pregnant ewe and newborn lamb. Additionally, ethanol exposure altered guide to passenger strand cirmiRNA ratios in the pregnant ewe, but not in the lamb. Conclusion Shared profiles between pregnant dam and neonate suggest possible maternal-fetal miRNA transfer. CirmiRNAs are biomarkers for alcohol exposure during pregnancy, in both mother and neonate, and may constitute an important shared endocrine biomarker that is vulnerable to the maternal environment. PMID:24588274

Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review.

PubMed

Frank, D A; Augustyn, M; Knight, W G; Pell, T; Zuckerman, B

2001-03-28

Despite recent studies that failed to show catastrophic effects of prenatal cocaine exposure, popular attitudes and public policies still reflect the belief that cocaine is a uniquely dangerous teratogen. To critically review outcomes in early childhood after prenatal cocaine exposure in 5 domains: physical growth; cognition; language skills; motor skills; and behavior, attention, affect, and neurophysiology. Search of MEDLINE and Psychological Abstracts from 1984 to October 2000. Studies selected for detailed review (1) were published in a peer-reviewed English-language journal; (2) included a comparison group; (3) recruited samples prospectively in the perinatal period; (4) used masked assessment; and (5) did not include a substantial proportion of subjects exposed in utero to opiates, amphetamines, phencyclidine, or maternal human immunodeficiency virus infection. Thirty-six of 74 articles met criteria and were reviewed by 3 authors. Disagreements were resolved by consensus. After controlling for confounders, there was no consistent negative association between prenatal cocaine exposure and physical growth, developmental test scores, or receptive or expressive language. Less optimal motor scores have been found up to age 7 months but not thereafter, and may reflect heavy tobacco exposure. No independent cocaine effects have been shown on standardized parent and teacher reports of child behavior scored by accepted criteria. Experimental paradigms and novel statistical manipulations of standard instruments suggest an association between prenatal cocaine exposure and decreased attentiveness and emotional expressivity, as well as differences on neurophysiologic and attentional/affective findings. Among children aged 6 years or younger, there is no convincing evidence that prenatal cocaine exposure is associated with developmental toxic effects that are different in severity, scope, or kind from the sequelae of multiple other risk factors. Many findings once thought to be specific effects of in utero cocaine exposure are correlated with other factors, including prenatal exposure to tobacco, marijuana, or alcohol, and the quality of the child's environment. Further replication is required of preliminary neurologic findings.

Exposure to preeclampsia in utero affects growth from birth to late childhood dependent on child’s sex and severity of exposure: Follow-up of a nested case-control study

PubMed Central

Øymar, Knut; Eide, Geir Egil; Forman, Michele R.; Júlíusson, Pétur Benedikt

2017-01-01

Background and objective An adverse intrauterine environment may affect offspring growth and development. Our aim was to explore whether preeclampsia (PE) exposure in utero influences growth from birth to 13 years. Methods In a nested case-control study, 229 children were exposed to PE (mild/moderate: n = 164, severe: n = 54) and 385 were unexposed. Length/height and weight were abstracted from records at birth, 3 and 6 months, 1 and 4 years, and measured along with waist circumference and skinfolds at follow-up at 11/12 (girls/boys) and 13 years (both sexes). Associations between PE and z-scores for growth were analyzed by multiple linear and fractional polynomial regression with adjustment for potential confounders. Results In boys, exposure to mild/moderate PE was positively associated with linear growth after 0.5 years, but severe PE was negatively associated with linear growth in all ages. In girls, both exposure to mild/moderate and severe PE were negatively associated with linear growth. Exposure to PE was negatively associated with weight and body mass index (BMI) during infancy, but positively associated with weight and BMI thereafter, except that boys exposed to severe PE consistently had a lower weight and BMI compared to the unexposed. Exposure to severe PE only was positively associated with waist-to-height ratio at 11/12 (girls/boys) and 13 years (both sexes). Conclusions From birth to adolescence, linear growth, weight and BMI trajectories differed between the sexes by severity of exposure to PE. In general, PE exposure was negatively associated with linear growth, while in girls; positive associations with weight and BMI were observed. This underlines fetal life as a particularly sensitive period affecting subsequent growth and this may have implications for targeted approaches for healthy growth and development. PMID:28486480

Growth, Development, and Behavior in Early Childhood Following Prenatal Cocaine Exposure

PubMed Central

Frank, Deborah A.; Augustyn, Marilyn; Knight, Wanda Grant; Pell, Tripler; Zuckerman, Barry

2008-01-01

Context Despite recent studies that failed to show catastrophic effects of prenatal cocaine exposure, popular attitudes and public policies still reflect the belief that cocaine is a uniquely dangerous teratogen. Objective To critically review outcomes in early childhood after prenatal cocaine exposure in 5 domains: physical growth; cognition; language skills; motor skills; and behavior, attention, affect, and neurophysiology. Data Sources Search of MEDLINE and Psychological Abstracts from 1984 to October 2000. Study Selection Studies selected for detailed review (1) were published in a peerreviewed English-language journal; (2) included a comparison group; (3) recruited samples prospectively in the perinatal period; (4) used masked assessment; and (5) did not include a substantial proportion of subjects exposed in utero to opiates, amphetamines, phencyclidine, or maternal human immunodeficiency virus infection. Data Extraction Thirty-six of 74 articles met criteria and were reviewed by 3 authors. Disagreements were resolved by consensus. Data Synthesis After controlling for confounders, there was no consistent negative association between prenatal cocaine exposure and physical growth, developmental test scores, or receptive or expressive language. Less optimal motor scores have been found up to age 7 months but not thereafter, and may reflect heavy tobacco exposure. No independent cocaine effects have been shown on standardized parent and teacher reports of child behavior scored by accepted criteria. Experimental paradigms and novel statistical manipulations of standard instruments suggest an association between prenatal cocaine exposure and decreased attentiveness and emotional expressivity, as well as differences on neurophysiologic and attentional/affective findings. Conclusions Among children aged 6 years or younger, there is no convincing evidence that prenatal cocaine exposure is associated with developmental toxic effects that are different in severity, scope, or kind from the sequelae of multiple other risk factors. Many findings once thought to be specific effects of in utero cocaine exposure are correlated with other factors, including prenatal exposure to tobacco, marijuana, or alcohol, and the quality of the child’s environment. Further replication is required of preliminary neurologic findings. PMID:11268270

Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure

PubMed Central

Hagan, Joseph F.; Balachova, Tatiana; Bertrand, Jacquelyn; Chasnoff, Ira; Dang, Elizabeth; Fernandez-Baca, Daniel; Kable, Julie; Kosofsky, Barry; Senturias, Yasmin N.; Singh, Natasha; Sloane, Mark; Weitzman, Carol; Zubler, Jennifer

2017-01-01

Children and adolescents affected by prenatal exposure to alcohol who have brain damage that is manifested in functional impairments of neurocognition, self-regulation, and adaptive functioning may most appropriately be diagnosed with neurobehavioral disorder associated with prenatal exposure. This Special Article outlines clinical implications and guidelines for pediatric medical home clinicians to identify, diagnose, and refer children regarding neurobehavioral disorder associated with prenatal exposure. Emphasis is given to reported or observable behaviors that can be identified as part of care in pediatric medical homes, differential diagnosis, and potential comorbidities. In addition, brief guidance is provided on the management of affected children in the pediatric medical home. Finally, suggestions are given for obtaining prenatal history of in utero exposure to alcohol for the pediatric patient. PMID:27677572

Behavioral Effects of Developmental Methylmercury Drinking Water Exposure in Rodents

PubMed Central

Bisen-Hersh, Emily B.; Farina, Marcelo; Barbosa, Fernando; Rocha, Joao BT; Aschner, Michael

2013-01-01

Early methylmercury (MeHg) exposure can have long-lasting consequences likely arising from impaired developmental processes, the outcome of which has been exposed in several longitudinal studies of affected populations. Given the large number of newborns at an increased risk of learning disabilities associated with in utero MeHg exposure, it is important to study neurobehavioral alterations using ecologically valid and physiologically relevant models. This review highlights the benefits of using the MeHg drinking water exposure paradigm and outlines behavioral outcomes arising from this procedure in rodents. Combination treatments that exacerbate or ameliorate MeHg-induced effects, and possible molecular mechanisms underlying behavioral impairment are also discussed. PMID:24210169

A multimodal imaging workflow to visualize metal mixtures in the human placenta and explore colocalization with biological response markers.

PubMed

Niedzwiecki, Megan M; Austin, Christine; Remark, Romain; Merad, Miriam; Gnjatic, Sacha; Estrada-Gutierrez, Guadalupe; Espejel-Nuñez, Aurora; Borboa-Olivares, Hector; Guzman-Huerta, Mario; Wright, Rosalind J; Wright, Robert O; Arora, Manish

2016-04-01

Fetal exposure to essential and toxic metals can influence life-long health trajectories. The placenta regulates chemical transmission from maternal circulation to the fetus and itself exhibits a complex response to environmental stressors. The placenta can thus be a useful matrix to monitor metal exposures and stress responses in utero, but strategies to explore the biologic effects of metal mixtures in this organ are not well-developed. In this proof-of-concept study, we used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to measure the distributions of multiple metals in placental tissue from a low-birth-weight pregnancy, and we developed an approach to identify the components of metal mixtures that colocalized with biological response markers. Our novel workflow, which includes custom-developed software tools and algorithms for spatial outlier identification and background subtraction in multidimensional elemental image stacks, enables rapid image processing and seamless integration of data from elemental imaging and immunohistochemistry. Using quantitative spatial statistics, we identified distinct patterns of metal accumulation at sites of inflammation. Broadly, our multiplexed approach can be used to explore the mechanisms mediating complex metal exposures and biologic responses within placentae and other tissue types. Our LA-ICP-MS image processing workflow can be accessed through our interactive R Shiny application 'shinyImaging', which is available at or through our laboratory's website, .

Hypothesis: does ochratoxin A cause testicular cancer?

PubMed

Schwartz, Gary G

2002-02-01

Little is known about the etiology of testicular cancer, which is the most common cancer among young men. Epidemiologic data point to a carcinogenic exposure in early life or in utero, but the nature of the exposure is unknown. We hypothesize that the mycotoxin, ochratoxin A, is a cause of testicular cancer. Ochratoxin A is a naturally occurring contaminant of cereals, pigmeat, and other foods and is a known genotoxic carcinogen in animals. The major features of the descriptive epidemiology of testicular cancer (a high incidence in northern Europe, increasing incidence over time, and associations with high socioeconomic status, and with poor semen quality) are all associated with exposure to ochratoxin A. Exposure of animals to ochratoxin A via the diet or via in utero transfer induces adducts in testicular DNA. We hypothesize that consumption of foods contaminated with ochratoxin A during pregnancy and/or childhood induces lesions in testicular DNA and that puberty promotes these lesions to testicular cancer. We tested the ochratoxin A hypothesis using ecologic data on the per-capita consumption of cereals, coffee, and pigmeat, the principal dietary sources of ochratoxin A. Incidence rates for testicular cancer in 20 countries were significantly correlated with the per-capita consumption of coffee and pigmeat (r = 0.49 and 0.54, p = 0.03 and 0.01). The ochratoxin A hypothesis offers a coherent explanation for much of the descriptive epidemiology of testicular cancer and suggests new avenues for analytic research.

CHRONIC EXPOSURE TO DIBROMOACETIC ACID, A WATER DISINFECTION BY-PRODUCT, DIMINISHES PRIMORDIAL FOLLICLE POPULATIONS IN THE RABBIT

EPA Science Inventory

To determine if dibromoacetic acid (DBA) affects folliculogenesis, four groups of female Dutch-belted rabbits were exposed daily to 0, 1, 5, or 50 mg DBA/kg body wt. in drinking water beginning in utero from gestation day 15 throughout life. Functionality of the endocrine axis w...

A mixture of five phthalate diesters cummulatively inhibit fetal testicular testoserone production in a manner consisent with their predicted reporduction toxicity in the Sprague Dawley rat.

EPA Science Inventory

Phthalate diesters are commonly-used plasticizers in intravenous bags, plastic food wrap and children’s toys, and the metabolites of multiple phthalates are detected in humans. In utero exposure to certain phthalates during sexual differentiation causes male reproductive tract m...

Deviant ERP Response to Spoken Non-Words among Adolescents Exposed to Cocaine in Utero

ERIC Educational Resources Information Center

Landi, Nicole; Crowley, Michael J.; Wu, Jia; Bailey, Christopher A.; Mayes, Linda C.

2012-01-01

Concern for the impact of prenatal cocaine exposure (PCE) on human language development is based on observations of impaired performance on assessments of language skills in these children relative to non-exposed children. We investigated the effects of PCE on speech processing ability using event-related potentials (ERPs) among a sample of…

Impaired Performance of Children Exposed in Utero to Cocaine on a Novel Test of Visuospatial Working Memory

ERIC Educational Resources Information Center

Schroder, Marie D.; Snyder, Peter J.; Sielski, Ireneusz; Mayes, Linda

2004-01-01

The present study examines the potentially harmful effects of prenatal cocaine exposure on later visuospatial memory functions. A novel neuropsychological measure of immediate- and short-term memory for visuospatial information was administered to 40 children, who were identified as cocaine-exposed, and 11 age and socioeconomic status matched…

STRAIN-SPECIFIC SENSITIVITY TO INDUCTION OF MURINE LUNG TUMORS FOLLOWING IN UTERO EXPOSURE TO 3-METHYLCHOLANTHRENE

EPA Science Inventory

We previously demonstrated that different strains of fetal mice were more sensitive to lung tumor induction by 3-methylcholanthrene (MC) than were adults. Offspring from either a D2 x B6D2F1 backcross or from parental Balb/c mice exhibited a similar high incidence of lung tumors ...

Are anti-androgenic effects of phthalates on the fetal testis mediated via a peroxisome proliferator activated receptor-α (PPAR-α) associated molecular initiating event?

EPA Science Inventory

In utero exposure to certain phthalate esters (PE) during the critical window of male sex differentiation reduces both fetal testis testosterone (T) production and expression of steroid transport and synthesis genes, resulting in reproductive tract malformations in adult male rod...

Simvastatin and Dipentyl Phthalate Display Different Mechanisms of Action but Exhibit Dose Additive Effects on Fetal Testicular Testosterone Production in Sprague Dawley Rats

EPA Science Inventory

Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero exposure to some phthalate esters (PEs) alters fetal Leydig cell differentiation, reducing the expression of several genes associated with steroid synthesis/tr...

Maternal obesity during gestation impairs fatty acid oxidation and mitochondrial SIRT3 expression in rat offspring at weaning

USDA-ARS?s Scientific Manuscript database

In utero exposure to maternal obesity increases the offspring’s risk of obesity in later life. We have also previously reported that offspring of obese rat dams develop hepatic steatosis, mild hyperinsulinemia, and a lipogenic gene signature in the liver at postnatal day (PND) 21. In the current s...

INDUCTION OF URINARY BLADDER PATHOLOGY IN MALE AND FEMALE C3H MICE EXPOSED TO SODIUM ARSENITE FROM GESTATION THROUGH YOUNG ADULTHOOD

EPA Science Inventory

Epidemiology studies suggest that chronic exposure to inorganic arsenic is associated with cancer of the skin, urinary bladder and lung as well as the kidney and liver. Recently, an in utero animal model was developed to characterize the carcinogenic properties of inorganic arsen...

In Utero exposure of soy protein diet inhibits atherosclerosis in F1 offsprings by promoting Th2 anti-inflammatory T cell responses

USDA-ARS?s Scientific Manuscript database

Maternal hypercholesterolemia has been implicated with a higher incidence and earlier onset of atherosclerotic lesions in neonatal offspring. We have reported that feeding soy protein isolate (SPI) diet starting at postnatal day (PND) 21 prevented the progression of atherosclerosis in the hyperlipid...

In utero exposure to di(n)butyl phthalate reduces testicular testosterone and testis size in a dose-dependent manner in Harlan Sprague Dawley fetal rats

EPA Science Inventory

Phthalate esters are widely used to impart flexibility to plastics (e.g. plastic medical devices and children’s toys) as well as other uses in health and beauty products and some pharmaceuticals. Certain phthalate esters cause reproductive malformations and decrease androgen-dep...

Assessment of fetal testis function and postnatal development of the male rat following in utero exposure to diethylhexyl phthalate, dipentyl phthalate, diisobutyl phthalate, diisoheptyl phthalate and diisononyl phthalate

EPA Science Inventory

Phthalate esters are a large class of plasticizer compounds widely used in many consumer product applications. Some phthalates induce male fetal endocrine toxicity and reproductive malformations through disruption of hormone production during sexual differentiation. Regulatory ag...

Born Substance Exposed, Educationally Vulnerable. Exceptional Children at Risk: CEC Mini-Library.

ERIC Educational Resources Information Center

Vincent, Lisbeth J.; And Others

This booklet examines what is known about the long-term effects of exposure in utero to alcohol and other drugs, as well as the educational implications of those effects. Research is synthesized on biological and medical risk factors, psychosocial risk factors, and the interaction of biology and environment. A section on implications for…

Analysis of PFOA in Dosed CD-1 Mice Part 2: Disposition of PFOA in Tissues and fluids from pregnant and lactating mice and their pups

EPA Science Inventory

Previous studies in mice with multiple gestational exposures to perfluorooctanoic acid (PFOA) demonstrate numerous dose dependent growth and developmental effects which appeared to worsen if offspring exposed in utero nursed from PFOA-exposed dams. To evaluate the disposition of ...

Chronic exposure to low levels of dibromoacetic acid, a water disinfection by-product, adversely affects reproductive function in male rabbits

EPA Science Inventory

Four groups (minimum of 10/dose group) of male Dutch-Belted rabbits were treated daily to dibromoacetic acid (DBA) via drinking water beginning in utero from gestation day 15 throughout life; target dosages were 1, 5, and 50 mg DBA /kg body weight. Developmental, prepubertal as ...

2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) DISRUPTS EARLY MORPHOGENETIC EVENTS THAT FORM THE LOWER REPRODUCTIVE TRACT IN FEMALE RAT FETUSES

EPA Science Inventory

In female rats, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during critical periods of organogenesis causes a permanent thread of tissue across the vaginal opening, which consists of a core of mesenchyme surrounded by keratinized epithelia. The objective of t...

Educational attainment of children born to mothers with epilepsy.

PubMed

Lacey, Arron S; Pickrell, William Owen; Thomas, Rhys H; Kerr, Mike P; White, Cathy P; Rees, Mark I

2018-03-27

Small prospective studies have identified that children exposed to valproate in utero have poorer scores on cognitive testing. We wanted to identify whether children exposed to antiepileptic drugs (AEDs) in utero have poorer school performance. We used anonymised, linked, routinely collected healthcare records to identify children born to mothers with epilepsy. We linked these children to their national attainment Key Stage 1 (KS1) tests in mathematics, language and science at the age of 7 and compared them with matched children born to mothers without epilepsy, and with the national KS1 results. We used the core subject indicator (CSI) as an outcome measure (the proportion of children achieving a minimum standard in all subjects) and the results in individual subjects. We identified 440 children born to mothers with epilepsy with available KS1 results. Compared with a matched control group, fewer children with mothers being prescribed sodium valproate during pregnancy achieved the national minimum standard in CSI (-12.7% less than the control group), mathematics (-12.1%), language (-10.4%) and in science (-12.2%). Even fewer children with mothers being prescribed multiple AEDs during pregnancy achieved a national minimum standard: CSI (by -20.7% less than the control group), mathematics (-21.9%), language (-19.3%) and science (-19.4%). We did not observe any significant difference in children whose mothers were prescribed carbamazepine or were not taking an AED when compared with the control group. In utero exposure to AEDs in combination, or sodium valproate alone, is associated with a significant decrease in attainment in national educational tests for 7-year-old children compared with both a matched control group and the all-Wales national average. These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis

PubMed Central

Bonde, Jens Peter; Flachs, Esben Meulengracht; Rimborg, Susie; Glazer, Clara Helene; Giwercman, Aleksander; Ramlau-Hansen, Cecilia Høst; Hougaard, Karin Sørig; Høyer, Birgit Bjerre; Hærvig, Katia Keglberg; Petersen, Sesilje Bondo; Rylander, Lars; Specht, Ina Olmer; Toft, Gunnar; Bräuner, Elvira Vaclavik

2017-01-01

BACKGROUND More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91–1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p′-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04–1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure–response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure–outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field. PMID:27655588

Towards Prenatal Biomonitoring in North Carolina: Assessing Arsenic, Cadmium, Mercury, and Lead Levels in Pregnant Women

PubMed Central

Sanders, Alison P.; Flood, Kaye; Chiang, Shu; Herring, Amy H.; Wolf, Leslie; Fry, Rebecca C.

2012-01-01

Exposure to toxic metals during the prenatal period carries the potential for adverse developmental effects to the fetus, yet such exposure remains largely unmonitored in the United States. The aim of this study was to assess maternal exposure to four toxic metals (arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb)) in a cohort of pregnant women in North Carolina. We analyzed blood samples submitted to the North Carolina Department of Health and Human Services for blood typing to assess toxic metal levels in pregnant women (n = 211) across six North Carolina counties. Whole blood metal concentrations were measured by inductively coupled plasma mass spectrometry. The association between maternal characteristics, including county of residence, age, and race, and metal exposure was analyzed using multiple linear regression analysis. A large fraction of the blood samples showed detectable levels for each of the four metals. Specifically, As (65.7%), Cd (57.3%), Hg (63.8%), and Pb (100%) were detected in blood samples. Moreover, compared with adult females participating in the Fourth National Report on Human Exposure to Environmental Chemicals and guidelines for pregnant women, some women in the sample population exceeded benchmark levels of Cd, Hg, and Pb. Evidence from this pilot study indicates that pregnant women in North Carolina are exposed to As, Cd, Hg, and Pb and suggests that factors related to maternal county of residence and race may impact maternal exposure levels. As increased levels of one or more of these metals in utero have been associated with detrimental developmental and reproductive outcomes, further study is clearly warranted to establish the impacts to newborns. PMID:22427803

Exposures of children to organophosphate pesticides and their potential adverse health effects.

PubMed Central

Eskenazi, B; Bradman, A; Castorina, R

1999-01-01

Recent studies show that young children can be exposed to pesticides during normal oral exploration of their environment and their level of dermal contact with floors and other surfaces. Children living in agricultural areas may be exposed to higher pesticide levels than other children because of pesticides tracked into their homes by household members, by pesticide drift, by breast milk from their farmworker mother, or by playing in nearby fields. Nevertheless, few studies have assessed the extent of children's pesticide exposure, and no studies have examined whether there are adverse health effects of chronic exposure. There is substantial toxicologic evidence that repeated low-level exposure to organophosphate (OP) pesticides may affect neurodevelopment and growth in developing animals. For example, animal studies have reported neurobehavorial effects such as impairment on maze performance, locomotion, and balance in neonates exposed (italic)in utero(/italic) and during early postnatal life. Possible mechanisms for these effects include inhibition of brain acetylcholinesterase, downregulation of muscarinic receptors, decreased brain DNA synthesis, and reduced brain weight in offspring. Research findings also suggest that it is biologically plausible that OP exposure may be related to respiratory disease in children through dysregulation of the autonomic nervous system. The University of California Berkeley Center for Children's Environmental Health Research is working to build a community-university partnership to study the environmental health of rural children. This Center for the Health Assessment of Mothers and Children of Salinas, or CHAMACOS in Monterey County, California, will assess (italic)in utero(/italic) and postnatal OP pesticide exposure and the relationship of exposure to neurodevelopment, growth, and symptoms of respiratory illness in children. The ultimate goal of the center is to translate research findings into a reduction of children's exposure to pesticides and other environmental agents, and thereby reduce the incidence of environmentally related disease. PMID:10346990

Cumulative reproductive effects of in utero administration of mixtures of antiandrogens in male SD rats: synergy or additivity?

EPA Science Inventory

In 1996 the USEPA was charged under the FQPA to consider the cumulative effects of chemicals in their risk assessments. Our studies were conducted to provide a framework for assessing the cumulative effects of antiandrogens. Toxicants were administered individually or as mixtures...

EVALUATION OF PHYSIOLOGICALLY BASED MODELS OF PREGNANCY AND LACTATION FOR THEIR APPLICATION IN CHILDREN'S HEALTH RISK ASSESSMENTS

EPA Science Inventory

In today's scientific and regulatory climates, an increased emphasis is placed upon the potential health impacts for children exposed either in utero or by nursing to drugs of abuse, pharmaceuticals, industrial or consumer chemicals. As a result, there is a renewed interest in th...

Induction of Immune Tolerance to Foreign Protein via Adeno-Associated Viral Vector Gene Transfer in Mid-Gestation Fetal Sheep

PubMed Central

Davey, Marcus G.; Riley, John S.; Andrews, Abigail; Tyminski, Alec; Limberis, Maria; Pogoriler, Jennifer E.; Partridge, Emily; Olive, Aliza; Hedrick, Holly L.; Flake, Alan W.; Peranteau, William H.

2017-01-01

A major limitation to adeno-associated virus (AAV) gene therapy is the generation of host immune responses to viral vector antigens and the transgene product. The ability to induce immune tolerance to foreign protein has the potential to overcome this host immunity. Acquisition and maintenance of tolerance to viral vector antigens and transgene products may also permit repeat administration thereby enhancing therapeutic efficacy. In utero gene transfer (IUGT) takes advantage of the immunologic immaturity of the fetus to induce immune tolerance to foreign antigens. In this large animal study, in utero administration of AAV6.2, AAV8 and AAV9 expressing green fluorescent protein (GFP) to ~60 day fetal sheep (term: ~150 days) was performed. Transgene expression and postnatal immune tolerance to GFP and viral antigens were assessed. We demonstrate 1) hepatic expression of GFP 1 month following in utero administration of AAV6.2.GFP and AAV8.GFP, 2) in utero recipients of either AAV6.2.GFP or AAV8.GFP fail to mount an anti-GFP antibody response following postnatal GFP challenge and lack inflammatory cellular infiltrates at the intramuscular site of immunization, 3) a serotype specific anti-AAV neutralizing antibody response is elicited following postnatal challenge of in utero recipients of AAV6.2 or AAV8 with the corresponding AAV serotype, and 4) durable hepatic GFP expression was observed up to 6 months after birth in recipients of AAV8.GFP but expression was lost between 1 and 6 months of age in recipients of AAV6.2.GFP. The current study demonstrates, in a preclinical large animal model, the potential of IUGT to achieve host immune tolerance to the viral vector transgene product but also suggests that a single exposure to the vector capsid proteins at the time of IUGT is inadequate to induce tolerance to viral vector antigens. PMID:28141818

The Mexican Drug War and Early-Life Health: The Impact of Violent Crime on Birth Outcomes.

PubMed

Brown, Ryan

2018-02-01

This study examines the relationship between exposure to violent crime in utero and birth weight using longitudinal data from a household survey conducted in Mexico. Controlling for selective migration and fertility, the results suggest that early gestational exposure to the recent escalation of the Mexican Drug War is associated with a substantial decrease in birth weight. This association is especially pronounced among children born to mothers of low socioeconomic status and among children born to mothers who score poorly on a mental health index.

Treatment of neonatal abstinence syndrome.

PubMed

Johnson, K; Gerada, C; Greenough, A

2003-01-01

Neonatal abstinence syndrome (NAS) is suffered by infants withdrawing from substances on which they have become physically dependent after in utero exposure. They may require prolonged treatment and spend weeks or even months in hospital. A wide range of drugs have been used to treat NAS. The efficacy of few, however, have been adequately investigated. Evidence suggests that opioids are the most appropriate, at least in infants exposed to diamorphine or methadone. In all "head to head" trials, diazepam has been shown to be ineffective. Morphine and methadone are currently the most commonly prescribed opioids to treat NAS, but randomised trials have not been undertaken to determine which is the more beneficial. Many infants with NAS have been exposed to multiple substances in utero. Further research is required into whether a single opiate or a multiple drug regimen is the best option for such patients.

Behavioral characteristics and cognitive development among school age children born to women with epilepsy.

PubMed

Güveli, Betül T; Gürses, Candan; Ataklı, Dilek; Akça Kalem, Şükriye; Dirican, Ahmet; Bebek, Nerses; Baykan, Betül; Gökyiğit, Aysen

2015-04-01

Greater risks of congenital malformation as well as cognitive and behavioral development in later childhood occur as a result of in utero exposure to antiepileptic drugs (AEDs). We examined the effects of AEDs on behavioral characteristics and cognitive development among school age children born to women with epilepsy. Children aged 6-15 years and born to women with epilepsy were enrolled in the study. Information was collected on the women's demographics and the details of their usage/non-usage of AEDs during pregnancy. The Wechsler Intelligence Scale for the Children-Revised (WICS-R) test was administered to the children. The Alexander IQ test and the Conner Parent Rating Scale (CPRS) were administered to the mothers. Comparisons were made between children who had been exposed and not exposed to AEDs in utero and if exposed, according to exposure to AED monotherapy or polytherapy. The mother's education level and IQ score and data from the same parent's siblings were evaluated with respect to consanguinity. Forty-one children born to 28 women with epilepsy were enrolled. Seven mothers had multiple pregnancies. Twenty-three pregnancies (56%) were exposed to monotherapy and five (12·1%) to polytherapy. The remaining 13 (31·7%) were not exposed to AEDs. Maternal education level was a significant major factor in child IQ development (P < 0·05). The performance IQ-coding scale results were lower in children exposed to polytherapy than in children exposed to monotherapy in utero (P < 0·05). Although it is difficult to assert with confidence, the sibling assessment indicated a negative effect of valproate on IQ. It is important that the AED dosage be reduced to a minimum to maintain seizure control for healthy cognitive and behavioral development of a child.

Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

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

Ovacik, Meric A.; Sen, Banalata; Euling, Susan Y.

Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significancemore » analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data.« less

In utero exposure to valproic acid changes sleep in juvenile rats: a model for sleep disturbances in autism.

PubMed

Cusmano, Danielle M; Mong, Jessica A

2014-09-01

To determine whether sleep disturbances are found in the valproic acid model of autism spectrum disorders (ASD). Comparative study for sleep behavior, sleep architecture, electroencephalogram (EEG) spectral analysis, and glutamic acid decarboxylase (GAD) 65/67 protein expression in juvenile rats exposed to valproic acid (VPA), sodium salt, or saline in utero. N/A. Juvenile (postnatal day 32) male and female Sprague-Dawley rats. In utero exposure to either saline or 400 mg/kg VPA administered intraperitoneally to the dams on gestational day 12.5. On postnatal days 22-24, all rats were implanted with transmitters to record EEG and electromyogram (EMG) activity. During the light phase, when nocturnal animals are typically quiescent, the VPA-exposed animals spent significantly more time in wake (∼35 min) and significantly less time in non-rapid eye movement (NREM) sleep (∼26 min) compared to the saline controls. Furthermore, spectral analysis of the EEG revelled that VPA-exposed animals exhibited increased high-frequency activity during wake and rapid eye movement (REM) sleep and reduced theta power across all vigilance states. Interestingly, the gamma-aminobutyric acid (GABA)-ergic system, which modulates the induction and maintenance of sleep states, was also disrupted, with reduced levels of both GAD 65 and GAD67 in the cortical tissue of VPA-exposed animals compared to saline controls. To date, the current animal models of ASD have been underutilized in the investigation of associated sleep disturbances. The VPA animal model recapitulates aspects of sleep disruptions reported clinically, providing a tool to investigate cellular and molecular dysregulation contributing to sleep disruptions in ASD. © 2014 Associated Professional Sleep Societies, LLC.

Influenza and its treatment during pregnancy: A review.

PubMed

Ghulmiyyah, L M; Alame, M M; Mirza, F G; Zaraket, H; Nassar, A H

2015-01-01

The influenza viral infection has dramatic effects during pregnancy on the mother and the fetus. We present a review article on the prevention and treatment recommendations of influenza infection in pregnant women, and the effects of antiviral medications on maternal-fetal outcomes. This viral infection not only leads to miscarriages, preterm deliveries and a high maternal mortality rate, but it also poses negative risks to the fetus including small-for-gestational age infants, and admissions to neonatal intensive care units. Vaccination is the most effective strategy for preventing influenza infection during pregnancy whereby can protect both maternal and fetal immunities. The safety profiles of antiviral drugs during pregnancy are limited. Available risk-benefit evidence has indicated that pregnant women with suspected or confirmed influenza should receive prompt antiviral therapy where these medications reduce the risk of complications among pregnant women, and attenuate the teratogenic effects of the influenza infection. Post-exposure prophylaxis is not recommended for most pregnant women, but it may be prescribed in pandemic settings, particularly to non-vaccinated women. Although some ex vivo models for pharmacokinetic studies have revealed that the transplacental transfer of oseltamivir to fetal circuits may occur, there is no evidence of adverse fetal outcomes as a result of most in utero exposures to neuraminidase inhibitors. Due to the large number of confounding variables, large, population-based studies are needed to assess the association between in utero oseltamivir exposure and fetal outcome.

In Utero Estrogen Exposure Increases Antiestrogen Resistance by Inducing EMT

DTIC Science & Technology

2015-02-01

a modified AIN93G control diet (soybean replaced with corn oil), that contained either 0 (control, C; n=12) or 0.1 ppm EE2 (n=12) between gestation...Today: Disease Mechanisms, 9 (1-2); e11-17. Aiyer HS, Bouker KB, Cook KL, Facey COB , Hu R, Schwartz JL, Shajahan AN, Hilakivi- Clarke L, Clarke R

Approaches for Strengthening Causal Inference Regarding Prenatal Risk Factors for Childhood Behavioural and Psychiatric Disorders

ERIC Educational Resources Information Center

Lewis, Sarah J.; Relton, Caroline; Zammit, Stanley; Smith, George Davey

2013-01-01

Background: The risk of childhood behavioural and psychiatric diseases could be substantially reduced if modifiable risk factors for these disorders were identified. The critical period for many of these exposures is likely to be in utero as this is the time when brain development is most rapid. However, due to confounding and other limitations of…

THE FREQUENCY OF T(14;18) IN BLOOD LYMPHOCYTES IS STABLE OVER A 2 YEAR PERIOD IN ADULTS

EPA Science Inventory

The Frequency of t(14;18) in Blood Lymphocytes Is Stable over a 2 Year Period in Adults

As part of a multi-endpoint molecular epidemiology study on in utero environmental exposures, umbilical cord and adult blood lymphocytes were examined for the frequency of t(14;18) by ...

Effects of In Utero Exposure to Di-n-Butyl Phthalate on Testicular Development in Rat

PubMed Central

Ma, Tan; Yin, Xiaoqin; Han, Ruitong; Ding, Jie; Zhang, Huan; Han, Xiaodong

2017-01-01

Humans are inevitably exposed to ubiquitous phthalate esters (PAEs). In utero exposure to di-n-butyl phthalate (DBP) induces abnormal development of the testis and reproductive tract in male offspring, which correspond closely with the human condition of testicular dysgenesis syndrome (TDS)-like syndrome. However, the underlying mechanisms have not been elucidated in detail. In this study, pregnant rats were orally exposed to either corn oil (controls) or DBP at three different doses by gavage during Gestational Days 12.5–21.5. Pathological examinations were performed for toxicity evaluation. Proliferation and apoptosis related proteins (ras related dexamethasone induced 1 (Rasd1), mitogen-activated protein kinase kinases1/2 (MEK1/2), Bcl-2, and Bax) were measured for mechanisms exploration. The results showed that different doses of DBP caused male developmental and reproductive toxicity in rats, including the decrease of anogenital distance (AGD), the histological damage of testis, and apoptosis of seminiferous tubule cells. Our data suggested that DBP played chronic and continuous toxic roles on male reproductive system by disrupting expression of Rasd1 and MEK1/2 as well as Bcl-2/Bax ratio. Further research is warranted. PMID:29064414

Morphological abnormalities of embryonic cranial nerves after in utero exposure to valproic acid: implications for the pathogenesis of autism with multiple developmental anomalies.

PubMed

Tashiro, Yasura; Oyabu, Akiko; Imura, Yoshio; Uchida, Atsuko; Narita, Naoko; Narita, Masaaki

2011-06-01

Autism is often associated with multiple developmental anomalies including asymmetric facial palsy. In order to establish the etiology of autism with facial palsy, research into developmental abnormalities of the peripheral facial nerves is necessary. In the present study, to investigate the development of peripheral cranial nerves for use in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero and their cranial nerves were visualized by immunostaining. Treatment with VPA after embryonic day 9 had a significant effect on the peripheral fibers of several cranial nerves. Following VPA treatment, immunoreactivity within the trigeminal, facial, glossopharyngeal and vagus nerves was significantly reduced. Additionally, abnormal axonal pathways were observed in the peripheral facial nerves. Thus, the morphology of several cranial nerves, including the facial nerve, can be affected by prenatal VPA exposure as early as E13. Our findings indicate that disruption of early facial nerve development is involved in the etiology of asymmetric facial palsy, and may suggest a link to the etiology of autism. Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

In Utero Exposure to Di( n-butyl)phthalate Induces Morphological and Biochemical Changes in Rats Postpuberty.

PubMed

Okayama, Yuya; Wakui, Shin; Wempe, Michael F; Sugiyama, Mitsuru; Motohashi, Masaya; Mutou, Tomoko; Takahashi, Hiroyuki; Kume, Eisuke; Ikegami, Hiroshi

2017-06-01

Pregnant Sprague-Dawley rats were orally administered di( n-butyl)phthalate (DBP; 100 mg/kg/day) on gestation days (GD) 12 to 21. We investigated the male offspring and probed morphological alterations in Sertoli cells at 7, 9, 14, and 17 weeks of age. Parameters assessed in this study included offspring number, sex ratios, body weights, testis weights, seminiferous tubule (ST) profile numbers and diameters, number of vimentin-labeled Sertoli cells, and both testosterone and follicle-stimulating hormone (FSH) levels. Testicular weight/body weight ratios and the numbers and diameters of ST in maximum transverse testicular sections were statistically similar at weeks 7 and 9; however, at weeks 14 and 17, they were statistically different and displayed higher BrdU-positive Sertoli cells/Sertoli cell ratios in the DBP treatment group. Noteworthily, the serum FSH levels were higher and testicular testosterone levels were lower in the DBP treatment group. To our knowledge, the present study is the first to report that in utero DBP exposure significantly increased Sertoli cell numbers and their cellular proliferation from postpuberty to adulthood, with a significant decrease in testicular testosterone and an increase in FSH.

Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation

PubMed Central

Cropley, Jennifer E.; Suter, Catherine M.; Beckman, Kenneth B.; Martin, David I. K.

2006-01-01

Environmental effects on phenotype can be mediated by epigenetic modifications. The epigenetic state of the murine Avy allele is highly variable, and determines phenotypic effects that vary in a mosaic spectrum that can be shifted by in utero exposure to methyl donor supplementation. We have asked if methyl donor supplementation affects the germ-line epigenetic state of the Avy allele. We find that the somatic epigenetic state of Avy is affected by in utero methyl donor supplementation only when the allele is paternally contributed. Exposure to methyl donor supplementation during midgestation shifts Avy phenotypes not only in the mice exposed as fetuses, but in their offspring. This finding indicates that methyl donors can change the epigenetic state of the Avy allele in the germ line, and that the altered state is retained through the epigenetic resetting that takes place in gametogenesis and embryogenesis. Thus a mother's diet may have an enduring influence on succeeding generations, independent of later changes in diet. Although other reports have suggested such heritable epigenetic changes, this study demonstrates that a specific mammalian gene can be subjected to germ-line epigenetic change. PMID:17101998

Germ-line epigenetic modification of the murine A vy allele by nutritional supplementation.

PubMed

Cropley, Jennifer E; Suter, Catherine M; Beckman, Kenneth B; Martin, David I K

2006-11-14

Environmental effects on phenotype can be mediated by epigenetic modifications. The epigenetic state of the murine A vy allele is highly variable, and determines phenotypic effects that vary in a mosaic spectrum that can be shifted by in utero exposure to methyl donor supplementation. We have asked if methyl donor supplementation affects the germ-line epigenetic state of the A vy allele. We find that the somatic epigenetic state of A vy is affected by in utero methyl donor supplementation only when the allele is paternally contributed. Exposure to methyl donor supplementation during midgestation shifts A vy phenotypes not only in the mice exposed as fetuses, but in their offspring. This finding indicates that methyl donors can change the epigenetic state of the A vy allele in the germ line, and that the altered state is retained through the epigenetic resetting that takes place in gametogenesis and embryogenesis. Thus a mother's diet may have an enduring influence on succeeding generations, independent of later changes in diet. Although other reports have suggested such heritable epigenetic changes, this study demonstrates that a specific mammalian gene can be subjected to germ-line epigenetic change.

Effects of maternal diet and environmental exposure to organochlorine pesticides on newborn weight in Southern Spain.

PubMed

Monteagudo, C; Mariscal-Arcas, M; Heras-Gonzalez, L; Ibañez-Peinado, D; Rivas, A; Olea-Serrano, F

2016-08-01

An appropriate eating pattern is essential during childbearing years and pregnancy to ensure a healthy pregnancy and newborn. Our group developed a Mediterranean Diet Score for Pregnancy (MDS-P) based on the MD and the specific need of pregnant women for Fe, Ca, and folic acid. Humans are daily exposed to endocrine disruptors, which may alter body weight and hormone system regulation. This study analyzed the relationship of maternal diet and in utero exposure to organochlorine pesticides (OCPs) with newborn weight in mothers and newborns from Southern Spain. Higher MDS-P score, folic acid supplementation, and greater in utero exposure to endosulfan-diol and endosulfan-1 were related to higher newborn weight. MDS-P score was not associated with maternal weight gain during pregnancy (above or below 12 Kg). Residues from one or more OCPs were detected in 96.5% of umbilical cord serum samples from 320 newborns. The most frequent residues were endosulfans (96.5%). The presence of endosulfan-diol, endosulfan-I, p-p´DDT, folic acid supplementation, and a higher MDS-P (>8) were predictive factors for newborn overweight (>3500 g). Conversely, smoking during pregnancy, shorter gestation time (32-36 vs. 37-39 weeks), and lesser maternal weight gain during pregnancy predicted lower newborn weight (<2500 g). These results indicate prenatal exposure to OCPs in Southern Spain and its possible impact on the weight of healthy full-term newborns. Further studies are warranted to interpret the consequences of this exposure and identify preventive measures. Adherence to the MD and folic acid supplementation during pregnancy emerged as predictive factors for overweight in newborns. Copyright © 2016 Elsevier Ltd. All rights reserved.

Induction and persistence of abnormal testicular germ cells following gestational exposure to di-(n-butyl) phthalate in p53-null mice.

PubMed

Saffarini, Camelia M; Heger, Nicholas E; Yamasaki, Hideki; Liu, Tao; Hall, Susan J; Boekelheide, Kim

2012-01-01

Phthalate esters are commonly used plasticizers found in many household items, personal care products, and medical devices. Animal studies have shown that in utero exposure to di-(n-butyl) phthalate (DBP) within a critical window during gestation causes male reproductive tract abnormalities resembling testicular dysgenesis syndrome. Our studies utilized p53-deficient mice for their ability to display greater resistance to apoptosis during development. This model was chosen to determine whether multinucleated germ cells (MNG) induced by gestational DBP exposure could survive postnatally and evolve into testicular germ cell cancer. Pregnant dams were exposed to DBP (500 mg/kg/day) by oral gavage from gestational day 12 until birth. Perinatal effects were assessed on gestational day 19 and postnatal days 1, 4, 7, and 10 for the number of MNGs present in control and DBP-treated p53-heterozygous and null animals. As expected, DBP exposure induced MNGs, with greater numbers found in p53-null mice. Additionally, there was a time-dependent decrease in the incidence of MNGs during the early postnatal period. Histologic examination of adult mice exposed in utero to DBP revealed persistence of abnormal germ cells only in DBP-treated p53-null mice, not in p53-heterozygous or wild-type mice. Immunohistochemical staining of perinatal MNGs and adult abnormal germ cells was negative for both octamer-binding protein 3/4 and placental alkaline phosphatase. This unique model identified a role for p53 in the perinatal apoptosis of DBP-induced MNGs and provided insight into the long-term effects of gestational DBP exposure within a p53-null environment.

Circulatory Responses to Asphyxia Differ if the Asphyxia Occurs In Utero or Ex Utero in Near-Term Lambs

PubMed Central

Sobotka, Kristina S.; Morley, Colin; Ong, Tracey; Polglase, Graeme R.; Aridas, James D. S.; Miller, Suzanne L.; Schmölzer, Georg M.; Klingenberg, Claus; Moss, Timothy J. M.; Jenkin, Graham; Hooper, Stuart B.

2014-01-01

Background A cornerstone of neonatal resuscitation teaching suggests that a rapid vagal-mediated bradycardia is one of the first signs of perinatal compromise. As this understanding is based primarily on fetal studies, we investigated whether the heart rate and blood pressure response to total asphyxia is influenced by whether the animal is in utero or ex utero. Methods Fetal sheep were instrumented at ∼139 days of gestation and then asphyxiated by umbilical cord occlusion until mean arterial blood pressure decreased to ∼20 mmHg. Lambs were either completely submerged in amniotic fluid (in utero; n = 8) throughout the asphyxia or were delivered and then remained ex utero (ex utero; n = 8) throughout the asphyxia. Heart rate and arterial blood pressure were continuously recorded. Results Heart rate was higher in ex utero lambs than in utero lambs. Heart rates in in utero lambs rapidly decreased, while heart rates in ex utero lambs initially increased following cord occlusion (for ∼1.5 min) before they started to decrease. Mean arterial pressure initially increased then decreased in both groups. Conclusions Heart rate response to asphyxia was markedly different depending upon whether the lamb was in utero or ex utero. This indicates that the cardiovascular responses to perinatal asphyxia are significantly influenced by the newborn's local environment. As such, based solely on heart rate, the stage and severity of a perinatal asphyxic event may not be as accurate as previously assumed. PMID:25393411

Circulatory responses to asphyxia differ if the asphyxia occurs in utero or ex utero in near-term lambs.

PubMed

Sobotka, Kristina S; Morley, Colin; Ong, Tracey; Polglase, Graeme R; Aridas, James D S; Miller, Suzanne L; Schmölzer, Georg M; Klingenberg, Claus; Moss, Timothy J M; Jenkin, Graham; Hooper, Stuart B

2014-01-01

A cornerstone of neonatal resuscitation teaching suggests that a rapid vagal-mediated bradycardia is one of the first signs of perinatal compromise. As this understanding is based primarily on fetal studies, we investigated whether the heart rate and blood pressure response to total asphyxia is influenced by whether the animal is in utero or ex utero. Fetal sheep were instrumented at ∼ 139 days of gestation and then asphyxiated by umbilical cord occlusion until mean arterial blood pressure decreased to ∼ 20 mmHg. Lambs were either completely submerged in amniotic fluid (in utero; n = 8) throughout the asphyxia or were delivered and then remained ex utero (ex utero; n = 8) throughout the asphyxia. Heart rate and arterial blood pressure were continuously recorded. Heart rate was higher in ex utero lambs than in utero lambs. Heart rates in in utero lambs rapidly decreased, while heart rates in ex utero lambs initially increased following cord occlusion (for ∼ 1.5 min) before they started to decrease. Mean arterial pressure initially increased then decreased in both groups. Heart rate response to asphyxia was markedly different depending upon whether the lamb was in utero or ex utero. This indicates that the cardiovascular responses to perinatal asphyxia are significantly influenced by the newborn's local environment. As such, based solely on heart rate, the stage and severity of a perinatal asphyxic event may not be as accurate as previously assumed.

Hemoglobin Adducts of Benzene Oxide in Neonatal and Adult Dried Blood Spots

PubMed Central

Funk, William E.; Waidyanatha, Suramya; Chaing, Shu H.; Rappaport, Stephen M.

2010-01-01

Adducts of reactive chemicals with hemoglobin (Hb) or human serum albumin can be used as biomarkers of internal doses of carcinogens. Since dried blood spots (DBS) are easier to collect and store than conventional venous blood samples, they encourage applications of biomarkers of exposure in large epidemiology studies. Also, neonatal DBS can be used to investigate chemical exposures in utero. Here, we report a simple method to isolate Hb from DBS with high recovery and purity using the addition of ethanol to aqueous DBS extracts. To prove the concept that DBS-derived proteins can be used to assay for adducts, we measured Hb adducts of benzene oxide, a reactive metabolite of the ubiquitous air pollutant, benzene, in 9 neonatal and 9 adult DBS (from volunteer subjects), using a gas chromatography-mass spectrometry method that we had previously developed. For comparison, benzene oxide-Hb adducts (BO-Hb) were measured in the same 9 adult subjects, using Hb that had been isolated and purified using our conventional method for venous blood. The geometric mean BO-Hb levels in all DBS samples ranged from 27.7 to 33.1 pmol/g globin. Neither of the comparisons of mean (logged) BO-Hb levels between sources (adult conventional vs. adult DBS and adult DBS vs. newborn DBS) showed a significant difference. Based upon the estimated variance of the BO-Hb levels, we had 80% power to detect a 1.7-fold difference in geometric mean levels of BO-Hb in our samples of 9 subjects. PMID:18708378

Effect of fetal alcohol exposure on adult symptoms of nicotine, alcohol, and drug dependence.

PubMed

Yates, W R; Cadoret, R J; Troughton, E P; Stewart, M; Giunta, T S

1998-06-01

The objective of this study is to examine the effect of fetal alcohol exposure on later substance dependence using an adoption study method. One hundred ninety-seven adoptees were interviewed for substance abuse disorders, including nicotine, alcohol, and drug dependence. Twenty-one adoptees had mothers who drank during pregnancy. Adoptees with fetal alcohol exposure were compared with those without fetal alcohol exposure for symptoms of adult nicotine, alcohol, and drug dependence. Adoptee symptom counts for alcohol, drug, and nicotine dependence were higher for those exposed to alcohol in utero. The effect of fetal alcohol exposure remained after controlling for gender, biological parent alcohol dependence diagnosis, birth weight, gestational age and other environmental variables. Fetal alcohol exposure may produce increased risk for later nicotine, alcohol, and drug dependence. Possible effects of fetal alcohol exposure on development of adult substance use patterns needs attention in genetic studies of substance abuse.

Effects of perinatal exposure to palatable diets on body weight and sensitivity to drugs of abuse in rats

PubMed Central

Bocarsly, Miriam E.; Barson, Jessica R.; Hauca, Jenna M.; Hoebel, Bartley G.; Leibowitz, Sarah F.; Avena, Nicole M.

2012-01-01

The aim of the present study was to determine the effects of fat- and sugar-rich diets in utero and during the pre-weaning period on bodyweight and responses to drugs of abuse. In Exp. 1, dams were fed a balanced control diet or high-fat diet (HFD), and female offspring were cross-fostered to dams consuming the balanced diet. The HFD-exposed offspring, compared to controls, were heavier in body weight, had increased circulating triglyceride levels, and consumed more alcohol and HFD in adulthood. In Exp. 2, dams were fed standard chow alone or standard chow plus a 16% high-fructose corn syrup (HFCS) or 10% sucrose solution. Sets of offspring from each group were cross-fostered to dams in the other groups, allowing for the effects of HFCS or sucrose exposure during the gestational period or pre-weaning period to be determined. The offspring (both female and male) exposed to HFCS or sucrose in utero had higher body weights in adulthood and exhibited increased alcohol intake as shown in female offspring and increased amphetamine-induced locomotor activity as shown in males. Exposure to HFCS or sucrose only during the pre-weaning period had a similar effect of increasing amphetamine-induced locomotor activity in males, but produced no change in circulating triglycerides or alcohol intake. Collectively, these data suggest that prenatal as well as pre-weaning exposure to fat- and sugar-rich diets, in addition to increasing body weight, can affect responses to drugs of abuse. PMID:22564493

Prenatal vitamin intake during pregnancy and offspring obesity

PubMed Central

Dougan, Marcelle M.; Willett, Walter C.; Michels, Karin B.

2014-01-01

Background/Objectives In animal studies, exposure to multi-vitamins may be associated with obesity in the offspring; however, data in humans is sparse. We therefore examined the association between prenatal vitamin intake during pregnancy and offspring obesity. Subjects/Methods We investigated the association between prenatal vitamin intake and obesity among 29 160 mother-daughter dyads in the Nurses’ Health Study II. Mothers of participants provided information on prenatal vitamin use during pregnancy with the nurse daughter. Information on body fatness at ages 5 and 10, body mass index (BMI) at age 18, weight in 1989 and 2009, waist circumference, and height was obtained from the daughter. Polytomous logistic regression was used to predict BMI in early adulthood and adulthood, and body fatness in childhood. Linear regression was used to predict waist circumference in adulthood. Results In utero exposure to prenatal vitamins was not associated with body fatness, either in childhood or adulthood. Women whose mothers took prenatal vitamins during pregnancy had a covariate-adjusted odds ratio of being obese in adulthood of 0.99 (95% CI 0.92 – 1.05, P-value = 0.68) compared to women whose mothers did not take prenatal vitamins. Women whose mothers took prenatal vitamins during pregnancy had a covariate-adjusted odds ratio of having the largest body shape at age 5 of 1.02 (95% CI 0.90 – 1.15, P-value = 0.78). In additional analyses, in utero exposure to prenatal vitamins was also unrelated to adult abdominal adiposity. Conclusions Exposure to prenatal vitamins was not associated with body fatness either in childhood or in adulthood. PMID:24942869

Maternal exposure to brominated flame retardants and infant Apgar Scores

PubMed Central

Terrell, Metrecia L.; Hartnett, Kathleen P.; Lim, Hyeyeun; Wirth, Julie; Marcus, Michele

2014-01-01

Brominated flame retardants (BFRs) and other persistent organic pollutants have been associated with adverse health outcomes in humans and may be particularly toxic to the developing fetus. We investigated the association between in utero polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB) exposures and infant Apgar scores in a cohort of Michigan residents exposed to PBB through contaminated food after an industrial accident. PBB and PCB concentrations were measured in serum at the time the women were enrolled in the cohort. PBB concentrations were also estimated at the time of conception for each pregnancy using a validated elimination model. Apgar scores, a universal measure of infant health at birth, measured at 1 and 5 minutes, were taken from birth certificates for 613 offspring born to 330 women. Maternal PCB concentrations at enrollment were not associated with below–median Apgar scores in this cohort. However, maternal PBB exposure was associated with a dose–related increase in the odds of a below–median Apgar score at 1 minute and 5 minutes. Among infants whose mothers had an estimated PBB at conception above the limit of detection of 1 part per billion, the odds ratio was 2.32 (95 % CI: 1.22– 4.40); for those with PBB ≥ 2.5 ppb the OR=2.62 (95% CI: 1.38-4.96; test for trend p< 0.01). Likewise, the odds of a below–median 5–minute Apgar increased with higher maternal PBB at conception. It remains critical that future studies examine possible relationships between in utero exposures to brominated compounds and adverse health outcomes. PMID:25203650

Subtle Decreases in DNA Methylation and Gene Expression at the Mouse Igf2 Locus Following Prenatal Alcohol Exposure: Effects of a Methyl-Supplemented Diet

PubMed Central

Downing, Chris; Johnson, Thomas E; Larson, Colin; Leakey, Tatiana I; Siegfried, Rachel N; Rafferty, Tonya M; Cooney, Craig A

2010-01-01

C57BL/6J (B6) mice are susceptible to in utero growth retardation and a number of morphological malformations following prenatal alcohol exposure, while DBA/2J (D2) mice are relatively resistant. We have previously shown that genomic imprinting may play a role in differential sensitivity between B6 and D2 (Downing and Gilliam 1999). The best characterized mechanism mediating genomic imprinting is differential DNA methylation. In the present study we examined DNA methylation and gene expression, in both embryonic and placental tissue, at the mouse Igf2 locus following in utero ethanol exposure. We also examined the effects of a methyl-supplemented diet on methylation and ethanol teratogenesis. In embryos from susceptible B6 mice, we found small decreases in DNA methylation at four CpG sites in one of the differentially methylated regions of the Igf2 locus; only one of the four sites showed a statistically significant decrease. We observed no significant decreases in methylation in placentae. All Igf2 transcripts showed approximately 1.5 fold decreases following intrauterine alcohol exposure. Placing dams on a methyl-supplemented diet before pregnancy and throughout gestation brought methylation back up to control levels. Methyl-supplementation also resulted in lower prenatal mortality, greater prenatal growth, and decreased digit malformations; it dramatically reduced vertebral malformations. Thus, while prenatal alcohol had only small effects on DNA methylation at the Igf2 locus, placing dams on a methyl-supplemented diet partially ameliorated ethanol teratogenesis. PMID:20705422

Prenatal stress-induced increases in hippocampal von Willebrand factor expression are prevented by concurrent prenatal escitalopram

PubMed Central

Neigh, Gretchen N.; Nemeth, Christina L; Kelly, Sean D.; Hardy, Emily E.; Bourke, Chase; Stowe, Zachary N.; Owens, Michael J.

2016-01-01

Prenatal stress has been linked to deficits in neurological function including deficient social behavior, alterations in learning and memory, impaired stress regulation, and susceptibility to adult disease. In addition, prenatal environment is known to alter cardiovascular health; however, limited information is available regarding the cerebrovascular consequences of prenatal stress exposure. Vascular disturbances late in life may lead to cerebral hypoperfusion which is linked to a variety of neurodegenerative and psychiatric diseases. The known impact of cerebrovascular compromise on neuronal function and behavior highlights the importance of characterizing the impact of stress on not just neurons and glia, but also cerebrovasculature. Von Willebrand factor has previously been shown to be impacted by prenatal stress and is predictive of cerebrovascular health. Here we assess the impact of prenatal stress on von Willebrand factor and related angiogenic factors. Furthermore, we assess the potential protective effects of concurrent anti-depressant treatment during in utero stress exposure on the assessed cerebrovascular endpoints. Prenatal stress augmented expression of von Willebrand factor which was prevented by concurrent in utero escitalopram treatment. The functional implications of this increase in von Willebrand factor remain elusive, but the presented data demonstrate that although prenatal stress did not independently impact total vascularization, exposure to chronic stress in adulthood decreased blood vessel length. In addition, the current study demonstrates that production of reactive oxygen species in the hippocampus is decreased by prenatal exposure to escitalopram. Collectively, these findings demonstrate that the prenatal experience can cause complex changes in adult cerebral vascular structure and function. PMID:27422674

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

PubMed Central

Olivas-Calderón, Edgar; Recio-Vega, Rogelio; Gandolfi, A. Jay; Lantz, R. Clark; González-Cortes, Tania; Alba, Cesar Gonzalez-De; Froines, John R.; Espinosa-Fematt, Jorge A.

2016-01-01

Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero is associated with an increase in respiratory symptoms and diseases in adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that exposure to arsenic during early childhood or in utero was associated with impairment in the lung function in children and suggested that this adverse effect could be due to a chronic inflammatory response to the metalloid. Therefore, a cross-sectional study was designed in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their As levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the Soluble Receptor for Advanced Glycation Endproducts (sRAGE) sputum level was significantly lower and Matrix Metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsenic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/Tissue Inhibitor of Metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. PMID:26048584

Home-based detoxification for neonatal abstinence syndrome reduces length of hospital admission without prolonging treatment.

PubMed

Smirk, Cameron L; Bowman, Ellen; Doyle, Lex W; Kamlin, Omar

2014-06-01

Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome, secondary to in utero chemical exposure and characterised by tremor, irritability and feed intolerance. It often requires prolonged hospital treatment and separation of families. Outpatient therapy may reduce this burden, but current literature is sparse. This review aimed to evaluate the safety and efficacy of our home-based detoxification programme and compare it with standard inpatient care. Infants requiring treatment for NAS between January 2004 and December 2010 were reviewed. Data on demographics, drug exposure, length of stay and type of therapy were compared between infants selected for home-based therapy and those treated conventionally. Of the 118 infants who were admitted for treatment of NAS, 38 (32%) were managed at home. Infants receiving home-based detoxification had shorter hospital stays (mean 19 days vs. 39 days), with no increase in total duration of treatment (mean 36 days vs. 41 days), and were more likely to be breastfeeding on discharge from hospital care (45% vs. 22%). In selected infants, home-based detoxification is associated with reduced hospital stays and increased rates of breastfeeding, without prolonging therapy. Safety of the infants remains paramount, which precludes many from entering such a programme. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Effects of in utero tributyltin chloride exposure in the rat on pregnancy outcome.

PubMed

Adeeko, Adedayo; Li, Daming; Forsyth, Don S; Casey, Valerie; Cooke, Gerard M; Barthelemy, Johanna; Cyr, Daniel G; Trasler, Jacquetta M; Robaire, Bernard; Hales, Barbara F

2003-08-01

Tributyltin, an organotin, is ubiquitous in the environment. The consumption of contaminated marine species leads to human dietary exposure to this compound. Tributyltin is an endocrine disruptor in many wildlife species and inhibits aromatase in mammalian placental and granulosa-like tumor cell lines. We investigated the effects of tributyltin chloride exposure on pregnancy outcome in the Sprague-Dawley rat. Timed pregnant rats were gavaged either with vehicle (olive oil) or tributyltin chloride (0.25, 2.5, 10, or 20 mg/kg) from days 0-19 or 8-19 of gestation. On gestational day 20, dams were sacrificed, and pregnancy outcome was determined. Tributyltin and its metabolites (dibutyltin, monobutyltin) were measured in maternal blood by gas chromatography. Both tributyltin and dibutyltin were present in maternal blood at approximately equal concentrations, whereas monobutyltin contributed minimally to total organotins. Organotin concentrations increased in a dose-dependent pattern in dams, independent of the window of exposure. Tributyltin chloride administration significantly reduced maternal weight gain only at the highest dose (20 mg/kg); a significant increase in post-implantation loss and decreased litter sizes, in addition to decreased fetal weights, was observed in this group. Tributyltin chloride exposure did not result in external malformations, nor was there a change in sex ratios. However, exposure to 0.25, 2.5, or 10 mg/kg tributyltin chloride from gestation days (GD) 0-19 resulted in a significant increase in normalized anogenital distances in male fetuses; exposure from days 8-19 had no effect. There was a dramatic increase in the incidence of low weight (< or =0.75 of the mean) fetuses after exposure to 20 mg/kg tributyltin chloride. Delayed ossification of the fetal skeleton was observed after in utero exposure to either 10 mg/kg or 20 mg/kg tributyltin chloride. Serum thyroxine and triiodothyronine levels were reduced significantly in dams exposed to 10 and 20 mg/kg tributyltin chloride throughout gestation; in dams treated with tributyltin from GD 8-19, serum thyroxine concentrations, but not triiodothyronine, were significantly decreased at both the 2.5 and 10 mg/kg exposures. Thus, maternal thyroid hormone homeostasis may be important in mediating the developmental toxicity of organotins.

Perfluoroalkyl acids (PFAAs) and anthropometric measures in the first year of life: Results from the Duisburg Birth Cohort.

PubMed

Alkhalawi, Eman; Kasper-Sonnenberg, Monika; Wilhelm, Michael; Völkel, Wolfgang; Wittsiepe, Jürgen

2016-01-01

In the context of the Duisburg Birth Cohort, this retrospective cohort study provides results of internal exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in 156 mother-child pairs, and investigates whether and to what extent in utero exposure of these chemicals at German background levels exerts an effect on newborn and infant weight and length, and weight in relation to length expressed by ponderal index, in order to examine whether any reduction in weight is disproportionate to length. The levels of PFOA, PFOS, and PFHxS were determined in 81 maternal and 83 umbilical cord stored frozen plasma samples and 105 umbilical cord blood samples. Calculated factors were used to convert umbilical cord values to maternal levels. Weights and lengths were retrieved at birth and at 1, 4, 6, and 12 mo from examination booklets and ponderal index (kg/m 3 ) was calculated. Subsequently, correlations were assessed using multiple linear regressions and generalized estimation equations with each of the measures as a continuous outcome variable and with PFOA, PFOS, and PFHxS concentration quartiles as categorized predictor variables, while adjusting for relevant covariates. PFOA, PFOS, and PFHxS were generally within German background exposure levels. There was a significant association between PFOA, PFOS, and PFHxS concentration quartiles and decrease in ponderal index at birth but not weight or height. A nonsignificant negative association between exposure to all three compounds and birth weight was noted. Follow-up showed no sustained effect of the PFAA on anthropometric measures during the first year.

Prenatal phthalate exposure and 8-isoprostane among Mexican-American children with high prevalence of obesity.

PubMed

Tran, V; Tindula, G; Huen, K; Bradman, A; Harley, K; Kogut, K; Calafat, A M; Nguyen, B; Parra, K; Ye, X; Eskenazi, B; Holland, N

2017-04-01

Oxidative stress has been linked to many obesity-related conditions among children including cardiovascular disease, diabetes mellitus and hypertension. Exposure to environmental chemicals such as phthalates, ubiquitously found in humans, may also generate reactive oxygen species and subsequent oxidative stress. We examined longitudinal changes of 8-isoprostane urinary concentrations, a validated biomarker of oxidative stress, and associations with maternal prenatal urinary concentrations of phthalate metabolites for 258 children at 5, 9 and 14 years of age participating in a birth cohort residing in an agricultural area in California. Phthalates are endocrine disruptors, and in utero exposure has been also linked to altered lipid metabolism, as well as adverse birth and neurodevelopmental outcomes. We found that median creatinine-corrected 8-isoprostane concentrations remained constant across all age groups and did not differ by sex. Total cholesterol, systolic and diastolic blood pressure were positively associated with 8-isoprostane in 14-year-old children. No associations were observed between 8-isoprostane and body mass index (BMI), BMI Z-score or waist circumference at any age. Concentrations of three metabolites of high molecular weight phthalates measured at 13 weeks of gestation (monobenzyl, monocarboxyoctyl and monocarboxynonyl phthalates) were negatively associated with 8-isoprostane concentrations among 9-year olds. However, at 14 years of age, isoprostane concentrations were positively associated with two other metabolites (mono(2-ethylhexyl) and mono(2-ethyl-5-carboxypentyl) phthalates) measured in early pregnancy. Longitudinal data on 8-isoprostane in this pediatric population with a high prevalence of obesity provides new insight on certain potential cardiometabolic risks of prenatal exposure to phthalates.

Prenatal Phthalate Exposure and 8-Isoprostane among Mexican-American Children with High Prevalence of Obesity

PubMed Central

Tran, Vy; Tindula, Gwen; Huen, Karen; Bradman, Asa; Harley, Kim; Kogut, Katherine; Calafat, Antonia M.; Nguyen, Brian; Parra, Kimberly; Ye, Xiaoyun; Eskenazi, Brenda; Holland, Nina

2016-01-01

Oxidative stress has been linked to many obesity-related conditions among children including cardiovascular disease, diabetes mellitus and hypertension. Exposure to environmental chemicals such as phthalates, ubiquitously found in humans, may also generate reactive oxygen species (ROS) and subsequent oxidative stress. We examined longitudinal changes of 8-isoprostane urinary concentrations, a validated biomarker of oxidative stress, and associations with maternal prenatal urinary concentrations of phthalate metabolites for 258 children at 5-, 9- and 14-years of age participating in a birth cohort residing in an agricultural area in California. Phthalates are endocrine disruptors, and in utero exposure has been also linked to altered lipid metabolism, as well as adverse birth and neurodevelopmental outcomes. We found that median creatinine-corrected 8-isoprostane concentrations remained constant across all age groups and did not differ by sex. Total cholesterol, systolic and diastolic blood pressure were positively associated with 8-isoprostane in 14-year old children. No associations were observed between 8-isoprostane and BMI, BMI Z-score or waist circumference at any age. Concentrations of three metabolites of high molecular weight phthalates measured at 13 weeks gestation [monobenzyl, monocarboxyoctyl and monocarboxynonyl phthalates] were negatively associated with 8-isoprostane concentrations among 9 year olds. However, at 14 years of age, isoprostane concentrations were positively associated with two other metabolites (mono(2-ethylhexyl) and mono(2-ethyl-5-carboxypentyl) phthalates) measured in early pregnancy. Longitudinal data on 8-isoprostane in this pediatric population with a high prevalence of obesity provides new insight on certain potential cardiometabolic risks of prenatal exposure to phthalates. PMID:28031075

Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: an experimental study in mice

PubMed Central

Buckley, Jill; Willingham, Emily; Agras, Koray; Baskin, Laurence S

2006-01-01

Background Vinclozolin is a fungicide that has been reported to have anti-androgenic effects in rats. We have found that in utero exposure to natural or synthetic progesterones can induce hypospadias in mice, and that the synthetic progesterone medroxyprogesterone acetate (MPA) feminizes male and virilizes female genital tubercles. In the current work, we selected a relatively low dose of vinclozolin to examine its in utero effects on the development of the genital tubercle, both at the morphological and molecular levels. Methods We gave pregnant dams vinclozolin by oral gavage from gestational days 13 through 17. We assessed the fetal genital tubercles from exposed fetuses at E19 to determine location of the urethral opening. After determination of gonadal sex, either genital tubercles were harvested for mRNA quantitation, or urethras were injected with a plastic resin for casting. We analyzed quantified mRNA levels between treated and untreated animals for mRNA levels of estrogen receptors α and β, progesterone receptor, and androgen receptor using nonparametric tests or ANOVA. To determine effects on urethral length (males have long urethras compared to females), we measured the lengths of the casts and performed ANOVA analysis on these data. Results Our morphological results indicated that vinclozolin has morphological effects similar to those of MPA, feminizing males (hypospadias) and masculinizing females (longer urethras). Because these results reflected our MPA results, we investigated the effects of in utero vinclozolin exposure on the mRNA expression levels of androgen, estrogen α and β, and progesterone receptors. At the molecular level, vinclozolin down-regulated estrogen receptor α mRNA in females and up-regulated progesterone receptor mRNA. Vinclozolin-exposed males exhibited up-regulated estrogen receptor α and progesterone receptor mRNA, effects we have also seen with exposure to the synthetic estrogen, ethinyl estradiol. Conclusion The results suggest that vinclozolin virilizes females and directly or indirectly affects progesterone receptor expression. It also affects estrogen receptor expression in a sex-based manner. We found no in vivo effect of vinclozolin on androgen receptor expression. We propose that vinclozolin, which has been designated an anti-androgen, may also exert its effects by involving additional steroid-signaling pathways. PMID:16504050