Thyroid Hormone Disruption Effects Lamination of the Neocortex but not the Cerebellum in a Model of Developmental Hypothyroidism and Hypothyroxinemia

EPA Science Inventory

Introduction: Research on neurodevelopmental changes resulting from thyroid hormone (TH) disruption has important basic and clinical implications. We previously demonstrated, in a rodent model, that developmental hypothyroidism or hypothyroxinemia can cause ...

Comparison of in vitro and in vivo bioassays to measure thyroid hormone disrupting activity in water extracts.

PubMed

Leusch, Frederic D L; Aneck-Hahn, Natalie H; Cavanagh, Jo-Anne E; Du Pasquier, David; Hamers, Timo; Hebert, Armelle; Neale, Peta A; Scheurer, Marco; Simmons, Steven O; Schriks, Merijn

2018-01-01

Environmental chemicals can induce thyroid disruption through a number of mechanisms including altered thyroid hormone biosynthesis and transport, as well as activation and inhibition of the thyroid receptor. In the current study six in vitro bioassays indicative of different mechanisms of thyroid disruption and one whole animal in vivo assay were applied to 9 model compounds and 4 different water samples (treated wastewater, surface water, drinking water and ultra-pure lab water; both unspiked and spiked with model compounds) to determine their ability to detect thyroid active compounds. Most assays correctly identified and quantified the model compounds as agonists or antagonists, with the reporter gene assays being the most sensitive. However, the reporter gene assays did not detect significant thyroid activity in any of the water samples, suggesting that activation or inhibition of the thyroid hormone receptor is not a relevant mode of action for thyroid endocrine disruptors in water. The thyroperoxidase (TPO) inhibition assay and transthyretin (TTR) displacement assay (FITC) detected activity in the surface water and treated wastewater samples, but more work is required to assess if this activity is a true measure of thyroid activity or matrix interference. The whole animal Xenopus Embryonic Thyroid Assay (XETA) detected some activity in the unspiked surface water and treated wastewater extracts, but not in unspiked drinking water, and appears to be a suitable assay to detect thyroid activity in environmental waters. Copyright © 2017 Elsevier Ltd. All rights reserved.

A yeast bioassay for direct measurement of thyroid hormone disrupting effects in water without sample extraction, concentration, or sterilization.

PubMed

Li, Jian; Ren, Shujuan; Han, Shaolun; Li, Na

2014-04-01

The present study introduces an improved yeast bioassay for rapid yet sensitive evaluation of thyroid hormone disruption at the level of thyroid receptor (TR) in environmental water samples. This assay does not require water sample preparation and thus requires very little hands-on time. Based on different β-galactosidase substrates, two modified bioassays, a colorimetric bioassay and a chemiluminescent bioassay, were developed. The compounds tested included the known thyroid hormone 3,3',5-triiodo-l-thyronine (T3), the specific TR antagonist amiodarone hydrochloride (AH) and phthalate esters (PAEs), which potentially disrupt thyroid hormone signaling. The EC50 values for T3 were similar to those previously obtained using a 96-well plate bioassay. TR antagonism by AH was studied in the presence of 2.5 × 10(-7)M T3, and the concentration producing 20% of the maximum effect (RIC20) for AH was 3.1 × 10(-7)M and 7.8 × 10(-9)M for the colorimetric bioassay and chemiluminescent bioassay, respectively. None of the tested PAEs induced β-galactosidase expression, but diethylhexyl phthalate, benzyl butyl phthalate and dibutyl phthalate demonstrated TR antagonism. Furthermore, water samples collected from Guanting reservoir in Beijing were evaluated. Although TR agonism was not observed, antagonism was detected in all water samples and is expressed as AH equivalents. The toxicology equivalent quantity values obtained by the chemiluminescent bioassay ranged from 21.2 ± 1.6 to 313.9 ± 28.8 μg L(-1) AH, and similar values were obtained for the colorimetric bioassay. The present study shows that the modified yeast bioassay can be used as a valuable tool for quantification of thyroid hormone disrupting effects in environmental water samples. Copyright © 2013 Elsevier Ltd. All rights reserved.

Environmental endocrine disruption: an effects assessment and analysis.

PubMed Central

Crisp, T M; Clegg, E D; Cooper, R L; Wood, W P; Anderson, D G; Baetcke, K P; Hoffmann, J L; Morrow, M S; Rodier, D J; Schaeffer, J E; Touart, L W; Zeeman, M G; Patel, Y M

1998-01-01

This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analyze the available information, and provide a reasonable assessment of the problem. Emphasis is placed on disruption of central nervous system--pituitary integration of hormonal and sexual behavioral activity, female and male reproductive system development and function, and thyroid function. In addition, the potential role of environmental endocrine disruption in the induction of breast, testicular, and prostate cancers, as well as endometriosis, is evaluated. The interrelationship of the endocrine and immune system is documented. With respect to endocrine-related ecological effects, specific case examples from the peer-reviewed literature of marine invertebrates and representatives of the five classes of vertebrates are presented and discussed. The report identifies some data gaps in our understanding of the environmental endocrine disruption issue and recommends a few research needs. Finally, the report states the U.S. Environmental Protection Agency Science Policy Council's interim position on endocrine disruption and lists some of the ongoing activities to deal with this matter. PMID:9539004

An AOP-based alternative testing strategy to predict the impact of thyroid hormone disruption on swim bladder inflation in zebrafish

EPA Science Inventory

Within the field of chemical safety assessment, there is a desire to replace costly whole organism testing with more efficient and cost-effective alternatives based on in vitro test systems. Disruption of thyroid hormone signaling via inhibition of enzymes called deiodinases is o...

In vitro assessment of thyroid hormone disrupting activities in drinking water sources along the Yangtze River.

PubMed

Hu, Xinxin; Shi, Wei; Zhang, Fengxian; Cao, Fu; Hu, Guanjiu; Hao, Yingqun; Wei, Si; Wang, Xinru; Yu, Hongxia

2013-02-01

The thyroid hormone disrupting activities of drinking water sources from the lower reaches of Yangtze River were examined using a reporter gene assay based on African green monkey kidney fibroblast (CV-1) cells. None of the eleven tested samples showed thyroid receptor (TR) agonist activity. Nine water samples exhibited TR antagonist activities with the equivalents referring to Di-n-butyl phthalate (DNBP) (TR antagonist activity equivalents, ATR-EQ(50)s) ranging from 6.92 × 10(1) to 2.85 × 10(2) μg DNBP/L. The ATR-EQ(50)s and TR antagonist equivalent ranges (ATR-EQ(30-80) ranges) for TR antagonist activities indicated that the water sample from site WX-8 posed the greatest health risks. The ATR-EQ(80)s of the water samples ranging from 1.56 × 10(3) to 6.14 × 10(3) μg DNBP/L were higher than the NOEC of DNBP. The results from instrumental analysis showed that DNBP might be responsible for the TR antagonist activities in these water samples. Water sources along Yangtze River had thyroid hormone disrupting potential. Copyright © 2012 Elsevier Ltd. All rights reserved.

Alternatives to in vivo tests to detect endocrine disrupting chemicals (EDCs) in fish and amphibians--screening for estrogen, androgen and thyroid hormone disruption.

PubMed

Scholz, S; Renner, P; Belanger, S E; Busquet, F; Davi, R; Demeneix, B A; Denny, J S; Léonard, M; McMaster, M E; Villeneuve, D L; Embry, M R

2013-01-01

Endocrine disruption is considered a highly relevant hazard for environmental risk assessment of chemicals, plant protection products, biocides and pharmaceuticals. Therefore, screening tests with a focus on interference with estrogen, androgen, and thyroid hormone pathways in fish and amphibians have been developed. However, they use a large number of animals and short-term alternatives to animal tests would be advantageous. Therefore, the status of alternative assays for endocrine disruption in fish and frogs was assessed by a detailed literature analysis. The aim was to (i) determine the strengths and limitations of alternative assays and (ii) present conclusions regarding chemical specificity, sensitivity, and correlation with in vivo data. Data from 1995 to present were collected related to the detection/testing of estrogen-, androgen-, and thyroid-active chemicals in the following test systems: cell lines, primary cells, fish/frog embryos, yeast and cell-free systems. The review shows that the majority of alternative assays measure effects directly mediated by receptor binding or resulting from interference with hormone synthesis. Other mechanisms were rarely analysed. A database was established and used for a quantitative and comparative analysis. For example, a high correlation was observed between cell-free ligand binding and cell-based reporter cell assays, between fish and frog estrogenic data and between fish embryo tests and in vivo reproductive effects. It was concluded that there is a need for a more systematic study of the predictive capacity of alternative tests and ways to reduce inter- and intra-assay variability.

Simultaneous profiling of 17 steroid hormones for the evaluation of endocrine-disrupting chemicals in H295R cells.

PubMed

Jumhawan, Udi; Yamashita, Toshiyuki; Ishida, Kazuya; Fukusaki, Eiichiro; Bamba, Takeshi

2017-01-01

There is urgent need to develop a new protocol for the evaluation of chemical substances to potentially interact with the endocrine system and induce numerous pathological issues. The recently validated in vitro screening assay is limited on monitoring two steroid hormones. Methodology & results: The H295R model cell was exposed to seven endocrine disrupting chemicals (EDCs). The levels of 17 steroid hormones in cell extracts were subsequently determined by a quantitative targeted GC/MS/MS method. Through wide coverage, this system managed to capture the effects of exposure to increasing EDCs concentrations in the entire steroidogenic pathways. The developed approach could be beneficial for the mechanistic investigation of EDCs.

Thyroid hormone increases fibroblast growth factor receptor expression and disrupts cell mechanics in the developing organ of corti

PubMed Central

2013-01-01

Background Thyroid hormones regulate growth and development. However, the molecular mechanisms by which thyroid hormone regulates cell structural development are not fully understood. The mammalian cochlea is an intriguing system to examine these mechanisms, as cellular structure plays a key role in tissue development, and thyroid hormone is required for the maturation of the cochlea in the first postnatal week. Results In hypothyroid conditions, we found disruptions in sensory outer hair cell morphology and fewer microtubules in non-sensory supporting pillar cells. To test the functional consequences of these cytoskeletal defects on cell mechanics, we combined atomic force microscopy with live cell imaging. Hypothyroidism stiffened outer hair cells and supporting pillar cells, but pillar cells ultimately showed reduced cell stiffness, in part from a lack of microtubules. Analyses of changes in transcription and protein phosphorylation suggest that hypothyroidism prolonged expression of fibroblast growth factor receptors, and decreased phosphorylated Cofilin. Conclusions These findings demonstrate that thyroid hormones may be involved in coordinating the processes that regulate cytoskeletal dynamics and suggest that manipulating thyroid hormone sensitivity might provide insight into the relationship between cytoskeletal formation and developing cell mechanical properties. PMID:23394545

An AOP-based alternative testing strategy to predict the impact of thyroid hormone disruption on swim bladder inflation in zebrafish (poster)

EPA Science Inventory

Within the field of chemical safety assessment, there is a desire to replace costly whole organism testing with more efficient and cost-effective alternatives based on in vitro test systems. Disruption of thyroid hormone signaling via inhibition of enzymes called deiodinases is o...

Neurotoxicity of Thyroid Disrupting Contaminants

EPA Science Inventory

Thyroid hormones playa critical role in the normal development ofthe mammalian brain. Thyroid disrupting chemicals (TDCs) are environmental contaminants that alter the structure or function ofthe thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeost...

Endocrine Disrupting Chemicals and Disease Susceptibility

PubMed Central

Schug, Thaddeus T.; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J.

2011-01-01

Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products– including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption. PMID:21899826

Endocrine disrupting chemicals and disease susceptibility.

PubMed

Schug, Thaddeus T; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J

2011-11-01

Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products--including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption. Published by Elsevier Ltd.

Suppressive effects of long-term exposure to P-nitrophenol on gonadal development, hormonal profile with disruption of tissue integrity, and activation of caspase-3 in male Japanese quail (Coturnix japonica).

PubMed

Ahmed, Eman; Nagaoka, Kentaro; Fayez, Mostafa; Abdel-Daim, Mohamed M; Samir, Haney; Watanabe, Gen

2015-07-01

P-Nitrophenol (PNP) is considered to be one of nitrophenol derivatives of diesel exhaust particles. PNP is a major metabolite of some organophosphorus compounds. PNP is a persistent organic pollutant as well as one of endocrine-disrupting compounds. Consequently, bioaccumulation of PNP potentiates toxicity. The objectives of the current study were to assess in vivo adverse effects of long-term low doses of PNP exposure on reproductive system during development stage. Twenty-eight-day-old male Japanese quails were orally administered different doses of PNP (0, 0.01, 0.1, 1 mg/kg body weight) daily for 2.5 months. Testicular histopathology, hormones, caspase-3 (CASP3), and claudin-1 (CLDN1) tight junction protein, as well as plasma hormones were analyzed. The results revealed that long-term PNP exposure caused testicular histopathological changes such as vacuolation of spermatogenic cell and spermatocyte with significant testicular and cloacal gland atrophy. PNP activated CASP3 enzyme that is an apoptosis-related cysteine peptidase. Besides, it disrupted the expression of CLDN1. Furthermore, a substantial decrease in plasma concentrations of luteinizing hormone (LH) and testosterone was observed after 2 and 2.5 months in the PNP-treated groups. Meanwhile, the pituitary LH did not significantly change. Site of action of PNP may be peripheral on testicular development and/or centrally on the hypothalamic-pituitary-gonadal axis through reduction of pulsatile secretion of gonadotrophin-releasing hormone. Consequently, it may reduce the sensitivity of the anterior pituitary gland to secrete LH. In conclusion, PNP induced profound endocrine disruption in the form of hormonal imbalance, induction of CASP3, and disruption of CLDN1 expression in the testis. Hence, it may hinder the reproductive processes.

Large-scale integrative network-based analysis identifies common pathways disrupted by copy number alterations across cancers

PubMed Central

2013-01-01

Background Many large-scale studies analyzed high-throughput genomic data to identify altered pathways essential to the development and progression of specific types of cancer. However, no previous study has been extended to provide a comprehensive analysis of pathways disrupted by copy number alterations across different human cancers. Towards this goal, we propose a network-based method to integrate copy number alteration data with human protein-protein interaction networks and pathway databases to identify pathways that are commonly disrupted in many different types of cancer. Results We applied our approach to a data set of 2,172 cancer patients across 16 different types of cancers, and discovered a set of commonly disrupted pathways, which are likely essential for tumor formation in majority of the cancers. We also identified pathways that are only disrupted in specific cancer types, providing molecular markers for different human cancers. Analysis with independent microarray gene expression datasets confirms that the commonly disrupted pathways can be used to identify patient subgroups with significantly different survival outcomes. We also provide a network view of disrupted pathways to explain how copy number alterations affect pathways that regulate cell growth, cycle, and differentiation for tumorigenesis. Conclusions In this work, we demonstrated that the network-based integrative analysis can help to identify pathways disrupted by copy number alterations across 16 types of human cancers, which are not readily identifiable by conventional overrepresentation-based and other pathway-based methods. All the results and source code are available at http://compbio.cs.umn.edu/NetPathID/. PMID:23822816

Modeling Steroidogenesis Disruption Using High-Throughput ...

EPA Pesticide Factsheets

Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on steroidogenesis. The steroidogenic pathway is a series of hydroxylation and dehydrogenation steps carried out by CYP450 and hydroxysteroid dehydrogenase enzymes, yet the only enzyme in the pathway for which a high-throughput screening (HTS) assay has been developed is aromatase (CYP19A1), responsible for the aromatization of androgens to estrogens. Recently, the ToxCast HTS program adapted the OECD validated H295R steroidogenesis assay using human adrenocortical carcinoma cells into a high-throughput model to quantitatively assess the concentration-dependent (0.003-100 µM) effects of chemicals on 10 steroid hormones including progestagens, androgens, estrogens and glucocorticoids. These results, in combination with two CYP19A1 inhibition assays, comprise a large dataset amenable to clustering approaches supporting the identification and characterization of putative mechanisms of action (pMOA) for steroidogenesis disruption. In total, 514 chemicals were tested in all CYP19A1 and steroidogenesis assays. 216 chemicals were identified as CYP19A1 inhibitors in at least one CYP19A1 assay. 208 of these chemicals also altered hormone levels in the H295R assay, suggesting 96% sensitivity in the

Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues.

PubMed

Sherwood, Andrew; Holland, Peter C; Adamantidis, Antoine; Johnson, Alexander W

2015-12-01

Exposure to environmental cues associated with food can evoke eating behavior in the absence of hunger. This capacity for reward cues to promote feeding behaviors under sated conditions can be examined in the laboratory using cue-potentiated feeding (CPF). The orexigenic neuropeptide Melanin Concentrating Hormone (MCH) is expressed throughout brain circuitry critical for CPF. We examined whether deletion of the MCH receptor, MCH-1R, would in KO mice disrupt overeating in the presence of a Pavlovian CS+ associated with sucrose delivery. While both wild-type controls and KO mice showed comparable food magazine approach responses during the CPF test, MCH-1R deletion significantly impaired the ability of the CS+ to evoke overeating of sucrose under satiety. Through the use of a refined analysis of meal intake, it was revealed that this disruption to overeating behavior in KO mice reflected a reduction in the capacity for the CS+ to initiate and maintain bursts of licking behavior. These findings suggest that overeating during CPF requires intact MCH-1R signaling and may be due to an influence of the CS+ on the palatability of food and on regulatory mechanisms of peripheral control. Thus, disruptions to MCH-1R signaling may be a useful pharmacological tool to inhibit this form of overeating behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

Embryonic treatment with xenobiotics disrupts steroid hormone profiles in hatchling red-eared slider turtles (Trachemys scripta elegans).

PubMed Central

Willingham, E; Rhen, T; Sakata, J T; Crews, D

2000-01-01

Many compounds in the environment capable of acting as endocrine disruptors have been assayed for their developmental effects on morphogenesis; however, few studies have addressed how such xenobiotics affect physiology. In the current study we examine the effects of three endocrine-disrupting compounds, chlordane, trans-nonachlor, and the polychlorinated biphenyl (PCB) mixture Aroclor 1242, on the steroid hormone concentrations of red-eared slider turtle (Trachemys scripta elegans) hatchlings treated in ovo. Basal steroid concentrations and steroid concentrations in response to follicle-stimulating hormone were examined in both male and female turtles treated with each of the three compounds. Treated male turtles exposed to Aroclor 1242 or chlordane exhibited significantly lower testosterone concentrations than controls, whereas chlordane-treated females had significantly lower progesterone, testosterone, and 5[alpha]-dihydrotestosterone concentrations relative to controls. The effects of these endocrine disruptors extend beyond embryonic development, altering sex-steroid physiology in exposed animals. Images Figure 1 Figure 2 PMID:10753091

Arsenic as an endocrine disruptor: arsenic disrupts retinoic acid receptor-and thyroid hormone receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis.

PubMed

Davey, Jennifer C; Nomikos, Athena P; Wungjiranirun, Manida; Sherman, Jenna R; Ingram, Liam; Batki, Cavus; Lariviere, Jean P; Hamilton, Joshua W

2008-02-01

Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01-5 microM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element-luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element-luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1- 4.0 microM As. As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.

PubMed

Ruth, Katherine S; Campbell, Purdey J; Chew, Shelby; Lim, Ee Mun; Hadlow, Narelle; Stuckey, Bronwyn G A; Brown, Suzanne J; Feenstra, Bjarke; Joseph, John; Surdulescu, Gabriela L; Zheng, Hou Feng; Richards, J Brent; Murray, Anna; Spector, Tim D; Wilson, Scott G; Perry, John R B

2016-02-01

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

THYROID HORMONE INSUFFICIENCY DURING BRAIN DEVELOPMENT REDUCES PARVALBUMIN IMMUNOREACTIVITY AND INHIBITORY FUNCTION IN THE HIPPOCAMPUS.

EPA Science Inventory

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

Endocrine disrupters--testing strategies to assess human hazard.

PubMed

Baker, V A

2001-01-01

During the last decade an hypothesis has been developed linking certain chemicals (natural and synthetic) to observed and suspected adverse effects on reproduction in both wildlife and humans. The issue of 'endocrine disruption' originally focused on chemicals that mimic the action of the natural hormone oestrogen. However, the concern is now encompassing effects on the whole endocrine system. In response to public awareness, regulatory agencies (including the US EPA) and the OECD are formulating potential testing strategies and have begun the process of validating defined tests to systematically assess chemicals for their endocrine-disrupting activities. In order to investigate chemicals that have the potential to cause endocrine disruption, a large number of in vitro and in vivo assays have been identified. In vitro test systems (particularly when used in combination) offer the possibility of providing an early screen for large numbers of chemicals and can be useful in characterising the mechanism of action and potency. In vitro assays in widespread use for the screening/characterisation of endocrine disrupting potential include hormone receptor ligand binding assays (determination of the ability of a chemical to bind to the hormone receptor), cell proliferation assays (analysis of the ability of a chemical to stimulate growth of oestrogen sensitive cells), reporter gene assays in yeast or mammalian cells (analysis of the ability of a chemical to stimulate the transcription of a reporter gene construct in cell culture), and the analysis of the regulation of endogenous oestrogen sensitive genes in cell lines. However, in vitro assays do not always reliably predict the outcome in vivo due to differences in metabolic capabilities of the test systems used and the diverse range of mechanisms by which endocrine disrupting chemicals may act. Therefore a complementary battery of short- and long-term in vitro and in vivo assays (that assess both receptor and non

Diverse Peptide Hormones Affecting Root Growth Identified in the Medicago truncatula Secreted Peptidome.

PubMed

Patel, Neha; Mohd-Radzman, Nadiatul A; Corcilius, Leo; Crossett, Ben; Connolly, Angela; Cordwell, Stuart J; Ivanovici, Ariel; Taylor, Katia; Williams, James; Binos, Steve; Mariani, Michael; Payne, Richard J; Djordjevic, Michael A

2018-01-01

Multigene families encoding diverse secreted peptide hormones play important roles in plant development. A need exists to efficiently elucidate the structures and post-translational-modifications of these difficult-to-isolate peptide hormones in planta so that their biological functions can be determined. A mass spectrometry and bioinformatics approach was developed to comprehensively analyze the secreted peptidome of Medicago hairy root cultures and xylem sap. We identified 759 spectra corresponding to the secreted products of twelve peptide hormones including four CEP ( C -TERMINALLY E NCODED P EPTIDE), two CLE ( CL V3/ E NDOSPERM SURROUNDING REGION RELATED) and six XAP ( X YLEM SAP A SSOCIATED P EPTIDE) peptides. The MtCEP1, MtCEP2, MtCEP5 and MtCEP8 peptides identified differed in post-translational-modifications. Most were hydroxylated at conserved proline residues but some MtCEP1 derivatives were tri-arabinosylated. In addition, many CEP peptides possessed unexpected N - and C -terminal extensions. The pattern of these extensions suggested roles for endo- and exoproteases in CEP peptide maturation. Longer than expected, hydroxylated and homogeneously modified mono- and tri-arabinosylated CEP peptides corresponding to their in vivo structures were chemically synthesized to probe the effect of these post-translational-modifications on function. The ability of CEP peptides to elevate root nodule number was increased by hydroxylation at key positions. MtCEP1 peptides with N -terminal extensions or with tri-arabinosylation modification, however, were unable to impart increased nodulation. The MtCLE5 and MtCLE17 peptides identified were of precise size, and inhibited main root growth and increased lateral root number. Six XAP peptides, each beginning with a conserved DY sulfation motif, were identified including MtXAP1a, MtXAP1b, MtXAP1c, MtXAP3, MtXAP5 and MtXAP7. MtXAP1a and MtXAP5 inhibited lateral root emergence. Transcriptional analyses demonstrated peptide

The water flea Daphnia magna (Crustacea, Cladocera) as a test species for screening and evaluation of chemicals with endocrine disrupting effects on crustaceans.

PubMed

Tatarazako, Norihisa; Oda, Shigeto

2007-02-01

The water flea Daphnia magna (Crustacea, Cladocera) is a cyclical parthenogen, which can reproduce both by parthenogenesis and by sexual reproduction. With its ease of handling in the laboratory, several testing methods using D. magna exist for regulatory toxicity testing. Recently, several studies revealed that one of the major hormone groups in insects and crustaceans, juvenile hormones, are involved in the shift of reproductive mode from parthenogenesis to sexual reproduction (production of male neonates). Using offspring sex ratio as a new endpoint has made it possible to identify chemicals with juvenile hormone-like effects on crustaceans. The testing method using D. magna, in which offspring sex ratio is incorporated as a new endpoint, is now being proposed to the OECD as an enhanced version of the existing OECD Test Guideline 211: Daphnia magna reproduction test. No other clear-cut endpoint for identifying juvenile-hormone disrupting effects has ever been found in crustaceans than the induction of male neonates production in cladocerans. In this regard, it is expected that testing methods using D. magna are suitable for screening and risk assessment of chemicals with juvenile-hormone disrupting effects.

Juvenile hormone-binding proteins of Melanoplus bivittatus identified by EFDA photoaffinity labeling

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

Winder, B.S.

1988-01-01

Proteins that bind juvenile hormone in the hemolymph and fat body of the grasshopper, Melanoplus bivittatus were identified by photoaffinity labeling with radiolabeled epoxyfarnesyl diazoacetate ({sup 3}H-EFDA), and were characterized by electrophoretic analysis. A protocol was developed which allowed detection of {sup 3}H-EFDA that was covalently linked to proteins upon exposure to ultraviolet light at 254 nm. Quantification of protein-linked {sup 3}H-EFDA by liquid scintillation spectrometry took advantage of the differential solubility of unlinked {sup 3}H-EFDA in toluene alone, and of the protein-linked {sup 3}H-EFDA in toluene plus the detergent, Triton X-100. Competition between EFDA and juvenile hormone (JH) formore » binding to JH-specific binding sites was measured by hydroxyapatite protein binding assays in the presence of radiolabeled JH or EFDA and competing non-radiolabeled hormone. The protein-linked EFDA was detected on fluorograms of SDS or nondenaturing polyacrylamide gels (PAGE), and by liquid scintillation spectrometry of membranes to which the proteins had been electrophoretically transferred. Proteins which specifically bound JH were identified by photolabeling proteins in the presence and absence of nonlabeled JH-III.« less

CUMULATIVE DEVELOPMENTAL EFFECTS OF ENDOCRINE DISRUPTERS: SYNERGY OR ADDITIVITY?

EPA Science Inventory

Exposure to chemicals with hormonal activity during critical developmental periods can disrupt reproductive function and development. Within the last decade, several classes of pesticides and toxic substances have been shown to disrupt differentiation of the male rat reproductive...

Comparison of UV photolysis, nanofiltration, and their combination to remove hormones from a drinking water source and reduce endocrine disrupting activity.

PubMed

Sanches, Sandra; Rodrigues, Alexandre; Cardoso, Vitor V; Benoliel, Maria J; Crespo, João G; Pereira, Vanessa J

2016-06-01

A sequential water treatment combining low pressure ultraviolet direct photolysis with nanofiltration was evaluated to remove hormones from water, reduce endocrine disrupting activity, and overcome the drawbacks associated with the individual processes (production of a nanofiltration-concentrated retentate and formation of toxic by-products). 17β-Estradiol, 17α-ethinylestradiol, estrone, estriol, and progesterone were spiked into a real water sample collected after the sedimentation process of a drinking water treatment plant. Even though the nanofiltration process alone showed similar results to the combined treatment in terms of the water quality produced, the combined treatment offered advantage in terms of the load of the retentate and decrease in the endocrine-disrupting activity of the samples. Moreover, the photolysis by-products produced, with higher endocrine disrupting activity than the parent compounds, were effectively retained by the membrane. The combination of direct LP/UV photolysis with nanofiltration is promising for a drinking water utility that needs to cope with sudden punctual discharges or deterioration of the water quality and wants to decrease the levels of chemicals in the nanofiltration retentate.

Anthropogenic tracers, endocrine disrupting chemicals, and endocrine disruption in Minnesota lakes

USGS Publications Warehouse

Writer, J.H.; Barber, L.B.; Brown, G.K.; Taylor, Howard E.; Kiesling, R.L.; Ferrey, M.L.; Jahns, N.D.; Bartell, S.E.; Schoenfuss, H.L.

2010-01-01

Concentrations of endocrine disrupting chemicals and endocrine disruption in fish were determined in 11 lakes across Minnesota that represent a range of trophic conditions and land uses (urban, agricultural, residential, and forested) and in which wastewater treatment plant discharges were absent. Water, sediment, and passive polar organic integrative samplers (POCIS) were analyzed for steroidal hormones, alkylphenols, bisphenol A, and other organic and inorganic molecular tracers to evaluate potential non-point source inputs into the lakes. Resident fish from the lakes were collected, and caged male fathead minnows were deployed to evaluate endocrine disruption, as indicated by the biological endpoints of plasma vitellogenin and gonadal histology. Endocrine disrupting chemicals, including bisphenol A, 17??-estradiol, estrone, and 4-nonylphenol were detected in 90% of the lakes at part per trillion concentrations. Endocrine disruption was observed in caged fathead minnows and resident fish in 90% of the lakes. The widespread but variable occurrence of anthropogenic chemicals in the lakes and endocrine disruption in fish indicates that potential sources are diverse, not limited to wastewater treatment plant discharges, and not entirely predictable based on trophic status and land use. ?? 2010.

Developmental programming: Impact of fetal exposure to endocrine disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus

PubMed Central

Mahoney, Megan M.; Padmanabhan, Vasantha

2010-01-01

Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine disrupting chemicals (EDCs) with estrogenic and anti-androgenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude and MXC on LH surge timing in sheep. The neural mechanisms involved in differential disruption of the LH surge by these two EDCs remains to be elucidated. We tested the hypothesis that differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2 mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC or BPA (5 mg/kg/day) from day 30 to 90 of gestation (term 147 d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F2α, just prior to the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female. PMID:20621667

Chemical communication threatened by endocrine-disrupting chemicals.

PubMed Central

Fox, Jennifer E

2004-01-01

Communication on a cellular level--defined as chemical signaling, sensing, and response--is an essential and universal component of all living organisms and the framework that unites all ecosystems. Evolutionarily conserved signaling "webs," existing both within an organism and between organisms, rely on efficient and accurate interpretation of chemical signals by receptors. Therefore, endocrine-disrupting chemicals (EDCs), which have been shown to disrupt hormone signaling in laboratory animals and exposed wildlife, may have broader implications for disrupting signaling webs that have yet to be identified as possible targets. In this article, I explore common evolutionary themes of chemical signaling (e.g., estrogen signaling in vertebrates and phytoestrogen signaling from plants to symbiotic soil bacteria) and show that such signaling systems are targets of disruption by EDCs. Recent evolutionary phylogenetic data have shown that the estrogen receptor (ER) is the ancestral receptor from which all other steroid receptors have evolved. In addition to binding endogenous estrogens, ERs also bind phytoestrogens, an ability shared in common with nodulation D protein (NodD) receptors found in Rhizobium soil bacteria. Recent data have shown that many of the same synthetic and natural environmental chemicals that disrupt endocrine signaling in vertebrates also disrupt phytoestrogen-NodD receptor signaling in soil bacteria, which is necessary for nitrogen-fixing symbiosis. Bacteria-plant symbiosis is an unexpected target of EDCs, and other unexpected nontarget species may also be vulnerable to EDCs found in the environment. PMID:15121505

Hormonal alterations in PCOS and its influence on bone metabolism.

PubMed

Krishnan, Abhaya; Muthusami, Sridhar

2017-02-01

According to the World Health Organization (WHO) polycystic ovary syndrome (PCOS) occurs in 4-8% of women worldwide. The prevalence of PCOS in Indian adolescents is 12.2% according to the Indian Council of Medical Research (ICMR). The National Institute of Health has documented that it affects approximately 5 million women of reproductive age in the United States. Hormonal imbalance is the characteristic of many women with polycystic ovarian syndrome (PCOS). The influence of various endocrine changes in PCOS women and their relevance to bone remains to be documented. Hormones, which include gonadotrophin-releasing hormone (GnRH), insulin, the leutinizing/follicle-stimulating hormone (LH/FSH) ratio, androgens, estrogens, growth hormones (GH), cortisol, parathyroid hormone (PTH) and calcitonin are disturbed in PCOS women. These hormones influence bone metabolism in human subjects directly as well as indirectly. The imbalance in these hormones results in increased prevalence of osteoporosis in PCOS women. Limited evidence suggests that the drugs taken during the treatment of PCOS increase the risk of bone fracture in PCOS patients through endocrine disruption. This review is aimed at the identification of the relationship between bone mineral density and hormonal changes in PCOS subjects and identifies potential areas to study bone-related disorders in PCOS women. © 2017 Society for Endocrinology.

Metabolic function of the CTRP family of hormones

PubMed Central

Seldin, Marcus M.; Tan, Stefanie Y.; Wong, G. William

2013-01-01

Maintaining proper energy balance in mammals entails intimate crosstalk between various tissues and organs. These inter-organ communications are mediated, to a great extent, by secreted hormones that circulate in blood. Regulation of the complex metabolic networks by secreted hormones (e.g., insulin, glucagon, leptin, adiponectin, FGF21) constitutes an important mechanism governing the integrated control of whole-body metabolism. Disruption of hormone-mediated metabolic circuits frequently results in dysregulated energy metabolism and pathology. As part of an effort to identify novel metabolic hormones, we recently characterized a highly conserved family of fifteen secreted proteins, the C1q/TNF-related proteins (CTRP1–15). While related to adiponectin in sequence and structural organization, each CTRP has its own unique tissue expression profile and non-redundant function in regulating sugar and/or fat metabolism. Here, we summarize the current understanding of the physiological functions of CTRPs, emphasizing their metabolic roles. Future studies using gain-of-function and loss-of-function mouse models will provide greater mechanistic insights into the critical role CTRPs play in regulating systemic energy homeostasis. PMID:23963681

Tumor RNA disruption predicts survival benefit from breast cancer chemotherapy.

PubMed

Parissenti, Amadeo M; Guo, Baoqing; Pritzker, Laura B; Pritzker, Kenneth P H; Wang, Xiaohui; Zhu, Mu; Shepherd, Lois E; Trudeau, Maureen E

2015-08-01

In a prior substudy of the CAN-NCIC-MA.22 clinical trial (ClinicalTrials.gov identifier NCT00066443), we observed that neoadjuvant chemotherapy reduced tumor RNA integrity in breast cancer patients, a phenomenon we term "RNA disruption." The purpose of the current study was to assess in the full patient cohort the relationship between mid-treatment tumor RNA disruption and both pCR post-treatment and, subsequently, disease-free survival (DFS) up to 108 months post-treatment. To meet these objectives, we developed the RNA disruption assay (RDA) to quantify RNA disruption and stratify it into 3 response zones of clinical importance. Zone 1 is a level of RNA disruption inadequate for pathologic complete response (pCR); Zone 2 is an intermediate level, while Zone 3 has high RNA disruption. The same RNA disruption cut points developed for pCR response were then utilized for DFS. Tumor RDA identified >fourfold more chemotherapy non-responders than did clinical response by calipers. pCR responders were clustered in RDA Zone 3, irrespective of tumor subtype. DFS was about 2-fold greater for patients with tumors in Zone 3 compared to Zone 1 patients. Kaplan-Meier survival curves corroborated these findings that high tumor RNA disruption was associated with increased DFS. DFS values for patients in zone 3 that did not achieve a pCR were similar to that of pCR recipients across tumor subtypes, including patients with hormone receptor positive tumors that seldom achieve a pCR. RDA appears superior to pCR as a chemotherapy response biomarker, supporting the prospect of its use in response-guided chemotherapy.

Endocrine-Disrupting Compounds in Aquatic Ecosystems.

EPA Science Inventory

Endocrine disrupting chemicals (EDCs) are a ubiquitous issue of concern in our aquatic systems. Commonly detected EDCs include natural and synthetic hormones, surfactants, plasticizers, disinfectants, herbicides and metals. The potency of these chemicals varies substantially, as ...

The Physiology of Growth Hormone-Releasing Hormone (GHRH) in Breast Cancer

DTIC Science & Technology

2003-06-01

production of growth hormone-releasing factor by carcinoid and pancreatic islet tumors associated with acromegaly . Prog Clin Biol Res 1981; 74:259-271. (16...promotion of apop- cause of acromegaly . More recently, expression has been tosis. These results indicate that disruption of enaog- demonstrated in tumors

Perfluoroalkyl substances exposure and thyroid hormones in humans: epidemiological observations and implications

PubMed Central

Lee, Jung Eun

2017-01-01

Thyroid hormones play crucial roles in normal neurodevelopment of fetus and child. Many chemicals can affect control and homeostasis of thyroid hormones, and eventually lead to various adverse health effects including neurodevelopmental disorders. Perfluoroalkyl substances (PFASs) are among the thyroid disrupting chemicals that can be encountered among general human population. Due to their unique physicochemical characteristics, PFASs have been used as surfactants and surface coating materials in many applications. Therefore, PFASs have been frequently detected in humans and environment worldwide. In cross-sectional studies using nationally representative general human populations of United States, several PFASs have shown significant associations with thyroid hormones. Moreover, among pregnant women and their infants, not only major PFASs such as perfluorooctane sulfonic acid and perfluorooctanoic acid, but also those with shorter or longer carbon chains showed significant associations with thyroid hormones. Often demographic characteristics such as sex, age, and disease status appear to influence the associations between PFASs exposure and thyroid hormones. In general, major PFASs showed hypothyroidism effects among pregnant women and infants. As 8 carbon based PFASs have been phased out, those with shorter or longer carbon chains have been used in growing amount as replacement. However, only limited information is available for their occurrences and toxicity among humans. Further investigations on these substituting PFASs are required. In addition, efforts are warranted to identify sources of and mitigate exposure to these thyroid disrupting chemicals especially during pregnancy and early stages of life. PMID:28443254

Biosensor discovery of thyroxine transport disrupting chemicals

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

Marchesini, Gerardo R.; Meimaridou, Anastasia; Haasnoot, Willem

2008-10-01

Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites,more » halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds.« less

Developmental programming: Impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus

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

Mahoney, Megan M.; Padmanabhan, Vasantha, E-mail: vasantha@umich.ed

Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine-disrupting chemicals (EDCs) with estrogenic and antiandrogenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude, and MXC has profound effects on on LH surge timing in sheep. The neural mechanisms involved in the differential disruption of the LH surge by these two EDCs remain to be elucidated. We tested the hypothesis that the differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2, mRNA expression. Pregnant sheep were given daily injections of cottonseedmore » oil (controls), MXC, or BPA (5 mg/kg/day) from day 30 to 90 of gestation (term 147 d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F{sub 2{alpha}}, just before the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast, ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female.« less

Developmental programming: impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus.

PubMed

Mahoney, Megan M; Padmanabhan, Vasantha

2010-09-01

Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine-disrupting chemicals (EDCs) with estrogenic and antiandrogenic effects, disrupt the reproductive system. BPA has profound effects on luteinizing hormone (LH) surge amplitude, and MXC has profound effects on on LH surge timing in sheep. The neural mechanisms involved in the differential disruption of the LH surge by these two EDCs remain to be elucidated. We tested the hypothesis that the differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2, mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC, or BPA (5mg/kg/day) from day 30 to 90 of gestation (term 147d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F(2alpha), just before the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast, ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female. 2010 Elsevier Inc. All rights reserved.

Estrogens prevent metabolic dysfunctions induced by circadian disruptions in female mice

USDA-ARS?s Scientific Manuscript database

Circadian disruption has become a significant factor contributing to the epidemics of obesity and insulin resistance. However, interventions to treat metabolic dysfunctions induced by circadian disruptions are limited. The ovarian hormone, estrogen, produces important antiobesity and antidiabetic ef...

GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects.

PubMed

Marui, Suemi; Trarbach, Ericka B; Boguszewski, Margaret C S; França, Marcela M; Jorge, Alexander A L; Inoue, Hiroshi; Nishi, Mirian Y; de Lacerda Filho, Luiz; Aguiar-Oliveira, Manuel H; Mendonca, Berenice B; Arnhold, Ivo J P

2012-01-01

Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c.1146G>A (p.E382E) mutation. A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD. Copyright © 2012 S. Karger AG, Basel.

The interruption of thyroid and interrenal and the inter-hormonal interference in fish: does it promote physiologic adaptation or maladaptation?

PubMed

Peter, Valsa S; Peter, M C Subhash

2011-12-01

Endocrines, the chief components of chemical centers which produce hormones in tune with intrinsic and extrinsic clues, create a chemical bridge between the organism and the environment. In fishes also hormones integrate and modulate many physiologic functions and its synthesis, release, biological actions and metabolic clearance are well regulated. Consequently, thyroid hormones (THs) and cortisol, the products of thyroid and interrenal axes, have been identified for their common integrative actions on metabolic and osmotic functions in fish. On the other hand, many anthropogenic chemical substances, popularly known as endocrine disrupting chemicals, have been shown to disrupt the hormone-receptor signaling pathways in a number fish species. These chemicals which are known for their ability to induce endocrine disruption particularly on thyroid and interrenals can cause malfunction or maladaptation of many vital processes which are involved in the development, growth and reproduction in fish. On the contrary, evidence is presented that the endocrine interrupting agents (EIAs) can cause interruption of thyroid and interrenals, resulting in physiologic compensatory mechanisms which can be adaptive, though such hormonal interactions are less recognized in fishes. The EIAs of physical, chemical and biological origins can specifically interrupt and modify the hormonal interactions between THs and cortisol, resulting in specific patterns of inter-hormonal interference. The physiologic analysis of these inter-hormonal interruptions during acclimation and post-acclimation to intrinsic or extrinsic EIAs reveals that combinations of anti-hormonal, pro-hormonal or stati-hormonal interference may help the fish to fine-tune their metabolic and osmotic performances as part of physiologic adaptation. This novel hypothesis on the phenomenon of inter-hormonal interference and its consequent physiologic interference during thyroid and interrenal interruption thus forms the basis of

Human biological monitoring of suspected endocrine-disrupting compounds

PubMed Central

Faniband, Moosa; Lindh, Christian H; Jönsson, Bo AG

2014-01-01

Endocrine-disrupting compounds are exogenous agents that interfere with the natural hormones of the body. Human biological monitoring is a powerful method for monitoring exposure to endocrine disrupting compounds. In this review, we describe human biological monitoring systems for different groups of endocrine disrupting compounds, polychlorinated biphenyls, brominated flame retardants, phthalates, alkylphenols, pesticides, metals, perfluronated compounds, parabens, ultraviolet filters, and organic solvents. The aspects discussed are origin to exposure, metabolism, matrices to analyse, analytical determination methods, determinants, and time trends. PMID:24369128

[Perspectives on endocrine disruption].

PubMed

Olea, N; Fernández, M F; Araque, P; Olea-Serrano, F

2002-01-01

Two decades ago, reports of alterations in the reproductive function of some wild animal species and clear evidence of human and animal exposure to chemical substances with hormonal activity agonist and antagonist generated what is known now as the hypothesis of endocrine disruption. This is an emerging environmental health problem that has challenged some of the paradigms on which the control and regulation of the use of chemical compounds is based. The need to include in routine toxicology tests new research objectives that specifically refer to the development and growth of species and to the homeostasis and functionality of hormonal systems, has served to complicate both the evaluation of new compounds and the re-evaluation of existing ones. The repercussions on regulation and international trade have not taken long to be felt. On both sides of the Atlantic, screening systems for endocrine disrupters have been designed and established, and research programmes have been launched to characterise and quantify adverse effects on human and animal health and to develop preventive measures.

Thyroid disrupting chemicals: Mechanisms and mixtures

EPA Science Inventory

Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis, or change circulating o...

Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression*

PubMed Central

Wang, Qian; Jia, Jingjing; Chikina, Maria; Pincas, Hanna; Dolios, Georgia; Sasaki, Kazuki; Wang, Rong; Minamino, Naoto; Sealfon, Stuart C.

2016-01-01

Reproductive function is controlled by the pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates the expression of the gonadotropins luteinizing hormone and FSH in pituitary gonadotropes. Paradoxically, Fshb gene expression is maximally induced at lower frequency GnRH pulses, which provide a very low average concentration of GnRH stimulation. We studied the role of secreted factors in modulating gonadotropin gene expression. Inhibition of secretion specifically disrupted gonadotropin subunit gene regulation but left early gene induction intact. We characterized the gonadotrope secretoproteome and global mRNA expression at baseline and after Gαs knockdown, which has been found to increase Fshb gene expression (1). We identified 1077 secreted proteins or peptides, 19 of which showed mRNA regulation by GnRH or/and Gαs knockdown. Among several novel secreted factors implicated in Fshb gene regulation, we focused on the neurosecretory protein VGF. Vgf mRNA, whose gene has been implicated in fertility (2), exhibited high induction by GnRH and depended on Gαs. In contrast with Fshb induction, Vgf induction occurred preferentially at high GnRH pulse frequency. We hypothesized that a VGF-derived peptide might regulate Fshb gene induction. siRNA knockdown or extracellular immunoneutralization of VGF augmented Fshb mRNA induction by GnRH. GnRH stimulated the secretion of the VGF-derived peptide NERP1. NERP1 caused a concentration-dependent decrease in Fshb gene induction. These findings implicate a VGF-derived peptide in selective regulation of the Fshb gene. Our results support the concept that signaling specificity from the cell membrane GnRH receptor to the nuclear Fshb gene involves integration of intracellular signaling and exosignaling regulatory motifs. PMID:27466366

Endocrine-disrupting chemicals in aquatic environment: what are the risks for fish gametes?

PubMed

Carnevali, Oliana; Santangeli, Stefania; Forner-Piquer, Isabel; Basili, Danilo; Maradonna, Francesca

2018-06-11

Over the past 25 years, extensive research in vertebrate species has identified several genomic pathways altered by exposures to anthropogenic chemicals with hormone-like activity mediated by their interaction with nuclear receptors. In addition, many pollutants have been shown to interfere with non-genomic (non-classical) pathways, but this mechanism of endocrine disruption is still poorly understood. Recently, the number of publications describing the effects of Endocrine disrupting chemicals (EDCs) on fish reproduction, focusing on the deregulation of the hypothalamus-pituitary-gonadal axis as well as on gamete quality, significantly increased. Depending on their ability to mimic endogenous hormones, the may differently affect male or female reproductive physiology. Inhibition of gametogenesis, development of intersex gonads, alteration of the gonadosomatic index, and decreased fertility rate have been largely documented. In males, alterations of sperm density, motility, and fertility have been observed in several wild species. Similar detrimental effects were described in females, including negative outcomes on oocyte growth and maturation plus the occurrence of apoptotic/autophagic processes. These pathways may affect gamete viability considered as one of the major indicators of reproductive endocrine disruption. Pollutants act also at DNA level producing DNA mutations and changes in epigenetic pathways inducing specific mechanisms of toxicity and/or aberrant cellular responses that may affect subsequent generation(s) through the germline. In conclusion, this review summarizes the effects caused by EDC exposure on fish reproduction, focusing on gametogenesis, giving a general overview of the different aspects dealing with this issue, from morphological alteration, deregulation of steroidogenesis, hormonal synthesis, and occurrence of epigenetic process.

Thyroid-disrupting chemicals and brain development: an update

PubMed Central

Mughal, Bilal B; Fini, Jean-Baptiste; Demeneix, Barbara A

2018-01-01

This review covers recent findings on the main categories of thyroid hormone–disrupting chemicals and their effects on brain development. We draw mostly on epidemiological and experimental data published in the last decade. For each chemical class considered, we deal with not only the thyroid hormone–disrupting effects but also briefly mention the main mechanisms by which the same chemicals could modify estrogen and/or androgen signalling, thereby exacerbating adverse effects on endocrine-dependent developmental programmes. Further, we emphasize recent data showing how maternal thyroid hormone signalling during early pregnancy affects not only offspring IQ, but also neurodevelopmental disease risk. These recent findings add to established knowledge on the crucial importance of iodine and thyroid hormone for optimal brain development. We propose that prenatal exposure to mixtures of thyroid hormone–disrupting chemicals provides a plausible biological mechanism contributing to current increases in the incidence of neurodevelopmental disease and IQ loss. PMID:29572405

Can Chemicals in the Environment That Affect Hormone Function Disrupt Development?

EPA Science Inventory

Hormones, including estrogens and androgens, regulate the expression of genes that play critical roles in guiding the development of organ systems in the embryo. Changes in either the amount or the timing of hormone exposure can lead to altered human development. For example, hum...

Observational Progress in Identifying and Characterizing Tidal Disruption Flares

NASA Astrophysics Data System (ADS)

Cenko, S. Bradley

I present an overview of observational efforts across the electromagnetic spectrum to identify and study tidal disruption flares (TDFs), when a star wanders too close to a super-massive black hole and is torn apart by tidal forces. In particular I will focus on four unexpected surprises that challenge the most basic analytic picture of these events: 1) large inferred radii for the optical/UV-emitting material; 2) the ubiquity of outflows, detected at radio, X-ray, and UV wavelengths, ranging from speeds of 100 km/s to near the speed of light; 3) the peculiar atomic abundances observed in the UV and optical spectra of these objects; and, 4) the preference for these events to occur in post-starburst galaxies.

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

DOSE-DEPENDENT REDUCTIONS IN SPATIAL LEARING AND SYNAPTIC FUNCTION IN THE DENTATE GYRUS OF ADULT RATS FOLLOWING DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY.

EPA Science Inventory

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period i...

Comparing postnatal development of gonadal hormones and associated social behaviors in rats, mice, and humans.

PubMed

Bell, Margaret R

2018-05-14

Postnatal development includes dramatic changes in gonadal hormones and the many social behaviors they help regulate, both in rodents and humans. Parental care-seeking is the most salient social interaction in neonates and infants, play and pro-social behaviors are commonly studied in juveniles, and the development of aggression and sexual behavior begins in peripubertal stages but continues through late adolescence into adulthood. While parental behaviors are shown after reproductive success in adulthood, alloparenting behaviors are actually high in juveniles as well. These behaviors are sensitive to both early life organizational effects of gonadal hormones and later life activational regulation. However, changes in circulating gonadal hormones and the display of the above behaviors over development differs between rats, mice and humans. These endpoints are of interest to endocrinologist, toxicologists, neuroscientists because of their relevance to mental health disorders and their vulnerability to effects of endocrine disrupting chemical exposure. As such, the goal of this minireview is to succinctly describe and relate the postnatal development of gonadal hormones and social behaviors to each other, over time and across animal models. Ideally, this will help identify appropriate animal models and age ranges for continued study of both normative development and in contexts of environmental disruption.

Designing Endocrine Disruption Out of the Next Generation of Chemicals.

PubMed

Schug, T T; Abagyan, R; Blumberg, B; Collins, T J; Crews, D; DeFur, P L; Dickerson, S M; Edwards, T M; Gore, A C; Guillette, L J; Hayes, T; Heindel, J J; Moores, A; Patisaul, H B; Tal, T L; Thayer, K A; Vandenberg, L N; Warner, J; Watson, C S; Saal, F S Vom; Zoeller, R T; O'Brien, K P; Myers, J P

2013-01-01

A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via

Designing Endocrine Disruption Out of the Next Generation of Chemicals

PubMed Central

Schug, T.T; Abagyan, R.; Blumberg, B.; Collins, T.J.; Crews, D.; DeFur, P.L.; Dickerson, S.M.; Edwards, T.M.; Gore, A.C.; Guillette, L.J.; Hayes, T.; Heindel, J.J.; Moores, A.; Patisaul, H.B.; Tal, T.L.; Thayer, K.A.; Vandenberg, L.N.; Warner, J.; Watson, C.S.; Saal, F.S. vom; Zoeller, R.T.; O’Brien, K.P.; Myers, J.P.

2013-01-01

A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical’s potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at “the drawing board.” It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a ‘proof-of-principle’ test, we ran 6 endocrine disrupting chemicals (EDCs) that act

A path forward in the debate over health impacts of endocrine disrupting chemicals.

PubMed

Zoeller, R Thomas; Bergman, Åke; Becher, Georg; Bjerregaard, Poul; Bornman, Riana; Brandt, Ingvar; Iguchi, Taisen; Jobling, Susan; Kidd, Karen A; Kortenkamp, Andreas; Skakkebaek, Niels E; Toppari, Jorma; Vandenberg, Laura N

2014-12-22

Several recent publications reflect debate on the issue of "endocrine disrupting chemicals" (EDCs), indicating that two seemingly mutually exclusive perspectives are being articulated separately and independently. Considering this, a group of scientists with expertise in basic science, medicine and risk assessment reviewed the various aspects of the debate to identify the most significant areas of dispute and to propose a path forward. We identified four areas of debate. The first is about the definitions for terms such as "endocrine disrupting chemical", "adverse effects", and "endocrine system". The second is focused on elements of hormone action including "potency", "endpoints", "timing", "dose" and "thresholds". The third addresses the information needed to establish sufficient evidence of harm. Finally, the fourth focuses on the need to develop and the characteristics of transparent, systematic methods to review the EDC literature. Herein we identify areas of general consensus and propose resolutions for these four areas that would allow the field to move beyond the current and, in our opinion, ineffective debate.

Characteristics of Reticent and Disruptive Children As Identified by the Barclay Classroom Climate Inventory.

ERIC Educational Resources Information Center

Barclay, James R.

The Barclay Classroom Climate Inventory was employed to identify the psychometric characteristics of reticent and disruptive children. The BCCI utilizes self-competency judgments, peer nominations, vocational interests and teacher adjectival ratings in an effort to measure the various expectations which interact in the elementary classroom. A…

An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

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

Frizzell, Caroline; Ndossi, Doreen; Sokoine University of Agriculture, Morogoro

2013-08-15

Alternariol (AOH) is a mycotoxin commonly produced by Alternaria alternata on a wide range of foods. Few studies to date have been performed to evaluate the effects of AOH on endocrine activity. The present study makes use of in vitro mammalian cellular based assays and gene expression to investigate the ability of AOH to act as an endocrine disruptor by various modes of action. Reporter gene assays (RGAs), incorporating natural steroid hormone receptors for oestrogens, androgens, progestagens and glucocorticoids were used to identify endocrine disruption at the level of nuclear receptor transcriptional activity, and the H295R steroidogenesis assay was usedmore » to assess endocrine disruption at the level of gene expression and steroid hormone production. AOH exhibited a weak oestrogenic response when tested in the oestrogen responsive RGA and binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of AOH. H295R cells when exposed to 0.1–1000 ng/ml AOH, did not cause a significant change in testosterone and cortisol hormones but exposure to 1000 ng/ml (3.87 μM) AOH resulted in a significant increase in estradiol and progesterone production. In the gene expression study following exposure to 1000 ng/ml (3.87 μM) AOH, only one gene NR0B1 was down-regulated, whereas expression of mRNA for CYP1A1, MC2R, HSD3B2, CYP17, CYP21, CYP11B2 and CYP19 was up-regulated. Expression of the other genes investigated did not change significantly. In conclusion AOH is a weak oestrogenic mycotoxin that also has the ability to interfere with the steroidogenesis pathway. - Highlights: • Alternariol was investigated for endocrine disrupting activity. • Reporter gene assays and the H295R steroidogenesis assay have been used. • An oestrogenic effect of alternariol was observed. • This can lead to an increase in expression of the progesterone receptor. • Alternariol is capable of modulating hormone production and gene

Disruption of Calcium Homeostasis During Exercise as a Mediator of Bone Metabolism

DTIC Science & Technology

2015-10-01

Meeting of the American College of Sports Medicine (Appendix A). 15. SUBJECT TERMS calcium homeostasis, exercise, bone resorption, parathyroid hormone ... hormone (PTH). PTH can defend serum Ca by reducing urinary Ca excretion, increasing intestinal Ca absorption, and increasing mobilization of skeletal Ca...certain conditions. It is our contention that disruptions in calcium homeostasis during exercise lead to increases in parathyroid hormone (PTH) and

Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression.

PubMed

Choi, Soon Gang; Wang, Qian; Jia, Jingjing; Chikina, Maria; Pincas, Hanna; Dolios, Georgia; Sasaki, Kazuki; Wang, Rong; Minamino, Naoto; Salton, Stephen R J; Sealfon, Stuart C

2016-09-30

Reproductive function is controlled by the pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates the expression of the gonadotropins luteinizing hormone and FSH in pituitary gonadotropes. Paradoxically, Fshb gene expression is maximally induced at lower frequency GnRH pulses, which provide a very low average concentration of GnRH stimulation. We studied the role of secreted factors in modulating gonadotropin gene expression. Inhibition of secretion specifically disrupted gonadotropin subunit gene regulation but left early gene induction intact. We characterized the gonadotrope secretoproteome and global mRNA expression at baseline and after Gα s knockdown, which has been found to increase Fshb gene expression (1). We identified 1077 secreted proteins or peptides, 19 of which showed mRNA regulation by GnRH or/and Gα s knockdown. Among several novel secreted factors implicated in Fshb gene regulation, we focused on the neurosecretory protein VGF. Vgf mRNA, whose gene has been implicated in fertility (2), exhibited high induction by GnRH and depended on Gα s In contrast with Fshb induction, Vgf induction occurred preferentially at high GnRH pulse frequency. We hypothesized that a VGF-derived peptide might regulate Fshb gene induction. siRNA knockdown or extracellular immunoneutralization of VGF augmented Fshb mRNA induction by GnRH. GnRH stimulated the secretion of the VGF-derived peptide NERP1. NERP1 caused a concentration-dependent decrease in Fshb gene induction. These findings implicate a VGF-derived peptide in selective regulation of the Fshb gene. Our results support the concept that signaling specificity from the cell membrane GnRH receptor to the nuclear Fshb gene involves integration of intracellular signaling and exosignaling regulatory motifs. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

PubMed Central

Sapkota, Yadav; Steinthorsdottir, Valgerdur; Morris, Andrew P.; Fassbender, Amelie; Rahmioglu, Nilufer; De Vivo, Immaculata; Buring, Julie E.; Zhang, Futao; Edwards, Todd L.; Jones, Sarah; O, Dorien; Peterse, Daniëlle; Rexrode, Kathryn M.; Ridker, Paul M.; Schork, Andrew J.; MacGregor, Stuart; Martin, Nicholas G.; Becker, Christian M.; Adachi, Sosuke; Yoshihara, Kosuke; Enomoto, Takayuki; Takahashi, Atsushi; Kamatani, Yoichiro; Matsuda, Koichi; Kubo, Michiaki; Thorleifsson, Gudmar; Geirsson, Reynir T.; Thorsteinsdottir, Unnur; Wallace, Leanne M.; Werge, Thomas M.; Thompson, Wesley K.; Yang, Jian; Velez Edwards, Digna R.; Nyegaard, Mette; Low, Siew-Kee; Zondervan, Krina T.; Missmer, Stacey A.; D'Hooghe, Thomas; Montgomery, Grant W.; Chasman, Daniel I.; Stefansson, Kari; Tung, Joyce Y.; Nyholt, Dale R.

2017-01-01

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10−8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts. PMID:28537267

Phytoestrogen signaling and symbiotic gene activation are disrupted by endocrine-disrupting chemicals.

PubMed Central

Fox, Jennifer E; Starcevic, Marta; Jones, Phillip E; Burow, Matthew E; McLachlan, John A

2004-01-01

Some organochlorine pesticides and other synthetic chemicals mimic hormones in representatives of each vertebrate class, including mammals, reptiles, amphibians, birds, and fish. These compounds are called endocrine-disrupting chemicals (EDCs). Similarly, hormonelike signaling has also been observed when vertebrates are exposed to plant chemicals called phytoestrogens. Previous research has shown the mechanism of action for EDCs and phytoestrogens is as unintended ligands for the estrogen receptor (ER). Although pesticides have been synthesized to deter insects and weeds, plants produce phytoestrogens to deter herbivores, as attractant cues for insects, and as recruitment signals for symbiotic soil bacteria. Our data present the first evidence that some of the same organochlorine pesticides and EDCs known to disrupt endocrine signaling through ERs in exposed wildlife and humans also disrupt the phytoestrogen signaling that leguminous plants use to recruit Sinorhizobium meliloti soil bacteria for symbiotic nitrogen fixation. Here we report that a variety of EDCs and pesticides commonly found in agricultural soils interfere with the symbiotic signaling necessary for nitrogen fixation, suggesting that the principles underlying endocrine disruption may have more widespread biological and ecological importance than had once been thought. PMID:15121509

The Fate and Transport of Reproductive Hormones and Their Conjugates in the Environment

USDA-ARS?s Scientific Manuscript database

Reproductive steroid hormones can disrupt the endocrine system of some species at ng/L concentrations. Sources of steroid hormones to the environment include human waste water effluents or manure produced at animal feeding operations (AFOs). Steroid hormones, such as 17ß-estradiol (E2) and estrone (...

Neurodevelopmental Consequences of Low-Level Thyroid Hormone Disruption Induced by Environmental Contaminants

EPA Science Inventory

Inadequate levels of thyroid hormone during critical developmental periods lead to stunted growth, mental retardation, and neurological 'cretinism'. Animal models of developmental thyroid hormone deficiency mirror well the impact of severe insults to the thyroid system. However, ...

Disruption of sex-hormone levels and steroidogenic-related gene expression on Mongolia Racerunner (Eremias argus) after exposure to triadimefon and its enantiomers.

PubMed

Li, Jitong; Chang, Jing; Li, Wei; Guo, Baoyuan; Li, Jianzhong; Wang, Huili

2017-03-01

Triadimefon (TF) is a widely used chiral fungicide with one chiral centre and two enantiomers (TF 1 and TF 2 ). However, little is reported about the ecological toxicity of reptiles on an enantioselective level. TF is a potential endocrine disruptor that may interfere with sex steroid hormones, such as testosterone (T) and 17beta-estradiol (E 2 ). In our study, the lizards Mongolia Racerunner (Eremias argus) were orally exposed to TF and its enantiomers for 21 days. Plasma sex steroid hormones and steroidogenic-related genes, including 17-beta-hydroxysteroid (hsd17β), cytochrome P450 enzymes (cyp19 and cyp17), and steroid hormone receptors (erα and Ar) were evaluated. After exposure, the plasma testosterone level in the 100 mg/kg bw group was elevated, while the oestradiol level was reduced. This phenomenon may be caused by the transformation of cyp19, which may inhibit the conversion of testosterone to oestradiol and affect sexual behaviour. In addition, the two enantiomers have different effects on hormone levels, which testified to the previously reported biotoxic dissimilarity between TF 1 and TF 2 in organisms. Furthermore, the cyp19 mRNA level in liver and gonad of the TF 2 and TF group (100 mg/kg bw ) were significantly down-regulated, while the cyp17 and hsd17β mRNA levels were up-regulated. The expression of erα and Ar mRNA levels were up-regulated in males but not in females, which may indicate that TF has sex differences on these two genes. As seen from the above results, TF and its enantiomers may have endocrine-disrupting effects on lizards (E. argus) by acting sensitively on sex steroid hormones and steroidogenic-related genes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of wastewater treatment configuration and seasonal conditions on thyroid hormone disruption and stress effects in Rana catesbeiana tailfin.

PubMed

Wojnarowicz, Pola; Ogunlaja, Olumuyiwa O; Xia, Chen; Parker, Wayne J; Helbing, Caren C

2013-12-03

Improved endocrine disrupting compound (EDC) removal is desirable in municipal wastewater treatment plants (MWWTPs) although increased removal does not always translate into reduced biological activity. Suitable methods for determining reduction in biological activity of effluents are needed. In order to determine which MWWTPs are the most effective at removing EDC activities, we operated three configurations of pilot sized biological reactors (conventional activated sludge, CAS; nitrifying activated sludge, NAS; and biological nutrient removal, BNR) receiving the same influent under simulated winter and summer conditions. As frogs are model organisms for the study of thyroid hormone (TH) action, we used the North American species Rana catesbeiana in a cultured tadpole tailfin (C-fin) assay to compare the effluents. TH-responsive (thyroid hormone receptors alpha (thra) and beta (thrb)) and stress-responsive (superoxide dismutase, catalase, and heat shock protein 30) mRNA transcript levels were examined. Effluents infrequently perturbed stress-responsive transcript abundance but thra/thrb levels were significantly altered. In winter conditions, CAS caused frequent TH perturbations while BNR caused none. In summer conditions, however, BNR caused substantial TH perturbations while CAS caused few. Our findings contrast other studies of seasonal variations of EDC removal and accentuate the importance of utilizing appropriate biological readouts for assessing EDC activities.

INTERLABORATORY STUDY ON THE USE OF STEROID HORMONES IN EXAMINING ENDOCRINE DISRUPTION.

EPA Science Inventory

In recent years, there has been an increased use of the measurement of sex steroid hormone levels in the blood of animals exposed to chemicals as an indicator of reproductive impairment or an alteration in endocrine function. Although levels of hormones are often compared among ...

Isolation and characterization of juvenile hormone esterase from gypsy moth (Lymantria dispar)

Treesearch

Algimantas P. Valaitis; Joan Jolliff

1991-01-01

Insect metamorphosis is under precise hormonal control. During the last larval stadium, the degradation of juvenile hormone by juvenile hormone esterase (JHE) is essential for the initiation of pupation. Therefore, we have targeted this system for disruption with a strategy to produce a recombinant gypsy moth virus which expresses JHE. In order to clone and insert the...

The characteristics of railway service disruption: implications for disruption management.

PubMed

Golightly, D; Dadashi, N

2017-03-01

Rail disruption management is central to operational continuity and customer satisfaction. Disruption is not a unitary phenomenon - it varies by time, cause, location and complexity of coordination. Effective, user-centred technology for rail disruption must reflect this variety. A repertory grid study was conducted to elicit disruption characteristics. Construct elicitation with a group of experts (n = 7) captured 26 characteristics relevant to rail disruption. A larger group of operational staff (n = 28) rated 10 types of rail incident against the 26 characteristics. The results revealed distinctions such as business impact and public perception, and the importance of management of the disruption over initial detection. There were clear differences between those events that stop the traffic, as opposed to those that only slow the traffic. The results also demonstrate the utility of repertory grid for capturing the characteristics of complex work domains. Practitioner Summary: The aim of the paper is to understand how variety in rail disruption influences socio-technical design. It uses repertory grid to identify and prioritise 26 constructs, and group 10 disruption types, identifying critical factors such as whether an incident stops or merely slows the service, and business reputation.

Growth hormone transgenesis in coho salmon disrupts muscle immune function impacting cross-talk with growth systems.

PubMed

Alzaid, Abdullah; Kim, Jin-Hyoung; Devlin, Robert H; Martin, Samuel A M; Macqueen, Daniel J

2018-04-26

Suppression of growth during infection may aid resource allocation towards effective immune function. Past work supporting this hypothesis in salmonid fish revealed an immune-responsive regulation of the insulin-like growth factor (IGF) system, an endocrine pathway downstream of growth hormone (GH). Skeletal muscle is the main target for growth and energetic storage in fish, yet little is known about how its growth is regulated during an immune response. We addressed this knowledge gap by characterizing muscle immune responses in size-matched coho salmon ( Oncorhynchus kisutch ) achieving different growth rates. We compared a wild-type strain with two GH transgenic groups from the same genetic background achieving either maximal or suppressed growth, a design separating GH's direct effects from its influence on growth rate and nutritional state. Fish were sampled 30h post-injection with PBS (control) or mimics of bacterial or viral infection. We quantified mRNA expression levels for genes from the GH, GH receptor, IGF hormone, IGF1 receptor and IGF-binding protein families, along with immune genes involved in inflammatory or antiviral responses and muscle growth status marker genes. We demonstrate dampened immune function in GH transgenics compared to wild-type. The muscle of GH transgenics achieving rapid growth showed no detectable antiviral response, coupled with evidence of a constitutive inflammatory state. GH and IGF system gene expression was strongly altered by GH transgenesis and fast growth, both for baseline expression and responses to immune stimulation. Thus, GH transgenesis strongly disrupts muscle immune status and normal GH and IGF system expression responses to immune stimulation. © 2018. Published by The Company of Biologists Ltd.

Rapid Actions of Xenoestrogens Disrupt Normal Estrogenic Signaling

PubMed Central

Watson, Cheryl S.; Hu, Guangzhen; Paulucci-Holthauzen, Adriana A.

2014-01-01

Some chemicals used in consumer products or manufacturing (eg. plastics, surfactants, pesticides, resins) have estrogenic activities; these xenoestrogens (XEs) chemically resemble physiological estrogens and are one of the major categories of synthesized compounds that disrupt endocrine actions. Potent rapid actions of XEs via nongenomic mechanisms contribute significantly to their disruptive effects on functional endpoints (eg. cell proliferation/death, transport, peptide release). Membrane-initiated hormonal signaling in our pituitary cell model is predominantly driven by mERα with mERβ and GPR30 participation. We visualized ERα on plasma membranes using many techniques in the past (impeded ligands, antibodies to ERα ) and now add observations of epitope proximity with other membrane signaling proteins. We have demonstrated a range of rapid signals/protein activations by XEs including: calcium channels, cAMP/PKA, MAPKs, G proteins, caspases, and transcription factors. XEs can cause disruptions of the oscillating temporal patterns of nongenomic signaling elicited by endogenous estrogens. Concentration effects of XEs are nonmonotonic (a trait shared with natural hormones), making it difficult to design efficient (single concentration) toxicology tests to monitor their harmful effects. A plastics monomer, Bisphenol A, modified by waste treatment (chlorination) and other processes causes dephosphorylation of extracellular-regulated kinases, in contrast to having no effects as it does in genomic signaling. Mixtures of XEs, commonly found in contaminated environments, disrupt the signaling actions of physiological estrogens even more severely than do single XEs. Understanding the features of XEs that drive these disruptive mechanisms will allow us to redesign useful chemicals that exclude estrogenic or anti-estrogenic activities. PMID:24269739

Gene Expression as a Biomarker of Effect of Thyroid Hormone Action in Developing Brain: Relation to Serum Hormones.

EPA Science Inventory

Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have proved more diffic...

Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

PubMed Central

Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

2012-01-01

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

Role of Growth Hormone in Prostate Cancer

DTIC Science & Technology

2007-02-01

syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci USA 94:13215... Laron mouse, in which the gene coding for both GHR and GH binding protein has been disrupted or knocked out, with the C3(1)/Tag mouse, which develops...the Laron mouse). Nevertheless, the new model presented here demonstrates that the loss of GHR produced a significant reduction in the level of PIN in

THYROID HORMONE INSUFFICIENCY AND BRAIN DEVELOPMENT -- DETERMINATION OF NEUROTOXICITY AT LOW LEVELS OF HORMONE DISRUPTION.

EPA Science Inventory

Thyroid hormone (TH) deficiencies during development produce deleterious effects on brain structure and function. The degree to which TH must be perturbed to induce neurotoxicity remains unclear. The present study was conducted as part of a Cooperative Agreement between US EPA, U...

Effect of Chlorotriazine Pesticides on Gonadotrophin Releasing Hormone in the Neuronal GT1-7 Cell Line and Hypothalamic Explants

EPA Science Inventory

Gonadotrophin releasing hormone (GnRH) stimulates the release of pituitary luteinizing hormone (LH) and follicle stimulating hormone. These pituitary hormones are necessary for normal reproductive function in both males and females. It is well recognized that disruption of nor...

Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice.

PubMed

Li, Yuesheng; Knapp, Joanne R; Kopchick, John J

2003-02-01

Growth hormone (GH) acts on adipose tissue by accelerating fat expenditure, preventing triglyceride accumulation, and facilitating lipid mobilization. To investigate whether GH is involved in the development and metabolism of interscapular brown adipose tissue (BAT), a site of nonshivering thermogenesis, we employed three lines of transgenic mice. Two of the lines are dwarf due to expression of a GH antagonist (GHA) or disruption of the GH receptor/binding-protein gene. A third mouse line is giant due to overexpression of a bovine GH (bGH) transgene. We have found that the body weights of those animals are proportional to their body lengths at 10 weeks of age. However, GHA dwarf mice tend to catch up with the nontransgenic (NT) littermates in body weight but not in body length at 52 weeks of age. The increase of body mass index (BMI) for GHA mice accelerates rapidly relative to controls as a function of age. We have also observed that BAT in both dwarf mouse lines but not in giant mice is enlarged in contrast to nontransgenic littermates. This enlargement occurs as a function of age. Northern analysis suggests that BAT can be a GH-responsive tissue because GHR/BP mRNAs were found there. Finally, the level of uncoupling protein-1 (UCP1) RNA was found to be higher in dwarf mice and lower in giant animals relative to controls, suggesting that GH-mediated signaling may negatively regulate UCP1 gene expression in BAT.

Endocrine Disrupting Contaminants—Beyond the Dogma

PubMed Central

Guillette, Louis J.

2006-01-01

Descriptions of endocrine disruption have largely been associated with wildlife and driven by observations documenting estrogenic, androgenic, antiandrogenic, and antithyroid actions. These actions, in response to exposure to ecologically relevant concentrations of various environmental contaminants, have now been established in numerous vertebrate species. However, many potential mechanisms and endocrine actions have not been studied. For example, the DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] metabolite, p,p′-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] is known to disrupt prostaglandin synthesis in the uterus of birds, providing part of the explanation for DDT-induced egg shell thinning. Few studies have examined prostaglandin synthesis as a target for endocrine disruption, yet these hormones are active in reproduction, immune responses, and cardiovascular physiology. Future studies must broaden the basic science approach to endocrine disruption, thereby expanding the mechanisms and endocrine end points examined. This goal should be accomplished even if the primary influence and funding continue to emphasize a narrower approach based on regulatory needs. Without this broader approach, research into endocrine disruption will become dominated by a narrow dogma, focusing on a few end points and mechanisms. PMID:16818240

The Growth Hormone Receptor Gene-Disrupted (GHR-KO) Mouse Fails to Respond to an Intermittent Fasting (IF) Diet

PubMed Central

Arum, Oge; Bonkowski, Michael S.; Rocha, Juliana S.; Bartke, Andrzej

2009-01-01

SUMMARY The interaction of longevity-conferring genes with longevity-conferring diets is poorly understood. The growth hormone receptor gene-disrupted (GHR-KO) mouse is long-lived; and this longevity is not responsive to 30% caloric restriction (CR), in contrast to wild-type animals from the same strain. To determine whether this may have been limited to a particular level of dietary restriction (DR), we subjected GHR-KO mice to a different dietary restriction regimen, an intermittent fasting (IF) diet. The IF diet increased the survivorship and improved insulin sensitivity of normal males, but failed to affect either parameter in GHR-KO mice. From the results of two paradigms of dietary restriction we postulate that GHR-KO mice would be resistant to any manner of DR; potentially due to their inability to further enhance insulin sensitivity. Insulin sensitivity may be a mechanism and/or a marker of the lifespan-extending potential of an intervention. PMID:19747233

Developmental Thyroid Hormone Disruption: Prevalence, Environmental Contaminants and Neurodevelopmental Consequences

EPA Science Inventory

Thyroid hormones (TH) are critical for growth and development and particularly brain development. There are numerous environmental agents that lead to marginal reductions of circulating TH. Although it is clear that severe developmental hypothyroidism is profoundly detrimental to...

ISSUES IN ENDOCRINE DISRUPTION: COMPARING CRITICAL PERIODS OF HORMONE SENSITIVITY

EPA Science Inventory

Japanese medaka (Oryzias latipes) have been developed as a model species to compare the effects of endocrine active chemicals at critical life-stage periods of hormonal sensitivity, specifically as reproductively active adults, during the developmental period of differentiation, ...

Spatiotemporal variations in estrogenicity, hormones, and endocrine-disrupting compounds in influents and effluents of selected wastewater-treatment plants and receiving streams in New York, 2008-09

USGS Publications Warehouse

Baldigo, Barry P.; Phillips, Patrick J.; Ernst, Anne G.; Gray, James L.; Hemming, Jocelyn D.C.

2014-01-01

Endocrine-disrupting compounds (EDCs) in wastewater effluents have been linked to changes in sex ratios, intersex (in males), behavioral modifications, and developmental abnormalities in aquatic organisms. Yet efforts to identify and regulate specific EDCs in complex mixtures are problematic because little is known about the estrogen activity (estrogenicity) levels of many common and emerging contaminants. The potential effects of EDCs on the water quality and health of biota in streams of the New York City water supply is especially worrisome because more than 150 wastewater-treatment plants (WWTPs) are permitted to discharge effluents into surface waters and groundwaters of watersheds that provide potable water to more than 9 million people. In 2008, the U.S. Geological Survey (USGS), the New York State Department of Environmental Conservation (NYSDEC), New York State Department of Health (NYSDOH), and New York City Department of Environmental Protection (NYCDEP) began a pilot study to increase the understanding of estrogenicity and EDCs in effluents and receiving streams mainly in southeastern New York. The primary goals of this study were to document and assess the spatial and temporal variability of estrogenicity levels; the effectiveness of various treatment-plant types to remove estrogenicity; the concentrations of hormones, EDCs, and pharmaceuticals, personal care products (PPCPs); and the relations between estrogenicity and concentrations of hormones, EDCs, and PPCPs. The levels of estrogenicity and selected hormones, non-hormone EDCs, and PPCPs were characterized in samples collected seasonally in effluents from 7 WWTPs, once or twice in effluents from 34 WWTPs, and once in influents to 6 WWTPs. Estrogenicity was quantified, as estradiol equivalents, using both the biological e-screen assay and a chemical model. Results generally show that (1) estrogenicity levels in effluents varied spatially and seasonally, (2) a wide range of known and unknown EDCs

Endocrine disrupting chemicals in the atmosphere: Their effects on humans and wildlife.

PubMed

Annamalai, Jayshree; Namasivayam, Vasudevan

2015-03-01

Endocrine disrupting chemicals (EDCs) are exogenous agents that interfere or disrupt the normal synthesis, secretion, transportation, binding and metabolism of natural hormones; eventually dysregulating homeostatic mechanisms, reproduction and development. They are emitted into the atmosphere during anthropogenic activities and physicochemical reactions in nature. Inhalation of these EDCs as particulate and gaseous vapors triggers their interaction with endocrine glands and exerts agonist or antagonists actions at hormone receptors. The endocrine disruption at nanogram levels of EDC's has gained concern in the last decade, due to infertility among men and women, early puberty, obesity, diabetes and cancer. Thus, the review explores the literature that addresses the major occurring EDCs in the atmosphere including phthalates, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), brominated flame retardants (BFRs), dioxins, alkylphenols (APs) and perfluorinated chemicals (PFCs). Sources, fate, half-life, mechanism, measured concentrations in air, bioaccumulation in tissues, laboratory exposures correlating to toxicological effects of these EDCs in humans and wildlife are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

AN INTERLABORATORY STUDY ON THE USE OF STEROID HORMONES IN EVALUATING ENDOCRINE DISRUPTION

EPA Science Inventory

In recent years, there has been an increased use of the measurement of sex steroid hormone levels in the blood of animals exposed to chemicals as an indicator of reproductive impairment or an alteration in endocrine function. Although levels of hormones are often compared among a...

AN INTERLABORATORY STUDY ON THE USE OF STERIOD HORMONES IN EXAMINING ENDOCRINE DISRUPTION.

EPA Science Inventory

In recent years, there has been an increased use of the measurement of sex steroid hormone levels in the blood of animals exposed to chemicals as an indicator of reproductive impairment or an alteration in endocrine function. Although levels of hormones are often compared among a...

DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY ALTERS THE AMPLITUDE OF THE ACOUSTIC STARTLE RESPONSE IN RATS

EPA Science Inventory

Purpose: The thyroid hormone (TH) system is one of the targets of endocrine disrupting chemicals. Since TH is essential for proper brain development, disruption by exposure to chemicals during development can result in adverse neurological outcomes. Previous studies revealed th...

The Use of MS-based Metabolomics to Determine Markers Associated with Endocrine Disruption in Small Fish Species

EPA Science Inventory

Endocrine disrupting chemicals (EDCs) are exogenous substances that disrupt the physiological function of endogenous hormones. In fish, these xenobiotics are capable of interfering with the dynamic equilibrium of the hypothalamic-pituitary-gonadal (HPG) axis resulting in adverse ...

A novel workflow combining plaque imaging, plaque and plasma proteomics identifies biomarkers of human coronary atherosclerotic plaque disruption.

PubMed

Lee, Regent; Fischer, Roman; Charles, Philip D; Adlam, David; Valli, Alessandro; Di Gleria, Katalin; Kharbanda, Rajesh K; Choudhury, Robin P; Antoniades, Charalambos; Kessler, Benedikt M; Channon, Keith M

2017-01-01

Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation. We developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption. We compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption. This novel approach for biomarker

Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding

PubMed Central

Purushotham, Aparna; Xu, Qing; Li, Xiaoling

2012-01-01

SIRT1 is a highly-conserved NAD+-dependent protein deacetylase that plays essential roles in the regulation of energy metabolism, genomic stability, and stress response. Although the functions of SIRT1 in many organs have been extensively studied in tissue-specific knockout mouse models, the systemic role of SIRT1 is still largely unknown as a result of severe developmental defects that result from whole-body knockout in mice. Here, we investigated the systemic functions of SIRT1 in metabolic homeostasis by utilizing a whole-body SIRT1 heterozygous mouse model. These mice are phenotypically normal under standard feeding conditions. However, when chronically challenged with a 40% fat diet, they become obese and insulin resistant, display increased serum cytokine levels, and develop hepatomegaly. Hepatic metabolomic analyses revealed that SIRT1 heterozygous mice have elevated gluconeogenesis and oxidative stress. Surprisingly, they are depleted of glycerolipid metabolites and free fatty acids, yet accumulate lysolipids. Moreover, high-fat feeding induces elevation of serum testosterone levels and enlargement of seminal vesicles in SIRT1 heterozygous males. Microarray analysis of liver mRNA indicates that they have altered expression of genes involved in steroid metabolism and glycerolipid metabolism. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of systemic energy and steroid hormone homeostasis.—Purushotham, A., Xu, Q., Li, X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. PMID:22006157

Modeling Steroidogenesis Disruption Using High-Throughput In Vitro Screening Data (SOT)

EPA Science Inventory

Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on ...

The role of feeding rhythm, adrenal hormones and neuronal inputs in synchronizing daily clock gene rhythms in the liver.

PubMed

Su, Yan; Cailotto, Cathy; Foppen, Ewout; Jansen, Remi; Zhang, Zhi; Buijs, Ruud; Fliers, Eric; Kalsbeek, Andries

2016-02-15

The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to distribute rhythmic information to the periphery via neural, humoral and/or behavioral connections. Until now, feeding, corticosterone and neural inputs are considered important signals for synchronizing daily rhythms in the liver. In this study, we investigated the necessity of neural inputs as well as of the feeding and adrenal hormone rhythms for maintaining daily hepatic clock gene rhythms. Clock genes kept their daily rhythm when only one of these three signals was disrupted, or when we disrupted hepatic neuronal inputs together with the adrenal hormone rhythm or with the daily feeding rhythm. However, all clock genes studied lost their daily expression rhythm after simultaneous disruption of the feeding and adrenal hormone rhythm. These data indicate that either a daily rhythm of feeding or adrenal hormones should be present to synchronize clock gene rhythms in the liver with the SCN. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

ASSESSMENT OF A FATHEAD MINNOW REPRODUCTION ASSAY FOR IDENTIFYING ENDOCRINE-DISRUPTING CHEMICALS WITH DIVERSE MODES OF ACTION

EPA Science Inventory

The US EPA has developed a short-term reproduction test with the fathead minnow to identify potential endocrine disrupting chemicals (EDCs). The assay is initiated by collecting baseline spawning data from reproductively-active adult fathead minnows for 21 d, followed by a 21 d e...

USE OF POPULATION STUDIES TO IDENTIFY ASSOCIATIONS BETWEEN ADVERSE HEALTH EFFECTS AND ENVIRONMENTAL EXPOSURES TO ENDOCRINE DISRUPTING HERBICIDES

EPA Science Inventory

Not only animal studies, but also population (ecologic) studies can contribute to the identification of endocrine disrupting chemicals. Population studies are fundamental in identifying public health hazards, and provide hypotheses for more targeted studies. Chlorophenoxy herb...

Arsenic as an Endocrine Disruptor: Arsenic Disrupts Retinoic Acid Receptor–and Thyroid Hormone Receptor–Mediated Gene Regulation and Thyroid Hormone–Mediated Amphibian Tail Metamorphosis

PubMed Central

Davey, Jennifer C.; Nomikos, Athena P.; Wungjiranirun, Manida; Sherman, Jenna R.; Ingram, Liam; Batki, Cavus; Lariviere, Jean P.; Hamilton, Joshua W.

2008-01-01

Background Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. Objectives The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Methods and results Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01–5 μM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element–luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element–luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1– 4.0 μM As. Conclusions As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are

Disrupting Mosquito Reproduction and Parasite Development for Malaria Control

PubMed Central

Gabrieli, Paolo; Buckee, Caroline O.; Catteruccia, Flaminia

2016-01-01

The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgently needed, including the identification of safe compounds that affect vectorial capacity via mechanisms that differ from fast-acting insecticides. Here, we show that compounds targeting steroid hormone signaling disrupt multiple biological processes that are key to the ability of mosquitoes to transmit malaria. When an agonist of the steroid hormone 20-hydroxyecdysone (20E) is applied to Anopheles gambiae females, which are the dominant malaria mosquito vector in Sub Saharan Africa, it substantially shortens lifespan, prevents insemination and egg production, and significantly blocks Plasmodium falciparum development, three components that are crucial to malaria transmission. Modeling the impact of these effects on Anopheles population dynamics and Plasmodium transmission predicts that disrupting steroid hormone signaling using 20E agonists would affect malaria transmission to a similar extent as insecticides. Manipulating 20E pathways therefore provides a powerful new approach to tackle malaria transmission by the mosquito vector, particularly in areas affected by the spread of insecticide resistance. PMID:27977810

2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice

PubMed Central

Lee, Dongoh; Ahn, Changhwan; Hong, Eui-Ju; An, Beum-Soo; Hyun, Sang-Hwan; Choi, Kyung-Chul; Jeung, Eui-Bae

2016-01-01

2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems PMID:27420076

2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice.

PubMed

Lee, Dongoh; Ahn, Changhwan; Hong, Eui-Ju; An, Beum-Soo; Hyun, Sang-Hwan; Choi, Kyung-Chul; Jeung, Eui-Bae

2016-07-12

2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems.

Tiered High-Throughput Screening Approach to Identify ...

EPA Pesticide Factsheets

High-throughput screening (HTS) for potential thyroid–disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the US EPA ToxCast screening assay portfolio. To fill one critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast Phase I and II chemical libraries, comprised of 1,074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single concentration screen were retested in concentration-response. Due to high false positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed two additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidation assay using

Species-specific considerations in using the fish embryo test as an alternative to identify endocrine disruption.

PubMed

Schiller, Viktoria; Zhang, Xiaowei; Hecker, Markus; Schäfers, Christoph; Fischer, Rainer; Fenske, Martina

2014-10-01

of anti-androgenic activity. In contrast, for medaka clear anti-androgenic response, e.g. transcriptional downregulation of 11β-hydroxylase, 3β-hydroxysteroid-dehydrogenase, gonadotropin-releasing hormone receptor 2, was already observed at the pre-hatch stage. Together, this data suggests that medaka and zebrafish embryos would provide a beneficial alternative testing platform for endocrine disruption that involves additive information on interspecies and exposure time variability when using both species. Copyright © 2014 Elsevier B.V. All rights reserved.

Early Life Exposure to Endocrine Disrupting Chemicals and Childhood Obesity and Neurodevelopment

PubMed Central

Braun, Joseph M.

2017-01-01

Endocrine disrupting chemicals (EDCs) may increase the risk of childhood diseases by disrupting hormonally mediated processes critical for growth and development during gestation, infancy, or childhood. The fetus, infant, and child may have enhanced sensitivity to environmental stressors like EDCs due to rapid development and greater exposure to some EDCs that results from their developmentally appropriate behavior, anatomy, and physiology. This review summarizes epidemiological studies examining the relations of early-life exposure to bisphenol A (BPA), phthalates, triclosan, and perfluoroalkyl substance (PFAS) with childhood neurobehavioral disorders and obesity. The available epidemiological evidence suggests that prenatal exposure to several of these ubiquitous EDCs is associated with adverse neurobehavior (BPA and phthalates) and excess adiposity or increased risk of obesity/overweight (PFAS). Quantifying the effects of EDC mixtures, improving EDC exposure assessment, reducing bias from confounding, identifying periods of heightened vulnerability, and elucidating the presence and nature of sexually dimorphic EDC effects would result in stronger inferences from epidemiological studies. Ultimately, better estimates of the causal effects of EDC exposures on child health could help identify susceptible sub-populations and lead to public health interventions to reduce these exposures. PMID:27857130

Structural Abnormalities and Learning Impairments Induced by Low Level Thyroid Hormone Insufficiency: A Cross-Fostering Study

EPA Science Inventory

Severe reductions in thyroid hormones (TH) during development alter brain structure and impair learning. Uncertainty surrounds both the impact oflower levels of TH disruption and the sensitivity of available metrics to detect neurodevelopmental deficits of this disruption. We ha...

USE OF MOLECULAR BIOLOGICAL TECHNIQUES TO EVALUATE EFFECT OF ENDOGENOUS HORMONES AND A XENOBIOTIC PESTICIDE ON GROWTH OF SHEEPSHEAD MINNOW

EPA Science Inventory

We have developed a teleost model to screen physiological effects of endocrine disrupting chemicals (EDCs) on somatic growth. Growth is largely controlled by the endocrine system via the growth-hormone releasing hormone (GRF) - growth hormone (GH) - insulin-like growth factor (IG...

THYROID DISRUPTING CHEMICALS: CHALLENGES IN ASSESSING NEUROTOXIC RISK FROM ENVIRONMENTAL MIXTURES.

EPA Science Inventory

Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis, or change circulating o...

Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone-resistance due to heterozygous Gαs disruption

PubMed Central

Turan, Serap; Fernandez-Rebollo, Eduardo; Aydin, Cumhur; Zoto, Teuta; Reyes, Monica; Bounoutas, George; Chen, Min; Weinstein, Lee S.; Erben, Reinhold G.; Marshansky, Vladimir; Bastepe, Murat

2013-01-01

Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of Gαs activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH-resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH-resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH-resistance caused by the maternal loss of Gαs, i.e. hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (three-weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH-resistance in patients with PHP-Ia. PMID:23956044

Developmental programming: contribution of prenatal androgen and estrogen to estradiol feedback systems and periovulatory hormonal dynamics in sheep.

PubMed

Veiga-Lopez, Almudena; Astapova, Olga I; Aizenberg, Esther F; Lee, James S; Padmanabhan, Vasantha

2009-04-01

Prenatal testosterone excess leads to neuroendocrine and periovulatory disruptions in the offspring culminating in progressive loss of cyclicity. It is unknown whether the mediary of these disruptions is androgen or estrogen, because testosterone can be aromatized to estrogen. Taking a reproductive life span approach of studying control, prenatal testosterone, and dihydrotestosterone-treated offspring, this study tested the hypothesis that disruptions in estradiol-negative but not -positive feedback effects are programmed by androgenic actions of testosterone and that these disruptions in turn will have an impact on the periovulatory hormonal dynamics. The approach was to test estradiol-negative and -positive feedback responses of all three groups of ovary-intact females during prepubertal age and then compare the periovulatory dynamics of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone during the first breeding season. The findings show that estradiol-negative but not estradiol-positive feedback disruptions in prenatal testosterone-treated females are programmed by androgenic actions of prenatal testosterone excess and that follicular phase estradiol and gonadotropins surge disruptions during reproductive life are consistent with estrogenic programming. Additional studies carried out testing estradiol-positive feedback response over time found progressive deterioration of estradiol-positive feedback in prenatal testosterone-treated sheep until the time of puberty. Together, these findings provide insight into the mechanisms by which prenatal testosterone disrupts the reproductive axis. The findings may be of translational relevance since daughters of mothers with hyperandrogenism are at risk of increased exposure to androgens.

Intergenerational effects of endocrine-disrupting compounds: a review of the Michigan polybrominated biphenyl registry.

PubMed

Curtis, Sarah W; Conneely, Karen N; Marder, Mary E; Terrell, Metrecia L; Marcus, Michele; Smith, Alicia K

2018-06-11

Endocrine-disrupting compounds (EDCs) are a broad class of chemicals present in many residential products that can disrupt hormone signaling and cause health problems in humans. Multigenerational cohorts, like the Michigan polybrominated biphenyl registry, are ideal for studying the effects of intergenerational exposure. Registry participants report hormone-related health problems, particularly in those exposed before puberty or those in the second generation exposed through placental transfer or breastfeeding. However, more research is needed to determine how EDCs cause health problems and the mechanisms underlying intergenerational exposure. Utilizing existing data in this registry, along with genetic and epigenetic approaches, could provide insight to how EDCs cause human disease and help to determine the risk to exposed populations and future generations.

Impact of endocrine disrupting chemicals on onset and development of female reproductive disorders and hormone-related cancer.

PubMed

Scsukova, Sona; Rollerova, Eva; Bujnakova Mlynarcikova, Alzbeta

2016-12-01

A growing body of evidence suggests that exposure to chemical substances designated as endocrine disrupting chemicals (EDCs) due to their ability to disturb endocrine (hormonal) activity in humans and animals, may contribute to problems with fertility, pregnancy, and other aspects of reproduction. The presence of EDCs has already been associated with reproductive malfunction in wildlife species, but it remains difficult to prove causal relationships between the presence of EDCs and specific reproductive problems in vivo, especially in females. On the other hand, the increasing number of experiments with laboratory animals and in vitro research indicate the ability of different EDCs to influence the normal function of female reproductive system, and even their association with cancer development or progression. Research shows that EDCs may pose the greatest risk during prenatal and early postnatal development when organ and neural systems are forming. In this review article, we aim to point out a possible contribution of EDCs to the onset and development of female reproductive disorders and endocrine-related cancers with regard to the period of exposure to EDCs and affected endpoints (organs or processes). Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling

PubMed Central

Koopman, Jacob J.E.; van Heemst, Diana; van Bodegom, David; Bonkowski, Michael S.; Sun, Liou Y.; Bartke, Andrzej

2016-01-01

Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species. PMID:26959761

Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling.

PubMed

Koopman, Jacob J E; van Heemst, Diana; van Bodegom, David; Bonkowski, Michael S; Sun, Liou Y; Bartke, Andrzej

2016-03-01

Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species.

RISK ASSESSMENT OF THYROID HORMONE DISRUPTION AND MIXTURES IN MARINE BIOTA

EPA Science Inventory

Varieties of chemicals alter thyroid hormones (THs) in vertabrates. The importance of THs during neurodevelopment, suggest that these chemicals would likely be developmental neurotoxicants. A number of epidemiological studies have demonstrated associations between exposure to p...

Brominated flame retardants as possible endocrine disrupters.

PubMed

Darnerud, P O

2008-04-01

Brominated flame retardants (BFR) are endocrine disrupters in experimental systems, both in vitro and in vivo. Although BFR effects on thyroid hormones are well confirmed, studies of effects on oestrogen/androgen systems are fewer but today growing in numbers. The effects of BFR on other hormone systems are still unknown. Hormonal effect levels in animals start from ca 1 mg/kg b.w., but there are exceptions: effects on spermatogenesis, suggesting hormonal causes, have been observed at a low dose (60 microg/kg b.w.) of a polybrominated diphenyl ether (PBDE) congener, BDE-99. It could be concluded that hormonal effects are of importance in risk assessment, and in some cases where effects are seen at low levels safety margins may be insufficient. One additional uncertainty is the lack of reliable human data that could be used to support animal BFR observations. In spite of the recent regulation of PBDE production, levels of both PBDE and of other BFR groups are still present in environmental samples. Thus, we have to deal with the possible effects of human BFR exposure for times to come. In order to reduce BFR exposure, the routes of exposure should be carefully examined and ways to reduce levels in major exposure routes considered.

Exposures to Endocrine Disrupting Chemicals in Consumer Products-A Guide for Pediatricians.

PubMed

Wong, Katelyn H; Durrani, Timur S

2017-05-01

Endocrine disrupting chemicals, a group of exogenous chemicals that can interfere with hormone action in the body, have been implicated in disrupting endocrine function, which negatively affects human health and development. Endocrine disrupting chemicals are ubiquitously detected in consumer products, foods, beverages, personal care products, and household cleaning products. Due to concerns about their negative effects on human health, several professional health provider societies have recommended the reduction of common endocrine disrupting chemical exposures. The purpose of this review is to provide a brief overview of common endocrine disrupting chemicals (bisphenol A, phthalates, triclosan, polybrominated ethers, and parabens) and potential effects on child development and health. In addition, we aim to provide guidance and resources for pediatricians and other health care providers with counseling strategies to help patients to minimize exposures to common endocrine disrupting chemicals. Copyright © 2017 Mosby, Inc. All rights reserved.

TRICLOSAN AND ENDOCRINE DISRUPTION: EVIDENCE FOR ALTERATIONS IN THYROID HORMONE HOMEOSTASIS.

EPA Science Inventory

Impact Statement: Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a chlorinated phenolic antibacterial compound found as an active ingredient in many personal care and household products. Recent studies suggest that triclosan may alter thyroid hormone (TH) homeostasis via ...

Developmental Programming: Contribution of Prenatal Androgen and Estrogen to Estradiol Feedback Systems and Periovulatory Hormonal Dynamics in Sheep1

PubMed Central

Veiga-Lopez, Almudena; Astapova, Olga I.; Aizenberg, Esther F.; Lee, James S.; Padmanabhan, Vasantha

2009-01-01

Prenatal testosterone excess leads to neuroendocrine and periovulatory disruptions in the offspring culminating in progressive loss of cyclicity. It is unknown whether the mediary of these disruptions is androgen or estrogen, because testosterone can be aromatized to estrogen. Taking a reproductive life span approach of studying control, prenatal testosterone, and dihydrotestosterone-treated offspring, this study tested the hypothesis that disruptions in estradiol-negative but not -positive feedback effects are programmed by androgenic actions of testosterone and that these disruptions in turn will have an impact on the periovulatory hormonal dynamics. The approach was to test estradiol-negative and -positive feedback responses of all three groups of ovary-intact females during prepubertal age and then compare the periovulatory dynamics of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone during the first breeding season. The findings show that estradiol-negative but not estradiol-positive feedback disruptions in prenatal testosterone-treated females are programmed by androgenic actions of prenatal testosterone excess and that follicular phase estradiol and gonadotropins surge disruptions during reproductive life are consistent with estrogenic programming. Additional studies carried out testing estradiol-positive feedback response over time found progressive deterioration of estradiol-positive feedback in prenatal testosterone-treated sheep until the time of puberty. Together, these findings provide insight into the mechanisms by which prenatal testosterone disrupts the reproductive axis. The findings may be of translational relevance since daughters of mothers with hyperandrogenism are at risk of increased exposure to androgens. PMID:19122183

Endocrine disrupting effects of butylated hydroxyanisole (BHA - E320)

PubMed Central

POP, ANCA; KISS, BELA; LOGHIN, FELICIA

2013-01-01

Butylated hydroxyanisole (BHA) is extensively used as antioxidant in foods, food packaging, cosmetics and pharmaceuticals. In the past years, it raised concerns regarding its possible endocrine disrupting effect. The existing in vitro studies indicate that BHA presents a weak estrogenic effect and also anti-androgenic properties while an in vivo study found it to have antiestrogenic properties. There is no sufficient data available at the moment to draw a conclusion regarding the safety of BHA when referring to its endocrine disrupting effect. Since a fraction of the population might be exposed to doses superior to the acceptable daily intake (ADI), it is important to gather more in vitro and in vivo data concerning the potential effects that BHA might have alone, but also in mixtures with natural hormones or other endocrine disrupting compounds. PMID:26527908

Biology of PXR: role in drug-hormone interactions

PubMed Central

Wang, Jing; Dai, Shu; Guo, Yan; Xie, Wen; Zhai, Yonggong

2014-01-01

Hormonal homeostasis is essential for a variety of physiological and pathological processes. Elimination and detoxification of xenobiotics, such as drugs introduced into the human body, could disrupt the balance of hormones due to the induction of drug metabolizing enzymes (DMEs) and transporters. Pregnane X receptor (PXR, NR1I2) functions as a master xenobiotic receptor involved in drug metabolism and drug-drug interactions by its coordinated transcriptional regulation of phase I and phase II DMEs and transporters. Recently, increasing evidences indicate that PXR can also mediate the endocrine disruptor function and thus impact the integrity of the endocrine system. This review focuses primarily on the recent advances in our understanding of the function of PXR in glucocorticoid, mineralocorticoid, androgen and estrogen homeostasis. The elucidation of PXR-mediated drug-hormone interactions might have important therapeutic implications in dealing with hormone-dependent diseases and safety assessment of drugs. PMID:26417296

Disruption of Zebrafish Follicle-Stimulating Hormone Receptor (fshr) But Not Luteinizing Hormone Receptor (lhcgr) Gene by TALEN Leads to Failed Follicle Activation in Females Followed by Sexual Reversal to Males.

PubMed

Zhang, Zhiwei; Lau, Shuk-Wa; Zhang, Lingling; Ge, Wei

2015-10-01

Gonadotropins are primary hormones that control vertebrate reproduction. In a recent study, we analyzed the impacts of FSH and LH on zebrafish reproduction by disrupting FSH and LH-β genes (fshb and lhb) using transcription activator-like effector nuclease (TALEN) technology. Using the same approach, we successfully deleted FSH and LH receptor genes (fshr and lhcgr) in the present study. In contrast to the deficiency of its cognate ligand FSH, the fshr-deficient females showed a complete failure of follicle activation with all ovarian follicles arrested at the primary growth-previtellogenic transition, which is the marker for puberty onset in females. Interestingly, after blockade at the primary growth stage for varying times, all females reversed to males, and all these males were fertile. In fshr-deficient males, spermatogenesis was normal in adults, but the initiation of spermatogenesis in juveniles was retarded. In contrast to fshr, the deletion of the lhcgr gene alone caused no obvious phenotypes in both males and females; however, double mutation of fshr and lhcgr resulted in infertile males. In summary, our results in the present study showed that Fshr was indispensable to folliculogenesis and the disruption of the fshr gene resulted in a complete failure of follicle activation followed by masculinization into males. In contrast, lhcgr does not seem to be essential to zebrafish reproduction in both males and females. Neither Fshr nor Lhcgr deficiency could phenocopy the deficiency of their cognate ligands FSH and LH, which is likely due to the fact that Fshr can be activated by both FSH and LH in the zebrafish.

Computational Modeling of Thyroid Hormone Regulated Neurodevelopment for Chemical Prioritization (SOT)

EPA Science Inventory

Thyroid hormones (TH) are critical for normal brain development. Environmental chemicals may disrupt TH homeostasis through a variety of physiological systems including membrane transporters, serum transporters, synthesis and catabolic enzymes, and nuclear receptors. Current comp...

Inhibition of the Thyroid Hormone Pathway in Xenopus by Mercaptobenzothiazole

EPA Science Inventory

Amphibian metamorphosis is a thyroid hormone-dependent process that provides a potential model system to assess chemicals for their ability to disrupt the hypothalamic-pituitary-thyroid (HPT) axis. Several studies have demonstrated the sensitivity of this system to a variety of ...

Endocrine-Disrupting Effects of Pesticides through Interference with Human Glucocorticoid Receptor.

PubMed

Zhang, Jianyun; Zhang, Jing; Liu, Rui; Gan, Jay; Liu, Jing; Liu, Weiping

2016-01-05

Many pesticides have been identified as endocrine-disrupting chemicals (EDCs) due to their ability to bind sex-steroid hormone receptors. However, little attention has been paid to the ability of pesticides to interfere with other steroid hormone receptors such as glucocorticoid receptor (GR) that plays a critical role in metabolic, endocrine, immune, and nervous systems. In this study, the glucocorticoidic and antiglucocorticoidic effects of 34 pesticides on human GR were investigated using luciferase reporter gene assay. Surprisingly, none of the test chemicals showed GR agonistic activity, but 12 chemicals exhibited apparent antagonistic effects. Bifenthrin, λ-cyhalothrin, cypermethrin, resmethrin, o,p'-DDT, p,p'-DDT, methoxychlor, ethiofencarb, and tolylfluanid showed remarkable GR antagonistic properties with RIC20 values lower than 10(-6) M. The disruption of glucocorticoid-responsive genes in H4IIE and J774A.1 cells was further evaluated on these 12 GR antagonists. In H4IIEcells, four organochlorine insecticides, bifenthrin, and 3-PBA decreased cortisol-induced PEPCK gene expression, while o,p'-DDT and methoxychlor inhibited cortisol-stimulated Arg and TAT gene expression. Cypermethrin and tolyfluanid attenuated cortisol-induced TAT expression. In J774A.1 cells, λ-cyhalothrin, resmethrin, 3-PBA, o,p'-DDT, p,p'-DDT, p,p'-DDE, methoxychlor- and tolylfluanid-reduced cortisol-stimulated GILZ expression. Furthermore, molecular docking simulation indicated that different interactions may stabilize the binding between molecules and GR. Our findings suggest that comprehensive screening and evaluation of GR antagonists and agonists should be considered to better understand the health and ecological risks of man-made chemicals such as pesticides.

Identifying Obstacles to a Multidisciplinary Understanding of "Disruptive" Behaviour

ERIC Educational Resources Information Center

Macleod, Gale

2010-01-01

This paper examines the possibilities and challenges presented by an interdisciplinary approach to the study of disruptive behaviour. It is argued that whilst such an approach is to be welcomed, work needs to be done in order to ensure that educational research joins the discussion as an equal partner. The paper begins with a demonstration of how…

Amphibian metamorphosis as a model for studying endocrine disruption on vertebrate development: effect of bisphenol A on thyroid hormone action.

PubMed

Heimeier, Rachel A; Shi, Yun-Bo

2010-09-01

Thyroid hormone (TH) is essential for proper development in vertebrates. TH deficiency during gestation and early postnatal development produces severe neurological, skeletal, metabolism and growth abnormalities. It is therefore important to consider environmental chemicals that may interfere with TH signaling. Exposure to environmental contaminants that disrupt TH action may underlie the increasing incidence of human developmental disorders worldwide. One contaminant of concern is the xenoestrogen bisphenol A (BPA), a chemical widely used to manufacture polycarbonate plastics and epoxy resins. The difficulty in studying uterus-enclosed mammalian embryos has hampered the analysis on the direct effects of BPA during vertebrate development. As TH action at the cellular level is highly conserved across vertebrate species, amphibian metamorphosis serves as an important TH-dependent in vivo vertebrate model for studying potential contributions of BPA toward human developmental disorders. Using Xenopus laevis as a model, we and others have demonstrated the inhibitory effects of BPA exposure on metamorphosis. Genome-wide gene expression analysis revealed that surprisingly, BPA primarily targets the TH-signaling pathway essential for metamorphosis in Xenopus laevis. Given the importance of the genomic effects of TH during metamorphosis and the conservation in its regulation in higher vertebrates, these observations suggest that the effect of BPA in human embryogenesis is through the inhibition of the TH pathway and warrants further investigation. Our findings further argue for the critical need to use in vivo animal models coupled with systematic molecular analysis to determine the developmental effects of endocrine disrupting compounds. Published by Elsevier Inc.

The Role of the Multiple Hormonal Dysregulation in the Onset of "Anemia of Aging": Focus on Testosterone, IGF-1, and Thyroid Hormones.

PubMed

Maggio, Marcello; De Vita, Francesca; Fisichella, Alberto; Lauretani, Fulvio; Ticinesi, Andrea; Ceresini, Graziano; Cappola, Anne; Ferrucci, Luigi; Ceda, Gian Paolo

2015-01-01

Anemia is a multifactorial condition whose prevalence increases in both sexes after the fifth decade of life. It is a highly represented phenomenon in older adults and in one-third of cases is "unexplained." Ageing process is also characterized by a "multiple hormonal dysregulation" with disruption in gonadal, adrenal, and somatotropic axes. Experimental studies suggest that anabolic hormones such as testosterone, IGF-1, and thyroid hormones are able to increase erythroid mass, erythropoietin synthesis, and iron bioavailability, underlining a potential role of multiple hormonal changes in the anemia of aging. Epidemiological data more consistently support an association between lower testosterone and anemia in adult-older individuals. Low IGF-1 has been especially associated with anemia in the pediatric population and in a wide range of disorders. There is also evidence of an association between thyroid hormones and abnormalities in hematological parameters under overt thyroid and euthyroid conditions, with limited data on subclinical statuses. Although RCTs have shown beneficial effects, stronger for testosterone and the GH-IGF-1 axis and less evident for thyroid hormones, in improving different hematological parameters, there is no clear evidence for the usefulness of hormonal treatment in improving anemia in older subjects. Thus, more clinical and research efforts are needed to investigate the hormonal contribution to anemia in the older individuals.

High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding.

PubMed

Chiang, Wei-Chung; Wei, Yongjie; Kuo, Yi-Chun; Wei, Shuguang; Zhou, Anwu; Zou, Zhongju; Yehl, Jenna; Ranaghan, Matthew J; Skepner, Adam; Bittker, Joshua A; Perez, Jose R; Posner, Bruce A; Levine, Beth

2018-06-21

Autophagy, a lysosomal degradation pathway, plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. We sought to establish a method for developing new chemical compounds that specifically induce autophagy. To do this, we developed two assays to identify compounds that target a key regulatory node of autophagy induction-specifically, the binding of Bcl-2 (a negative regulator of autophagy) to Beclin 1 (an allosteric modulator of the Beclin 1/VPS34 lipid kinase complex that functions in autophagy initiation). These assays use either a split-luciferase assay to measure Beclin 1/Bcl-2 binding in cells or an AlphaLISA assay to directly measure direct Beclin 1/Bcl-2 binding in vitro. We screened two different chemical compound libraries, comprising ∼300 K compounds, to identify small molecules that disrupt Beclin 1/Bcl-2 binding and induce autophagy. Three novel compounds were identified that directly inhibit Beclin 1/Bcl-2 interaction with an IC 50 in the micromolar range and increase autophagic flux. These compounds do not demonstrate significant cytotoxicity, and they exert selectivity for disruption of Bcl-2 binding to the BH3 domain of Beclin 1 compared with the BH3 domain of the pro-apoptotic Bcl-2 family members, Bax and Bim. Thus, we have identified candidate molecules that serve as lead templates for developing potent and selective Beclin 1/Bcl-2 inhibitors that may be clinically useful as autophagy-inducing agents.

The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism

PubMed Central

Kim, Tae Won; Jeong, Jong-Hyun; Hong, Seung-Chul

2015-01-01

The levels of several hormones fluctuate according to the light and dark cycle and are also affected by sleep, feeding, and general behavior. The regulation and metabolism of several hormones are influenced by interactions between the effects of sleep and the intrinsic circadian system; growth hormone, melatonin, cortisol, leptin, and ghrelin levels are highly correlated with sleep and circadian rhythmicity. There are also endogenous circadian mechanisms that serve to regulate glucose metabolism and similar rhythms pertaining to lipid metabolism, regulated through the actions of various clock genes. Sleep disturbance, which negatively impacts hormonal rhythms and metabolism, is also associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation. Circadian disruption, typically induced by shift work, may negatively impact health due to impaired glucose and lipid homeostasis, reversed melatonin and cortisol rhythms, and loss of clock gene rhythmicity. PMID:25861266

Disruption of histone modification and CARM1 recruitment by arsenic represses transcription at glucocorticoid receptor-regulated promoters.

PubMed

Barr, Fiona D; Krohmer, Lori J; Hamilton, Joshua W; Sheldon, Lynn A

2009-08-26

Chronic exposure to inorganic arsenic (iAs) found in the environment is one of the most significant and widespread environmental health risks in the U.S. and throughout the world. It is associated with a broad range of health effects from cancer to diabetes as well as reproductive and developmental anomalies. This diversity of diseases can also result from disruption of metabolic and other cellular processes regulated by steroid hormone receptors via aberrant transcriptional regulation. Significantly, exposure to iAs inhibits steroid hormone-mediated gene activation. iAs exposure is associated with disease, but is also used therapeutically to treat specific cancers complicating an understanding of iAs action. Transcriptional activation by steroid hormone receptors is accompanied by changes in histone and non-histone protein post-translational modification (PTM) that result from the enzymatic activity of coactivator and corepressor proteins such as GRIP1 and CARM1. This study addresses how iAs represses steroid receptor-regulated gene transcription. PTMs on histones H3 and H4 at the glucocorticoid receptor (GR)-activated mouse mammary tumor virus (MMTV) promoter were identified by chromatin immunoprecipitation analysis following exposure to steroid hormone+/-iAs. Histone H3K18 and H3R17 amino acid residues had significantly different patterns of PTMs after treatment with iAs. Promoter interaction of the coactivator CARM1 was disrupted, but the interaction of GRIP1, a p160 coactivator through which CARM1 interacts with a promoter, was intact. Over-expression of CARM1 was able to fully restore and GRIP1 partially restored iAs-repressed transcription indicating that these coactivators are functionally associated with iAs-mediated transcriptional repression. Both are essential for robust transcription at steroid hormone regulated genes and both are associated with disease when inappropriately expressed. We postulate that iAs effects on CARM1 and GRIP1 may underlie some

MATHEMATICAL MODEL OF METABOLIC PATHWAYS OF STEROIDOGENESIS TO PREDICT MOLECULAR RESPONSE FOR ENDOCRINE DISRUPTING CHEMICALS.

EPA Science Inventory

There is increasing evidence that exposure to endocrine disrupting chemicals (EDCs) in the environment can induce adverse effects on reproduction and development in both humans and wildlife, mediated through hormonal disturbances.

Wound Disruption Following Colorectal Operations.

PubMed

Moghadamyeghaneh, Zhobin; Hanna, Mark H; Carmichael, Joseph C; Mills, Steven; Pigazzi, Alessio; Nguyen, Ninh T; Stamos, Michael J

2015-12-01

Postoperative wound disruption is associated with high morbidity and mortality. We sought to identify the risk factors and outcomes of wound disruption following colorectal resection. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was used to examine the clinical data of patients who underwent colorectal resection from 2005 to 2013. Multivariate regression analysis was performed to identify risk factors of wound disruption. We sampled a total of 164,297 patients who underwent colorectal resection. Of these, 2073 (1.3 %) had wound disruption. Patients with wound disruption had significantly higher mortality (5.1 vs. 1.9 %, AOR: 1.46, P = 0.01). The highest risk of wound disruption was seen in patients with wound infection (4.8 vs. 0.9 %, AOR: 4.11, P < 0.01). A number of factors are associated with wound disruption such as chronic steroid use (AOR: 1.71, P < 0.01), smoking (AOR: 1.60, P < 0.01), obesity (AOR: 1.57, P < 0.01), operation length more than 3 h (AOR: 1.56, P < 0.01), severe Chronic Obstructive Pulmonary Disease (COPD) (AOR: 1.36, P < 0.01), urgent/emergent admission (AOR: 1.31, P = 0.01), and serum Albumin Level <3 g/dL (AOR: 1.27, P < 0.01). Laparoscopic surgery had significantly lower risk of wound disruption compared to open surgery (AOR: 0.61, P < 0.01). Wound disruption occurs in 1.3 % of colorectal resections, and it correlates with mortality of patients. Wound infection is the strongest predictor of wound disruption. Chronic steroid use, obesity, severe COPD, prolonged operation, non-elective admission, and serum albumin level are strongly associated with wound disruption. Utilization of the laparoscopic approach may decrease the risk of wound disruption when possible.

Environmental Analysis of Endocrine Disrupting Effects from Hydrocarbon Contaminants in the Ecosystem - Final Report - 09/15/1996 - 09/14/2000

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

McLachlan, John A.

The three major components of the research included: (a) a biotechnology based screening system to identify potential hormone mimics and antagonists (b) an animal screening system to identify biomarkers of endocrine effects and (c) a literature review to identify compounds at various DOE sites that are potential endocrine disruptors. Species of particular interest in this study were those that can serve as sentinel species (e.g., amphibians) and thus provide early warning signals for more widespread impacts on an ecosystem and its wildlife and human inhabitants. The objective of this basic research is to characterize the potential of common hydrocarbon contaminantsmore » in ecosystems to act as endocrine disruptors. Although the endocrine disrupting effects of contaminants such as dioxin and PCBs have been well characterized in both animals and humans, little is known about the capacities of other hydrocarbon contaminants to act as endocrine disruptors. Results obtained from this research project have provided information on endocrine disrupting contaminants for consideration in DOE's risk analyses for determining clean-up levels and priorities at contaminated DOE sites.« less

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.

Early Temporal Effects of Three Thyroid Hormone Synthesis Inhibitors in Xenopus laevis

EPA Science Inventory

Thyroid axis disruption is an important consideration when evaluating the risks associated with chemicals. Bioassay methods that include thyroid-related endpoints have been developed in a variety of species, including amphibians, whose metamorphic development is thyroid hormone ...

Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours

PubMed Central

Patisaul, Heather B.

2017-01-01

A wide range of health benefits have been ascribed to soya intake including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms. Because it is a hormonally active diet, however, soya can also be endocrine disrupting, suggesting that intake has the potential to cause adverse health effects in certain circumstances, particularly when exposure occurs during development. Consequently, the question of whether or not soya phyto-oestrogens are beneficial or harmful to human health is neither straightforward nor universally applicable to all groups. Possible benefits and risks depend on age, health status, and even the presence or absence of specific gut microflora. As global consumption increases, greater awareness and consideration of the endocrine-disrupting properties of soya by nutrition specialists and other health practitioners is needed. Consumption by infants and small children is of particular concern because their hormone-sensitive organs, including the brain and reproductive system, are still undergoing sexual differentiation and maturation. Thus, their susceptibility to the endocrine-disrupting activities of soya phyto-oestrogens may be especially high. As oestrogen receptor partial agonists with molecular and cellular properties similar to anthropogenic endocrine disruptors such as bisphenol A, the soya phyto-oestrogens provide an interesting model for how attitudes about what is ‘synthetic’ v. what is ‘natural,’ shapes understanding and perception of what it means for a compound to be endocrine disrupting and/or potentially harmful. This review describes the endocrine-disrupting properties of soya phyto-oestrogens with a focus on neuroendocrine development and behaviour. PMID:27389644

Building a scientific framework for studying hormonal effects on behavior and on the development of the sexually dimorphic nervous system

EPA Science Inventory

There has been increasing concern that low-dose exposure to hormonally active chemicals disrupts sexual differentiation of the brain and peripheral nervous system. There also has been active drug development research on the therapeutic potential of hormone therapy on behaviors. T...

Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging

PubMed Central

Arum, Oge; Saleh, Jamal; Boparai, Ravneet; Turner, Jeremy; Kopchick, John; Khardori, Romesh; Bartke, Andrzej

2014-01-01

The correlation of physiological sensitivity to insulin ( vis-à-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR) by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric) restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L.) counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice. PMID:25789159

Flow cytometry analysis of hormone receptors on human peripheral blood mononuclear cells to identify stress-induced neuroendocrine effects

NASA Technical Reports Server (NTRS)

Meehan, R. T.

1986-01-01

Understanding the role of circulating peptide hormones in the pathogenesis of space-flight induced disorders would be greatly facilitated by a method which monitors chronic levels of hormones and their effects upon in vivo cell physiology. Single and simultaneous multiparameter flow cytometry analysis was employed to identify subpopulations of mononuclear cells bearing receptors for ACTH, Endorphin, and Somatomedin-C using monoclonal antibodies and monospecific antisera with indirect immunofluorescence. Blood samples were obtained from normal donors and subjects participating in decompression chamber studies (acute stress), medical student academic examination (chronic stress), and a drug study (Dexamethasone). Preliminary results indicate most ACTH and Endorphin receptor positive cells are monocytes and B-cells, exhibit little diurnal variation but the relative percentages of receptor positive cells are influenced by exposure to various stressors and ACTH inhibition. This study demonstrates the capability of flow cytometry analysis to study cell surface hormone receptor regulation which should allow insight into neuroendocrine modulation of the immune and other cellular systems during exposure to stress or microgravity.

HORMONAL PROCESSES IN DECAPOD CRUSTACEAN LARVAE AS BIOMARKERS OF ENDOCRINE DISRUPTING CHEMICALS IN THE MARINE ENVIRONMENT

EPA Science Inventory

Knowledge of endocrine control of the complex larval developmental processes in insects (metamorphosis) has led to the introduction of insect hormones and their analogues as insecticides known as insect growth regulators (IGRs) with the largest group being juvenile hormone analog...

Quantifying light-dependent circadian disruption in humans and animal models.

PubMed

Rea, Mark S; Figueiro, Mariana G

2014-12-01

Although circadian disruption is an accepted term, little has been done to develop methods to quantify the degree of disruption or entrainment individual organisms actually exhibit in the field. A variety of behavioral, physiological and hormonal responses vary in amplitude over a 24-h period and the degree to which these circadian rhythms are synchronized to the daily light-dark cycle can be quantified with a technique known as phasor analysis. Several studies have been carried out using phasor analysis in an attempt to measure circadian disruption exhibited by animals and by humans. To perform these studies, species-specific light measurement and light delivery technologies had to be developed based upon a fundamental understanding of circadian phototransduction mechanisms in the different species. When both nocturnal rodents and diurnal humans, experienced different species-specific light-dark shift schedules, they showed, based upon phasor analysis of the light-dark and activity-rest patterns, similar levels of light-dependent circadian disruption. Indeed, both rodents and humans show monotonically increasing and quantitatively similar levels of light-dependent circadian disruption with increasing shift-nights per week. Thus, phasor analysis provides a method for quantifying circadian disruption in the field and in the laboratory as well as a bridge between ecological measurements of circadian entrainment in humans and parametric studies of circadian disruption in animal models, including nocturnal rodents.

The Role of the Multiple Hormonal Dysregulation in the Onset of “Anemia of Aging”: Focus on Testosterone, IGF-1, and Thyroid Hormones

PubMed Central

Maggio, Marcello; De Vita, Francesca; Fisichella, Alberto; Lauretani, Fulvio; Ticinesi, Andrea; Ceresini, Graziano; Cappola, Anne; Ferrucci, Luigi; Ceda, Gian Paolo

2015-01-01

Anemia is a multifactorial condition whose prevalence increases in both sexes after the fifth decade of life. It is a highly represented phenomenon in older adults and in one-third of cases is “unexplained.” Ageing process is also characterized by a “multiple hormonal dysregulation” with disruption in gonadal, adrenal, and somatotropic axes. Experimental studies suggest that anabolic hormones such as testosterone, IGF-1, and thyroid hormones are able to increase erythroid mass, erythropoietin synthesis, and iron bioavailability, underlining a potential role of multiple hormonal changes in the anemia of aging. Epidemiological data more consistently support an association between lower testosterone and anemia in adult-older individuals. Low IGF-1 has been especially associated with anemia in the pediatric population and in a wide range of disorders. There is also evidence of an association between thyroid hormones and abnormalities in hematological parameters under overt thyroid and euthyroid conditions, with limited data on subclinical statuses. Although RCTs have shown beneficial effects, stronger for testosterone and the GH-IGF-1 axis and less evident for thyroid hormones, in improving different hematological parameters, there is no clear evidence for the usefulness of hormonal treatment in improving anemia in older subjects. Thus, more clinical and research efforts are needed to investigate the hormonal contribution to anemia in the older individuals. PMID:26779261

Endocrine-Disrupting Chemicals and Public Health Protection: A Statement of Principles from The Endocrine Society

PubMed Central

Brown, T. R.; Doan, L. L.; Gore, A. C.; Skakkebaek, N. E.; Soto, A. M.; Woodruff, T. J.; Vom Saal, F. S.

2012-01-01

An endocrine-disrupting chemical (EDC) is an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action. The potential for deleterious effects of EDC must be considered relative to the regulation of hormone synthesis, secretion, and actions and the variability in regulation of these events across the life cycle. The developmental age at which EDC exposures occur is a critical consideration in understanding their effects. Because endocrine systems exhibit tissue-, cell-, and receptor-specific actions during the life cycle, EDC can produce complex, mosaic effects. This complexity causes difficulty when a static approach to toxicity through endocrine mechanisms driven by rigid guidelines is used to identify EDC and manage risk to human and wildlife populations. We propose that principles taken from fundamental endocrinology be employed to identify EDC and manage their risk to exposed populations. We emphasize the importance of developmental stage and, in particular, the realization that exposure to a presumptive “safe” dose of chemical may impact a life stage when there is normally no endogenous hormone exposure, thereby underscoring the potential for very low-dose EDC exposures to have potent and irreversible effects. Finally, with regard to the current program designed to detect putative EDC, namely, the Endocrine Disruptor Screening Program, we offer recommendations for strengthening this program through the incorporation of basic endocrine principles to promote further understanding of complex EDC effects, especially due to developmental exposures. PMID:22733974

A quantitative adverse outcome pathway model for thyroid axis disruption in Xenopus laevis tadpoles

EPA Science Inventory

The development of Xenopus laevis tadpoles is tightly controlled by the thyroid hormones tetraiodothyronine (T4) and triiodothyronine (T3). Toxicity testing efforts have shown that several compounds interfere with development in X. laevis tadpoles by disrupting the thyroid axis a...

Disruption of thyroid hormone (TH) levels and TH-regulated gene expression by polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and hydroxylated PCBs in e-waste recycling workers.

PubMed

Zheng, Jing; He, Chun-Tao; Chen, She-Jun; Yan, Xiao; Guo, Mi-Na; Wang, Mei-Huan; Yu, Yun-Jiang; Yang, Zhong-Yi; Mai, Bi-Xian

2017-05-01

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are the primary toxicants released by electronic waste (e-waste) recycling, but their adverse effects on people working in e-waste recycling or living near e-waste sites have not been studied well. In the present study, the serum concentrations of PBDEs, PCBs, and hydroxylated PCBs, the circulating levels of thyroid hormones (THs), and the mRNA levels of seven TH-regulated genes in peripheral blood leukocytes of e-waste recycling workers were analyzed. The associations of the hormone levels and gene expression with the exposure to these contaminants were examined using multiple linear regression models. There were nearly no associations of the TH levels with PCBs and hydroxylated PCBs, whereas elevated hormone (T 4 and T 3 ) levels were associated with certain lower-brominated BDEs. While not statistically significant, we did observe a negative association between highly brominated PBDE congeners and thyroid-stimulating hormone (TSH) levels in the e-waste workers. The TH-regulated gene expression was more significantly associated with the organohalogen compounds (OHCs) than the TH levels in these workers. The TH-regulated gene expression was significantly associated with certain PCB and hydroxylated PCB congeners. However, the expression of most target genes was suppressed by PBDEs (mostly highly brominated congeners). This is the first evidence of alterations in TH-regulated gene expression in humans exposed to OHCs. Our findings indicated that OHCs may interfere with TH signaling and/or exert TH-like effects, leading to alterations in related gene expression in humans. Further research is needed to investigate the mechanisms of action and associated biological consequences of the gene expression disruption by OHCs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hormones and endometrial carcinogenesis.

PubMed

Kamal, Areege; Tempest, Nicola; Parkes, Christina; Alnafakh, Rafah; Makrydima, Sofia; Adishesh, Meera; Hapangama, Dharani K

2016-02-01

Endometrial cancer (EC) is the commonest gynaecological cancer in the Western World with an alarmingly increasing incidence related to longevity and obesity. Ovarian hormones regulate normal human endometrial cell proliferation, regeneration and function therefore are implicated in endometrial carcinogenesis directly or via influencing other hormones and metabolic pathways. Although the role of unopposed oestrogen in the pathogenesis of EC has received considerable attention, the emerging role of other hormones in this process, such as androgens and gonadotropin-releasing hormones (GnRH) is less well recognised. This review aims to consolidate the current knowledge of the involvement of the three main endogenous ovarian hormones (oestrogens, progesterone and androgens) as well as the other hormones in endometrial carcinogenesis, to identify important avenues for future research.

Bisphenol S and F: A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes

PubMed Central

Bolden, Ashley L.

2015-01-01

Background Increasing concern over bisphenol A (BPA) as an endocrine-disrupting chemical and its possible effects on human health have prompted the removal of BPA from consumer products, often labeled “BPA-free.” Some of the chemical replacements, however, are also bisphenols and may have similar physiological effects in organisms. Bisphenol S (BPS) and bisphenol F (BPF) are two such BPA substitutes. Objectives This review was carried out to evaluate the physiological effects and endocrine activities of the BPA substitutes BPS and BPF. Further, we compared the hormonal potency of BPS and BPF to that of BPA. Methods We conducted a systematic review based on the Office of Health Assessment and Translation (OHAT) protocol. Results We identified the body of literature to date, consisting of 32 studies (25 in vitro only, and 7 in vivo). The majority of these studies examined the hormonal activities of BPS and BPF and found their potency to be in the same order of magnitude and of similar action as BPA (estrogenic, antiestrogenic, androgenic, and antiandrogenic) in vitro and in vivo. BPS also has potencies similar to that of estradiol in membrane-mediated pathways, which are important for cellular actions such as proliferation, differentiation, and death. BPS and BPF also showed other effects in vitro and in vivo, such as altered organ weights, reproductive end points, and enzyme expression. Conclusions Based on the current literature, BPS and BPF are as hormonally active as BPA, and they have endocrine-disrupting effects. Citation Rochester JR, Bolden AL. 2015. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environ Health Perspect 123:643–650; http://dx.doi.org/10.1289/ehp.1408989 PMID:25775505

Endocrine-disrupting chemicals and oil and natural gas operations: Potential environmental contamination and recommendations to assess complex environmental mixtures

USGS Publications Warehouse

Kassotis, Christopher D.; Tillitt, Donald E.; Lin, Chung-Ho; McElroy, Jane A.; Nagel, Susan C.

2016-01-01

Background: Hydraulic fracturing technologies, developed over the last 65 years, have only recently been combined with horizontal drilling to unlock oil and gas reserves previously deemed inaccessible. While these technologies have dramatically increased domestic oil and natural gas production, they have also raised concerns for the potential contamination of local water supplies with the approximately 1,000 chemicals used throughout the process, including many known or suspected endocrine-disrupting chemicals.Objectives: We discuss the need for an endocrine component to health assessments for drilling-dense regions in the context of hormonal and anti-hormonal activities for chemicals used.Methods: We discuss the literature on 1) surface and ground water contamination by oil and gas extraction operations, and 2) potential human exposure, particularly in context of the total hormonal and anti-hormonal activities present in surface and ground water from natural and anthropogenic sources, with initial analytical results and critical knowledge gaps discussed.Discussion: In light of the potential for environmental release of oil and gas chemicals that can disrupt hormone receptor systems, we recommend methods for assessing complex hormonally active environmental mixtures.Conclusions: We describe a need for an endocrine-centric component for overall health assessments and provide supporting information that using this may help explain reported adverse health trends as well as help develop recommendations for environmental impact assessments and monitoring programs.

Moderate Perinatal Thyroid Hormone Insufficiency Alters Visual System Function in Adult Rats

EPA Science Inventory

Thyroid hormone (TH) is critical for many aspects of neurodevelopment, such as the visual system, but may be disrupted by many environmental contaminants. The experimental data demonstrating a role for TH on visual system development generally derives from studies in which deve...

Disruption of thyroid hormone sulfotransferase activity by brominated flame retardant chemicals in the human choriocarcinoma placenta cell line, BeWo.

PubMed

Leonetti, Christopher P; Butt, Craig M; Stapleton, Heather M

2018-04-01

Brominated flame retardants (BFRs) have been shown to disrupt thyroid hormone (TH) homeostasis through multiple mechanisms, including inhibition of enzymes that regulate intracellular levels of THs, such as sulfotransferases (SULTs). The placenta plays a critical role in helping to maintain TH levels during fetal development and expresses SULTs. This is concerning given that disruption of TH regulation within the placenta could potentially harm the developing fetus. In this study, we investigated the effects of two polybrominated diphenyl ethers (PBDEs), two hydroxylated PBDEs, and 2,4,6-tribromophenol (2,4,6-TBP) on TH SULT activity in a choriocarcinoma placenta cell line (BeWo). BeWo cells were exposed to BFR concentrations up to 1 μM for 1-24 h to investigate changes in basal SULT activity and in mRNA expression of several TH regulating genes. 2,4,6-TBP was the most potent inhibitor of basal 3,3'-T2 SULT activity at all exposure durations, decreasing activity by as much as 86% after 24 h of exposure. BDE-99, 3-OH BDE-47, and 6-OH BDE-47 also decreased 3,3'-T2 SULT activity by 23-42% at concentrations of 0.5 μM and 1.0 μM following 24 h exposures. BDE-47 had no effect on SULT activity, and there was no observed effect of any BFR exposure on expression of SULT1A1, or thyroid nuclear receptors alpha or beta. This research demonstrates that total TH SULT activity in placental cells are sensitive to BFR exposure; however, the mechanisms and consequences have yet to be fully elucidated. Copyright © 2017 Elsevier Ltd. All rights reserved.

APPLICATION OF ORGANIC IODINE SPECIES ANALYTICS: DETERMINING THYROID HORMONE STATUS IN ADULT DANIO RERIO AND DEVELOPING XENOPUS LAEVIS USING LC/ICP-MS

EPA Science Inventory

Disruption of normal thyroid function by xenobiotic chemicals is an important ecological issue. Theoretically, normal thyroid hormone (TH) homeostasis and action can be disrupted at several sites in the synthetic and elimination pathways. Indeed, xenobiotic chemicals, which are k...

Phthalate exposure and reproductive hormones and sex-hormone binding globulin before puberty - Phthalate contaminated-foodstuff episode in Taiwan.

PubMed

Wen, Hui-Ju; Chen, Chu-Chih; Wu, Ming-Tsang; Chen, Mei-Lien; Sun, Chien-Wen; Wu, Wen-Chiu; Huang, I-Wen; Huang, Po-Chin; Yu, Tzu-Yun; Hsiung, Chao A; Wang, Shu-Li

2017-01-01

In May 2011, a major incident involving phthalates-contaminated foodstuffs occurred in Taiwan. Di-(2-ethylhexyl) phthalate (DEHP) was added to foodstuffs, mainly juice, jelly, tea, sports drink, and dietary supplements. Concerns arose that normal pubertal development, especially reproductive hormone regulation in children, could be disrupted by DEHP exposure. To investigate the association between phthalate exposure and reproductive hormone levels among children following potential exposure to phthalate-tainted foodstuffs. A total of 239 children aged <12 years old were recruited from 3 hospitals in north, central, and south Taiwan after the episode. Structured questionnaires were used to collect the frequency and quantity of exposures to 5 categories of phthalate-contaminated foodstuffs to assess phthalate exposure in children. Urine samples were collected for the measurement of phthalate metabolites. The estimated daily intake of DEHP exposure at the time of the contamination incident occurred was calculated using both questionnaire data and urinary DEHP metabolite concentrations. Multiple regression analyses were applied to assess associations between phthalate exposure and reproductive hormone levels in children. After excluding children with missing data regarding exposure levels and hormone concentrations and girls with menstruation, 222 children were included in the statistical analyses. After adjustment for age and birth weight, girls with above median levels of urinary mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and sum of mono-(2-ethylhexyl) phthalate concentrations had higher odds of above median follicle-stimulating hormone concentrations. Girls with above median estimated average daily DEHP exposures following the contamination episode also had higher odds of sex hormone-binding globulin above median levels. Phthalate exposure was associated with alterations of reproductive hormone levels in girls.

Generation and characterization of gsuα:EGFP transgenic zebrafish for evaluating endocrine-disrupting effects

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

Cheng, Xiaoxia; University of Chinese Academy of Sciences, Beijing; Chen, Xiaowen

The glycoprotein subunit α (gsuα) gene encodes the shared α subunit of the three pituitary heterodimeric glycoprotein hormones: follicle-stimulating hormone β (Fshβ), luteinizing hormone β (Lhβ) and thyroid stimulating hormone β (Tshβ). In our current study, we identified and characterized the promoter region of zebrafish gsuα and generated a stable gsuα:EGFP transgenic line, which recapitulated the endogenous gsuα expression in the early developing pituitary gland. A relatively conserved regulatory element set is presented in the promoter regions of zebrafish and three other known mammalian gsuα promoters. Our results also demonstrated that the expression patterns of the gsuα:EGFP transgene were allmore » identical to those expression patterns of the endogenous gsuα expression in the pituitary tissue when our transgenic fish were treated with various endocrine chemicals, including forskolin (FSK), SP600125, trichostatin A (TSA), KClO{sub 4}, dexamethasone (Dex), β-estradiol and progesterone. Thus, this gsuα:EGFP transgenic fish reporter line provides another valuable tool for investigating the lineage development of gsuα-expressing gonadotrophins and the coordinated regulation of various glycoprotein hormone subunit genes. These reporter fish can serve as a novel platform to perform screenings of endocrine-disrupting chemicals (EDCs) in vivo as well. - Highlights: • Identification of the promoter of zebrafish glycoprotein subunit α (gsuα) gene • Generation of stable transmission gsuα:EGFP transgenic zebrafish reporter • Demonstration of the recapitulation of the gsuα:EGFP and endogenous gsuα expression • Suggestion of the gsuα:EGFP transgenic zebrafish as a novel platform for EDC study.« less

Genome-wide association study of sex hormones, gonadotropins and sex hormone-binding protein in Chinese men.

PubMed

Chen, Zhuo; Tao, Sha; Gao, Yong; Zhang, Ju; Hu, Yanling; Mo, Linjian; Kim, Seong-Tae; Yang, Xiaobo; Tan, Aihua; Zhang, Haiying; Qin, Xue; Li, Li; Wu, Yongming; Zhang, Shijun; Zheng, S Lilly; Xu, Jianfeng; Mo, Zengnan; Sun, Jielin

2013-12-01

Sex hormones and gonadotropins exert a wide variety of effects in physiological and pathological processes. Accumulated evidence shows a strong heritable component of circulating concentrations of these hormones. Recently, several genome-wide association studies (GWASs) conducted in Caucasians have identified multiple loci that influence serum levels of sex hormones. However, the genetic determinants remain unknown in Chinese populations. In this study, we aimed to identify genetic variants associated with major sex hormones, gonadotropins, including testosterone, oestradiol, follicle-stimulating hormone (FSH), luteinising hormone (LH) and sex hormone binding globulin (SHBG) in a Chinese population. A two-stage GWAS was conducted in a total of 3495 healthy Chinese men (1999 subjects in the GWAS discovery stage and 1496 in the confirmation stage). We identified a novel genetic region at 15q21.2 (rs2414095 in CYP19A1), which was significantly associated with oestradiol and FSH in the Chinese population at a genome-wide significant level (p=6.54×10(-31) and 1.59×10(-16), respectively). Another single nucleotide polymorphism in CYP19A1 gene was significantly associated with oestradiol level (rs2445762, p=7.75×10(-28)). In addition, we confirmed the previous GWAS-identified locus at 17p13.1 for testosterone (rs2075230, p=1.13×10(-8)) and SHBG level (rs2075230, p=4.75×10(-19)) in the Chinese population. This study is the first GWAS investigation of genetic determinants of FSH and LH. The identification of novel susceptibility loci may provide more biological implications for the synthesis and metabolism of these hormones. More importantly, the confirmation of the genetic loci for testosterone and SHBG suggests common genetic components shared among different ethnicities.

In vitro chemical screening assays to identify thyroid hormone disruptors.

EPA Science Inventory

Identification of chemicals with potential to impact thyroid hormone function is a priority of the US EPA’s Endocrine Disruptor Screening Program (EDSP). In vitro screening assays can be used to significantly reduce the number of chemicals that need to be considered for tes...

Development of QSAR models for predicting the binding affinity of endocrine disrupting chemicals to eight fish estrogen receptor.

PubMed

He, Junyi; Peng, Tao; Yang, Xianhai; Liu, Huihui

2018-02-01

Endocrine disrupting effect has become a central point of concern, and various biological mechanisms involve in the disruption of endocrine system. Recently, we have explored the mechanism of disrupting hormonal transport protein, through the binding affinity of sex hormone-binding globulin in different fish species. This study, serving as a companion article, focused on the mechanism of activating/inhibiting hormone receptor, by investigating the binding interaction of chemicals with the estrogen receptor (ER) of different fish species. We collected the relative binding affinity (RBA) of chemicals with 17β-estradiol binding to the ER of eight fish species. With this parameter as the endpoints, quantitative structure-activity relationship (QSAR) models were established using DRAGON descriptors. Statistical results indicated that the developed models had satisfactory goodness of fit, robustness and predictive ability. The Euclidean distance and Williams plot verified that these models had wide application domains, which covered a large number of structurally diverse chemicals. Based on the screened descriptors, we proposed an appropriate mechanism interpretation for the binding potency. Additionally, even though the same chemical had different affinities for ER from different fish species, the affinity of ER exhibited a high correlation for fish species within the same Order (i.e., Salmoniformes, Cypriniformes, Perciformes), which consistent with that in our previous study. Hence, when performing the endocrine disrupting effect assessment, the species diversity should be taken into account, but maybe the fish species in the same Order can be grouped together. Copyright © 2017 Elsevier Inc. All rights reserved.

Exaggerated gonadotropin response to luteinizing hormone-releasing hormone in amenorrheic runners.

PubMed

Yahiro, J; Glass, A R; Fears, W B; Ferguson, E W; Vigersky, R A

1987-03-01

Most studies of exercise-induced amenorrhea have compared amenorrheic athletes (usually runners) with sedentary control subjects. Such comparisons will identify hormonal changes that develop as a result of exercise training but cannot determine which of these changes play a role in causing amenorrhea. To obviate this problem, we assessed reproductive hormone status in a group of five amenorrheic runners and compared them to a group of six eumenorrheic runners matched for body fatness, training intensity, and exercise performance. Compared to the eumenorrheic runners, the amenorrheic runners had lower serum estradiol concentrations, similar basal serum luteinizing hormone and follicle-stimulating hormone concentrations, and exaggerated responses of serum gonadotropins after administration of luteinizing hormone-releasing hormone (100 micrograms intravenous bolus). Serum prolactin levels, both basally and after thyrotropin-releasing hormone administration (500 micrograms intravenous bolus) or treadmill exercise, was similar in the two groups, as were serum thyroid function tests (including thyrotropin response to thyrotropin-releasing hormone). Changes in serum cortisol levels after short-term treadmill exercise were similar in both groups, and serum testosterone levels increased after exercise only in the eumenorrheic group. In neither group did such exercise change serum luteinizing hormone, follicle-stimulating hormone, or thyrotropin levels. We concluded that exercise-induced amenorrhea is not solely related to the development of increased prolactin output after exercise training. The exaggerated gonadotropin response to luteinizing hormone-releasing hormone seen in amenorrheic runners in comparison with matched eumenorrheic runners is consistent with a hypothalamic etiology for the menstrual dysfunction, analogous to that previously described in "stress-induced" or "psychogenic" amenorrhea.

Low-dose effects of hormones and endocrine disruptors.

PubMed

Vandenberg, Laura N

2014-01-01

Endogenous hormones have effects on tissue morphology, cell physiology, and behaviors at low doses. In fact, hormones are known to circulate in the part-per-trillion and part-per-billion concentrations, making them highly effective and potent signaling molecules. Many endocrine-disrupting chemicals (EDCs) mimic hormones, yet there is strong debate over whether these chemicals can also have effects at low doses. In the 1990s, scientists proposed the "low-dose hypothesis," which postulated that EDCs affect humans and animals at environmentally relevant doses. This chapter focuses on data that support and refute the low-dose hypothesis. A case study examining the highly controversial example of bisphenol A and its low-dose effects on the prostate is examined through the lens of endocrinology. Finally, the chapter concludes with a discussion of factors that can influence the ability of a study to detect and interpret low-dose effects appropriately. © 2014 Elsevier Inc. All rights reserved.

Multi-tiered Approach to Development of Increased Throughput Assay Models to Assess Endocrine-Disrupting Activity of Chemicals

EPA Science Inventory

Screening for endocrine-disrupting chemicals (EDCs) requires sensitive, scalable assays. Current high-throughput screening (HTPS) approaches for estrogenic and androgenic activity yield rapid results, but many are not sensitive to physiological hormone concentrations, suggesting ...

Interrater reliability of identifying indicators of posterior ligamentous complex disruption when plain films are indeterminate in thoracolumbar injuries.

PubMed

Schweitzer, Karl M; Vaccaro, Alexander R; Harrop, James S; Hurlbert, John; Carrino, John A; Rechtine, Glenn R; Schwartz, David G; Alanay, Ahmet; Sharma, Dinesh K; Anderson, D Greg; Lee, Joon Y; Arnold, Paul M

2007-09-01

the reliability of identifying disrupted PLC components was poor.

Adult Hippocampal Neurogenesis is Impaired by Transient and Moderate Developmental Thyroid Hormone Disruption

EPA Science Inventory

Severe thyroid hormone (TH) deprivation during development impairs neurogenesis throughout the brain. The hippocampus also maintains a capacity for neurogenesis throughout life which is reduced in adult-onset hypothyroidism. This study examined hippocampal volume in the neonate a...

Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors within the ToxCast Phase I and II Chemical Libraries

EPA Science Inventory

High-throughput screening (HTS) for potential thyroid–disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limi...

Roles of plant hormones in the regulation of host-virus interactions.

PubMed

Alazem, Mazen; Lin, Na-Sheng

2015-06-01

Hormones are tuners of plant responses to biotic and abiotic stresses. They are involved in various complicated networks, through which they modulate responses to different stimuli. Four hormones primarily regulate plant defence to pathogens: salicylic acid (SA), jasmonic acid (JA), ethylene (Et) and abscisic acid (ABA). In susceptible plants, viral infections result in hormonal disruption, which manifests as the simultaneous induction of several antagonistic hormones. However, these antagonistic hormones may exhibit some sequential accumulation in resistant lines. Virus propagation is usually restricted by the activation of the small interfering RNA (siRNA) antiviral machinery and/or SA signalling pathway. Several studies have investigated these two systems, using different model viruses. However, the roles of hormones other than SA, especially those with antagonistic properties, such as ABA, have been neglected. Increasing evidence indicates that hormones control components of the small RNA system, which regulates many processes (including the siRNA antiviral machinery and the microRNA system) at the transcriptional or post-transcriptional level. Consequently, cross-talk between the antagonistic SA and ABA pathways modulates plant responses at multiple levels. In this review, we summarize recent findings on the different roles of hormones in the regulation of plant-virus interactions, which are helping us to elucidate the fine tuning of viral and plant systems by hormones. © 2014 THE AUTHORS. MOLECULAR PLANT PATHOLOGY PUBLISHED BY JOHN WILEY & SONS LTD AND BSPP.

Thyroid hormone accelerates the differentiation of adult hippocampal progenitors.

PubMed

Kapoor, R; Desouza, L A; Nanavaty, I N; Kernie, S G; Vaidya, V A

2012-09-01

Disrupted thyroid hormone function evokes severe physiological consequences in the immature brain. In adulthood, although clinical reports document an effect of thyroid hormone status on mood and cognition, the molecular and cellular changes underlying these behavioural effects are poorly understood. More recently, the subtle effects of thyroid hormone on structural plasticity in the mature brain, in particular on adult hippocampal neurogenesis, have come to be appreciated. However, the specific stages of adult hippocampal progenitor development that are sensitive to thyroid hormone are not defined. Using nestin-green fluorescent protein reporter mice, we demonstrate that thyroid hormone mediates its effects on hippocampal neurogenesis by influencing Type 2b and Type 3 progenitors, although it does not alter proliferation of either the Type 1 quiescent progenitor or the Type 2a amplifying neural progenitor. Thyroid hormone increases the number of doublecortin (DCX)-positive Type 3 progenitors, and accelerates neuronal differentiation into both DCX-positive immature neurones and neuronal nuclei-positive granule cell neurones. Furthermore, we show that this increase in neuronal differentiation is accompanied by a significant induction of specific transcription factors involved in hippocampal progenitor differentiation. In vitro studies using the neurosphere assay support a direct effect of thyroid hormone on progenitor development because neurospheres treated with thyroid hormone are shifted to a more differentiated state. Taken together, our results indicate that thyroid hormone mediates its neurogenic effects via targeting Type 2b and Type 3 hippocampal progenitors, and suggests a role for proneural transcription factors in contributing to the effects of thyroid hormone on neuronal differentiation of adult hippocampal progenitors. © 2012 The Authors. Journal of Neuroendocrinology © 2012 British Society for Neuroendocrinology.

Reconnaissance of 17 beta-estradiol, 11-ketotestosterone, vitellogenin, and gonad histopathology in common carp of United States streams; potential for contaminant-induced endocrine disruption

USGS Publications Warehouse

Goodbred, Steven L.; Gilliom, Robert J.; Gross, Timothy S.; Denslow, Nancy P.; Bryant, Wade B.; Schoeb, Trenton R.

1997-01-01

A reconnaissance of sex steroid hormones and other biomarkers in common carp was used to assess whether endocrine disruption may be occurring in fish in United States streams, to evaluate relations between endocrine disruption and contaminant levels, and to determine requirements for further studies. 17?-estradiol, 11-ketotestosterone, vitellogenin, and gonadal histopathology were measured in adult carp (usually 10--15 for each sex) at 25 sites (647 fish), representing a wide range of environmental settings typical of major regions of the nation. Fish were collected during August--December 1994, a period of gonadal maturation after spawning. Contaminants evaluated were organochlorine pesticides and polychlorinated biphenyls in tissue; phthalates, phenols, and polycyclic aromatic hydrocarbons in bed sediment; and dissolved pesticides in water. Mean site concentrations of steroid hormones spanned two orders of magnitude for both sexes. No significant regional differences in steroid hormones were detected for males, but females from the Northern and Southern Midcontinent were significantly different from other regions of the country in one or both hormones. Within all regions there were significant differences between sites in one or both hormones for both sexes. Most correlation coefficients between biomarkers and contaminants were negative. Contaminants that had significant (a=0.05) correlations with biomarkers were organochlorine pesticides, phenols, and dissolved pesticides. The strongest pattern common to both males and females was a negative correlation between the hormone ratio (E2/11-KT) and dissolved pesticides. The significant site-to-site differences in biomarkers, and the presence of significant correlations between biomarkers and contaminants, are evidence that fish in some streams may be experiencing endocrine disruption. Improved information is needed to evaluate whether endocrine disruption is actually occurring and if there are reproductive effects on

Endocrine Disrupting Effects of Triclosan on the Placenta in Pregnant Rats

PubMed Central

Zhang, Zhaobin; Shi, Jiachen; Jiao, Zhihao; Shao, Bing

2016-01-01

Triclosan (TCS) is a broad-spectrum antimicrobial agent that is frequently used in pharmaceuticals and personal care products. Reports have shown that TCS is a potential endocrine disruptor; however, the potential effects of TCS on placental endocrine function are unclear. The aim of this study was to investigate the endocrine disrupting effects of TCS on the placenta in pregnant rats. Pregnant rats from gestational day (GD) 6 to GD 20 were treated with 0, 30, 100, 300 and 600 mg/kg/d TCS followed by analysis of various biochemical parameters. Of the seven tissues examined, the greatest bioaccumulation of TCS was observed in the placenta. Reduction of gravid uterine weight and the occurrence of abortion were observed in the 600 mg/kg/d TCS-exposed group. Moreover, hormone detection demonstrated that the serum levels of progesterone (P), estradiol (E2), testosterone (T), human chorionic gonadotropin (hCG) and prolactin (PRL) were decreased in groups exposed to higher doses of TCS. Real-time quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR) analysis revealed a significant increase in mRNA levels for placental steroid metabolism enzymes, including UDP-glucuronosyltransferase 1A1 (UGT1A1), estrogen sulfotransferase 1E1 (SULT1E1), steroid 5α-reductase 1 (SRD5A1) and steroid 5α-reductase 2 (SRD5A2). Furthermore, the transcriptional expression levels of progesterone receptor (PR), estrogen receptor (ERα) and androgen receptor (AR) were up-regulated. Taken together, these data demonstrated that the placenta was a target tissue of TCS and that TCS induced inhibition of circulating steroid hormone production might be related to the altered expression of hormone metabolism enzyme genes in the placenta. This hormone disruption might subsequently affect fetal development and growth. PMID:27149376

A nonpeptidyl growth hormone secretagogue.

PubMed

Smith, R G; Cheng, K; Schoen, W R; Pong, S S; Hickey, G; Jacks, T; Butler, B; Chan, W W; Chaung, L Y; Judith, F

1993-06-11

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.

Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action

PubMed Central

De Coster, Sam; van Larebeke, Nicolas

2012-01-01

The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand. PMID:22991565

Genetic polymorphisms, hormone levels, and hot flashes in midlife women.

PubMed

Schilling, Chrissy; Gallicchio, Lisa; Miller, Susan R; Langenberg, Patricia; Zacur, Howard; Flaws, Jodi A

2007-06-20

Hot flashes disrupt the lives of millions of women each year. Although hot flashes are a public health concern, little is known about risk factors that predispose women to hot flashes. Thus, the objective of this study was to examine whether sex steroid hormone levels and genetic polymorphisms in hormone biosynthesis and degradation enzymes are associated with the risk of hot flashes. In a cross-sectional study design, midlife women aged 45-54 years (n=639) were recruited from Baltimore and its surrounding counties. Participants completed a questionnaire and donated a blood sample for steroid hormone analysis and genotyping. The associations between genetic polymorphisms and hormone levels, as well as the associations between genetic polymorphisms, hormone levels, and hot flashes were examined using statistical models. A polymorphism in CYP1B1 was associated with lower dehydroepiandrosterone-sulfate (DHEA-S) and progesterone levels, while a polymorphism in CYP19 (aromatase) was associated with higher testosterone and DHEA-S levels. Lower progesterone and sex hormone binding globulin levels, lower free estradiol index, and a higher ratio of total androgens to total estrogens were associated with the experiencing of hot flashes. A polymorphism in CYP1B1 and a polymorphism in 3betaHSD were both associated with hot flashes. Some genetic polymorphisms may be associated with altered levels of hormones in midlife women. Further, selected genetic polymorphisms and altered hormone levels may be associated with the risk of hot flashes in midlife women.

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

PubMed

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

2017-10-01

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

Pesticides in mixture disrupt metabolic regulation: in silico and in vivo analysis of cumulative toxicity of mancozeb and imidacloprid on body weight of mice.

PubMed

Bhaskar, Rakesh; Mohanty, Banalata

2014-09-01

Pesticides acting as endocrine disrupting chemicals disrupt the homeostasis of body metabolism. The present study elucidated that the low dose coexposure of thyroid disrupting dithiocarbamate fungicide mancozeb (MCZ) and neonicotinoid insecticide imidacloprid (IMI) during lactation increased the risk of body weight gain in mice later in life. Body weight gain has been linked to pesticide-induced hypothyroidism and hyperprolactinemia and alteration of lipid profiles. In vivo results were substantiated with in silico molecular docking (MD) analysis that predicted the binding affinity of pesticides with thyroid hormone receptors (TRα and TRβ) and peroxisome proliferator activated receptor gamma (PPARγ), the major nuclear receptors of peripheral fat metabolism. Binding potency of MCZ and IMI was compared with that of T3, and its antagonist ethylene thiourea (ETU) as well as PPARγ agonist (rosiglitazone) and antagonist (HL005). MD simulation predicted that both MCZ and IMI may compete with T3 for binding with TRs. Imidazole group of IMI formed hydrogen bonds with TRs like that of ETU. MCZ may compete with rosiglitazone and HL005 for PPARγ, but IMI showed no affinity. Thus while both MCZ and IMI could disrupt the TRs functioning, MCZ alone may affect PPARγ. Coexposure of pesticides decreased the plasma thyroid hormones and increased the cholesterol and triglyceride. Individual pesticide exposure in low dose might not exert the threshold response to affect the receptors signaling further to cause hormonal/metabolic impairment. Thus, cumulative response of the mixture of thyroid disrupting pesticides can disrupt metabolic regulation through several pathways and contribute to gain in body weight. Copyright © 2014 Elsevier Inc. All rights reserved.

Plant hormone signaling lightens up: integrators of light and hormones.

PubMed

Lau, On Sun; Deng, Xing Wang

2010-10-01

Light is an important environmental signal that regulates diverse growth and developmental processes in plants. In these light-regulated processes, multiple hormonal pathways are often modulated by light to mediate the developmental changes. Conversely, hormone levels in plants also serve as endogenous cues in influencing light responsiveness. Although interactions between light and hormone signaling pathways have long been observed, recent studies have advanced our understanding by identifying signaling integrators that connect the pathways. These integrators, namely PHYTOCHROME-INTERACTING FACTOR 3 (PIF3), PIF4, PIF3-LIKE 5 (PIL5)/PIF1 and LONG HYPOCOTYL 5 (HY5), are key light signaling components and they link light signals to the signaling of phytohormones, such as gibberellin (GA), abscisic acid (ABA), auxin and cytokinin, in regulating seedling photomorphogenesis and seed germination. This review focuses on these integrators in illustrating how light and hormone interact. Copyright © 2010 Elsevier Ltd. All rights reserved.

Studying the effects of genistein on gene expression of fish embryos as an alternative testing approach for endocrine disruption.

PubMed

Schiller, Viktoria; Wichmann, Arne; Kriehuber, Ralf; Muth-Köhne, Elke; Giesy, John P; Hecker, Markus; Fenske, Martina

2013-01-01

Assessment of endocrine disruption currently relies on testing strategies involving adult vertebrates. In order to minimize the use of animal tests according to the 3Rs principle of replacement, reduction and refinement, we propose a transcriptomics and fish embryo based approach as an alternative to identify and analyze an estrogenic activity of environmental chemicals. For this purpose, the suitability of 48 h and 7 days post-fertilization zebrafish and medaka embryos to test for estrogenic disruption was evaluated. The embryos were exposed to the phytoestrogen genistein and subsequently analyzed by microarrays and quantitative real-time PCR. The functional analysis showed that the genes affected related to multiple metabolic and signaling pathways in the early fish embryo, which reflect the known components of genistein's mode of actions, like apoptosis, estrogenic response, hox gene expression and steroid hormone synthesis. Moreover, the transcriptomic data also suggested a thyroidal mode of action and disruption of the nervous system development. The parallel testing of two fish species provided complementary data on the effects of genistein at gene expression level and facilitated the separation of common from species-dependent effects. Overall, the study demonstrated that combining fish embryo testing with transcriptomics can deliver abundant information about the mechanistic effects of endocrine disrupting chemicals, rendering this strategy a promising alternative approach to test for endocrine disruption in a whole organism in-vitro scale system. Copyright © 2012 Elsevier Inc. All rights reserved.

Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia.

PubMed

van Beveren, N J M; Schwarz, E; Noll, R; Guest, P C; Meijer, C; de Haan, L; Bahn, S

2014-08-26

Molecular abnormalities in metabolic, hormonal and immune pathways are present in peripheral body fluids of a significant subgroup of schizophrenia patients. The authors have tested whether such disturbances also occur in psychiatrically ill and unaffected siblings of schizophrenia patients with the aim of identifying potential contributing factors to disease vulnerability. The subjects were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study. The authors used multiplexed immunoassays to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls. Consistent with the findings of previous studies, serum from schizophrenia patients contained higher levels of insulin, C-peptide and proinsulin, decreased levels of growth hormone and altered concentrations of molecules involved in inflammation. In addition, significant differences were found in the levels of some of these proteins in siblings diagnosed with mood disorders (n=16) and in unaffected siblings (n=117). Most significantly, the insulin/growth hormone ratio was higher across all groups compared with the controls. Taken together, these findings suggest the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia.

The evaluation of endocrine disrupting effects of tert-butylphenols towards estrogenic receptor α, androgen receptor and thyroid hormone receptor β and aquatic toxicities towards freshwater organisms.

PubMed

Wang, Jiaying; Wang, Jingpeng; Liu, Jinsong; Li, Jianzhi; Zhou, Lihong; Zhang, Huanxin; Sun, Jianteng; Zhuang, Shulin

2018-05-09

The phenolic compounds have posed public concern for potential threats to human health and ecosystem. Tert-butylphenols (TBPs), as one group of emerging contaminants, showed potential endocrine disrupting effects and aquatic toxicities. In the present study, we detected concentrations of 2,4-DTBP ranging from <0.001 to 0.057 μg/L (detection limit: 0.001 μg/L) in drinking water source from the Qiantang River in East China in April 2016. The endocrine disrupting effects of 2-TBP, 2,4-DTBP and 2,6-DTBP toward human estrogen receptor α (ERα), androgen receptor (AR) and thyroid hormone receptor β (TRβ) were evaluated using human recombinant two-hybrid yeast bioassay. Their aquatic toxicities were investigated with indicator organisms including Photobacterium phosphoreum, Vibrio fischeri and freshwater green alga Chlamydomonas reinhardtii. 2-TBP and 2,4-DTBP exhibited moderate antagonistic effects toward human ERα and AR in a concentration-dependent manner. 2-TBP significantly inhibited the light emission of P. phosphoreum. 2-TBP, 2,4-DTBP and 2,6-DTBP significantly inhibited the growth of C. reinhardtii and reduced the chlorophyll content. Our results suggest the potential adverse effects of TBPs on human health and aquatic organisms. The data will facilitate further risk assessment of TBPs and related contaminants. Copyright © 2018 Elsevier Ltd. All rights reserved.

Executive Summary to EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

PubMed Central

Chappell, V. A.; Fenton, S. E.; Flaws, J. A.; Nadal, A.; Prins, G. S.; Toppari, J.; Zoeller, R. T.

2015-01-01

This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health. PMID:26414233

Developmental Thyroid Hormone Insufficiency Induces Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study

EPA Science Inventory

Thyroid hormones (TH) are essential for brain development, but animal models of well-defined and sensitive downstream apical neurotoxic outcomes associated with developmental TH disruption are lacking. A structural anomaly, a cortical heterotopia, in the brains of hypothyroid rat...

Fifteen Years after “Wingspread”—Environmental Endocrine Disrupters and Human and Wildlife Health: Where We are Today and Where We Need to Go

PubMed Central

Hotchkiss, Andrew K.; Rider, Cynthia V.; Blystone, Chad R.; Wilson, Vickie S.; Hartig, Phillip C.; Ankley, Gerald T.; Foster, Paul M.; Gray, Clark L.; Gray, L. Earl

2008-01-01

In 1991, a group of expert scientists at a Wingspread work session on endocrine-disrupting chemicals (EDCs) concluded that “Many compounds introduced into the environment by human activity are capable of disrupting the endocrine system of animals, including fish, wildlife, and humans. Endocrine disruption can be profound because of the crucial role hormones play in controlling development.” Since that time, there have been numerous documented examples of adverse effects of EDCs in invertebrates, fish, wildlife, domestic animals, and humans. Hormonal systems can be disrupted by numerous different anthropogenic chemicals including antiandrogens, androgens, estrogens, AhR agonists, inhibitors of steroid hormone synthesis, antithyroid substances, and retinoid agonists. In addition, pathways and targets for endocrine disruption extend beyond the traditional estrogen/androgen/thyroid receptor–mediated reproductive and developmental systems. For example, scientists have expressed concern about the potential role of EDCs in increasing trends in early puberty in girls, obesity and type II diabetes in the United States and other populations. New concerns include complex endocrine alterations induced by mixtures of chemicals, an issue broadened due to the growing awareness that EDCs present in the environment include a variety of potent human and veterinary pharmaceutical products, personal care products, nutraceuticals and phytosterols. In this review we (1) address what have we learned about the effects of EDCs on fish, wildlife, and human health, (2) discuss representative animal studies on (anti)androgens, estrogens and 2,3,7,8-tetrachlorodibenzo-p-dioxin–like chemicals, and (3) evaluate regulatory proposals being considered for screening and testing these chemicals. PMID:18281716

Endocrine-Disrupting Chemicals and Oil and Natural Gas Operations: Potential Environmental Contamination and Recommendations to Assess Complex Environmental Mixtures

PubMed Central

Kassotis, Christopher D.; Tillitt, Donald E.; Lin, Chung-Ho; McElroy, Jane A.; Nagel, Susan C.

2015-01-01

Background Hydraulic fracturing technologies, developed over the last 65 years, have only recently been combined with horizontal drilling to unlock oil and gas reserves previously deemed inaccessible. Although these technologies have dramatically increased domestic oil and natural gas production, they have also raised concerns for the potential contamination of local water supplies with the approximately 1,000 chemicals that are used throughout the process, including many known or suspected endocrine-disrupting chemicals. Objectives We discuss the need for an endocrine component to health assessments for drilling-dense regions in the context of hormonal and antihormonal activities for chemicals used. Methods We discuss the literature on a) surface and groundwater contamination by oil and gas extraction operations, and b) potential human exposure, particularly in the context of the total hormonal and antihormonal activities present in surface and groundwater from natural and anthropogenic sources; we also discuss initial analytical results and critical knowledge gaps. Discussion In light of the potential for environmental release of oil and gas chemicals that can disrupt hormone receptor systems, we recommend methods for assessing complex hormonally active environmental mixtures. Conclusions We describe a need for an endocrine-centric component for overall health assessments and provide information supporting the idea that using such a component will help explain reported adverse health trends as well as help develop recommendations for environmental impact assessments and monitoring programs. Citation Kassotis CD, Tillitt DE, Lin CH, McElroy JA, Nagel SC. 2016. Endocrine-disrupting chemicals and oil and natural gas operations: potential environmental contamination and recommendations to assess complex environmental mixtures. Environ Health Perspect 124:256–264; http://dx.doi.org/10.1289/ehp.1409535 PMID:26311476

Quantitative Adverse Outcome Pathway for Neurodevelopmental Effects of Thyroid Peroxidase-Induced Thyroid Hormone Synthesis Inhibition

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development and deficiencies lead to adverse neurological outcomes in humans and in animal models. Environmental chemicals have been shown to disrupt TH levels, yet the relationship between developmental exposur...

Endocrine Disrupting Chemicals Mediated through Binding Androgen Receptor Are Associated with Diabetes Mellitus

PubMed Central

Sakkiah, Sugunadevi; Wang, Tony; Zou, Wen; Wang, Yuping; Pan, Bohu; Tong, Weida; Hong, Huixiao

2017-01-01

Endocrine disrupting chemicals (EDCs) can mimic natural hormone to interact with receptors in the endocrine system and thus disrupt the functions of the endocrine system, raising concerns on the public health. In addition to disruption of the endocrine system, some EDCs have been found associated with many diseases such as breast cancer, prostate cancer, infertility, asthma, stroke, Alzheimer’s disease, obesity, and diabetes mellitus. EDCs that binding androgen receptor have been reported associated with diabetes mellitus in in vitro, animal, and clinical studies. In this review, we summarize the structural basis and interactions between androgen receptor and EDCs as well as the associations of various types of diabetes mellitus with the EDCs mediated through androgen receptor binding. We also discuss the perspective research for further understanding the impact and mechanisms of EDCs on the risk of diabetes mellitus. PMID:29295509

Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse

PubMed Central

Penatti, Carlos A A; Davis, Matthew C; Porter, Donna M; Henderson, Leslie P

2010-01-01

Gonadotropin–releasing hormone (GnRH) neurons are the central regulators of reproduction. GABAergic transmission plays a critical role in pubertal activation of pulsatile GnRH secretion. Self-administration of excessive doses of anabolic androgenic steroids (AAS) disrupts reproductive function and may have critical repercussions for pubertal onset in adolescent users. Here, we demonstrate that chronic treatment of adolescent male mice with the AAS, 17α-methyltestosterone (17αMT), significantly decreased action potential frequency in GnRH neurons, reduced the serum gonadotropin levels, and decreased testes mass. AAS treatment did not induce significant changes in GABAA receptor subunit mRNA levels or alter the amplitude or decay kinetics of GABAA receptor-mediated spontaneous postsynaptic currents (sPSC) or tonic currents in GnRH neurons. However, AAS treatment significantly increased action potential frequency in neighboring medial preoptic area (mPOA) neurons and GABAA receptor-mediated sPSC frequency in GnRH neurons. In addition, physical isolation of the more lateral aspects of the mPOA from the medially-localized GnRH neurons abrogated the AAS-induced increase in GABAA receptor-mediated sPSC frequency and the decrease in action potential firing in the GnRH cells. Our results indicate that AAS act predominantly on steroid-sensitive presynaptic neurons within the mPOA to impart significant increases in GABAA receptor-mediated inhibitory tone onto downstream GnRH neurons resulting in diminished activity of these pivotal mediators of reproductive function. These AAS-induced changes in central GABAergic circuits of the forebrain may significantly contribute to the disruptive actions of these drugs on pubertal maturation and the development of reproductive competence in male steroid abusers. PMID:20463213

2,3,7,8-Tetrachlorodibenzo-p-dioxin activates the aryl hydrocarbon receptor and alters sex steroid hormone secretion without affecting growth of mouse antral follicles in vitro

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

Karman, Bethany N., E-mail: bklement@illinois.edu; Basavarajappa, Mallikarjuna S., E-mail: mbshivapur@gmail.com; Craig, Zelieann R., E-mail: zelieann@illinois.edu

The persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an ovarian toxicant. These studies were designed to characterize the actions of TCDD on steroidogenesis and growth of intact mouse antral follicles in vitro. Specifically, these studies tested the hypothesis that TCDD exposure leads to decreased sex hormone production/secretion by antral follicles as well as decreased growth of antral follicles in vitro. Since TCDD acts through binding to the aryl hydrocarbon receptor (AHR), and the AHR has been identified as an important factor in ovarian function, we also conducted experiments to confirm the presence and activation of the AHR in our tissue culturemore » system. To do so, we exposed mouse antral follicles for 96 h to a series of TCDD doses previously shown to have effects on ovarian tissues and cells in culture, which also encompass environmentally relevant and pharmacological exposures (0.1–100 nM), to determine a dose response for TCDD in our culture system for growth, hormone production, and expression of the Ahr and Cyp1b1. The results indicate that TCDD decreases progesterone, androstenedione, testosterone, and estradiol levels in a non-monotonic dose response manner without altering growth of antral follicles. The addition of pregnenolone substrate (10 μM) restores hormone levels to control levels. Additionally, Cyp1b1 levels were increased by 3–4 fold regardless of the dose of TCDD exposure, evidence of AHR activation. Overall, these data indicate that TCDD may act prior to pregnenolone formation and through AHR transcriptional control of Cyp1b1, leading to decreased hormone levels without affecting growth of antral follicles. -- Highlights: ►TCDD disrupts sex steroid hormone levels, but not growth of antral follicles. ►Pregnenolone co-treatment by-passes TCDD-induced steroid hormone disruption. ►TCDD affects steroid hormone levels through an AHR pathway in antral follicles.« less

In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles

EPA Science Inventory

As in vitro assays are increasingly used to screen chemicals for their potential to produce endocrine disrupting adverse effects, it is important to understand their predictive capacity. The potential for a set of six benzothiazoles to affect endpoints related to thyroid hormone ...

Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice.

PubMed

Liu, Jun-Li; Coschigano, Karen T; Robertson, Katie; Lipsett, Mark; Guo, Yubin; Kopchick, John J; Kumar, Ujendra; Liu, Ye Lauren

2004-09-01

Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR(-/-)) mice exhibit severe growth retardation and proportionate dwarfism. To assess the physiological relevance of growth hormone actions, GHR(-/-) mice were used to investigate their phenotype in glucose metabolism and pancreatic islet function. Adult GHR(-/-) mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size. The average size of the islets found in GHR(-/-) mice was only one-third of that in wild-type littermates. Total beta-cell mass was reduced 4.5-fold in GHR(-/-) mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR(-/-) mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity. We conclude that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis.

[Circadian rhythm disruption and human development].

PubMed

Kohyama, Jun

2013-12-01

Ontogenetic developments of rest-activity, sleep-wakefulness, temperature and several hormone rhythms in humans were reviewed. The reported effects of environment on these alterations were also summarized. Then, disorders or conditions which often encounter during early stage of life and reveal circadian rhythm disruptions were described. These disorders or conditions included severe brain damage, visual disturbance, developmental disorders(autistic spectrum disorder and attention deficit/hyperactivity disorder), Rett syndrome, Angelman syndrome, Smith-Magenis syndrome, epilepsy, Yonaki, and inadequate sleep hygiene. Finally, it was emphasized that we should pay special attention on the development of youngsters who showed sleep disturbance during early stage of life with special reference to the later occurrence of developmental disorders.

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)

PubMed Central

Zhou, Yihua; Xu, Bixiong C.; Maheshwari, Hiralal G.; He, Li; Reed, Michael; Lozykowski, Maria; Okada, Shigeru; Cataldo, Lori; Coschigamo, Karen; Wagner, Thomas E.; Baumann, Gerhard; Kopchick, John J.

1997-01-01

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans. PMID:9371826

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse).

PubMed

Zhou, Y; Xu, B C; Maheshwari, H G; He, L; Reed, M; Lozykowski, M; Okada, S; Cataldo, L; Coschigamo, K; Wagner, T E; Baumann, G; Kopchick, J J

1997-11-25

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.

Arabidopsis Hormone Database: a comprehensive genetic and phenotypic information database for plant hormone research in Arabidopsis

PubMed Central

Peng, Zhi-yu; Zhou, Xin; Li, Linchuan; Yu, Xiangchun; Li, Hongjiang; Jiang, Zhiqiang; Cao, Guangyu; Bai, Mingyi; Wang, Xingchun; Jiang, Caifu; Lu, Haibin; Hou, Xianhui; Qu, Lijia; Wang, Zhiyong; Zuo, Jianru; Fu, Xiangdong; Su, Zhen; Li, Songgang; Guo, Hongwei

2009-01-01

Plant hormones are small organic molecules that influence almost every aspect of plant growth and development. Genetic and molecular studies have revealed a large number of genes that are involved in responses to numerous plant hormones, including auxin, gibberellin, cytokinin, abscisic acid, ethylene, jasmonic acid, salicylic acid, and brassinosteroid. Here, we develop an Arabidopsis hormone database, which aims to provide a systematic and comprehensive view of genes participating in plant hormonal regulation, as well as morphological phenotypes controlled by plant hormones. Based on data from mutant studies, transgenic analysis and gene ontology (GO) annotation, we have identified a total of 1026 genes in the Arabidopsis genome that participate in plant hormone functions. Meanwhile, a phenotype ontology is developed to precisely describe myriad hormone-regulated morphological processes with standardized vocabularies. A web interface (http://ahd.cbi.pku.edu.cn) would allow users to quickly get access to information about these hormone-related genes, including sequences, functional category, mutant information, phenotypic description, microarray data and linked publications. Several applications of this database in studying plant hormonal regulation and hormone cross-talk will be presented and discussed. PMID:19015126

Arabidopsis Hormone Database: a comprehensive genetic and phenotypic information database for plant hormone research in Arabidopsis.

PubMed

Peng, Zhi-yu; Zhou, Xin; Li, Linchuan; Yu, Xiangchun; Li, Hongjiang; Jiang, Zhiqiang; Cao, Guangyu; Bai, Mingyi; Wang, Xingchun; Jiang, Caifu; Lu, Haibin; Hou, Xianhui; Qu, Lijia; Wang, Zhiyong; Zuo, Jianru; Fu, Xiangdong; Su, Zhen; Li, Songgang; Guo, Hongwei

2009-01-01

Plant hormones are small organic molecules that influence almost every aspect of plant growth and development. Genetic and molecular studies have revealed a large number of genes that are involved in responses to numerous plant hormones, including auxin, gibberellin, cytokinin, abscisic acid, ethylene, jasmonic acid, salicylic acid, and brassinosteroid. Here, we develop an Arabidopsis hormone database, which aims to provide a systematic and comprehensive view of genes participating in plant hormonal regulation, as well as morphological phenotypes controlled by plant hormones. Based on data from mutant studies, transgenic analysis and gene ontology (GO) annotation, we have identified a total of 1026 genes in the Arabidopsis genome that participate in plant hormone functions. Meanwhile, a phenotype ontology is developed to precisely describe myriad hormone-regulated morphological processes with standardized vocabularies. A web interface (http://ahd.cbi.pku.edu.cn) would allow users to quickly get access to information about these hormone-related genes, including sequences, functional category, mutant information, phenotypic description, microarray data and linked publications. Several applications of this database in studying plant hormonal regulation and hormone cross-talk will be presented and discussed.

Exposure to PFDoA causes disruption of the hypothalamus-pituitary-thyroid axis in zebrafish larvae.

PubMed

Zhang, Shengnan; Guo, Xiaochun; Lu, Shaoyong; Sang, Nan; Li, Guangyu; Xie, Ping; Liu, Chunsheng; Zhang, Liguo; Xing, Yi

2018-04-01

Perfluorododecanoic acid (PFDoA), a kind of perfluorinated carboxylic acid (PFCA) with 12 carbon atoms, has an extensive industrial utilization and is widespread in both wildlife and the water environment, and was reported to have the potential to cause a disruption in the thyroid hormone system homeostasis. In this study, zebrafish embryos/larvae were exposed to different concentrations of PFDoA (0, 0.24, 1.2, 6 mg/L) for 96 h post-fertilization (hpf). PFDoA exposure caused obvious growth restriction connected with the reduced thyroid hormones (THs) contents in zebrafish larvae, strengthening the interference effect on the growth of fish larvae. The transcriptional level of genes within the hypothalamic-pituitary-thyroid (HPT) axis was analyzed. The gene expression levels of thyrotropin-releasing hormone (trh) and corticotrophin-releasing hormone (crh) were upregulated upon exposure to 6 mg/L of PFDoA, and iodothyronine deiodinases (dio2) was upregulated in the 1.2 mg/L PFDoA group. The transcription of thyroglobulin (tg) and thyroid receptor (trβ) were significantly downregulated upon exposure to 1.2 mg/L and 6 mg/L of PFDoA. PFDoA could also decrease the levels of sodium/iodide symporter (nis) and transthyretin (ttr) gene expression in a concentration-dependent manner after exposure. A significant decrease in thyroid-stimulating hormoneβ (tshβ), uridinediphosphate-glucuronosyltransferase (ugt1ab) and thyroid receptor (trα) gene expression were observed at 6 mg/L PFDoA exposure. Upregulation and downregulation of iodothyronine deiodinases (dio1) gene expression were observed upon the treatment of 1.2 mg/L and 6 mg/L PFDoA, respectively. All the data demonstrated that gene expression in the HPT axis altered after different PFDoA treatment and the potential mechanisms of the disruption of thyroid status could occur at several steps in the process of synthesis, regulation, and action of thyroid hormones. Copyright © 2018 Elsevier Ltd. All

Gene Expression in Developing Brain is Altered by Modest Reductions in Circulating Levels of Thyroid Hormone.

EPA Science Inventory

Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequatel...

Environmental analysis of endocrine disrupting effects from hydrocarbon contaminants in the ecosystem. 1998 annual progress report

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

McLachlan, J.

1998-06-01

'The objective of this project is to determine how environmental contaminants, namely hydrocarbons, can act as hormones or anti-hormones (i.e., environmental hormones) in different species present in aquatic ecosystems. Species of particular focus are those which can serve as sentinel species (e.g., amphibians) and, thus, provide early warning signals for more widespread impacts on an ecosystem and its wildlife and human inhabitants. This reports the progress of 1.5 years of a three-year grant awarded to the Tulane/Xavier Center for Bioenvironmental Research (CBR). A growing body of evidence suggests that chemicals in the environment can disrupt the endocrine system of animalsmore » (i.e., wildlife and humans) and adversely impact the development of these species. Because of the multitude of known endocrine-disrupting chemicals and the numerous industrial and government sectors producing these chemicals, almost every federal agency has initiated research on the endocrine effects of chemicals relevant to their operations. This study represents the Department of Energy (DOE) Basic Energy Sciences'' only research on the impacts of endocrine-disrupting chemicals. The activities employed by this project to determine these impacts include development of biotechnology screens (in vitro), animal screens (in vivo), and other analyses of aquatic ecosystem biomarkers of exposure. The results from this study can elucidate how chemicals in the environment, including those from DOE activities, can signal (and alter) the development of a number of species in aquatic ecosystems. These signals can have detrimental impacts not only on an organismal level, but also on community, population, and entire ecosystem levels, including humans.'« less

Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia

PubMed Central

Armitage, Andrew E.; Lim, Pei Jin; Frost, Joe N.; Pasricha, Sant-Rayn; Soilleux, Elizabeth J.; Evans, Emma; Morovat, Alireza; Santos, Ana; Diaz, Rebeca; Biggs, Daniel; Davies, Benjamin; Gileadi, Uzi; Robbins, Peter A.; Lakhal-Littleton, Samira; Drakesmith, Hal

2016-01-01

Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation. PMID:27423740

Thyroid endocrine system disruption by pentachlorophenol: an in vitro and in vivo assay.

PubMed

Guo, Yongyong; Zhou, Bingsheng

2013-10-15

The present study aimed to evaluate the disruption caused to the thyroid endocrine system by pentachlorophenol (PCP) using in vitro and in vivo assays. In the in vitro assay, rat pituitary GH3 cells were exposed to 0, 0.1, 0.3, and 1.0 μM PCP. PCP exposure significantly downregulated basal and triiodothyronine (T3)-induced Dio 1 transcription, indicating the antagonistic activity of PCP in vitro. In the in vivo assay, zebrafish embryos were exposed to 0, 1, 3, and 10 μg/L of PCP until 14 days post-fertilization. PCP exposure resulted in decreased thyroxine (T4) levels, but elevated contents of whole-body T3. PCP exposure significantly upregulated the mRNA expression of genes along hypothalamic-pituitary-thyroid (HPT) axis, including those encoding thyroid-stimulating hormone, sodium/iodide symporter, thyroglobulin, Dio 1 and Dio 2, alpha and beta thyroid hormone receptor, and uridinediphosphate-glucuronosyl-transferase. PCP exposure did not influence the transcription of the transthyretin (TTR) gene. The results indicate that PCP potentially disrupts the thyroid endocrine system both in vitro and in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

In vivo deiodinase inhibition by iopanoic acid causes thyroid axis disruption and dysmorphogenesis in model amphibian species Xenopus laevis

EPA Science Inventory

Deiodinase (DIO) enzymes activate, deactivate and catabolize thyroid hormones (THs) and play an important role in thyroid-mediated amphibian metamorphosis. DIOs have been implicated as putative targets of xenobiotics leading to thyroid disruption. In an effort to characterize bi...

Plant peptide hormone signalling.

PubMed

Motomitsu, Ayane; Sawa, Shinichiro; Ishida, Takashi

2015-01-01

The ligand-receptor-based cell-to-cell communication system is one of the most important molecular bases for the establishment of complex multicellular organisms. Plants have evolved highly complex intercellular communication systems. Historical studies have identified several molecules, designated phytohormones, that function in these processes. Recent advances in molecular biological analyses have identified phytohormone receptors and signalling mediators, and have led to the discovery of numerous peptide-based signalling molecules. Subsequent analyses have revealed the involvement in and contribution of these peptides to multiple aspects of the plant life cycle, including development and environmental responses, similar to the functions of canonical phytohormones. On the basis of this knowledge, the view that these peptide hormones are pivotal regulators in plants is becoming increasingly accepted. Peptide hormones are transcribed from the genome and translated into peptides. However, these peptides generally undergo further post-translational modifications to enable them to exert their function. Peptide hormones are expressed in and secreted from specific cells or tissues. Apoplastic peptides are perceived by specialized receptors that are located at the surface of target cells. Peptide hormone-receptor complexes activate intracellular signalling through downstream molecules, including kinases and transcription factors, which then trigger cellular events. In this chapter we provide a comprehensive summary of the biological functions of peptide hormones, focusing on how they mature and the ways in which they modulate plant functions. © 2015 Authors; published by Portland Press Limited.

Developing a model of plant hormone interactions

PubMed Central

Wang, Yu Hua

2011-01-01

Plant growth and development is influenced by mutual interactions among plant hormones. The five classical plant hormones are auxins, cytokinins, gibberellins, abscisic acid and ethylene. They are small diffusible molecules that easily penetrate between cells. In addition, newer classes of plant hormones have been identified such as brassinosteroids, jasmonic acid, salicylic acid and various small proteins or peptides. These hormones also play important roles in the regulation of plant growth and development. This review begins with a brief summary of the current findings on plant hormones. Based on this knowledge, a conceptual model about interactions among plant hormones is built so as to link and develop an understanding of the diverse functions of different plant hormones as a whole in plants. PMID:21406974

Endocrine-Disrupting Chemicals and Oil and Natural Gas Operations: Potential Environmental Contamination and Recommendations to Assess Complex Environmental Mixtures.

PubMed

Kassotis, Christopher D; Tillitt, Donald E; Lin, Chung-Ho; McElroy, Jane A; Nagel, Susan C

2016-03-01

Hydraulic fracturing technologies, developed over the last 65 years, have only recently been combined with horizontal drilling to unlock oil and gas reserves previously deemed inaccessible. Although these technologies have dramatically increased domestic oil and natural gas production, they have also raised concerns for the potential contamination of local water supplies with the approximately 1,000 chemicals that are used throughout the process, including many known or suspected endocrine-disrupting chemicals. We discuss the need for an endocrine component to health assessments for drilling-dense regions in the context of hormonal and antihormonal activities for chemicals used. We discuss the literature on a) surface and groundwater contamination by oil and gas extraction operations, and b) potential human exposure, particularly in the context of the total hormonal and antihormonal activities present in surface and groundwater from natural and anthropogenic sources; we also discuss initial analytical results and critical knowledge gaps. In light of the potential for environmental release of oil and gas chemicals that can disrupt hormone receptor systems, we recommend methods for assessing complex hormonally active environmental mixtures. We describe a need for an endocrine-centric component for overall health assessments and provide information supporting the idea that using such a component will help explain reported adverse health trends as well as help develop recommendations for environmental impact assessments and monitoring programs.

Ergonomics perspective for identifying and reducing internal operative flow disruption for laparoscopic urological surgery.

PubMed

Al-Hakim, Latif; Xiao, Jiaquan; Sengupta, Shomik

2017-12-01

The aim of this study is to examine operative flow disruption that occurs inside the surgical field, (internal operative flow disruption (OFD)), during urological laparoscopies, and to relate those events to external ergonomics environment in terms of monitor location, level of instruments' handles, and location of surgical team members. According to the our best knowledge, this is the first study of its kind. A combination of real and video-aided observational study was conducted in the operating rooms at hospitals in Australia and China. Brain storming sessions were first conducted to identify the main internal OFD events, and the observable reasons, potential external, and latent ergonomic factors were listed. A prospective observational study was then conducted. The observer's records and the related video records of internal surgical fields were analysed. Procedures were categorised into groups based on similarity in ergonomics environment. The mapping process revealed 39 types of internal OFD events resulted from six reasons. A total of 24 procedures were selected and arranged into two groups, each with twelve procedures. Group A was carried out under satisfactory ergonomics environment, while Group B was conducted under unsatisfactory ergonomics environment. A total of 1178 OFD events were detected delaying the total observed operative times (2966 min) by 220 min (7.43%). Average OFD/h in group A was less than 15, while in group B about 29 OFD/h. There are two main latent ergonomics factors affecting the surgeon's performance; non-physiological posture and long-period static posture. The delays and number of internal OFD were nearly doubled where procedures were conducted under unsatisfactory external ergonomics environment. Some events such as stopping operation and irrelevant conversations during long procedures may have a positive influence on the surgeon's performance.

Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development, deficiencies may lead to adverse neurological outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures an...

Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis

PubMed Central

Roepke, Torsten K.; King, Elizabeth C.; Reyna-Neyra, Andrea; Paroder, Monika; Purtell, Kerry; Koba, Wade; Fine, Eugene; Lerner, Daniel J.; Carrasco, Nancy; Abbott, Geoffrey W.

2009-01-01

Thyroid dysfunction affects 1–4% of the population worldwide, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that KCNQ1 and KCNE2 form a TSH-stimulated, constitutively-active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 impaired thyroid iodide accumulation up to 8-fold, impaired maternal milk ejection and halved milk T4 content, causing hypothyroidism, 50% reduced litter size, dwarfism, alopecia, goiter, and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by T3/T4 administration to pups, by supplementing dams with T4 pre- and postpartum, or by pre-weaning surrogacy with Kcne2+/+ dams; conversely these symptoms were elicited in Kcne2+/+ pups by surrogacy with Kcne2−/− dams. The data identify a critical thyrocyte K+ channel, provide a possible novel therapeutic avenue for thyroid disorders, and predict an endocrine component to some previously-identified KCNE2- and KCNQ1-linked human cardiac arrhythmias. PMID:19767733

Cellular and Hormonal Disruption of Fetal Testis Development in Sheep Reared on Pasture Treated with Sewage Sludge

PubMed Central

Paul, Catriona; Rhind, Stewart M.; Kyle, Carol E.; Scott, Hayley; McKinnell, Chris; Sharpe, Richard M.

2005-01-01

The purpose of this study was to evaluate whether experimental exposure of pregnant sheep to a mixture of environmental chemicals added to pasture as sewage sludge (n = 9 treated animals) exerted effects on fetal testis development or function; application of sewage sludge was undertaken so as to maximize exposure of the ewes to its contents. Control ewes (n = 9) were reared on pasture treated with an equivalent amount of inorganic nitrogenous fertilizer. Treatment had no effect on body weight of ewes, but it reduced body weight by 12–15% in male (n = 12) and female (n = 8) fetuses on gestation day 110. In treated male fetuses (n = 11), testis weight was significantly reduced (32%), as were the numbers of Sertoli cells (34% reduction), Leydig cells (37% reduction), and gonocytes (44% reduction), compared with control fetuses (n = 8). Fetal blood levels of testosterone and inhibin A were also reduced (36% and 38%, respectively) in treated compared with control fetuses, whereas blood levels of luteinizing hormone and follicle-stimulating hormone were unchanged. Based on immunoexpression of anti-Müllerian hormone, cytochrome P450 side chain cleavage enzyme, and Leydig cell cytoplasmic volume, we conclude that the hormone changes in treated male fetuses probably result from the reduction in somatic cell numbers. This reduction could result from fetal growth restriction in male fetuses and/or from the lowered testosterone action; reduced immunoexpression of α-smooth muscle actin in peritubular cells and of androgen receptor in testes of treated animals supports the latter possibility. These findings indicate that exposure of the developing male sheep fetus to real-world mixtures of environmental chemicals can result in major attenuation of testicular development and hormonal function, which may have consequences in adulthood. PMID:16263515

MODE OF ACTION: NEUROTOXICITY INDUCED BY DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY -- NEUROLOGICAL ABNORMALITIES RESULTING FROM EXPOSURE TO PROPYLTHIOURACIL.

EPA Science Inventory

A manuscript summarizes a workshop aimed at developing a framework to determine the relevancy of animal modes-of-action for extrapolation to humans. This specific report used animal data on neurodevelopmental effects of thyroid hormone disruption to test the framework. Polyhaloge...

Bisphenol A and reproductive hormones and cortisol in peripubertal boys: The INMA-Granada cohort.

PubMed

Mustieles, Vicente; Ocón-Hernandez, Olga; Mínguez-Alarcón, Lidia; Dávila-Arias, Cristina; Pérez-Lobato, Rocío; Calvente, Irene; Arrebola, Juan P; Vela-Soria, Fernando; Rubio, Soledad; Hauser, Russ; Olea, Nicolás; Fernández, Mariana F

2018-03-15

Bisphenol A (BPA) is a well-known endocrine disrupting compound. Although several studies have investigated the effect of BPA exposure and reproductive hormones in humans, results have been inconsistent. To explore the cross-sectional relationship between bisphenol A (BPA) exposure and reproductive hormones/cortisol among peripubertal boys. Urinary BPA and serum hormones were assessed in 172 boys belonging to the INMA "Environment and Childhood" Granada birth cohort in their follow-up at 9-11years of age. BPA concentrations were quantified by liquid chromatography-mass spectrometry, and levels of serum total testosterone (TT), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and cortisol were measured by electrochemiluminescence immunoassay. After adjustment for confounders, linear regression models showed that each natural-log unit increase in urinary BPA concentrations was associated with a 19% increase in geometric mean (GM) serum TT levels, and a 16% decrease in GM serum cortisol levels. When urinary BPA concentrations were categorized in tertiles, boys in the 3rd tertile showed 49% higher TT levels and 23% lower cortisol concentrations compared to boys in the 1st tertile. Additionally, urinary BPA concentrations were also significantly associated with higher TT:LH and TT:cortisol ratios, but not with serum LH or FSH levels. Our results suggest the possible endocrine disrupting potential of BPA during this important period of development. Although action at the testis or pituitary cannot be ruled out, our findings are compatible with a possible involvement of BPA at the adrenal gland, resulting in a differential production of androgens/cortisol. However, given the cross-sectional design of our study, the heterogeneous results reported in the literature, and the scant experimental research on BPA effects at the adrenal gland, the present findings should be interpreted with caution. Copyright © 2017 Elsevier B.V. All rights reserved.

Disrupting incrementalism in health care innovation.

PubMed

Soleimani, Farzad; Zenios, Stefanos

2011-08-01

To build enabling innovation frameworks for health care entrepreneurs to better identify, evaluate, and pursue entrepreneurial opportunities. Powerful frameworks have been developed to enable entrepreneurs and investors identify which opportunity areas are worth pursuing and which start-up ideas have the potential to succeed. These frameworks, however, have not been clearly defined and interpreted for innovations in health care. Having a better understanding of the process of innovation in health care allows physician entrepreneurs to innovate more successfully. A review of academic literature was conducted. Concepts and frameworks related to technology innovation were analyzed. A new set of health care specific frameworks was developed. These frameworks were then applied to innovations in various health care subsectors. Health care entrepreneurs would greatly benefit from distinguishing between incremental and disruptive innovations. The US regulatory and reimbursement systems favor incrementalism with a greater chance of success for established players. Small companies and individual groups, however, are more likely to thrive if they adopt a disruptive strategy. Disruption in health care occurs through various mechanisms as detailed in this article. While the main mechanism of disruption might vary across different health care subsectors, it is shown that disruptive innovations consistently require a component of contrarian interpretation to guarantee considerable payoff. If health care entrepreneurs choose to adopt an incrementalist approach, they need to build the risk of disruption into their models and also ascertain that they have a very strong intellectual property (IP) position to weather competition from established players. On the contrary, if they choose to pursue disruption in the market, albeit the competition will be less severe, they need to recognize that the regulatory and reimbursement hurdles are going to be very high. Thus, they would benefit

Endocrine Parameters and Phenotypes of the Growth Hormone Receptor Gene Disrupted (GHR−/−) Mouse

PubMed Central

List, Edward O.; Sackmann-Sala, Lucila; Berryman, Darlene E.; Funk, Kevin; Kelder, Bruce; Gosney, Elahu S.; Okada, Shigeru; Ding, Juan; Cruz-Topete, Diana

2011-01-01

Disruption of the GH receptor (GHR) gene eliminates GH-induced intracellular signaling and, thus, its biological actions. Therefore, the GHR gene disrupted mouse (GHR−/−) has been and is a valuable tool for helping to define various parameters of GH physiology. Since its creation in 1995, this mouse strain has been used by our laboratory and others for numerous studies ranging from growth to aging. Some of the most notable discoveries are their extreme insulin sensitivity in the presence of obesity. Also, the animals have an extended lifespan, which has generated a large number of investigations into the roles of GH and IGF-I in the aging process. This review summarizes the many results derived from the GHR−/− mice. We have attempted to present the findings in the context of current knowledge regarding GH action and, where applicable, to discuss how these mice compare to GH insensitivity syndrome in humans. PMID:21123740

Protective effect of Growth Hormone-Releasing Hormone agonist in bacterial toxin-induced pulmonary barrier dysfunction.

PubMed

Czikora, Istvan; Sridhar, Supriya; Gorshkov, Boris; Alieva, Irina B; Kasa, Anita; Gonzales, Joyce; Potapenko, Olena; Umapathy, Nagavedi S; Pillich, Helena; Rick, Ferenc G; Block, Norman L; Verin, Alexander D; Chakraborty, Trinad; Matthay, Michael A; Schally, Andrew V; Lucas, Rudolf

2014-01-01

Antibiotic treatment of patients infected with G(-) or G(+) bacteria promotes release of the toxins lipopolysaccharide (LPS) and pneumolysin (PLY) in their lungs. Growth Hormone-releasing Hormone (GHRH) agonist JI-34 protects human lung microvascular endothelial cells (HL-MVEC), expressing splice variant 1 (SV-1) of the receptor, from PLY-induced barrier dysfunction. We investigated whether JI-34 also blunts LPS-induced hyperpermeability. Since GHRH receptor (GHRH-R) signaling can potentially stimulate both cAMP-dependent barrier-protective pathways as well as barrier-disruptive protein kinase C pathways, we studied their interaction in GHRH agonist-treated HL-MVEC, in the presence of PLY, by means of siRNA-mediated protein kinase A (PKA) depletion. Barrier function measurements were done in HL-MVEC monolayers using Electrical Cell substrate Impedance Sensing (ECIS) and VE-cadherin expression by Western blotting. Capillary leak was assessed by Evans Blue dye (EBD) incorporation. Cytokine generation in broncho-alveolar lavage fluid (BALF) was measured by multiplex analysis. PKA and PKC-α activity were assessed by Western blotting. GHRH agonist JI-34 significantly blunts LPS-induced barrier dysfunction, at least in part by preserving VE-cadherin expression, while not affecting inflammation. In addition to activating PKA, GHRH agonist also increases PKC-α activity in PLY-treated HL-MVEC. Treatment with PLY significantly decreases resistance in control siRNA-treated HL-MVEC, but does so even more in PKA-depleted monolayers. Pretreatment with GHRH agonist blunts PLY-induced permeability in control siRNA-treated HL-MVEC, but fails to improve barrier function in PKA-depleted PLY-treated monolayers. GHRH signaling in HL-MVEC protects from both LPS and PLY-mediated endothelial barrier dysfunction and concurrently induces a barrier-protective PKA-mediated and a barrier-disruptive PKC-α-induced pathway in the presence of PLY, the former of which dominates the latter.

SMALL FISH MODELS FOR IDENTIFYING AND ASSESSING THE EFFECTS OF ENDOCRINE DISRUPTING CHEMICALS

EPA Science Inventory

Endocrine-disrupting chemicals (EDCs), in particular those which affect the hypothalamic-pituitary-gonadal (HPG) axis of vertebrates, have become a focus of regulatory screening and testing throughout the world. Small fish species, principally the fathead minnow (Pimephales prom...

Determining Baseline Stress-Related Hormone Values in Large Cetaceans

DTIC Science & Technology

2014-09-30

reconstructed chemical profiles provided a unique window into stress-related hormone (cortisol, aldosterone , T3 and T4) concentrations and...Stress-related hormone radioimmunoassay technique Cortisol, aldosterone , hormones thyroxine (T4) and triiodothyronine (T3) levels in each identified...contaminant concentrations will be calculated using Pearson correlation coefficients. These measurements will include all hormones ( aldosterone , T3

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

NASA Astrophysics Data System (ADS)

Fini, Jean-Baptiste; Mughal, Bilal B.; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A.

2017-03-01

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

Stereoselective degradation and thyroid endocrine disruption of lambda-cyhalothrin in lizards (Eremias argus) following oral exposure.

PubMed

Chang, Jing; Hao, Weiyu; Xu, Yuanyuan; Xu, Peng; Li, Wei; Li, Jianzhong; Wang, Huili

2018-01-01

The disturbance of the thyroid system and elimination of chiral pyrethroid pesticides with respect to enantioselectivity in reptiles have so far received limited attention by research. In this study, bioaccumulation, thyroid gland lesions, thyroid hormone levels, and hypothalamus-pituitary-thyroid axis-related gene expression in male Eremias argus were investigated after three weeks oral administration of lambda-cyhalothrin (LCT) enantiomers. In the lizard liver, the concentration of LCT was negatively correlated with the metabolite-3-phenoxybenzoic acid (PBA) level during 21 days of exposure. (+)-LCT exposure induced a higher thyroid follicular epithelium height than (-)-LCT exposure. The thyroxine levels were increased in both treated groups while only (+)-LCT exposure induced a significant change in the triiodothyronine (T3) level. In addition, the expressions of hypothalamus-pituitary-thyroid axis-related genes including thyroid hormone receptors (trs), deiodinases (dios), uridinediphosphate glucuronosyltransferase (udp), and sulfotransferase (sult) were up-regulated after exposure to the two enantiomers. (+)-LCT treatment resulted in higher expression of trs and (-)-LCT exposure led to greater stimulation of dios in the liver, which indicated PBA-induced antagonism on thyroid hormone receptors and LCT-induced disruption of thyroxine (T4) deiodination. The results suggest the (-)-LCT exposure causes higher residual level in lizard liver while induces less disruption on lizard thyroid activity than (+)-LCT. Copyright © 2017 Elsevier Ltd. All rights reserved.

Endocrine disruption, parasites and pollutants in wild freshwater fish.

PubMed

Jobling, S; Tyler, C R

2003-01-01

Disruption of the endocrine system has been shown to occur in wild freshwater fish populations across the globe. Effects range from subtle changes in the physiology and sexual behaviour of fish to permanently altered sexual differentiation, impairment of gonad development and/or altered fertility. A wide variety of adverse environmental conditions may induce endocrine disruption, including sub-optimal temperatures, restricted food supply, low pH, environmental pollutants, and/or parasites. Furthermore, it is conceivable that any/all of these factors could act simultaneously to cause a range of disparate or inter-related effects. Some of the strongest evidence for a link between an adverse health effect, as a consequence of endocrine disruption, and a causative agent(s) is between the condition of intersex in wild roach (Rutlius rutilus) in UK rivers and exposure to effluents from sewage treatment works. The evidence to indicate that intersex in roach (and other cyprinid fish living in these rivers) is caused by chemicals that mimic and/or disrupt hormone function/balance in treated sewage effluent is substantial. There are a few parasites that affect the endocrine system directly in fish, including the tape worm Ligula intestinalis and a few parasites from the micropsora phylum. L. intestinalis acts at the level of the hypothalamus restricting GnRH secretion (resulting in poorly developed gonads) and is one of the very few examples where an endocrine disrupting event has been shown to result in a population-level effect (reducing it). It is well established that many parasites affect the immune system and thus the most common effect of parasites on the endocrine system in fish is likely to be an indirect one.

Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals

EPA Science Inventory

The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endo...

EFFECTS OF BDE-47 ON NUCLEAR RECEPTOR REGULATED GENES AND IMPLICATIONS FOR THYROID HORMONE DISRUPTION.

EPA Science Inventory

Previous studies have shown that exposure to polybrominated diphenyl ethers (PBDEs) can decrease thyroid hormone levels via the induction of hepatic uridinediphosphate-glucoronosyltransferase, (UGTs) which catalyze glucuronidation of T4 resulting in T4-glucuronide excretion. Bas...

Interruptions disrupt reading comprehension.

PubMed

Foroughi, Cyrus K; Werner, Nicole E; Barragán, Daniela; Boehm-Davis, Deborah A

2015-06-01

Previous research suggests that being interrupted while reading a text does not disrupt the later recognition or recall of information from that text. This research is used as support for Ericsson and Kintsch's (1995) long-term working memory (LT-WM) theory, which posits that disruptions while reading (e.g., interruptions) do not impair subsequent text comprehension. However, to fully comprehend a text, individuals may need to do more than recognize or recall information that has been presented in the text at a later time. Reading comprehension often requires individuals to connect and synthesize information across a text (e.g., successfully identifying complex topics such as themes and tones) and not just make a familiarity-based decision (i.e., recognition). The goal for this study was to determine whether interruptions while reading disrupt reading comprehension when the questions assessing comprehension require participants to connect and synthesize information across the passage. In Experiment 1, interruptions disrupted reading comprehension. In Experiment 2, interruptions disrupted reading comprehension but not recognition of information from the text. In Experiment 3, the addition of a 15-s time-out prior to the interruption successfully removed these negative effects. These data suggest that the time it takes to process the information needed to successfully comprehend text when reading is greater than that required for recognition. Any interference (e.g., an interruption) that occurs during the comprehension process may disrupt reading comprehension. This evidence supports the need for transient activation of information in working memory for successful text comprehension and does not support LT-WM theory. (c) 2015 APA, all rights reserved).

Changes of thyroid hormone levels and related gene expression in zebrafish on early life stage exposure to triadimefon.

PubMed

Liu, Shaoying; Chang, Juhua; Zhao, Ying; Zhu, Guonian

2011-11-01

In this study, zebrafish was exposed to triadimefon. Thyroid hormones levels and the expression of related genes in the hypothalamic-pituitary-thyroid (HPT) axis, including thyroid-stimulating hormone (TSH-beta), deiodinases (dio1 and dio2) and the thyroid hormone receptor (thraa and thrb) were evaluated. After triadimefon exposure, increased T4 can be explained by increased thyroid-stimulating hormone (TSH-beta). The conversion of T4 to T3 (deiodinase type I-dio1) was decreased, which reduced the T3 level. Thyroid hormone receptor beta (thrb) mRNA levels were significantly down-regulated, possibly as a response to the decreased T3 levels. The overall results indicated that triadimefon exposure could alter gene expression in the HPT axis and that mechanisms of disruption of thyroid status by triadimefon could occur at several steps in the synthesis, regulation, and action of thyroid hormones. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Prenatal exposure to vinclozolin disrupts selective aspects of the gonadotrophin-releasing hormone neuronal system of the rabbit.

PubMed

Wadas, B C; Hartshorn, C A; Aurand, E R; Palmer, J S; Roselli, C E; Noel, M L; Gore, A C; Veeramachaneni, D N R; Tobet, S A

2010-06-01

Developmental exposure to the agricultural fungicide vinclozolin can impair reproductive function in male rabbits and was previously found to decrease the number of immunoreactive-gonadotrophin-releasing hormone (GnRH) neurones in the region of the organum vasculosum of the lamina terminalis and rostral preoptic area by postnatal week (PNW) 6. In the present study, in an aim to further examine the disruption of GnRH neurones by foetal vinclozolin exposure, pregnant rabbits were dosed orally with vinclozolin, flutamide or carrot paste vehicle for the last 2 weeks of gestation. Offspring were euthanised at birth (males and females), PNW 6 (females), PNW 26 (adult males) or PNW 30 (adult females) of age. At birth and in adults, brains were sectioned and processed for immunoreactive GnRH. The numbers of immunoreactive GnRH neuronal perikarya were significantly decreased in vinclozolin-treated rabbits at birth and in adult littermates. By contrast, there was an increase in GnRH immunoreactivity in the terminals in the region of the median eminence. Analysis of PNW 6 female brains by radioimmunoassay revealed a two-fold increase in GnRH peptide content in the mediobasal hypothalamus in vinclozolin-treated rabbits. This finding was complemented by immunofluorescence analyses, which revealed a 2.8-fold increase in GnRH immunoreactivity in the median eminence of vinclozolin compared to vehicle-treated females at PNW 30. However, there was no difference between treatment groups in the measures of reproduction that were evaluated: ejaculation latency, conception rates or litter size. These results indicate that sub-acute, prenatal vinclozolin treatment is sufficient to create perdurable alterations in the GnRH neuronal network that forms an important input into the reproductive axis. Finally, the effect of vinclozolin on the GnRH neuronal network was not comparable to that of flutamide, suggesting that vinclozolin was not acting through anti-androgenic mechanisms.

Prenatal exposure to vinclozolin disrupts selective aspects of the gonadotropin-releasing hormone neuronal system of the rabbit

PubMed Central

Wadas, B.C.; Hartshorn, C.A.; Aurand, E.R.; Palmer, J.S.; Roselli, C.E.; Noel, M.L.; Gore, A.C.; Veeramachaneni, D.N.R.; Tobet, S.A.

2010-01-01

Developmental exposure to the agricultural fungicide vinclozolin can impair reproductive function in male rabbits and was previously found to decrease the number of immunoreactive-gonadotropin-releasing hormone (ir-GnRH) neurons in the region of the organum vasculosum of the lamina terminalis (OVLT) and rostral preoptic area (rPOA) by postnatal week (PNW) 6. To further examine the disruption of GnRH neurons by fetal vinclozolin exposure, in the current study, pregnant rabbits were dosed orally with vinclozolin, flutamide, or carrot paste vehicle for the last two weeks of gestation. Offspring were euthanized at birth (males and females), PNW6 (females), PNW26 (adult males), or PNW30 (adult females) of age. At birth and in adults, brains were sectioned and processed for immunoreactive GnRH. The numbers of immunoreactive GnRH neuronal perikarya were significantly decreased in vinclozolin-treated rabbits at birth and in adult littermates. By contrast, there was an increase in GnRH immunoreactivity in the terminals in the region of the median eminence. Analysis of PNW6 female brains by radioimmunoassay (RIA) revealed a two-fold increase in GnRH peptide content in the mediobasal hypothalamus in vinclozolin-treated rabbits. This finding was complemented by immunofluorescence analyses that showed a 2.8-fold increase in GnRH immunoreactivity in the median eminence of vinclozolin compared to vehicle-treated females at PNW30. However, there was no difference between treatment groups in the measures of reproduction that were evaluated: ejaculation latency, conception rates or litter size. These results indicate that subacute, prenatal vinclozolin treatment is sufficient to create perdurable alterations in the GnRH neuronal network that forms an important input into the reproductive axis. Finally, the effect of vinclozolin on the GnRH neuronal network was not comparable to that of flutamide, suggesting that vinclozolin was not acting through anti-androgenic mechanisms. PMID

Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event

EPA Science Inventory

Signal transducer and activator of transcription 5b (STAT5b) is a growth hormone (GH)-activated transcription factor and a master regulator of sexually dimorphic gene expression in the liver. Disruption ofthe GH hypothalamo-pituitary-liver axis controlling STAT5b activation can ...

Emerging and Disruptive Technologies.

PubMed

Kricka, Larry J

2016-08-01

Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home testing formats), new types of specimens (e.g., cell free DNA), big biology/data (e.g., million genome projects), and new regulations (e.g., for laboratory developed tests). In addition, there are many emerging technologies (e.g., planar arrays, mass spectrometry) that might find even broader application in the future and therefore also disrupt current practice. One interesting source of disruptive technology may prove to be the Qualcomm Tricorder XPrize, currently in its final stages.

Emerging and Disruptive Technologies

PubMed Central

2016-01-01

Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home testing formats), new types of specimens (e.g., cell free DNA), big biology/data (e.g., million genome projects), and new regulations (e.g., for laboratory developed tests). In addition, there are many emerging technologies (e.g., planar arrays, mass spectrometry) that might find even broader application in the future and therefore also disrupt current practice. One interesting source of disruptive technology may prove to be the Qualcomm Tricorder XPrize, currently in its final stages. PMID:27683538

Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*

EPA Science Inventory

The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degr...

Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is modulated by, but not dependent on, adrenal hormones.

PubMed

Yan, Rongzi; Nguyen, Quang; Gonzaga, James; Johnson, Mai; Ritzmann, Ronald F; Taylor, Eve M

2003-04-01

AIT-082 (Neotrofin), a hypoxanthine derivative, has been shown to improve memory in both animals and humans. In animals, adrenal hormones modulate the efficacy of many memory-enhancing compounds, including piracetam and tacrine (Cognex). To investigate the role of adrenal hormones in the memory-enhancing action of AIT-082. Plasma levels of adrenal hormones (corticosterone and aldosterone) in mice were significantly reduced by surgical or chemical (aminoglutethimide) adrenalectomy or significantly elevated by oral administration of corticosterone. The effects of these hormone level manipulations on the memory-enhancing activity of AIT-082 and piracetam were evaluated using a cycloheximide-induced amnesia/passive avoidance model. As previously reported by others, the memory enhancing action of piracetam was abolished by adrenalectomy. In contrast, the memory enhancement by 60 mg/kg AIT-082 (IP) was unaffected. However, a sub-threshold dose of AIT-082 (0.1 mg/kg, IP) that did not improve memory in control animals did improve memory in adrenalectomized animals. These data suggested that, similar to piracetam and tacrine, the memory enhancing action of AIT-082 might be inhibited by high levels of adrenal hormones. As expected, corticosterone (30 and 100 mg/kg) inhibited the action of piracetam, however no dose up to 100 mg/kg corticosterone inhibited the activity of AIT-082. These data suggest that while AIT-082 function is not dependent on adrenal hormones, it is modulated by them. That memory enhancement by AIT-082 was not inhibited by high plasma corticosterone levels may have positive implications for its clinical utility, given that many Alzheimer's disease patients have elevated plasma cortisol levels.

Quo vadis plant hormone analysis?

PubMed

Tarkowská, Danuše; Novák, Ondřej; Floková, Kristýna; Tarkowski, Petr; Turečková, Veronika; Grúz, Jiří; Rolčík, Jakub; Strnad, Miroslav

2014-07-01

Plant hormones act as chemical messengers in the regulation of myriads of physiological processes that occur in plants. To date, nine groups of plant hormones have been identified and more will probably be discovered. Furthermore, members of each group may participate in the regulation of physiological responses in planta both alone and in concert with members of either the same group or other groups. The ideal way to study biochemical processes involving these signalling molecules is 'hormone profiling', i.e. quantification of not only the hormones themselves, but also their biosynthetic precursors and metabolites in plant tissues. However, this is highly challenging since trace amounts of all of these substances are present in highly complex plant matrices. Here, we review advances, current trends and future perspectives in the analysis of all currently known plant hormones and the associated problems of extracting them from plant tissues and separating them from the numerous potentially interfering compounds.

Using in Vitro High Throughput Screening Assays to Identify Potential Endocrine-Disrupting Chemicals

EPA Science Inventory

Over the past 20 years, an increased focus on detecting environmental chemicals posing a risk of adverse effects due to endocrine disruption has driven the creation of the U.S. EPA Endocrine Disruptor Screening Program (EDSP). Thousands of chemicals are subject to the EDSP, whic...

An Ecological Perspective on Sleep Disruption.

PubMed

Tougeron, Kévin; Abram, Paul K

2017-09-01

Despite its evolutionary importance and apparent ubiquity among animals, the ecological significance of sleep is largely unresolved. The ecology of sleep has been particularly neglected in invertebrates. In insects, recent neurobehavioral research convincingly demonstrates that resting behavior shares several common characteristics with sleep in vertebrates. Laboratory studies have produced compelling evidence that sleep disruption can cause changes in insect daily activity patterns (via "sleep rebound") and have consequences for behavioral performance during active periods. However, factors that could cause insect sleep disruption in nature have not been considered nor have the ecological consequences. Drawing on evidence from laboratory studies, we argue that sleep disruption may be an overlooked component of insect ecology and could be caused by a variety of anthropogenic and nonanthropogenic factors in nature. We identify several candidate sleep-disrupting factors and provide new insights on the potential consequences of sleep disruption on individual fitness, species interactions, and ecosystem services. We propose an experimental framework to bridge the current gap in knowledge between laboratory and field studies. We conclude that sleep disruption is a potential mechanism underpinning variation in behavioral, population, and community-level processes associated with several aspects of global change.

Influence of Treatment for Disruptive Behavior Disorders on Adrenal and Gonadal Hormones in Youth

ERIC Educational Resources Information Center

Dorn, Lorah D.; Kolko, David J.; Shenk, Chad E.; Susman, Elizabeth J.; Bukstein, Oscar

2011-01-01

The study examined whether psychosocial intervention for children diagnosed with a disruptive behavior disorder (DBD; n = 84) changed concentrations of cortisol and testosterone across a 3-year follow-up when compared to a matched, nonclinical, healthy comparison (HC; n = 69) group. Boys and girls (6-11 years) with a DBD were randomly assigned to…

STEROID HORMONES AS BIOMARKERS OF ENDOCRINE DISRUPTION IN WILDLIFE. IN: ENVIRONMENTAL TOXICOLOGY AND RISK ASSESSMENT

EPA Science Inventory

Standardization of Biomarkers for Endocrine Disruption and Environmental Assessment. 8th Volume, ASTM STP 1364. D.S. Henshel, M.C. Black, and M.C. Harrass, Editors. American Society for Testing and Materials, West Conshohocken, PA. Pp. 254-270.

An overview of estrogen-associated endocrine disruption in fishes: evidence of effects on reproductive and immune physiology

USGS Publications Warehouse

Iwanowicz, L.R.; Blazer, V.S.

2011-01-01

Simply and perhaps intuitively defined, endocrine disruption is the abnormal modulation of normal hormonal physiology by exogenous chemicals. In fish, endocrine disruption of the reproductive system has been observed worldwide in numerous species and is known to affect both males and females. Observations of biologically relevant endocrine disruption most commonly occurs near waste water treatment plant outfalls, pulp and paper mills, and areas of high organic loading sometimes associated with agricultural practices. Estrogenic endocrine disrupting chemicals (EEDCs) have received an overwhelmingly disproportionate amount of scientific attention compared to other EDCs in recent years. In male fishes, exposure to EEDCs can lead to the induction of testicular oocytes (intersex), measurable plasma vitellogenin protein, altered sex steroid profiles, abnormal spawning behavior, skewed population sex ratios, and lessened reproductive success. Interestingly, contemporary research purports that EDCs modulate aspects of non-reproductive physiology including immune function. Here we present an overview of endocrine disruption in fishes associated with estrogenic compounds, implications of this phenomenon, and examples of EDC related research findings by our group in the Potomac River Watershed, USA.

Unexplained high thyroid stimulating hormone: a "BIG" problem.

PubMed

Mendoza, Heidi; Connacher, Alan; Srivastava, Rajeev

2009-01-01

Macro-hormones and macro-enzymes are high molecular weight conjugates of hormones or enzymes, respectively, often with immunoglobulins. These are referred to as macromolecular complexes, and may cause artefactually elevated biochemical tests results. Macro enzymes of the most commonly measured serum enzymes have been identified and are recognised as a source of elevated measurements that may cause diagnostic confusion; macro-creatine kinase and macro-amylase are the two better known macro-enzymes in clinical practice. Literature on macro-hormones is largely restricted to macro-prolactin. We present a case of a clinically euthyroid patient, who had persistently elevated thyroid stimulating hormone (TSH) but free thyroxine within the reference limits. She underwent repeated thyroid investigations and thyroid hormone interference studies, until macro-TSH was identified as the most likely cause of unexplained elevated TSH. Following the identification and characterisation of this biochemical abnormality, she is no longer subject to repeated blood tests for assessment of thyroid function; the patient currently remains clinically euthyroid.

Juvenile Hormone Prevents 20-Hydroxyecdysone-induced Metamorphosis by Regulating the Phosphorylation of a Newly Identified Broad Protein*

PubMed Central

Cai, Mei-Juan; Liu, Wen; Pei, Xu-Yang; Li, Xiang-Ru; He, Hong-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

2014-01-01

The steroid hormone 20-hydroxyecdysone (20E) initiates insect molting and metamorphosis. By contrast, juvenile hormone (JH) prevents metamorphosis. However, the mechanism by which JH inhibits metamorphosis remains unclear. In this study, we propose that JH induces the phosphorylation of Broad isoform Z7 (BrZ7), a newly identified protein, to inhibit 20E-mediated metamorphosis in the lepidopteran insect Helicoverpa armigera. The knockdown of BrZ7 in larvae inhibited metamorphosis by repressing the expression of the 20E response gene. BrZ7 was weakly expressed and phosphorylated during larval growth but highly expressed and non-phosphorylated during metamorphosis. JH regulated the rapid phosphorylation of BrZ7 via a G-protein-coupled receptor-, phospholipase C-, and protein kinase C-triggered pathway. The phosphorylated BrZ7 bound to the 5′-regulatory region of calponin to regulate its expression in the JH pathway. Exogenous JH induced BrZ7 phosphorylation to prevent metamorphosis by suppressing 20E-related gene transcription. JH promoted non-phosphorylated calponin interacting with ultraspiracle protein to activate the JH pathway and antagonize the 20E pathway. This study reveals one of the possible mechanisms by which JH counteracts 20E-regulated metamorphosis by inducing the phosphorylation of BrZ7. PMID:25096576

Persistent Organochlorine Pollutants with Endocrine Activity and Blood Steroid Hormone Levels in Middle-Aged Men

PubMed Central

Emeville, Elise; Giton, Frank; Giusti, Arnaud; Oliva, Alejandro; Fiet, Jean; Thomé, Jean-Pierre; Blanchet, Pascal; Multigner, Luc

2013-01-01

Background Studies relating long-term exposure to persistent organochlorine pollutants (POPs) with endocrine activities (endocrine disrupting chemicals) on circulating levels of steroid hormones have been limited to a small number of hormones and reported conflicting results. Objective We examined the relationship between serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulphate, androstenedione, androstenediol, testosterone, free and bioavailable testosterone, dihydrotestosterone, estrone, estrone sulphate, estradiol, sex-hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone as a function of level of exposure to three POPs known to interfere with hormone-regulated processes in different way: dichlorodiphenyl dichloroethene (DDE), polychlorinated biphenyl (PCB) congener 153, and chlordecone. Methods We collected fasting, morning serum samples from 277 healthy, non obese, middle-aged men from the French West Indies. Steroid hormones were determined by gas chromatography-mass spectrometry, except for dehydroepiandrosterone sulphate, which was determined by immunological assay, as were the concentrations of sex-hormone binding globulin, follicle-stimulating hormone and luteinizing hormone. Associations were assessed by multiple linear regression analysis, controlling for confounding factors, in a backward elimination procedure, in multiple bootstrap samples. Results DDE exposure was negatively associated to dihydrotestosterone level and positively associated to luteinizing hormone level. PCB 153 was positively associated to androstenedione and estrone levels. No association was found for chlordecone. Conclusions These results suggested that the endocrine response pattern, estimated by determining blood levels of steroid hormones, varies depending on the POPs studied, possibly reflecting differences in the modes of action generally attributed to these compounds. It remains to be investigated whether this response pattern

Toxicogenomics to Evaluate Endocrine Disrupting Effects of Environmental Chemicals Using the Zebrafish Model

PubMed Central

Caballero-Gallardo, Karina; Olivero-Verbel, Jesus; Freeman, Jennifer L.

2016-01-01

The extent of our knowledge on the number of chemical compounds related to anthropogenic activities that can cause damage to the environment and to organisms is increasing. Endocrine disrupting chemicals (EDCs) are one group of potentially hazardous substances that include natural and synthetic chemicals and have the ability to mimic endogenous hormones, interfering with their biosynthesis, metabolism, and normal functions. Adverse effects associated with EDC exposure have been documented in aquatic biota and there is widespread interest in the characterization and understanding of their modes of action. Fish are considered one of the primary risk organisms for EDCs. Zebrafish (Danio rerio) are increasingly used as an animal model to study the effects of endocrine disruptors, due to their advantages compared to other model organisms. One approach to assess the toxicity of a compound is to identify those patterns of gene expression found in a tissue or organ exposed to particular classes of chemicals, through new technologies in genomics (toxicogenomics), such as microarrays or whole-genome sequencing. Application of these technologies permit the quantitative analysis of thousands of gene expression changes simultaneously in a single experiment and offer the opportunity to use transcript profiling as a tool to predict toxic outcomes of exposure to particular compounds. The application of toxicogenomic tools for identification of chemicals with endocrine disrupting capacity using the zebrafish model system is reviewed. PMID:28217008

Growth hormone response to growth hormone-releasing peptide-2 in growth hormone-deficient Little mice

PubMed Central

Peroni, Cibele N.; Hayashida, Cesar Y.; Nascimento, Nancy; Longuini, Viviane C.; Toledo, Rodrigo A.; Bartolini, Paolo; Bowers, Cyril Y.; Toledo, Sergio P.A.

2012-01-01

OBJECTIVE: To investigate a possible direct, growth hormone-releasing, hormone-independent action of a growth hormone secretagogue, GHRP-2, in pituitary somatotroph cells in the presence of inactive growth hormone-releasing hormone receptors. MATERIALS AND METHODS: The responses of serum growth hormone to acutely injected growth hormone-releasing P-2 in lit/lit mice, which represent a model of GH deficiency arising from mutated growth hormone-releasing hormone-receptors, were compared to those observed in the heterozygous (lit/+) littermates and wild-type (+/+) C57BL/6J mice. RESULTS: After the administration of 10 mcg of growth hormone-releasing P-2 to lit/lit mice, a growth hormone release of 9.3±1.5 ng/ml was observed compared with 1.04±1.15 ng/ml in controls (p<0.001). In comparison, an intermediate growth hormone release of 34.5±9.7 ng/ml and a higher growth hormone release of 163±46 ng/ml were induced in the lit/+ mice and wild-type mice, respectively. Thus, GHRP-2 stimulated growth hormone in the lit/lit mice, and the release of growth hormone in vivo may be only partially dependent on growth hormone-releasing hormone. Additionally, the plasma leptin and ghrelin levels were evaluated in the lit/lit mice under basal and stimulated conditions. CONCLUSIONS: Here, we have demonstrated that lit/lit mice, which harbor a germline mutation in the Growth hormone-releasing hormone gene, maintain a limited but statistically significant growth hormone elevation after exogenous stimulation with GHRP-2. The present data probably reflect a direct, growth hormone-independent effect on Growth hormone S (ghrelin) stimulation in the remaining pituitary somatotrophs of little mice that is mediated by growth hormone S-R 1a. PMID:22473409

Characterization of AvaR1, a butenolide-autoregulator receptor for biosynthesis of a Streptomyces hormone in Streptomyces avermitilis.

PubMed

Sultan, Suandi Pratama; Kitani, Shigeru; Miyamoto, Kiyoko T; Iguchi, Hiroyuki; Atago, Tokitaka; Ikeda, Haruo; Nihira, Takuya

2016-11-01

Streptomyces hormones, sometimes called as autoregulators, are important signaling molecules to trigger secondary metabolism across many Streptomyces species. We recently identified a butenolide-type autoregulator (termed avenolide) as a new class of Streptomyces hormone from Streptomyces avermitilis that produces important anthelmintic agent avermectin. Avenolide triggers the production of avermectin with minimum effective concentration of nanomolar. Here, we describe the characterization of avaR1 encoding an avenolide receptor in the regulation of avermectin production and avenolide biosynthesis. The disruption of avaR1 resulted in transcriptional derepression of avenolide biosynthetic gene with an increase in avenolide production, with no change in the avermectin production profile. Moreover, the avaR1 mutant showed increased transcription of avaR1. Together with clear DNA-binding capacity of AvaR1 toward avaR1 upstream region, it suggests that AvaR1 negatively controls the expression of avaR1 through the direct binding to the promoter region of avaR1. These findings revealed that the avenolide receptor AvaR1 functions as a transcriptional repressor for avenolide biosynthesis and its own synthesis.

A whole genome screening and RNA interference identify a juvenile hormone esterase-like gene of the diamondback moth, Plutella xylostella.

PubMed

Gu, Xiaojun; Kumar, Sunil; Kim, Eunjin; Kim, Yonggyun

2015-09-01

Juvenile hormone (JH) plays a crucial role in preventing precocious metamorphosis and stimulating reproduction. Thus, its hemolymph titer should be under a tight control. As a negative controller, juvenile hormone esterase (JHE) performs a rapid breakdown of residual JH in the hemolymph during last instar to induce a larval-to-pupal metamorphosis. A whole genome of the diamondback moth (DBM), Plutella xylostella, has been annotated and proposed 11 JHE candidates. Sequence analysis using conserved motifs commonly found in other JHEs proposed a putative JHE (Px004817). Px004817 (64.61 kDa, pI=5.28) exhibited a characteristic JHE expression pattern by showing high peak at the early last instar, at which JHE enzyme activity was also at a maximal level. RNA interference of Px004817 reduced JHE activity and interrupted pupal development with a significant increase of larval period. This study identifies Px004817 as a JHE-like gene of P. xylostella. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pyrethroid Insecticide Cypermethrin Accelerates Pubertal Onset in Male Mice via Disrupting Hypothalamic-Pituitary-Gonadal Axis.

PubMed

Ye, Xiaoqing; Li, Feixue; Zhang, Jianyun; Ma, Huihui; Ji, Dapeng; Huang, Xin; Curry, Thomas E; Liu, Weiping; Liu, Jing

2017-09-05

Pyrethroids, a class of insecticides that are widely used worldwide, have been identified as endocrine-disrupting chemicals (EDCs). Our recent epidemiological study reported on an association of increased pyrethroids exposure with elevated gonadotropins levels and earlier pubertal development in Chinese boys. In this study, we further investigated the effects of cypermethrin (CP), one of the most ubiquitous pyrethroid insecticides, on hypothalamic-pituitary-gonadal (HPG) axis and pubertal onset in male animal models. Early postnatal exposure to CP at environmentally relevant doses (0.5, 5, and 50 μg/kg CP) significantly accelerated the age of puberty onset in male mice. Administration of CP induced a dose-dependent increase in serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone in male mice. CP did not affect gonadotropin-releasing hormone (GnRH) gene expression in the hypothalamus, but CP at higher concentrations stimulated GnRH pulse frequency. CP could induce the secretion of LH and FSH, as well as the expression of gonadotropin subunit genes [chorionic gonadotropin α (CGα), LHβ, and FSHβ] in pituitary gonadotropes. CP stimulated testosterone production and the expression of steroidogenesis-related genes [steroidogenic acute regulatory (StAR) and Cytochrome p 450, family 11, subfamily A, polypeptide 1 (CYP11A1)] in testicular Leydig cells. The interference with hypothalamic sodium channels as well as calcium channels in pituitary gonadotropes and testicular Leydig cells was responsible for CP-induced HPG axis maturation. Our findings established in animal models provide further evidence for the biological plausibility of pyrethroid exposure as a potentially environmental contributor to earlier puberty in males.

Divorce in the socially monogamous zebra finch: Hormonal mechanisms and reproductive consequences.

PubMed

Crino, Ondi L; Buchanan, Katherine L; Fanson, Benjamin G; Hurley, Laura L; Smiley, Kristina O; Griffith, Simon C

2017-01-01

Up to 80% of all bird species are socially monogamous. Divorce (switching partners) or pair disruption (due to the death of a partner) has been associated with decreased reproductive success, suggesting social monogamy is a strategy that may maximize fitness via coordination between partners. Previous studies have demonstrated the effects of divorce and pair disruption on immediate reproductive success. Here, we used a paired experimental design in the zebra finch (Taeniopygia guttata) to examine the hormonal mechanisms that modulate parental behavior and reproductive success in response to a partnership change (hereafter divorce). Specifically, we examined the effects of divorce on the avian stress hormone corticosterone (CORT) in both parents and nestlings, parental behaviors (incubation and nestling provisioning), prolactin (PRL), and reproductive success. We found that divorce resulted in delayed clutch initiation, reduced clutch mass, and an increase in nestling CORT response to a standardized stressor. These effects on reproductive investment and chick CORT response were not clearly determined by parental endocrine responses. Divorce had no effect on the level of parental CORT. PRL levels were highly correlated within a pair regardless of treatment, were negatively related to the investment that males made in incubation, and increased in experimental males as a result of pair disruption. This study demonstrates the fundamental impact which divorce has not only on reproduction, but also the physiological stress responses of offspring and suggests that in socially monogamous animals the maintenance of a stable partnership over time could be advantageous for long term fitness. Copyright © 2016 Elsevier Inc. All rights reserved.

DETERMINATION OF SEX HORMONES AND NONYLPHENOL ETHOXYLATES IN THE AQUEOUS MATRIXES OF TWO PILOT-SCALE MUNICIPAL WASTEWATER TREATMENT PLANTS

EPA Science Inventory

Two analytical methods were developed and refined for the detection and quantitation of two groups of endocrine-disrupting chemicals (EDCs) in the liquid matrixes of two pilot-scale municipal wastewater treatment plants. The targeted compounds are seven sex hormones (estradiol, ...

Asprosin, a fasting-induced glucogenic protein hormone

USDA-ARS?s Scientific Manuscript database

Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is t...

Perspectives of Foster Parents and Social Workers on Foster Placement Disruption

ERIC Educational Resources Information Center

Taylor, Brian J.; McQuillan, Karen

2014-01-01

The potential human and financial costs of foster placement disruption for the children, families, professionals and agencies involved are widely accepted. This service evaluation identified and described perspectives of foster parents and social workers regarding placement disruptions in order to identify the main issues of concern and to derive…

Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice.

PubMed

Sadagurski, Marianna; Landeryou, Taylor; Cady, Gillian; Kopchick, John J; List, Edward O; Berryman, Darlene E; Bartke, Andrzej; Miller, Richard A

2015-12-01

Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived. Median longevity is also increased in mice with deletion of hypothalamic GH-releasing hormone (GHRH), which leads to isolated GH deficiency. The remarkable extension of longevity in hypopituitary Ames dwarf mice can be reversed by a 6-week course of GH injections started at the age of 2 weeks. Here, we demonstrate that mutations that interfere with GH production or response, in the Snell dwarf, Ames dwarf, or GHR(-/-) mice lead to reduced formation of both orexigenic agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the main hypothalamic projection areas: the arcuate nucleus (ARH), paraventricular nucleus (PVH), and dorsomedial nucleus (DMH). These mutations also reduce hypothalamic inflammation in 18-month-old mice. GH injections, between 2 and 8 weeks of age, reversed both effects in Ames dwarf mice. Disruption of GHR specifically in liver (LiGHRKO), a mutation that reduces circulating IGF-1 but does not lead to lifespan extension, had no effect on hypothalamic projections or inflammation, suggesting an effect of GH, rather than peripheral IGF-1, on hypothalamic development. Hypothalamic leptin signaling, as monitored by induction of pStat3, is not impaired by GHR deficiency. Together, these results suggest that early-life disruption of GH signaling produces long-term hypothalamic changes that may contribute to the longevity of GH-deficient and GH-resistant mice. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Endocrine disrupting chemicals in indoor and outdoor air

NASA Astrophysics Data System (ADS)

Rudel, Ruthann A.; Perovich, Laura J.

The past 50 years have seen rapid development of new building materials, furnishings, and consumer products and a corresponding explosion in new chemicals in the built environment. While exposure levels are largely undocumented, they are likely to have increased as a wider variety of chemicals came into use, people began spending more time indoors, and air exchange rates decreased to improve energy efficiency. As a result of weak regulatory requirements for chemical safety testing, only limited toxicity data are available for these chemicals. Over the past 15 years, some chemical classes commonly used in building materials, furnishings, and consumer products have been shown to be endocrine disrupting chemicals - that is they interfere with the action of endogenous hormones. These include PCBs, used in electrical equipment, caulking, paints and surface coatings; chlorinated and brominated flame retardants, used in electronics, furniture, and textiles; pesticides, used to control insects, weeds, and other pests in agriculture, lawn maintenance, and the built environment; phthalates, used in vinyl, plastics, fragrances, and other products; alkylphenols, used in detergents, pesticide formulations, and polystyrene plastics; and parabens, used to preserve products like lotions and sunscreens. This paper summarizes reported indoor and outdoor air concentrations, chemical use and sources, and toxicity data for each of these chemical classes. While industrial and transportation-related pollutants have been shown to migrate indoors from outdoor sources, it is expected that indoor sources predominate for these consumer product chemicals; and some studies have identified indoor sources as the predominant factor influencing outdoor ambient air concentrations in densely populated areas. Mechanisms of action, adverse effects, and dose-response relationships for many of these chemicals are poorly understood and no systematic screening of common chemicals for endocrine disrupting

Endocrine disrupting chemicals in indoor and outdoor air

PubMed Central

Rudel, Ruthann A.; Perovich, Laura J.

2009-01-01

The past 50 years have seen rapid development of new building materials, furnishings, and consumer products and a corresponding explosion in new chemicals in the built environment. While exposure levels are largely undocumented, they are likely to have increased as a wider variety of chemicals came into use, people began spending more time indoors, and air exchange rates decreased to improve energy efficiency. As a result of weak regulatory requirements for chemical safety testing, only limited toxicity data are available for these chemicals. Over the past 15 years, some chemical classes commonly used in building materials, furnishings, and consumer products have been shown to be endocrine disrupting chemicals—that is they interfere with the action of endogenous hormones. These include PCBs, used in electrical equipment, caulking, paints and surface coatings; chlorinated and brominated flame retardants, used in electronics, furniture, and textiles; pesticides, used to control insects, weeds, and other pests in agriculture, lawn maintenance, and the built environment; phthalates, used in vinyl, plastics, fragrances, and other products; alkylphenols, used in detergents, pesticide formulations, and polystyrene plastics; and parabens, used to preserve products like lotions and sunscreens. This paper summarizes reported indoor and outdoor air concentrations, chemical use and sources, and toxicity data for each of these chemical classes. While industrial and transportation-related pollutants have been shown to migrate indoors from outdoor sources, it is expected that indoor sources predominate for these consumer product chemicals; and some studies have identified indoor sources as the predominant factor influencing outdoor ambient air concentrations in densely populated areas. Mechanisms of action, adverse effects, and dose-response relationships for many of these chemicals are poorly understood and no systematic screening of common chemicals for endocrine disrupting

Using short-term bioassays to evaluate the endocrine disrupting capacity of the pesticides linuron and fenoxycarb.

PubMed

Spirhanzlova, Petra; De Groef, Bert; Nicholson, Freda E; Grommen, Sylvia V H; Marras, Giulia; Sébillot, Anthony; Demeneix, Barbara A; Pallud-Mothré, Sophie; Lemkine, Gregory F; Tindall, Andrew J; Du Pasquier, David

2017-10-01

Several short-term whole-organism bioassays based on transgenic aquatic models are now under validation by the OECD (Organization for Economic Co-operation and Development) to become standardized test guidelines for the evaluation of the endocrine activity of substances. Evaluation of the endocrine disrupting capacity of pesticides will be a domain of applicability of these future reference tests. The herbicide linuron and the insecticide fenoxycarb are two chemicals commonly used in agricultural practices. While numerous studies indicate that linuron is likely to be an endocrine disruptor, there is little information available on the effect of fenoxycarb on vertebrate endocrine systems. Using whole-organism bioassays based on transgenic Xenopus laevis tadpoles and medaka fry we assessed the potential of fenoxycarb and linuron to disrupt thyroid, androgen and estrogen signaling. In addition we used in silico approach to simulate the affinity of these two pesticides to human hormone receptors. Linuron elicited thyroid hormone-like activity in tadpoles at all concentrations tested and, showed an anti-estrogenic activity in medaka at concentrations 2.5mg/L and higher. Our experiments suggest that, in addition to its previously established anti-androgenic action, linuron exhibits thyroid hormone-like responses, as well as acting at the estrogen receptor level to inhibit estrogen signaling. Fenoxycarb on the other hand, did not cause any changes in thyroid, androgen or estrogen signaling at the concentrations tested. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic and genome-wide transcriptomic analyses identify co-regulation of oxidative response and hormone transcript abundance with vitamin C content in tomato fruit.

PubMed

Lima-Silva, Viviana; Rosado, Abel; Amorim-Silva, Vitor; Muñoz-Mérida, Antonio; Pons, Clara; Bombarely, Aureliano; Trelles, Oswaldo; Fernández-Muñoz, Rafael; Granell, Antonio; Valpuesta, Victoriano; Botella, Miguel Ángel

2012-05-14

L-ascorbic acid (AsA; vitamin C) is essential for all living plants where it functions as the main hydrosoluble antioxidant. It has diverse roles in the regulation of plant cell growth and expansion, photosynthesis, and hormone-regulated processes. AsA is also an essential component of the human diet, being tomato fruit one of the main sources of this vitamin. To identify genes responsible for AsA content in tomato fruit, transcriptomic studies followed by clustering analysis were applied to two groups of fruits with contrasting AsA content. These fruits were identified after AsA profiling of an F8 Recombinant Inbred Line (RIL) population generated from a cross between the domesticated species Solanum lycopersicum and the wild relative Solanum pimpinellifollium. We found large variability in AsA content within the RIL population with individual RILs with up to 4-fold difference in AsA content. Transcriptomic analysis identified genes whose expression correlated either positively (PVC genes) or negatively (NVC genes) with the AsA content of the fruits. Cluster analysis using SOTA allowed the identification of subsets of co-regulated genes mainly involved in hormones signaling, such as ethylene, ABA, gibberellin and auxin, rather than any of the known AsA biosynthetic genes. Data mining of the corresponding PVC and NVC orthologs in Arabidopis databases identified flagellin and other ROS-producing processes as cues resulting in differential regulation of a high percentage of the genes from both groups of co-regulated genes; more specifically, 26.6% of the orthologous PVC genes, and 15.5% of the orthologous NVC genes were induced and repressed, respectively, under flagellin22 treatment in Arabidopsis thaliana. Results here reported indicate that the content of AsA in red tomato fruit from our selected RILs are not correlated with the expression of genes involved in its biosynthesis. On the contrary, the data presented here supports that AsA content in tomato fruit co

Exploring peptide hormones in plants: identification of four peptide hormone-receptor pairs and two post-translational modification enzymes.

PubMed

Matsubayashi, Yoshikatsu

2018-01-01

The identification of hormones and their receptors in multicellular organisms is one of the most exciting research areas and has lead to breakthroughs in understanding how their growth and development are regulated. In particular, peptide hormones offer advantages as cell-to-cell signals in that they can be synthesized rapidly and have the greatest diversity in their structure and function. Peptides often undergo post-translational modifications and proteolytic processing to generate small oligopeptide hormones. In plants, such small post-translationally modified peptides constitute the largest group of peptide hormones. We initially explored this type of peptide hormone using bioassay-guided fractionation and later by in silico gene screening coupled with biochemical peptide detection, which led to the identification of four types of novel peptide hormones in plants. We also identified specific receptors for these peptides and transferases required for their post-translational modification. This review summarizes how we discovered these peptide hormone-receptor pairs and post-translational modification enzymes, and how these molecules function in plant growth, development and environmental adaptation.

Observational Assessment of Preschool Disruptive Behavior, Part II: validity of the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS).

PubMed

Wakschlag, Lauren S; Briggs-Gowan, Margaret J; Hill, Carri; Danis, Barbara; Leventhal, Bennett L; Keenan, Kate; Egger, Helen L; Cicchetti, Domenic; Burns, James; Carter, Alice S

2008-06-01

To examine the validity of the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS), a new observational method for assessing preschool disruptive behavior. A total of 327 behaviorally heterogeneous preschoolers from low-income environments comprised the validation sample. Parent and teacher reports were used to identify children with clinically significant disruptive behavior. The DB-DOS assessed observed disruptive behavior in two domains, problems in Behavioral Regulation and Anger Modulation, across three interactional contexts: Examiner Engaged, Examiner Busy, and Parent. Convergent and divergent validity of the DB-DOS were tested in relation to parent and teacher reports and independently observed behavior. Clinical validity was tested in terms of criterion and incremental validity of the DB-DOS for discriminating disruptive behavior status and impairment, concurrently and longitudinally. DB-DOS scores were significantly associated with reported and independently observed behavior in a theoretically meaningful fashion. Scores from both DB-DOS domains and each of the three DB-DOS contexts contributed uniquely to discrimination of disruptive behavior status, concurrently and predictively. Observed behavior on the DB-DOS also contributed incrementally to prediction of impairment over time, beyond variance explained by meeting DSM-IV disruptive behavior disorder symptom criteria based on parent/teacher report. The multidomain, multicontext approach of the DB-DOS is a valid method for direct assessment of preschool disruptive behavior. This approach shows promise for enhancing accurate identification of clinically significant disruptive behavior in young children and for characterizing subtypes in a manner that can directly inform etiological and intervention research.

Juvenile hormone prevents 20-hydroxyecdysone-induced metamorphosis by regulating the phosphorylation of a newly identified broad protein.

PubMed

Cai, Mei-Juan; Liu, Wen; Pei, Xu-Yang; Li, Xiang-Ru; He, Hong-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

2014-09-19

The steroid hormone 20-hydroxyecdysone (20E) initiates insect molting and metamorphosis. By contrast, juvenile hormone (JH) prevents metamorphosis. However, the mechanism by which JH inhibits metamorphosis remains unclear. In this study, we propose that JH induces the phosphorylation of Broad isoform Z7 (BrZ7), a newly identified protein, to inhibit 20E-mediated metamorphosis in the lepidopteran insect Helicoverpa armigera. The knockdown of BrZ7 in larvae inhibited metamorphosis by repressing the expression of the 20E response gene. BrZ7 was weakly expressed and phosphorylated during larval growth but highly expressed and non-phosphorylated during metamorphosis. JH regulated the rapid phosphorylation of BrZ7 via a G-protein-coupled receptor-, phospholipase C-, and protein kinase C-triggered pathway. The phosphorylated BrZ7 bound to the 5'-regulatory region of calponin to regulate its expression in the JH pathway. Exogenous JH induced BrZ7 phosphorylation to prevent metamorphosis by suppressing 20E-related gene transcription. JH promoted non-phosphorylated calponin interacting with ultraspiracle protein to activate the JH pathway and antagonize the 20E pathway. This study reveals one of the possible mechanisms by which JH counteracts 20E-regulated metamorphosis by inducing the phosphorylation of BrZ7. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Environmental Analysis of Endocrine Disrupting Effects from Hydrocarbon Contaminants in the Ecosystem

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

McLachlan, John A.

2000-06-01

This annual report summarizes the progress of three years of a three-year grant awarded to the Center for Bioenvironmental Research (CBR) at Tulane and Xavier Universities. The objective of this project is to determine how environmental contaminants, namely hydrocarbons, can act as hormones or anti-hormones in different species present in aquatic ecosystems. The three major areas of research include (1) a biotechnology based screening system to identify potential hormone mimics and antagonists; (2) an animal screening system to identify biomarkers of endocrine effects; and (3) a literature review to identify compounds at various DOE sites that are potential endocrine disruptors.more » Species of particular focus in this study are those which can serve as sentinel species (e.g., amphibians) and, thus, provide early warning signals for more widespread impacts on an ecosystem and its wildlife and human inhabitants. The focus of the literature research was to provide an analysis of the contaminants located on or around various Department of Energy (DOE) sites that are or have the potential to function as endocrine disruptors and to correlate the need for studying endocrine disruptors to DOE's programmatic needs. Previous research within the Center for Bioenvironmental Research at Tulane and Xavier Universities has focused on understanding the effects of environmental agents on the human and wildlife health and disease. In particular this research has focused on how exogenous agents can function to mimic or disrupt normal endocrine signaling, i.e. estrogen, thyroid within various systems from whole animal studies with fish, amphibians and insects to human cancer cell lines. Significant work has focused on the estrogenic and anti-estrogenic action of both synthetic organochlorine chemicals and naturally produced phytochemicals. Recent projects have extended these research objectives to examination of these environmental agents on the symbiotic relationship between

Meeting Report: The Role of Environmental Lighting and Circadian Disruption in Cancer and Other Diseases

PubMed Central

Stevens, Richard G.; Blask, David E.; Brainard, George C.; Hansen, Johnni; Lockley, Steven W.; Provencio, Ignacio; Rea, Mark S.; Reinlib, Leslie

2007-01-01

Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light–dark exposure (e.g., by nonday occupation or transmeridian travel) shift the timing of the circadian system such that internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes. Light can also have direct acute effects on neuroendocrine systems, for example, in suppressing melatonin synthesis or elevating cortisol production that may have untoward long-term consequences. For these reasons, the National Institute of Environmental Health Sciences convened a workshop of a diverse group of scientists to consider how best to conduct research on possible connections between lighting and health. According to the participants in the workshop, there are three broad areas of research effort that need to be addressed. First are the basic biophysical and molecular genetic mechanisms for phototransduction for circadian, neuroendocrine, and neurobehavioral regulation. Second are the possible physiologic consequences of disrupting these circadian regulatory processes such as on hormone production, particularly melatonin, and normal and neoplastic tissue growth dynamics. Third are effects of light-induced physiologic disruption on disease occurrence and prognosis, and how prevention and treatment could be improved by application of this knowledge. PMID:17805428

Hormonal and Local Regulation of Bone Formation.

ERIC Educational Resources Information Center

Canalis, Ernesto

1985-01-01

Reviews effects of hormones, systemic factors, and local regulators on bone formation. Identifies and explains the impact on bone growth of several hormones as well as the components of systemic and local systems. Concentrates on bone collagen and DNA synthesis. (Physicians may earn continuing education credit by completing an appended test). (ML)

Endocrine disruption: In silico interactions between phthalate plasticizers and corticosteroid binding globulin.

PubMed

Sheikh, Ishfaq A; Beg, Mohd A

2017-12-01

Endocrine disruption is a phenomenon when a man-made or natural compound interferes with normal hormone function in human or animal body systems. Endocrine-disrupting compounds (EDCs) have assumed considerable importance as a result of industrial activity, mass production of synthetic chemicals and environmental pollution. Phthalate plasticizers are a group of chemicals used widely and diversely in industry especially in the plastic industry, and many of the phthalate compounds have endocrine-disrupting properties. Increasing evidence indicates that steroid nuclear receptors and steroid binding proteins are the main targets of endocrine disruption. Corticosteroid-binding globulin (CBG) is a steroid binding protein that binds and transports cortisol in the blood circulation and is a potential target for endocrine disruption. An imbalance of cortisol in the body leads to many health problems. Induced fit docking of nine important and environmentally relevant phthalate plasticizers (DMP, BBP, DBP, DIBP, DnHP, DEHP, DINP, DnOP, DIDP) showed interactions with 10-19 amino acid residues of CBG. Comparison of the interacting residues of CBG with phthalate ligands and cortisol showed an overlapping of the majority (53-82%) of residues for each phthalate. Five of nine phthalate compounds and cortisol shared a hydrogen bonding interaction with the Arg-252 residue of CBG. Long-chain phthalates, such as DEHP, DINP, DnOP and DIDP displayed a higher binding affinity and formed a number of interactions with CBG in comparison to short-chain phthalates. The similarity in structural binding characteristics of phthalate compounds and native ligand cortisol suggested potential competitive conflicts in CBG-cortisol binding function and possible disruption of cortisol and progesterone homeostasis. Copyright © 2017 John Wiley & Sons, Ltd.

Foster Placement Disruptions Associated with Problem Behavior: Mitigating a Threshold Effect

ERIC Educational Resources Information Center

Fisher, Philip A.; Stoolmiller, Mike; Mannering, Anne M.; Takahashi, Aiko; Chamberlain, Patricia

2011-01-01

Objective: Placement disruptions have adverse effects on foster children. Identifying reliable predictors of placement disruptions might assist in the allocation of services to prevent disruptions. There were two objectives in this study: (a) to replicate a prior finding that the number of daily child problem behaviors at entry into a new foster…

Night shift work and hormone levels in women.

PubMed

Davis, Scott; Mirick, Dana K; Chen, Chu; Stanczyk, Frank Z

2012-04-01

Night shift work may disrupt the normal nocturnal rise in melatonin, resulting in increased breast cancer risk, possibly through increased reproductive hormone levels. We investigated whether night shift work is associated with decreased levels of urinary 6-sulfatoxymelatonin, the primary metabolite of melatonin, and increased urinary reproductive hormone levels. Participants were 172 night shift and 151 day shift-working nurses, aged 20-49 years, with regular menstrual cycles. Urine samples were collected throughout work and sleep periods and assayed for 6-sulfatoxymelatonin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrone conjugate (E1C). 6-Sulfatoxymelatonin levels were 62% lower and FSH and LH were 62% and 58% higher, respectively, in night shift-working women during daytime sleep than in day shift-working women during nighttime sleep (P ≤ 0.0001). Nighttime sleep on off-nights was associated with 42% lower 6-sulfatoxymelatonin levels among the night shift workers, relative to the day shift workers (P < 0.0001); no significant differences in LH or FSH were observed. 6-Sulfatoxymelatonin levels during night work were approximately 69% lower and FSH and LH were 35% and 38% higher, compared with day shift workers during nighttime sleep. No differences in E1C levels between night and day shift workers were observed. Within night shift workers, 6-sulfatoxymelatonin levels were lower and reproductive hormone levels were higher during daytime sleep and nighttime work, relative to nighttime sleep (P < 0.05). These results indicate that night shift workers have substantially reduced 6-sulfatoxymelatonin levels during night work and daytime sleep and that levels remain low even when a night shift worker sleeps at night. Shift work could be an important risk factor for many other cancers in addition to breast cancer. ©2012 AACR.

Risk Assessment of Growth Hormones and Antimicrobial Residues in Meat

PubMed Central

Jeong, Sang-Hee; Kang, Daejin; Lim, Myung-Woon; Kang, Chang Soo

2010-01-01

Growth promoters including hormonal substances and antibiotics are used legally and illegally in food producing animals for the growth promotion of livestock animals. Hormonal substances still under debate in terms of their human health impacts are estradiol-17β, progesterone, testosterone, zeranol, trenbolone, and melengestrol acetate (MGA) . Many of the risk assessment results of natural steroid hormones have presented negligible impacts when they are used under good veterinary practices. For synthetic hormonelike substances, ADIs and MRLs have been established for food safety along with the approval of animal treatment. Small amounts of antibiotics added to feedstuff present growth promotion effects via the prevention of infectious diseases at doses lower than therapeutic dose. The induction of antimicrobial resistant bacteria and the disruption of normal human intestinal flora are major concerns in terms of human health impact. Regulatory guidance such as ADIs and MRLs fully reflect the impact on human gastrointestinal microflora. However, before deciding on any risk management options, risk assessments of antimicrobial resistance require large-scale evidence regarding the relationship between antimicrobial use in food-producing animals and the occurrence of antimicrobial resistance in human pathogens. In this article, the risk profiles of hormonal and antibacterial growth promoters are provided based on recent toxicity and human exposure information, and recommendations for risk management to prevent human health impacts by the use of growth promoters are also presented. PMID:24278538

Hormone levels

MedlinePlus

Blood or urine tests can determine the levels of various hormones in the body. This includes reproductive hormones, thyroid hormones, adrenal hormones, pituitary hormones, and many others. For more information, see: ...

Endocrine disrupting chemicals in New Orleans surface waters and Mississippi Sound sediments.

PubMed

Wang, Guangdi; Ma, Peng; Zhang, Qiang; Lewis, John; Lacey, Michelle; Furukawa, Yoko; O'Reilly, S E; Meaux, Shelley; McLachlan, John; Zhang, Shaoyuan

2012-05-01

Endocrine disrupting compounds (EDCs), represented by steroid hormones, organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and bisphenol A have been determined in four sediment cores from the Gulf of Mexico, from New Orleans surface water (Lake Pontchartrain and Mississippi River), and from the influent and effluent of a New Orleans municipal sewage treatment plant. During the five-month monitoring of selected EDCs in the Mississippi River (MR) and Lake Pontchartrain (LP) in 2008, 21 of 29 OCPs in MR and 17 of 29 OCPs in LP were detected; bisphenol A was detected in all of the samples. Steroid hormones (estrone, 17β-estradiol and 17α-ethinylestradiol) were detected occasionally. Total EDC (OCPs + PCBs + steroid hormones + bisphenol A) concentrations in the two surface water samples were found to vary from 148 to 1112 ng L(-1). Strong correlation of the distribution of total OCPs, total PCBs and total EDCs between solid and water phases was found in LP, while moderate or no correlation existed in MR. OCPs, PCBs, steroid hormones, and bisphenol A were all detected in the ocean sediments, and total EDCs were measured in the range of 77 to 1796 ng g(-1) dry sediment weight. The EDCs were also found in untreated and treated municipal sewage samples with a removal efficiency of 83% for OCPs but no removal efficiency for 17α-ethinylestradiol.

Disruptive Pupils and Teacher Stress.

ERIC Educational Resources Information Center

Dunham, Jack

1981-01-01

Teachers have identified a number of stress situations in their work with disruptive children: insecurity due to student unpredictability, doubting their effectiveness, frustrated attempts at communication with other professionals, and feelings of isolation and limited social relationships (expressed by residential workers). (CT)

Activation of erythropoietin receptor in the absence of hormone by a peptide that binds to a domain different from the hormone binding site

PubMed Central

Naranda, Tatjana; Wong, Kenneth; Kaufman, R. Ilene; Goldstein, Avram; Olsson, Lennart

1999-01-01

Applying a homology search method previously described, we identified a sequence in the extracellular dimerization site of the erythropoietin receptor, distant from the hormone binding site. A peptide identical to that sequence was synthesized. Remarkably, it activated receptor signaling in the absence of erythropoietin. Neither the peptide nor the hormone altered the affinity of the other for the receptor; thus, the peptide does not bind to the hormone binding site. The combined activation of signal transduction by hormone and peptide was strongly synergistic. In mice, the peptide acted like the hormone, protecting against the decrease in hematocrit caused by carboplatin. PMID:10377456

Bisphenol A and Hormone-Associated Cancers: Current Progress and Perspectives

PubMed Central

Gao, Hui; Yang, Bao-Jun; Li, Nan; Feng, Li-Min; Shi, Xiao-Yu; Zhao, Wei-Hong; Liu, Si-Jin

2015-01-01

Abstract Bisphenol A (BPA), a carbon-based synthetic compound, exhibits hormone-like properties and is present ubiquitously in the environment and in human tissues due to its widespread use and biological accumulation. BPA can mimic estrogen to interact with estrogen receptors α and β, leading to changes in cell proliferation, apoptosis, or migration and thereby, contributing to cancer development and progression. At the genetic level, BPA has been shown to be involved in multiple oncogenic signaling pathways, such as the STAT3, MAPK, and PI3K/AKT pathways. Moreover, BPA may also interact with other steroid receptors (such as androgen receptor) and plays a role in prostate cancer development. This review summarizes the current literature regarding human exposure to BPA, the endocrine-disrupting effects of BPA, and the role of BPA in hormone-associated cancers of the breast, ovary, and prostate. PMID:25569640

The common molecular players in plant hormone crosstalk and signaling.

PubMed

Ohri, Puja; Bhardwaj, Renu; Bali, Shagun; Kaur, Ravinderjit; Jasrotia, Shivam; Khajuria, Anjali; Parihar, Ripu D

2015-01-01

Plant growth and development is under the control of mutual interactions among plant hormones. The five classical categories of plant hormones include auxins, cytokinins, gibberellins, abscisic acid and ethylene. Additionally, newer classes of plant hormones have been recognized like brassinosteroids, jasmonic acid, salicylic acid and polyamines. These hormones play significant roles in regulating the plant growth and development. Various receptors and key signaling components of these hormones have been studied and identified. At genetic level, crosstalk among the various plant hormones is found to be antagonistic or synergistic. In addition, components of signaling pathway of one plant hormone interact with the signaling components of other hormone. Thus, an attempt has been made to review the literature regarding the role of plant hormones in plant physiology and the common molecular players in their signaling and crosstalk.

Concordance of self-reported hormonal contraceptive use and presence of exogenous hormones in serum among African women.

PubMed

Pyra, Maria; Lingappa, Jairam R; Heffron, Renee; Erikson, David W; Blue, Steven W; Patel, Rena C; Nanda, Kavita; Rees, Helen; Mugo, Nelly R; Davis, Nicole L; Kourtis, Athena P; Baeten, Jared M

2018-04-01

Studies that rely on self-report to investigate the relationship between hormonal contraceptive use and HIV acquisition and transmission, as well as other health outcomes, could have compromised results due to misreporting. We determined the frequency of misreported hormonal contraceptive use among African women with and at risk for HIV. We tested 1102 archived serum samples from 664 African women who had participated in prospective HIV prevention studies. Using a novel high-performance liquid chromatography-mass spectrometry assay, we quantified exogenous hormones for injectables (medroxyprogesterone acetate or norethisterone), oral contraceptives (OC) (levonorgestrel or ethinyl estradiol) and implants (levonorgestrel or etonogestrel) and compared them to self-reported use. Among women reporting hormonal contraceptive use, 258/358 (72%) of samples were fully concordant with self-report, as were 642/744 (86%) of samples from women reporting no hormonal contraceptive use. However, 42/253 (17%) of samples from women reporting injectable use, 41/66 (62%) of samples from self-reported OC users and 3/39 (8%) of samples from self-reported implant users had no quantifiable hormones. Among self-reported nonusers, 102/744 (14%) had ≥1 hormone present. Concordance between self-reported method and exogenous hormones did not differ by HIV status. Among African women with and at risk for HIV, testing of exogenous hormones revealed agreement with self-reported contraceptive use for most women. However, unexpected exogenous hormones were identified among self-reported hormonal contraceptive users and nonusers, and an important fraction of women reporting hormonal contraceptive use had no hormones detected; absence of oral contraceptive hormones could be due, at least in part, to samples taken during the hormone-free interval. Misreporting of hormonal contraceptive use could lead to biased results in observational studies of the relationship between contraceptive use and health

Exploring peptide hormones in plants: identification of four peptide hormone-receptor pairs and two post-translational modification enzymes

PubMed Central

MATSUBAYASHI, Yoshikatsu

2018-01-01

The identification of hormones and their receptors in multicellular organisms is one of the most exciting research areas and has lead to breakthroughs in understanding how their growth and development are regulated. In particular, peptide hormones offer advantages as cell-to-cell signals in that they can be synthesized rapidly and have the greatest diversity in their structure and function. Peptides often undergo post-translational modifications and proteolytic processing to generate small oligopeptide hormones. In plants, such small post-translationally modified peptides constitute the largest group of peptide hormones. We initially explored this type of peptide hormone using bioassay-guided fractionation and later by in silico gene screening coupled with biochemical peptide detection, which led to the identification of four types of novel peptide hormones in plants. We also identified specific receptors for these peptides and transferases required for their post-translational modification. This review summarizes how we discovered these peptide hormone–receptor pairs and post-translational modification enzymes, and how these molecules function in plant growth, development and environmental adaptation. PMID:29434080

Neuroendocrine disruption without direct endocrine mode of action: Polychloro-biphenyls (PCBs) and bisphenol A (BPA) as case studies.

PubMed

Pinson, Anneline; Franssen, Delphine; Gérard, Arlette; Parent, Anne-Simone; Bourguignon, Jean-Pierre

Endocrine disruption is commonly thought to be restricted to a direct endocrine mode of action i.e. the perturbation of the activation of a given type of hormonal receptor by its natural ligand. Consistent with the WHO definition of an endocrine disrupter, a key issue is the "altered function(s) of the endocrine system". Such altered functions can result from different chemical interactions, beyond agonistic or antagonistic effect at a given receptor. Based on neuroendocrine disruption by polychlorinated biphenyls and bisphenol A, this paper proposes different mechanistic paradigms that can result in adverse health effects. They are a consequence of altered endocrine function(s) secondary to chemical interaction with different steps in the physiological regulatory processes, thus accounting for a possibly indirect endocrine mode of action. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Sex Hormones Coordinate Neutrophil Immunity in the Vagina by Controlling Chemokine Gradients.

PubMed

Lasarte, Sandra; Samaniego, Rafael; Salinas-Muñoz, Laura; Guia-Gonzalez, Mauriel A; Weiss, Linnea A; Mercader, Enrique; Ceballos-García, Elena; Navarro-González, Teresa; Moreno-Ochoa, Laura; Perez-Millan, Federico; Pion, Marjorie; Sanchez-Mateos, Paloma; Hidalgo, Andres; Muñoz-Fernandez, Maria A; Relloso, Miguel

2016-02-01

Estradiol-based contraceptives and hormonal replacement therapy predispose women to Candida albicans infections. Moreover, during the ovulatory phase (high estradiol), neutrophil numbers decrease in the vaginal lumen and increase during the luteal phase (high progesterone). Vaginal secretions contain chemokines that drive neutrophil migration into the lumen. However, their expression during the ovarian cycle or in response to hormonal treatments are controversial and their role in vaginal defense remains unknown.To investigate the transepithelial migration of neutrophils, we used adoptive transfer of Cxcr2(-/-) neutrophils and chemokine immunofluorescence quantitative analysis in response to C. albicans vaginal infection in the presence of hormones.Our data show that the Cxcl1/Cxcr2 axis drives neutrophil transepithelial migration into the vagina. Progesterone promotes the Cxcl1 gradient to favor neutrophil migration. Estradiol disrupts the Cxcl1 gradient and favors neutrophil arrest in the vaginal stroma; as a result, the vagina becomes more vulnerable to pathogens. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

CHANGES IN FETAL TESTIS GENE EXPRESSION AND STEROID HORMONE SYNTHESIS INDUCED IN MALE OFFSPRING AFTER MATERNAL TREATMENT WITH PHTHALATE ESTERS

EPA Science Inventory

Targeted inactivation of the insulin-like hormone 3 (insl3) gene in male mice results in altered gubernacular development, disrupted testis decent, and cryptorchidism. Cryptorchidism is a fairly common human malformation, being displayed in 1-3% of males at birth. Since only a s...

Environmental exposure to polycyclic aromatic hydrocarbons (PAHs): The correlation with and impact on reproductive hormones in umbilical cord serum.

PubMed

Yin, Shanshan; Tang, Mengling; Chen, Fangfang; Li, Tianle; Liu, Weiping

2017-01-01

Polycyclic aromatic hydrocarbons (PAHs) are a type of ubiquitous pollutant with the potential ability to cause endocrine disruption that would have an adverse health impact on the general population. To assess the maternal exposure to PAHs in neonates and evaluate the possible impact of PAHs on reproductive hormone levels, the concentration of PAHs and reproductive hormone levels in the umbilical cord serum of 98 mother-infant pairs in the Shengsi Islands were investigated. The median concentration of total PAHs was determined to be 164 (Inter-Quartile Range, IQR 93.6-267) ng g -1 lipid, and 68% of the PAHs were lower-molecule congeners. The highest level was found for pyrene (PYR) and naphthalene (NAP), which contributed 54.6% of all the PAHs present in the samples. The exposure to PAHs negatively affected estradiol (E2) and Anti-Mullerian hormones (AMH) and positively affected FSH in the umbilical cord serum. The result expanded the database of the human burden of PAHs and suggested that PAHs can act as a type of Endocrine-Disrupting Chemical (EDC). These results may help to understand the complex pathways involved in disorders of human reproductive health associated with prenatal exposure to PAHs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification of endocrine disrupting chemicals acting on human aromatase.

PubMed

Baravalle, Roberta; Ciaramella, Alberto; Baj, Francesca; Di Nardo, Giovanna; Gilardi, Gianfranco

2018-01-01

Human aromatase is the cytochrome P450 catalysing the conversion of androgens into estrogens playing a key role in the endocrine system. Due to this role, it is likely to be a target of the so-called endocrine disrupting chemicals, a series of compounds able to interfere with the hormone system with toxic effects. If on one side the toxicity of some compounds such as bisphenol A is well known, on the other side the toxic concentrations of such compounds as well as the effect of the many other molecules that are in contact with us in everyday life still need a deep investigation. The availability of biological assays able to detect the interaction of chemicals with key molecular targets of the endocrine system represents a possible solution to identify potential endocrine disrupting chemicals. Here the so-called alkali assay previously developed in our laboratory is applied to test the effect of different compounds on the activity of human aromatase. The assay is based on the detection of the alkali product that forms upon strong alkali treatment of the NADP + released upon enzyme turnover. Here it is applied on human aromatase and validated using anastrozole and sildenafil as known aromatase inhibitors. Out of the small library of compounds tested, resveratrol and ketoconazole resulted to inhibit aromatase activity, while bisphenol A and nicotine were found to exert an inhibitory effect at relatively high concentrations (100μM), and other molecules such as lindane and four plasticizers did not show any significant effect. These data are confirmed by quantification of the product estrone in the same reaction mixtures through ELISA. Overall, the results show that the alkali assay is suitable to screen for molecules that interfere with aromatase activity. As a consequence it can also be applied to other molecular targets of EDCs that use NAD(P)H for catalysis in a high throughput format for the fast screening of many different compounds as endocrine disrupting

Growth hormone in intra-uterine growth retarded newborns.

PubMed

Setia, Sajita; Sridhar, M G; Bhat, Vishnu; Chaturvedula, Latha

2007-11-01

To study growth hormone levels in IUGR and healthy controls and its association with birth weight and ponderal index. We studied 50 Intra uterine growth retarded (IUGR) and 50 healthy newborns born at term by vaginal delivery in JIPMER, Pondicherry, India. Cord blood was collected at the time of delivery for measurement of growth hormone. When compared with healthy newborns, IUGR newborns had higher growth hormone levels (mean +/- SD, 23.5 +/- 15.6 vs 16.2 +/- 7.61 ngm/ml, P = 0.019). A negative correlation was identified between growth hormone levels and birth weight (r2 = - 0.22, P = 0.03) and ponderal index (r2 = - 0.36, P = 0.008). Correlation of growth hormone levels was much more confident with ponderal index than with birth weight. At birth IUGR infants display increased growth hormone levels which correlate with ponderal index much more confidently than with birth weight.

Update on the male hormonal contraceptive agents.

PubMed

Walton, Melanie; Anderson, Richard A

2004-09-01

There remains a need for new acceptable and effective male contraceptives to increase the choice for couples throughout the world. There have been no recent advances in available male contraceptive methods although a number of promising approaches have been identified, of which the hormonal approach is currently undergoing clinical investigation. In recent years the pace of research in this area has quickened significantly with increasing interest and now investment by the pharmaceutical industry. This is vital if the work undertaken so far by the public sector is to be transformed into a commercial reality. The hormonal approach is based on suppression of pituitary gonadotropin secretion resulting in a reversible reduction in spermatogenesis with azoospermia in all men being the ultimate aim. Without stimulation by luteinising hormone from the pituitary, testicular testosterone production also ceases. Therefore, androgen administration to restore physiological levels is an essential component of all male hormonal contraceptive regimes. Male hormonal contraceptives can consist of testosterone alone, or either a progestogen or gonadotropin-releasing hormone antagonist with 'add-back' testosterone. This article reviews the current state of progress in this field.

Naturally occurring menopause in cynomolgus monkeys: changes in hormone, lipid, and carbohydrate measures with hormonal status.

PubMed

Kavanagh, Kylie; Koudy Williams, J; Wagner, Janice D

2005-08-01

Naturally occurring post-menopausal (PM) female cynomolgus monkeys (Macaca fascicularis) were identified. Their sex hormone profile was characterized and compared with younger pre-menopausal females before and after ovariectomy (OVX). PM females had lower estrogens and increased follicle-stimulating hormone (FSH) concentrations. Two PM females had diabetes mellitus and elevated androgens (androstenodione and dihydroepiandrosterone sulfate). Non-diabetic PM females were given parenteral E(2) which normalized FSH, and caused improvements in body weight, plasma lipids and lipoprotein cholesterol. Androgens remained lower with E(2) treatment. OVX induced comparable increases in FSH seen with the PM monkeys, however they had lower body weights, and had higher estrone and androstenodione concentrations. Natural menopause occurs in cynomolgus monkeys and hormone changes with OVX are similar however, differences in sex hormones that can relate to body mass and age may be important. E(2) treatment restored estrogen levels and induced improvements in the lipid profile of PM females.

Microarray analysis reveals overlapping and specific transcriptional responses to different plant hormones in rice

PubMed Central

Garg, Rohini; Tyagi, Akhilesh K.; Jain, Mukesh

2012-01-01

Hormones exert pleiotropic effects on plant growth and development throughout the life cycle. Many of these effects are mediated at molecular level via altering gene expression. In this study, we investigated the exogenous effect of plant hormones, including auxin, cytokinin, abscisic acid, ethylene, salicylic acid and jasmonic acid, on the transcription of rice genes at whole genome level using microarray. Our analysis identified a total of 4171 genes involved in several biological processes, whose expression was altered significantly in the presence of different hormones. Further, 28% of these genes exhibited overlapping transcriptional responses in the presence of any two hormones, indicating crosstalk among plant hormones. In addition, we identified genes showing only a particular hormone-specific response, which can be used as hormone-specific markers. The results of this study will facilitate further studies in hormone biology in rice. PMID:22827941

Increased and mistimed sex hormone production in night shift workers.

PubMed

Papantoniou, Kyriaki; Pozo, Oscar J; Espinosa, Ana; Marcos, Josep; Castaño-Vinyals, Gemma; Basagaña, Xavier; Juanola Pagès, Elena; Mirabent, Joan; Martín, Jordi; Such Faro, Patricia; Gascó Aparici, Amparo; Middleton, Benita; Skene, Debra J; Kogevinas, Manolis

2015-05-01

Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes. We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers. Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17-2.32] and androgens (GMR: 1.44; 95% CI, 1.03-2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46). We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers. The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers. ©2015 American Association for Cancer Research.

A kinome-wide screen identifies the Insulin/IGF-1 receptor pathway as a mechanism of escape from hormone dependence in breast cancer

PubMed Central

Fox, Emily M.; Miller, Todd W.; Balko, Justin M.; Kuba, Maria G.; Sánchez, Violeta; Smith, R. Adam; Liu, Shuying; González-Angulo, Ana María; Mills, Gordon B.; Ye, Fei; Shyr, Yu; Manning, H. Charles; Buck, Elizabeth; Arteaga, Carlos L.

2011-01-01

Estrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER+ breast cancer cells resistant to long term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-1 receptor (IGF-1R) inhibited growth of 3/4 LTED cell lines. Inhibition of InsR and IGF-1R with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-1R monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-1 gene expression signature predicted recurrence-free survival in patients with ER+ breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-1R should be more effective than targeting IGF-1R alone in abrogating resistance to endocrine therapy in breast cancer. PMID:21908557

Steroid profiling in H295R cells to identify chemicals potentially disrupting the production of adrenal steroids.

PubMed

Strajhar, Petra; Tonoli, David; Jeanneret, Fabienne; Imhof, Raphaella M; Malagnino, Vanessa; Patt, Melanie; Kratschmar, Denise V; Boccard, Julien; Rudaz, Serge; Odermatt, Alex

2017-04-15

The validated OECD test guideline 456 based on human adrenal H295R cells promotes measurement of testosterone and estradiol production as read-out to identify potential endocrine disrupting chemicals. This study aimed to establish optimal conditions for using H295R cells to detect chemicals interfering with the production of key adrenal steroids. H295R cells' supernatants were characterized by liquid chromatography-mass spectrometry (LC-MS)-based steroid profiling, and the influence of experimental conditions including time and serum content was assessed. Steroid profiles were determined before and after incubation with reference compounds and chemicals to be tested for potential disruption of adrenal steroidogenesis. The H295R cells cultivated according to the OECD test guideline produced progestins, glucocorticoids, mineralocorticoids and adrenal androgens but only very low amounts of testosterone. However, testosterone contained in Nu-serum was metabolized during the 48h incubation. Thus, inclusion of positive and negative controls and a steroid profile of the complete medium prior to the experiment (t=0h) was necessary to characterize H295R cells' steroid production and indicate alterations caused by exposure to chemicals. Among the tested chemicals, octyl methoxycinnamate and acetyl tributylcitrate resembled the corticosteroid induction pattern of the positive control torcetrapib. Gene expression analysis revealed that octyl methoxycinnamate and acetyl tributylcitrate enhanced CYP11B2 expression, although less pronounced than torcetrapib. Further experiments need to assess the toxicological relevance of octyl methoxycinnamate- and acetyl tributylcitrate-induced corticosteroid production. In conclusion, the extended profiling and appropriate controls allow detecting chemicals that act on steroidogenesis and provide initial mechanistic evidence for prioritizing chemicals for further investigations. Copyright © 2017 Elsevier B.V. All rights reserved.

Data from Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors within the ToxCast Phase I and II Chemical Libraries

EPA Pesticide Factsheets

High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the U.S. Environmental Protection Agency ToxCast screening assay portfolio. To fill 1 critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast phase I and II chemical libraries, comprised of 1074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single-concentration screen were retested in concentration-response. Due to high false-positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed 2 additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidat

A right whale pootree: classification trees of faecal hormones identify reproductive states in North Atlantic right whales (Eubalaena glacialis).

PubMed

Corkeron, Peter; Rolland, Rosalind M; Hunt, Kathleen E; Kraus, Scott D

2017-01-01

Immunoassay of hormone metabolites extracted from faecal samples of free-ranging large whales can provide biologically relevant information on reproductive state and stress responses. North Atlantic right whales ( Eubalaena glacialis Müller 1776) are an ideal model for testing the conservation value of faecal metabolites. Almost all North Atlantic right whales are individually identified, most of the population is sighted each year, and systematic survey effort extends back to 1986. North Atlantic right whales number <500 individuals and are subject to anthropogenic mortality, morbidity and other stressors, and scientific data to inform conservation planning are recognized as important. Here, we describe the use of classification trees as an alternative method of analysing multiple-hormone data sets, building on univariate models that have previously been used to describe hormone profiles of individual North Atlantic right whales of known reproductive state. Our tree correctly classified the age class, sex and reproductive state of 83% of 112 faecal samples from known individual whales. Pregnant females, lactating females and both mature and immature males were classified reliably using our model. Non-reproductive [i.e. 'resting' (not pregnant and not lactating) and immature] females proved the most unreliable to distinguish. There were three individual males that, given their age, would traditionally be considered immature but that our tree classed as mature males, possibly calling for a re-evaluation of their reproductive status. Our analysis reiterates the importance of considering the reproductive state of whales when assessing the relationship between cortisol concentrations and stress. Overall, these results confirm findings from previous univariate statistical analyses, but with a more robust multivariate approach that may prove useful for the multiple-analyte data sets that are increasingly used by conservation physiologists.

Exposure to butachlor causes thyroid endocrine disruption and promotion of metamorphosis in Xenopus laevis.

PubMed

Li, Shuying; Li, Meng; Wang, Qiangwei; Gui, Wenjun; Zhu, Guonian

2016-06-01

Butachlor is extensively applied in rice paddy ecosystem in china, and has been widespread contaminant in the aquatic environment. Here, Xenopus laevis was used for the evaluation of teratogenesis developmental toxicity, and disruption of thyroid system when exposure to different concentrations of butachlor by window phase exposure. Acute toxicity investigation shown that 96 h-LC50 value of butachlor was 1.424 mg L(-1) and 0.962 mg L(-1) for tadpoles (starting from stages 46/47) and embryos (starting from stages 8/9), respectively. Exposure to butachlor caused malformation, including abnormal eye, pericardial edema, enlarged proctodaeum and bent tail. Window phase exposure test indicated that butachlor significantly promote the contents of whole-body thyroid hormones (THs, T3 and T4) at higher levels, indicating thyroid endocrine disruption. At 7 days, exposure to butachlor up-regulated the mRNA expression of genes involved in THs synthesis and metabolism (tshα, tg, tpo and dio1) and THs receptors (trα and trβ). At 14 days, up-regulation of the mRNA expression of genes related to THs synthesis and metabolism (tshα, tshβ, tg, tpo, dio1, dio2 and ttr) and THs receptors (trβ) were also observed after the exposure to butachlor. At 21 days, butachlor up-regulated the mRNA expression of tshα, tg, tpo genes and down-regulated the mRNA expression of tshβ, tg, dio1, ttr and trα genes. These results showed that butachlor could change the mRNA expression of genes involved in the HPT axis and increase whole-body thyroid hormones levels of X. laevis tadpoles in a dose- and time-dependent manner, causing thyroid endocrine disruption and developmental toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

POSSIBLE MECHANISMS OF THYROID HORMONE DISRUPTION IN MICE BY BDE 47, A MAJOR POLYBROMINATED DIPHENYL ETHER CONGENER

EPA Science Inventory

ABSTRACT Polybromindated diphenyl ethers (PBDEs) are a class of polyhalogenated aromatic compounds commercially used as fire retardants in consumer products. These compounds have been shown to decrease thyroid hormone concentrations in rodents after acute exposures. Based on t...

Changes in hormone and stress-inducing activities of municipal wastewater in a conventional activated sludge wastewater treatment plant.

PubMed

Wojnarowicz, Pola; Yang, Wenbo; Zhou, Hongde; Parker, Wayne J; Helbing, Caren C

2014-12-01

Conventional municipal wastewater treatment plants do not efficiently remove contaminants of emerging concern, and so are primary sources for contaminant release into the aquatic environment. Although these contaminants are present in effluents at ng-μg/L concentrations (i.e. microcontaminants), many compounds can act as endocrine disrupting compounds or stress-inducing agents at these levels. Chemical fate analyses indicate that additional levels of wastewater treatment reduce but do not always completely remove all microcontaminants. The removal of microcontaminants from wastewater does not necessarily correspond to a reduction in biological activity, as contaminant metabolites or byproducts may still be biologically active. To evaluate the efficacy of conventional municipal wastewater treatment plants to remove biological activity, we examined the performance of a full scale conventional activated sludge municipal wastewater treatment plant located in Guelph, Ontario, Canada. We assessed reductions in levels of conventional wastewater parameters and thyroid hormone disrupting and stress-inducing activities in wastewater at three phases along the treatment train using a C-fin assay. Wastewater treatment was effective at reducing total suspended solids, chemical and biochemical oxygen demand, and stress-inducing bioactivity. However, only minimal reduction was observed in thyroid hormone disrupting activities. The present study underscores the importance of examining multiple chemical and biological endpoints in evaluating and monitoring the effectiveness of wastewater treatment for removal of microcontaminants. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mate choice, sexual selection, and endocrine-disrupting chemicals.

PubMed

Gore, Andrea C; Holley, Amanda M; Crews, David

2018-05-01

Humans have disproportionately affected the habitat and survival of species through environmental contamination. Important among these anthropogenic influences is the proliferation of organic chemicals, some of which perturb hormone systems, the latter referred to as endocrine-disrupting chemicals (EDCs). EDCs are widespread in the environment and affect all levels of reproduction, including development of reproductive organs, hormone release and regulation through the life cycle, the development of secondary sexual characteristics, and the maturation and maintenance of adult physiology and behavior. However, what is not well-known is how the confluence of EDC actions on the manifestation of morphological and behavioral sexual traits influences mate choice, a process that requires the reciprocal evaluation of and/or acceptance of a sexual partner. Moreover, the outcomes of EDC-induced perturbations are likely to influence sexual selection; yet this has rarely been directly tested. Here, we provide background on the development and manifestation of sexual traits, reproductive competence, and the neurobiology of sexual behavior, and evidence for their perturbation by EDCs. Selection acts on individuals, with the consequences manifest in populations, and we discuss the implications for EDC contamination of these processes, and the future of species. Copyright © 2017 Elsevier Inc. All rights reserved.

Adverse Outcome Pathways for Embryonic Vascular Disruption and Alternative Methods to Identify Chemical Vascular Disruptor

EPA Science Inventory

Chemically induced vascular toxicity during embryonic development can result in a wide range of adverse prenatal outcomes. We used information from genetic mouse models linked to phenotypic outcomes and a vascular toxicity knowledge base to construct an embryonic vascular disrupt...

Impact of biosolids and wastewater effluent application to agricultural land on steroidal hormone content in lettuce plants.

PubMed

Shargil, Dorit; Gerstl, Zev; Fine, Pinchas; Nitsan, Ido; Kurtzman, Daniel

2015-02-01

One of the major concerns for human health in the past decade is the potential dangers posed by increased concentrations of steroidal hormones in soils and water. These hormones are considered to be endocrine disrupting compounds (EDCs), which may harm human health when exposed to high concentrations, or in the case of long term exposure to lower concentrations. In a 3 year study, two steroids, estrone and testosterone, were measured in lettuce plants irrigated with wastewater effluents and freshwater and treated with several types of biosolids. The relative contribution of the different factors, mainly irrigation water and biosolids, to the hormone levels in the lettuce plants was determined. It was found that irrigation water, which contained significant amounts of hormones, had the most substantial effect, whereas biosolids had only minor influence on hormone levels in the lettuce. The hormone levels in the plants were compared to the FDA recommendation for daily consumption in food, and were found to exceed the recommended level (when consumed by a typical individual), and therefore could have negative physiological impacts. Overall this study shows that biosolids have little effect on hormone uptake by lettuce, and it emphasizes the negative impact of irrigation water on these levels, which is of concern to public health. Copyright © 2014 Elsevier B.V. All rights reserved.

Role of plant hormones in plant defence responses.

PubMed

Bari, Rajendra; Jones, Jonathan D G

2009-03-01

Plant hormones play important roles in regulating developmental processes and signaling networks involved in plant responses to a wide range of biotic and abiotic stresses. Significant progress has been made in identifying the key components and understanding the role of salicylic acid (SA), jasmonates (JA) and ethylene (ET) in plant responses to biotic stresses. Recent studies indicate that other hormones such as abscisic acid (ABA), auxin, gibberellic acid (GA), cytokinin (CK), brassinosteroids (BR) and peptide hormones are also implicated in plant defence signaling pathways but their role in plant defence is less well studied. Here, we review recent advances made in understanding the role of these hormones in modulating plant defence responses against various diseases and pests.

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data.

PubMed

Rasier, G; Toppari, J; Parent, A-S; Bourguignon, J-P

2006-07-25

Natural hormones and some synthetic chemicals spread into our surrounding environment share the capacity to interact with hormone action and metabolism. Exposure to such compounds can cause a variety of developmental and reproductive detrimental abnormalities in wildlife species and, potentially, in human. Many experimental and epidemiological data have reported that exposure of the developing fetus or neonate to environmentally relevant concentrations of some among these endocrine disrupters induces morphological, biochemical and/or physiological disorders in brain and reproductive organs, by interfering with the hormone actions. The impact of such exposures on the hypothalamic-pituitary-gonadal axis and subsequent sexual maturation is the subject of the present review. We will highlight epidemiological human studies and the effects of early exposure during gestational, perinatal or postnatal life in female rodents.

TRIENNIAL REPRODUCTION SYMPOSIUM: Environmental programming of reproduction during fetal life: Effects of intrauterine position and the endocrine disrupting chemical bisphenol A.

PubMed

Vom Saal, F S

2016-07-01

During critical periods in fetal life, there is an increased vulnerability to perturbations in endocrine function due to environmental factors. Small shifts in concentrations of hormones that regulate the differentiation of organs, such as estradiol and testosterone, can have permanent effects on morphology, enzymatic activity, and hormone receptors in tissues as well as neurobehavioral effects. These changes can lead to effects throughout life, including impacting the risk for various diseases (referred to as the Developmental Origins of Adult Health and Disease hypothesis). The intrauterine position phenomenon concerns the consequence for fetuses of randomly implanting next to embryos of the same or opposite sex. An intrauterine position next to males vs. females results in small differences in serum testosterone and estradiol during fetal life that are associated with marked effects on life history (such as lifetime fecundity) in both males and females born in litters (mice, rats, gerbils, rabbits, and swine) as well as human twins. Research with mice subsequently demonstrated that a very small experimental change in fetal serum estradiol levels altered organogenesis and caused permanent changes in organ function. Taken together, these findings led to the hypothesis that environmental chemicals that mimic or antagonize hormone action (e.g., endocrine disrupting chemicals) could also be causing harm at very low exposures (the "low dose" hypothesis) within the range of exposure of humans, domesticated animals, and wildlife. There is now extensive evidence from experimental laboratory animals, sheep, and humans that fetal exposure to very low (presumably safe) doses of the endocrine disrupting chemical bisphenol A (BPA), which exhibits estrogenic activity, can cause permanent changes that can increase the risk of a wide array of diseases. The reasons that federal regulatory agencies are ignoring the massive literature showing adverse effects of BPA and other

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children.

PubMed

Loche, S; Carta, D; Muntoni, A C; Corda, R; Pintor, C

1993-10-01

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an i.v. bolus injection of growth hormone releasing hormone 1-29, 1 microgram/kg, significantly enhanced the growth hormone response to the neuropeptide, confirming the results of previous studies which used the i.v. route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.

An extensive molecular cytogenetic characterization in high-risk chronic lymphocytic leukemia identifies karyotype aberrations and TP53 disruption as predictors of outcome and chemorefractoriness

PubMed Central

Cavallari, Maurizio; Quaglia, Francesca Maria; Lista, Enrico; Urso, Antonio; Guardalben, Emanuele; Martinelli, Sara; Saccenti, Elena; Bassi, Cristian; Lupini, Laura; Bardi, Maria Antonella; Volta, Eleonora; Tammiso, Elisa; Melandri, Aurora; Negrini, Massimo

2017-01-01

We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases. A complex karyotype was present in 21 patients. Mutations were detected in 56 cases and were associated with unmutated IGHV status (p = 0.040) and complex karyotype (p = 0.047). TP53 disruption (i.e. TP53 mutations and/or 17p13 deletion by FISH) correlated with the presence of ≥ 2 mutations (p = 0.001) and a complex karyotype (p = 0.012). By multivariate analysis, an advanced Binet stage (p < 0.001) and an unfavorable karyotype (p = 0.001) predicted a shorter time to first treatment. TP53 disruption (p = 0.019) and the unfavorable karyotype (p = 0.028) predicted a worse overall survival. A shorter time to chemorefractoriness was associated with TP53 disruption (p = 0.001) and unfavorable karyotype (p = 0.025). Patients with both unfavorable karyotype and TP53 disruption presented a dismal outcome (median overall survival and time to chemorefractoriness of 28.7 and 15.0 months, respectively). In conclusion, karyotype analysis refines risk stratification in high-risk CLL patients and could identify a subset of patients with highly unfavorable outcome requiring alternative treatments. PMID:28427204

Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus

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

Dickerson, Sarah M.; Cunningham, Stephanie L.; Gore, Andrea C., E-mail: andrea.gore@mail.utexas.edu

Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; ormore » estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor {alpha} (ER{alpha}) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ER{alpha}, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA{sub B} receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGF{alpha}. Collectively, these results suggest that the

The Disruption of Celf6, a Gene Identified by Translational Profiling of Serotonergic Neurons, Results in Autism-Related Behaviors

PubMed Central

Dougherty, Joseph D.; Maloney, Susan E.; Wozniak, David F.; Rieger, Michael A.; Sonnenblick, Lisa; Coppola, Giovanni; Mahieu, Nathaniel G.; Zhang, Juliet; Cai, Jinlu; Patti, Gary J.; Abrahams, Brett S.; Geschwind, Daniel H.; Heintz, Nathaniel

2013-01-01

The immense molecular diversity of neurons challenges our ability to understand the genetic and cellular etiology of neuropsychiatric disorders. Leveraging knowledge from neurobiology may help parse the genetic complexity: identifying genes important for a circuit that mediates a particular symptom of a disease may help identify polymorphisms that contribute to risk for the disease as a whole. The serotonergic system has long been suspected in disorders that have symptoms of repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit translational profiling of serotonergic neurons. From this, we identified several thousand serotonergic-cell expressed transcripts, of which 174 were highly enriched, including all known markers of these cells. Analysis of common variants near the corresponding genes in the AGRE collection implicated the RNA binding protein CELF6 in autism risk. Screening for rare variants in CELF6 identified an inherited premature stop codon in one of the probands. Subsequent disruption of Celf6 in mice resulted in animals exhibiting resistance to change and decreased ultrasonic vocalization as well as abnormal levels of serotonin in the brain. This work provides a reproducible and accurate method to profile serotonergic neurons under a variety of conditions and suggests a novel paradigm for gaining information on the etiology of psychiatric disorders. PMID:23407934

The hypothalamus–pituitary–thyroid axis in teleosts and amphibians: Endocrine disruption and its consequences to natural populations

USGS Publications Warehouse

Carr, J.A.; Patino, Reynaldo

2011-01-01

Teleosts and pond-breeding amphibians may be exposed to a wide variety of anthropogenic, waterborne contaminants that affect the hypothalamus-pituitary-thyroid (HPT) axis. Because thyroid hormone is required for their normal development and reproduction, the potential impact of HPT-disrupting contaminants on natural teleost and amphibian populations raises special concern. There is laboratory evidence indicating that persistent organic pollutants, heavy metals, pharmaceutical and personal care products, agricultural chemicals, and aerospace products may alter HPT activity, development, and reproduction in teleosts and amphibians. However, at present there is no evidence to clearly link contaminant-induced HPT alterations to impairments in teleost or amphibian population health in the field. Also, with the exception of perchlorate for which laboratory studies have shown a direct link between HPT disruption and adverse impacts on development and reproductive physiology, little is known about if or how other HPT-disrupting contaminants affect organismal performance. Future field studies should focus on establishing temporal associations between the presence of HPT-disrupting chemicals, the occurrence of HPT alterations, and adverse effects on development and reproduction in natural populations; as well as determining how complex mixtures of HPT contaminants affect organismal and population health.

The hypothalamus-pituitary-thyroid axis in teleosts and amphibians: Endocrine disruption and its consequences to natural populations

USGS Publications Warehouse

Carr, J.A.; Patino, R.

2011-01-01

Teleosts and pond-breeding amphibians may be exposed to a wide variety of anthropogenic, waterborne contaminants that affect the hypothalamus-pituitary-thyroid (HPT) axis. Because thyroid hormone is required for their normal development and reproduction, the potential impact of HPT-disrupting contaminants on natural teleost and amphibian populations raises special concern. There is laboratory evidence indicating that persistent organic pollutants, heavy metals, pharmaceutical and personal care products, agricultural chemicals, and aerospace products may alter HPT activity, development, and reproduction in teleosts and amphibians. However, at present there is no evidence to clearly link contaminant-induced HPT alterations to impairments in teleost or amphibian population health in the field. Also, with the exception of perchlorate for which laboratory studies have shown a direct link between HPT disruption and adverse impacts on development and reproductive physiology, little is known about if or how other HPT-disrupting contaminants affect organismal performance. Future field studies should focus on establishing temporal associations between the presence of HPT-disrupting chemicals, the occurrence of HPT alterations, and adverse effects on development and reproduction in natural populations; as well as determining how complex mixtures of HPT contaminants affect organismal and population health. ?? 2010 Elsevier Inc.

Developmental neurotoxicity of monocrotophos and lead is linked to thyroid disruption

PubMed Central

Kumar, B. Kala; Reddy, A. Gopala; Krishna, A. Vamsi; Quadri, S. S. Y. H.; Kumar, P. Shiva

2016-01-01

Aim: A role of thyroid disruption in developmental neurotoxicity of monocrotophos (MCP) and lead is studied. Materials and Methods: A total of 24 female rats after conception were randomized into four groups of six each and treated as follows: Group I - Sham was administered distilled water orally. Group II - A positive control was administered methyl methimazole at 0.02% orally in drinking water. Group III - MCP orally at 0.3 mg/kg and Group IV - Lead acetate at 0.2% orally in drinking water. The drug was administered from gestation day 3 through post-natal day 21 in all the groups. Acetylcholinesterase (AChE) inhibition, thyroid profile (thyroid stimulating hormone, T3 and T4), neurodevelopment (brain wet weights, DNA, RNA and protein), and neurobehavioral (elevated plus maze, photoactometry, and Morris water maze) parameters were assessed in pups. A histopathology of thyroid of dams and brain of progeny was conducted. Results: Inhibition of AChE was <20%. Thyroid profile decreased in the treatment groups. Neurodevelopmental and neurobehavioral parameters did not reveal any significant changes. Thyroid architecture was affected significantly with MCP and lead. Cortical layers too were affected. The three layers of cerebellum either had abnormal arrangement or decreased cellularity in all treated groups relating to thyroid disruption. Conclusion: MCP and lead might have affected the development of cerebrum and cerebellum via thyroid disruption leading to developmental neurotoxicity. PMID:27051198

In silico methods in the discovery of endocrine disrupting chemicals.

PubMed

Vuorinen, Anna; Odermatt, Alex; Schuster, Daniela

2013-09-01

The prevalence of sex hormone-dependent cancers, reproductive problems, obesity, and cardiovascular complications has risen especially in the Western world. It has been suggested, that the exposure to various endocrine disrupting chemicals (EDCs) contributes to the development and progression of these diseases. EDCs can interfere with various proteins: nuclear steroid hormone receptors, such as estrogen-, androgen-, glucocorticoid- and mineralocorticoid receptors (ER, AR, GR, MR), and enzymes that are involved in steroid hormone synthesis and metabolism, for example hydroxysteroid dehydrogenases (HSDs). Numerous chemicals are known as endocrine disruptors. However, the mechanism of action for most of these EDCs is still unknown. It is exhaustive and time consuming to test in vitro all chemicals - potential EDCs - used in industry, agriculture or as food preservatives against their effects on the endocrine system. Computational methods, such as virtual screening, quantitative structure activity relationships and docking, are already well recognized and used in drug development. The same methods could also aid the research on EDCs. So far, the computational methods in the search of EDCs have been retrospective. There are, however, some prospective studies reporting the use of in silico methods: five studies reporting the identification of previously unknown 17β-HSD3 inhibitors, MR agonists, and ER antagonists/agonists. This review provides an overview of case studies and in silico methods that are used in the search of EDCs. This article is part of a Special Issue entitled 'CSR 2013'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide homeostasis

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

Park, Si Eun; Lim, Sa Rang; Choi, Hyung-kyoon

Triazines are herbicides that are widely used worldwide, and we previously observed that the maternal exposure of mice to simazine (50 or 500 μg/kg) resulted in smaller ovaries and uteri of their female offspring. Here, we investigated the underlying mechanism that may account for the reproductive dysfunction induced by simazine. We found that following maternal exposure, simazine is transmitted to the offspring, as evidenced by its presence in the offspring ovaries. Analyses of the simazine-exposed offspring revealed that the expression of the relaxin hormone receptor, relaxin-family peptide receptor 1 (RXFP1), prominently decreased in their ovaries and uteri. In addition, downstreammore » target genes of the relaxin pathway including nitric oxide (NO) synthase 2 (Nos2), Nos3, matrix metallopeptidase 9 (Mmp9), and vascular endothelial growth factor (Vegf) were downregulated in their ovaries. Moreover, AKT and extracellular signal-regulated kinases (ERK) levels and their phosphorylated active forms decreased in simazine-exposed ovaries. In vitro exposure of the human ovarian granulosa cells (KGN) and uterine endometrium cells (Hec-1A) to very low concentrations (0.001 to 1 nM) of triazines including atrazine, terbuthylazine, and propazine repressed NO production with a concurrent reduction in RXFP1, NOS2, and NOS3. The inhibitory action of triazines on NO release was dependent on RXFP1, phosphoinositol 3-kinase (PI3K)/AKT, and ERK. Radioligand-binding assay also confirmed that triazines competitively inhibited the binding of relaxin to its receptor. Therefore, the present study suggests that triazine herbicides act as endocrine disrupters by interfering with relaxin hormone signaling. Thus, further evaluation of their impact on human health is imperative. - Highlights: • Triazines downregulate critical molecules involved in the relaxin signaling pathway. • Triazines act as potent antagonists of binding of relaxin to its receptor. • Triazines disrupt nitric

Thyroid Hormone-Dependent Formation of a Subcortical Band Heterotopia (SBH) in the Neonatal Brain is not Exacerbated Under Conditions of Low Dietary Iron (FeD)

EPA Science Inventory

Although the critical role of thyroid hormone (TH) in brain development is well established - severe deficiency producing significant neurological dysfunction - there is a paucity of data on neurological impairments that accompany modest degrees of TH disruption. Quantitative m...

Girls’ childhood trajectories of disruptive behavior predict adjustment problems in early adolescence

PubMed Central

van der Molen, Elsa; Blokland, Arjan A. J.; Hipwell, Alison E.; Vermeiren, Robert R.J.M.; Doreleijers, Theo A.H.; Loeber, Rolf

2014-01-01

Background It is widely recognized that early onset of disruptive behavior is linked to a variety of detrimental outcomes in males later in life. In contrast, little is known about the association between girls’ childhood trajectories of disruptive behavior and adjustment problems in early adolescence. Methods The current study used 9 waves of data from the ongoing Pittsburgh Girls Study. A semi-parametric group based model was used to identify trajectories of disruptive behavior in 1,513 girls from age 6 to 12 years. Adjustment problems were characterized by depression, self-harm, PTSD, substance use, interpersonal aggression, sexual behavior, affiliation with delinquent peers, and academic achievement at ages 13 and 14. Results Three trajectories of childhood disruptive behavior were identified: low, medium, and high. Girls in the high group were at increased risk for depression, self-harm, PTSD, illegal substance use, interpersonal aggression, early and risky sexual behavior, and lower academic achievement. The likelihood of multiple adjustment problems increased with trajectories reflecting higher levels of disruptive behavior. Conclusion Girls following the high childhood trajectory of disruptive behavior require early intervention programs to prevent multiple, adverse outcomes in adolescence and further escalation in adulthood. PMID:25302849

Disruption of ion homeostasis by verrucosin and a related compound.

PubMed

Akiyama, Koichi; Tone, Junichi; Yamauchi, Satoshi; Sugahara, Takuya; Maruyama, Masafumi; Kakinuma, Yoshimi

2011-01-01

We have found that (-)-virgatusin and related compounds have antimicrobial and antifungal activity. To identify further biological activities of these compounds, we tested the activity of acridine orange efflux, which shows ionophore-like disruption of cellular ion homeostasis activity. After testing 31 compounds, we found that verrucosin and a related compound had disruption activity.

Perchlorate disrupts embryonic androgen synthesis and reproductive development in threespine stickleback without changing whole-body levels of thyroid hormone

PubMed Central

Petersen, Ann M.; Dillon, Danielle; Bernhardt, Richard A.; Torunsky, Roberta; Postlethwait, John H.; von Hippel, Frank A.; Buck, C. Loren; Cresko, William A.

2014-01-01

Perchlorate, an environmental contaminant, disrupts normal functioning of the thyroid. We previously showed that perchlorate disrupts behavior and gonad development, and induces external morphological changes in a vertebrate model organism, the threespine stickleback. Whether perchlorate alters these phenotypes via a thyroid-mediated mechanism, and the extent to which the effects depend on dose, are unknown. To address these questions, we chronically exposed stickleback to control conditions and to three concentrations of perchlorate (10, 30 and 100 ppm) at various developmental stages from fertilization to reproductive maturity. Adults chronically exposed to perchlorate had increased numbers of thyroid follicles and decreased numbers of thyrocytes. Surprisingly, T4 and T3 levels in larval, juvenile, and adult whole fish chronically exposed to perchlorate did not differ from controls, except at the lowest perchlorate dose, suggesting a non-monotonic dose response curve. We found no detectable abnormalities in external phenotype at any dose of perchlorate, indicating that the increased number of thyroid follicles compensated for the disruptive effects of these doses. In contrast to external morphology, gonadal development was altered substantially, with the highest dose of perchlorate causing the largest effects. Perchlorate increased the number both of early stage ovarian follicles in females and of advanced spermatogenic stages in males. Perchlorate also disrupted embryonic androgen levels. We conclude that chronic perchlorate exposure may not result in lasting adult gross morphological changes but can produce lasting modifications to gonads when compensation of T3 and T4 levels occurs by thyroid follicle hyperplasia. Perchlorate may therefore affect vertebrate development via both thyroidal and non-thyroidal mechanisms. PMID:25448260

Analysis of Gene Expression Profiles of Multiple Skin Diseases Identifies a Conserved Signature of Disrupted Homeostasis.

PubMed

Mills, Kevin J; Robinson, Michael K; Sherrill, Joseph D; Schnell, Daniel J; Xu, Jun

2018-05-28

Triggers of skin disease pathogenesis vary, but events associated with the elicitation of a lesion share many features in common. Our objective was to examine gene expression patterns in skin disease to develop a molecular signature of disruption of cutaneous homeostasis. Gene expression data from common inflammatory skin diseases (e.g., psoriasis, atopic dermatitis, seborrheic dermatitis and acne), and a novel statistical algorithm were used to define a unifying molecular signature referred to as the "Unhealthy Skin Signature" (USS). Using a pattern matching algorithm, analysis of public data repositories revealed that the USS is found in diverse epithelial diseases. Studies of milder disruptions of epidermal homeostasis have also shown that these conditions converge, to varying degrees, on the USS and that the degree of convergence is related directly to the severity of homeostatic disruption. The USS contains genes that had no prior published association with skin, but that play important roles in many different disease processes, supporting the importance of the USS to homeostasis. Finally, we show through pattern matching that the USS can be used to discover new potential dermatologic therapeutics. The USS provides a new means to further interrogate epithelial homeostasis and potentially develop novel therapeutics with efficacy across a spectrum of skin conditions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal site.

PubMed

Kassotis, Christopher D; Iwanowicz, Luke R; Akob, Denise M; Cozzarelli, Isabelle M; Mumford, Adam C; Orem, William H; Nagel, Susan C

2016-07-01

Currently, >95% of end disposal of hydraulic fracturing wastewater from unconventional oil and gas operations in the US occurs via injection wells. Key data gaps exist in understanding the potential impact of underground injection on surface water quality and environmental health. The goal of this study was to assess endocrine disrupting activity in surface water at a West Virginia injection well disposal site. Water samples were collected from a background site in the area and upstream, on, and downstream of the disposal facility. Samples were solid-phase extracted, and extracts assessed for agonist and antagonist hormonal activities for five hormone receptors in mammalian and yeast reporter gene assays. Compared to reference water extracts upstream and distal to the disposal well, samples collected adjacent and downstream exhibited considerably higher antagonist activity for the estrogen, androgen, progesterone, glucocorticoid and thyroid hormone receptors. In contrast, low levels of agonist activity were measured in upstream/distal sites, and were inhibited or absent at downstream sites with significant antagonism. Concurrent analyses by partner laboratories (published separately) describe the analytical and geochemical profiling of the water; elevated conductivity as well as high sodium, chloride, strontium, and barium concentrations indicate impacts due to handling of unconventional oil and gas wastewater. Notably, antagonist activities in downstream samples were at equivalent authentic standard concentrations known to disrupt reproduction and/or development in aquatic animals. Given the widespread use of injection wells for end-disposal of hydraulic fracturing wastewater, these data raise concerns for human and animal health nearby. Copyright © 2016 Elsevier B.V. All rights reserved.

Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal site

USGS Publications Warehouse

Kassotis, Christopher D.; Iwanowicz, Luke R.; Akob, Denise M.; Cozzarelli, Isabelle M.; Mumford, Adam; Orem, William H.; Nagel, Susan C.

2016-01-01

Currently, >95% of end disposal of hydraulic fracturing wastewater from unconventional oil and gas operations in the US occurs via injection wells. Key data gaps exist in understanding the potential impact of underground injection on surface water quality and environmental health. The goal of this study was to assess endocrine disrupting activity in surface water at a West Virginia injection well disposal site. Water samples were collected from a background site in the area and upstream, on, and downstream of the disposal facility. Samples were solid-phase extracted, and extracts assessed for agonist and antagonist hormonal activities for five hormone receptors in mammalian and yeast reporter gene assays. Compared to reference water extracts upstream and distal to the disposal well, samples collected adjacent and downstream exhibited considerably higher antagonist activity for the estrogen, androgen, progesterone, glucocorticoid and thyroid hormone receptors. In contrast, low levels of agonist activity were measured in upstream/distal sites, and were inhibited or absent at downstream sites with significant antagonism. Concurrent analyses by partner laboratories (published separately) describe the analytical and geochemical profiling of the water; elevated conductivity as well as high sodium, chloride, strontium, and barium concentrations indicate impacts due to handling of unconventional oil and gas wastewater. Notably, antagonist activities in downstream samples were at equivalent authentic standard concentrations known to disrupt reproduction and/or development in aquatic animals. Given the widespread use of injection wells for end-disposal of hydraulic fracturing wastewater, these data raise concerns for human and animal health nearby.

Utilization of Superheroes Social Skills to Reduce Disruptive and Aggressive Behavior

ERIC Educational Resources Information Center

O'Handley, Roderick D.; Radley, Keith C.; Cavell, Hannah J.

2016-01-01

The current pilot study investigated the effectiveness of the Superheroes Social Skills program in decreasing disruptive and aggressive behavior of elementary-age students with high-incidence disabilities. Six students in a self-contained classroom, identified as displaying high rates of disruptive and aggressive behavior toward peers, were…

Tissue architecture and breast cancer: the role of extracellular matrix and steroid hormones

PubMed Central

Hansen, R K; Bissell, M J

2010-01-01

The changes in tissue architecture that accompany the development of breast cancer have been the focus of investigations aimed at developing new cancer therapeutics. As we learn more about the normal mammary gland, we have begun to understand the complex signaling pathways underlying the dramatic shifts in the structure and function of breast tissue. Integrin-, growth factor-, and steroid hormone-signaling pathways all play an important part in maintaining tissue architecture; disruption of the delicate balance of signaling results in dramatic changes in the way cells interact with each other and with the extracellular matrix, leading to breast cancer. The extracellular matrix itself plays a central role in coordinating these signaling processes. In this review, we consider the interrelationships between the extracellular matrix, integrins, growth factors, and steroid hormones in mammary gland development and function. PMID:10903527

Tissue architecture and breast cancer: the role of extracellular matrix and steroid hormones

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

Hansen, R K; Bissell, M J

The changes in tissue architecture that accompany the development of breast cancer have been the focus of investigations aimed at developing new cancer therapeutics. As we learn more about the normal mammary gland, we have begun to understand the complex signaling pathways underlying the dramatic shifts in the structure and function of breast tissue. Integrin-, growth factor-, and steroid hormone-signaling pathways all play an important part in maintaining tissue architecture; disruption of the delicate balance of signaling results in dramatic changes in the way cells interact with each other and with the extracellular matrix, leading to breast cancer. The extracellularmore » matrix itself plays a central role in coordinating these signaling processes. In this review, we consider the interrelationships between the extracellular matrix, integrins, growth factors, and steroid hormones in mammary gland development and function.« less

Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

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

Sheng, Zhi-Guo; Tang, Yuan; Liu, Yu-Xiang

Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10{sup −9} Mmore » suppresses TR or steroid receptor coactivator-1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-β1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of β3 integrin or c-Src significantly reduces BPA-induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the β3 integrin/c-Src/MAPK/TR-β1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways, followed by recruiting N-CoR/SMRT to TR-β1, providing a novel insight regarding the TH disruption effects of low concentration BPA. -- Highlights: ► Environmentally relevant concentrations of BPA suppress TR transcription. ► BPA recruits the N-CoR/SMRT to TR under the physiologic concentrations of T3/T4. ► BPA disrupts T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways.« less

Inhibition of phospholipase C disrupts cytoskeletal organization and gravitropic growth in Arabidopsis roots.

PubMed

Andreeva, Zornitza; Barton, Deborah; Armour, William J; Li, Min Y; Liao, Li-Fen; McKellar, Heather L; Pethybridge, Kylie A; Marc, Jan

2010-10-01

The phospholipase protein superfamily plays an important role in hormonal signalling and cellular responses to environmental stimuli. There is also growing evidence for interactions between phospholipases and the cytoskeleton. In this report we used a pharmacological approach to investigate whether inhibiting a member of the phospholipase superfamily, phospholipase C (PLC), affects microtubules and actin microfilaments as well as root growth and morphology of Arabidopsis thaliana seedlings. Inhibiting PLC activity using the aminosteroid U73122 significantly inhibited root elongation and disrupted root morphology in a concentration-dependent manner, with the response being saturated at 5 μM, whereas the inactive analogue U73343 was ineffective. The primary root appeared to lose growth directionality accompanied by root waving and formation of curls. Immunolabelling of roots exposed to increasingly higher U73122 concentrations revealed that the normal transverse arrays of cortical microtubules in the elongation zone became progressively more disorganized or depolymerized, with the disorganization appearing within 1 h of incubation. Likewise, actin microfilament arrays also were disrupted. Inhibiting PLC using an alternative inhibitor, neomycin, caused similar disruptions to both cytoskeletal organization and root morphology. In seedlings gravistimulated by rotating the culture plates by 90°, both U73122 and neomycin disrupted the normal gravitropic growth of roots and etiolated hypocotyls. The effects of PLC inhibitors are therefore consistent with the notion that, as with phospholipases A and D, PLC likewise interacts with the cytoskeleton, alters growth morphology, and is involved in gravitropism.

Endocrine disrupting potential of PAHs and their alkylated analogues associated with oil spills.

PubMed

Lee, Sangwoo; Hong, Seongjin; Liu, Xiaoshan; Kim, Cheolmin; Jung, Dawoon; Yim, Un Hyuk; Shim, Won Joon; Khim, Jong Seong; Giesy, John P; Choi, Kyungho

2017-09-20

Polycyclic aromatic hydrocarbons (PAHs) and alkylated PAHs are known to be major toxic contaminants in spills of petroleum hydrocarbons (oil). Spilled oil undergoes weathering and over time, PAHs go through a series of compositional changes. PAHs can disrupt endocrine functions, and the type of functions affected and associated potencies vary with the type and alkylation status of PAH. In this study, the potential of five major PAHs of crude oil, i.e., naphthalene, fluorene, dibenzothiophene, phenanthrene, and chrysene, and their alkylated analogues (n = 25), to disrupt endocrine functions was evaluated by use of MVLN-luc and H295R cell lines. In the MVLN-luc bioassay, seven estrogen receptor (ER) agonists were detected among 30 tested PAHs. The greatest ER-mediated potency was observed for 1-methylchrysene (101.4%), followed by phenanthrene and its alkylated analogues (range of %-E2max from 1.6% to 47.3%). In the H295R bioassay, significantly greater syntheses of steroid hormones were observed for 20 PAHs. For major PAHs and their alkylated analogues, disruption of steroidogenesis appeared to be more significant than ER-mediated effects. The number and locations of alkyl-moieties alone could not explain differences in the types or the potencies of toxicities. This observation shows that disruption of endocrine functions by some constituents of oil spills could be underestimated if only parent compounds are considered in assessments of hazard and risk.

[Gender differences in cognitive functions and influence of sex hormones].

PubMed

Torres, A; Gómez-Gil, E; Vidal, A; Puig, O; Boget, T; Salamero, M

2006-01-01

To review scientific evidence on gender differences in cognitive functions and influence of sex hormones on cognitive performance. Systematical search of related studies identified in Medline. Women outperform men on verbal fluency, perceptual speed tasks, fine motor skills, verbal memory and verbal learning. Men outperform women on visuospatial ability, mathematical problem solving and visual memory. No gender differences on attention and working memory are found. Researchers distinguish four methods to investigate hormonal influence on cognitive performance: a) patient with hormonal disorders; b) neuroimaging in individuals during hormone administration; c) in women during different phases of menstrual cycle, and d) in patients receiving hormonal treatment (idiopathic hypogonadotropic hypogonadism, postmenopausal women and transsexuals). The findings mostly suggest an influence of sex hormones on some cognitive functions, but they are not conclusive because of limitations and scarcity of the studies. There are gender differences on cognitive functions. Sex hormones seem to influence cognitive performance.

Environmental signaling: from environmental estrogens to endocrine-disrupting chemicals and beyond.

PubMed

McLachlan, J A

2016-07-01

The landmark report (Herbst et al. 1971) linking prenatal treatment with a synthetic estrogen, diethylstilbestrol (DES), to cancer at puberty in women whose mothers took the drug while pregnant ushered in an era of research on delayed effects of such exposures on functional outcomes in offspring. An animal model developed in our laboratory at the National Institute of Environmental Health Sciences confirmed that DES was the carcinogen and exposure to DES caused, as well, functional alterations in the reproductive, endocrine, and immune systems of male and female mice treated in utero. DES was also being used in agriculture and we discovered, at the first meeting on Estrogens in the Environment in 1979 (Estrogens in the Environment, 1980), that many environmental contaminants were also estrogenic. Many laboratories sought to discern the basis for estrogenicity in environmental chemicals and to discover other hormonally active xenobiotics. Our laboratory elucidated how DES and other estrogenic compounds worked by altering differentiation through epigenetic gene imprinting, helping explain the transgenerational effects found in mice and humans. At the Wingspread Conference on the Human-Wildlife Connection in 1991 (Advances in Modern Environmental Toxicology, 1992), we learned that environmental disruption of the endocrine system occurred in many species and phyla, and the term endocrine disruption was introduced. Further findings of transgenerational effects of environmental agents that mimicked or blocked various reproductive hormones and the ubiquity of environmental signals, such as bisphenol A increased concern for human and ecological health. Scientists began to look at other endocrine system aspects, such as cardiovascular and immune function, and other nuclear receptors, with important observations regarding obesity and metabolism. Laboratories, such as ours, are now using stem cells to try to understand the mechanisms by which various environmental signals

Sleep Disruptions and Emotional Insecurity Are Pathways of Risk for Children

ERIC Educational Resources Information Center

El-Sheikh, Mona; Buckhalt, Joseph A.; Cummings, E. Mark; Keller, Peggy

2007-01-01

Background: Sleep problems are prevalent in American children. A critical need is to identify sources and processes related to sleep disruptions and their sequelae. We examined a model linking parental marital conflict and children's emotional insecurity, sleep disruptions, and their adjustment and academic problems. Method: One hundred and…

Universal versus tailored solutions for alleviating disruptive behavior in hospitals.

PubMed

Berman-Kishony, Talia; Shvarts, Shifra

2015-01-01

Disruptive behavior among hospital staff can negatively affect quality of care. Motivated by a standard on disruptive behavior issued by The Joint Commission (LD 3.10), as well as the desire to improve patient care, minimize liability, and improve staff retention, hospitals are setting policies to prevent and resolve disruptive behaviors. However, it is unknown whether uniform conflict management tools are equally effective among different hospital settings. We surveyed residents and nurses to identify similarities and differences among hospital departments in the antecedents, characteristics, and outcomes of disruptive behaviors, and in the effectiveness of conflict management tools. We used a quantitative questionnaire-based assessment to examine conflict perceptions in eight different hospital departments at Rambam Medical Center in Haifa, Israel. Most participants (89 %) reported witnessing disruptive behavior either directly or in other parties; the most significant causes were identified as intense work, miscommunication, and problematic personalities. The forms of these behaviors, however, varied significantly between departments, with some more prone to expressed conflicts, while others were characterized by hidden disruptive behaviors. These outcomes were correlated by the antecedents to disruptive behavior, which in turn affected the effectiveness of alleviating strategies and tools. Some tools, such as processes for evaluating complaints, teamwork and conflict management courses, and introducing a behavioral mission statement, are effective across many antecedents. Other tools, however, are antecedent-specific, falling into two principal categories: tools directly removing a specific problem and tools that offer a way to circumvent the problem. Conflict resolution tools and strategies, based on residents and nurse perceptions, may be more effective if tailored to the specific situation, rather than using a "one-size-fits-all" approach.

Association of Polybrominated Diphenyl Ethers (PBDEs) and Polychlorinated Biphenyls (PCBs) with Hyperthyroidism in Domestic Felines, Sentinels for Thyroid Hormone Disruption.

PubMed

Walter, Kyla M; Lin, Yan-Ping; Kass, Philip H; Puschner, Birgit

2017-05-03

Hyperthyroidism is the most common endocrine disorder observed in domestic felines; however, its etiology is largely unknown. Two classes of persistent organic pollutants, polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known to interfere with thyroid hormone (TH) signaling and regulation; thus, it is postulated that they contribute to the etiopathogenesis of feline hyperthyroidism and pose a risk to humans and other species. In this case-control study, the concentrations of 13 PBDE and 11 PCB congeners were measured by gas chromatography mass spectrometry in serum or plasma samples from 20 hyperthyroid and 31 control cats in order to investigate the association between concentration of PBDE and PCB congeners and feline hyperthyroidism. Logistic regression analysis was used to determine whether elevated concentrations of individual congeners were associated with a higher risk of feline hyperthyroidism. Hyperthyroid cats had higher concentrations of four PBDE congeners (BDE17, BDE100, BDE47, and BDE49) and five PCB congeners (PCB131, PCB153, PCB174, PCB180, and PCB196), compared to control cats. In addition, the sum of both PBDE and PCB congener concentrations were elevated in the hyperthyroid group compared to control cats; however, only the increased PCB concentrations were statistically significant. The sum total PBDE concentrations in our feline samples were approximately 50 times greater than concentrations previously reported in human populations from a geographically similar area, whereas sum total PCB concentrations were comparable to those previously reported in humans. These observational findings support the hypothesis that PBDEs and PCBs may contribute to the etiopathogenesis of hyperthyroidism in felines. As domestic house cats are often exposed to higher concentrations of PBDEs than humans, they may serve as sentinels for the risk of TH disruption that these pollutants pose to humans and other species.

Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice.

PubMed

Schneider, Mark J; Fiering, Steven N; Thai, B; Wu, Sing-yung; St Germain, Emily; Parlow, Albert F; St Germain, Donald L; Galton, Valerie Anne

2006-01-01

The type 1 deiodinase (D1) is thought to be an important source of T3 in the euthyroid state. To explore the role of the D1 in thyroid hormone economy, a D1-deficient mouse (D1KO) was made by targeted disruption of the Dio1 gene. The general health and reproductive capacity of the D1KO mouse were seemingly unimpaired. In serum, levels of T4 and rT3 were elevated, whereas those of TSH and T3 were unchanged, as were several indices of peripheral thyroid status. It thus appears that the D1 is not essential for the maintenance of a normal serum T3 level in euthyroid mice. However, D1 deficiency resulted in marked changes in the metabolism and excretion of iodothyronines. Fecal excretion of endogenous iodothyronines was greatly increased. Furthermore, when compared with both wild-type and D2-deficient mice, fecal excretion of [125I]iodothyronines was greatly increased in D1KO mice during the 48 h after injection of [125I]T4 or [125I]T3, whereas urinary excretion of [125I]iodide was markedly diminished. From these data it was estimated that a majority of the iodide generated by the D1 was derived from substrates other than T4. Treatment with T3 resulted in a significantly higher serum T3 level and a greater degree of hyperthyroidism in D1KO mice than in wild-type mice. We conclude that, although the D1 is of questionable importance to the wellbeing of the euthyroid mouse, it may play a major role in limiting the detrimental effects of conditions that alter normal thyroid function, including hyperthyroidism and iodine deficiency.

Reproduction impairment and endocrine disruption in female zebrafish after long-term exposure to MC-LR: A life cycle assessment.

PubMed

Hou, Jie; Li, Li; Wu, Ning; Su, Yujing; Lin, Wang; Li, Guangyu; Gu, Zemao

2016-01-01

Microcystin-LR (MC-LR) has been found to cause reproductive and developmental impairments as well as to disrupt sex hormone homeostasis of fish during acute and sub-chronic toxic experiments. However, fish in natural environments are continuously exposed to MC-LR throughout their entire life cycle as opposed to short-term exposure. Here, we tested the hypothesis that the mechanism by which MC-LR harms female fish reproduction and development within natural water bodies is through interference of the reproductive endocrine system. In the present study, zebrafish hatchlings (5 d post-fertilization) were exposed to 0, 0.3, 3 and 30 μg/L MC-LR for 90 d until reaching sexual maturity. Female zebrafish were selected, and the changes in growth and developmental indicators, ovarian ultrastructure as well as the levels of gonadal steroid hormones and vitellogenin (VTG) were examined along with the transcription of related genes in the hypothalamic-pituitary-gonadal-liver axis (HPGL-axis). The results showed for the first time, a life cycle exposure to MC-LR caused growth inhibition, decreased ovary weight and ovarian ultra-pathological lesions. Decreased ovarian testosterone levels indicated that MC-LR disrupted sex steroid hormone balance. Significantly up-regulated transcription of brain FSHβ and LHβ along with ovarian ERα, FSHR and LHR suggested positive feedback regulation in the HPGL-axis was induced as a compensatory mechanism for MC-LR damage. It was also noted that ovarian VTG content and hepatic ERα and VTG1 expression were all down-regulated, which might be responsible for reduced vitellus storage noted in our histological observations. Our findings indicate that a life cycle exposure to MC-LR impairs the development and reproduction of female zebrafish by disrupting the transcription of related HPGL-axis genes, suggesting that MC-LR has potential adverse effects on fish reproduction and thus population dynamics in MCs-contaminated aquatic environment

Effects of non-steroidal anti-inflammatory drugs on hormones and genes of the hypothalamic-pituitary-gonad axis, and reproduction of zebrafish.

PubMed

Ji, Kyunghee; Liu, Xiaoshan; Lee, Saeram; Kang, Sungeun; Kho, Younglim; Giesy, John P; Choi, Kyungho

2013-06-15

This study was conducted in two experiments, to identify non-steroidal anti-inflammatory drugs (NSAIDs) with high endocrine disruption potentials, and to understand consequences of exposure to such NSAIDs in fish. In the first experiment, the effects of five NSAIDs on hormones and gene transcriptions of the hypothalamic-pituitary-gonad (HPG) axis were evaluated after 14 d exposure of adult zebrafish. Ibuprofen and mefenamic acids were identified to increase the concentrations of 17β-estradiol and testosterone in females significantly, while decreased those of testosterone among male fish. Significant up-regulation of fshβ, lhβ, fshr and lhr were observed in females, whereas down-regulation was observed in males exposed to each NSAID. In the second experiment, ibuprofen was chosen as a model chemical. Adult zebrafish pairs were exposed to ibuprofen for 21 d, and the effects on reproduction and development of offspring were examined. The egg production was significantly decreased at ≥1 μg/L ibuprofen, and parental exposure resulted in delayed hatching even when they were transferred to clean water for hatching. The results demonstrated that ibuprofen could modulate hormone production and related gene transcription of the HPG axis in a sex-dependent way, which could cause adverse effects on reproduction and the development of offspring. Copyright © 2013 Elsevier B.V. All rights reserved.

The heterochronic gene Lin28 regulates amphibian metamorphosis through disturbance of thyroid hormone function.

PubMed

Faunes, Fernando; Gundermann, Daniel G; Muñoz, Rosana; Bruno, Renzo; Larraín, Juan

2017-05-15

Metamorphosis is a classic example of developmental transition, which involves important morphological and physiological changes that prepare the organism for the adult life. It has been very well established that amphibian metamorphosis is mainly controlled by Thyroid Hormone (TH). Here, we show that the heterochronic gene Lin28 is downregulated during Xenopus laevis metamorphosis. Lin28 overexpression before activation of TH signaling delays metamorphosis and inhibits the expression of TH target genes. The delay in metamorphosis is rescued by incubation with exogenous TH, indicating that Lin28 works upstream or parallel to TH. High-throughput analyses performed before any delay on metamorphosis or change in TH signaling showed that overexpression of Lin28 reduces transcript levels of several hormones secreted by the pituitary, including the Thyroid-Stimulating Hormone (TSH), and regulates the expression of proteins involved in TH transport, metabolism and signaling, showing that Lin28 disrupts TH function at different levels. Our data demonstrates that the role of Lin28 in controlling developmental transitions is evolutionary conserved and establishes a functional interaction between Lin28 and thyroid hormone function introducing a new regulatory step in perinatal development with implications for our understanding of endocrine disorders. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of bisphenol A, an environmental endocrine disruptor, on the endogenous hormones of plants.

PubMed

Wang, Shengman; Wang, Lihong; Hua, Weiqi; Zhou, Min; Wang, Qingqing; Zhou, Qing; Huang, Xiaohua

2015-11-01

Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical in the environment that exerts potential harm to plants. Phytohormones play important roles both in regulating multiple aspects of plant growth and in plants' responses to environmental stresses. But how BPA affects plant growth by regulating endogenous hormones remains poorly understood. Here, we found that treatment with 1.5 mg L(-1) BPA improved the growth of soybean seedlings, companied by increases in the contents of indole-3-acetic acid (IAA) and zeatin (ZT), and decreases in the ratios of abscisic acid (ABA)/IAA, ABA/gibberellic acid (GA), ABA/ZT, ethylene (ETH)/GA, ETH/IAA, and ETH/ZT. Treatment with higher concentrations of BPA (from 3 to 96 mg L(-1)) inhibited the growth of soybean seedlings, meanwhile, decreased the contents of IAA, GA, ZT, and ETH, and increased the content of ABA and the ratios of ABA/IAA, ABA/GA, ABA/ZT, ETH/GA, ETH/IAA, and ETH/ZT. The increases in the ratios of growth and stress hormones were correlated with the increase in the BPA content of the roots. Thus, BPA could affect plant growth through changing the levels of single endogenous hormone and the ratios of growth and stress hormones in the roots because of BPA absorption by the roots.

Methylprednisolone does not inhibit the release of growth hormone after intravenous injection of a novel growth hormone secretagogue in rats.

PubMed

Malmlöf, K; Johansen, P B; Haahr, P M; Wilken, M; Oxlund, H

1999-12-01

The present study was undertaken to study the growth hormone-releasing properties and growth-promoting effect of a GH secretagogue ipamorelin (IPA) in rats given the synthetic glucocorticoid methylprednisolone (MP). In a first experiment, rats received either saline or MP (5.0 mg/kg) for 8 days. Treatment with MP significantly (P< 0.001) decreased body weight gain, but the acute response to either IPA or growth hormone releasing hormone (GHRH) in terms of plasma GH was not changed. In a second experiment, venous catheters were surgically implanted. On the next day, rats were randomly allocated to receive saline alone, MP alone (5.0 mg/kg) or MP plus IPA in doses of 0.4 or 1.6 mg/kg/day for 10 days. IPA was administered intravenously four times a day.MP treatment significantly (P< 0.05) retarded recovery from surgery in terms of body weight. Thus, saline treated animals lost 4.0 +/- 3.5 g over the entire experimental period, whereas animals receiving MP lost 13. 6 +/- 2.9 g. When IPA was given together with MP, losses in body weight were significantly (P< 0.05) reduced to 2.3 +/- 2.0 and 1.6 +/- 2.0 g in animals given the high and low dose of IPA, respectively. In parallel with this IGF-I levels increased. In conclusion, this work shows that MP does not disrupt the response of the GH-IGF-I axis to an exogenous stimulus like IPA, and repeated stimulation leads to increases in IGF-I and of body weight gain. Copyright 1999 Harcourt Publishers Ltd.

Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency.

PubMed

Ziemnicka, K; Budny, B; Drobnik, K; Baszko-Błaszyk, D; Stajgis, M; Katulska, K; Waśko, R; Wrotkowska, E; Słomski, R; Ruchała, M

2016-08-01

The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis. We describe the clinical and molecular characteristics of two brothers aged 47 and 39 years presenting an uncommon manifestation of congenital hypopituitarism. Sequencing of the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes was performed to confirm the genetic origin of the disorder. A compound heterozygosity in the PROP1 gene has been identified for both probands. The first change represents a mutational hot spot (c.150delA, p.R53fsX164), whereas the second is a novel alteration (p.R112X) that leads to protein disruption. Based on precise genetic diagnosis, an in silico prediction of a p.R112X mutation on protein architecture was performed. The resulting clinical phenotype was surprisingly distinct compared to most patients with genetic alterations in PROP1 reported in the current literature. This may be caused by a residual activity of a newly identified p.R112X protein that preserves over 70 % of the homeodomain structure. This examination may confirm a key role of a DNA-binding homeodomain in maintaining PROP1 functionality and suggests a conceivable explanation of an unusual phenotype.

Associations between brominated flame retardants in house dust and hormone levels in men

PubMed Central

Johnson, Paula I.; Stapleton, Heather M.; Mukherjee, Bhramar; Hauser, Russ; Meeker, John D.

2013-01-01

Brominated flame retardants (BFRs) are used in the manufacture of a variety of materials and consumer products in order to meet fire safety standards. BFRs may persist in the environment and have been detected in wildlife, humans and indoor dust and air. Some BFRs have demonstrated endocrine and reproductive effects in animals, but human studies are limited. In this exploratory study, we measured serum hormone levels and flame retardant concentrations [31 polybrominated diphenyl ether (PBDE) congeners and 6 alternate flame retardants] in house dust from men recruited through a US infertility clinic. PBDE congeners in dust were grouped by commercial mixtures (i.e. penta-, octaand deca-BDE). In multivariable linear regression models adjusted by age and body mass index (BMI), significant positive associations were found between house dust concentrations of pentaBDEs and serum levels of free T4, total T3, estradiol, and sex hormone binding globulin (SHBG), along with an inverse association with follicle stimulating hormone (FSH). There were also positive associations of octaBDE concentrations with serum free T4, thyroid stimulating hormone (TSH), luteinizing hormone (LH) and testosterone and an inverse association of decaBDE concentrations with testosterone. Hexabromocyclododecane (HBCD) was associated with decreased SHBG and increased free androgen index. Dust concentrations of bis-tribromophenoxyethane (BTBPE) and tetrabromo-diethylhexylphthalate (TBPH) were positively associated with total T3. These findings are consistent with our previous report of associations between PBDEs (BDE 47, 99 and 100) in house dust and hormone levels in men, and further suggest that exposure to contaminants in indoor dust may be leading to endocrine disruption in men. PMID:23333513

Risk factors for wound disruption following cesarean delivery.

PubMed

Subramaniam, Akila; Jauk, Victoria C; Figueroa, Dana; Biggio, Joseph R; Owen, John; Tita, Alan T N

2014-08-01

Risk factors for post-cesarean wound infection, but not disruption, are well-described in the literature. The primary objective of this study was to identify risk factors for non-infectious post-cesarean wound disruption. Secondary analysis was conducted using data from a single-center randomized controlled trial of staple versus suture skin closure in women ≥24 weeks' gestation undergoing cesarean delivery. Wound disruption was defined as subcutaneous skin or fascial dehiscence excluding primary wound infections. Composite wound morbidity (disruption or infection) was examined as a secondary outcome. Patient demographics, medical co-morbidities, and intrapartum characteristics were evaluated as potential risk factors using multivariable logistic regression. Of the 398 randomized patients, 340, including 26 with disruptions (7.6%) met inclusion criteria and were analyzed. After multivariable adjustments, African-American race (aOR 3.9, 95% CI 1.1-13.8) and staple - as opposed to suture - wound closure (aOR 5.4, 95% CI 1.8-16.1) remained significant risk factors for disruption; non-significant increases were observed for body mass index ≥30 (aOR 2.1, 95% CI 0.6-7.5), but not for diabetes mellitus (aOR 0.9, 95% CI 0.3-2.9). RESULTS for composite wound morbidity were similar. Skin closure with staples, African-American race, and considering the relatively small sample size, potentially obesity are associated with increased risk of non-infectious post-cesarean wound disruption.

Digital disruption ?syndromes.

PubMed

Sullivan, Clair; Staib, Andrew

2017-05-18

The digital transformation of hospitals in Australia is occurring rapidly in order to facilitate innovation and improve efficiency. Rapid transformation can cause temporary disruption of hospital workflows and staff as processes are adapted to the new digital workflows. The aim of this paper is to outline various types of digital disruption and some strategies for effective management. A large tertiary university hospital recently underwent a rapid, successful roll-out of an integrated electronic medical record (EMR). We observed this transformation and propose several digital disruption "syndromes" to assist with understanding and management during digital transformation: digital deceleration, digital transparency, digital hypervigilance, data discordance, digital churn and post-digital 'depression'. These 'syndromes' are defined and discussed in detail. Successful management of this temporary digital disruption is important to ensure a successful transition to a digital platform. What is known about this topic? Digital disruption is defined as the changes facilitated by digital technologies that occur at a pace and magnitude that disrupt established ways of value creation, social interactions, doing business and more generally our thinking. Increasing numbers of Australian hospitals are implementing digital solutions to replace traditional paper-based systems for patient care in order to create opportunities for improved care and efficiencies. Such large scale change has the potential to create transient disruption to workflows and staff. Managing this temporary disruption effectively is an important factor in the successful implementation of an EMR. What does this paper add? A large tertiary university hospital recently underwent a successful rapid roll-out of an integrated electronic medical record (EMR) to become Australia's largest digital hospital over a 3-week period. We observed and assisted with the management of several cultural, behavioural and

Alteration of thyroid hormone concentrations in juvenile Chinook salmon (Oncorhynchus tshawytscha) exposed to polybrominated diphenyl ethers, BDE-47 and BDE-99.

PubMed

Arkoosh, Mary R; Van Gaest, Ahna L; Strickland, Stacy A; Hutchinson, Greg P; Krupkin, Alex B; Dietrich, Joseph P

2017-03-01

Polybrominated diphenyl ethers (PBDEs) have been used as flame-retardants in consumer products and are currently detected in salmon globally. The two most predominant PBDE congeners found in salmon are BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) and BDE-99 (2,2',4,4',5-pentabromodiphenyl ether). In the present study, groups of juvenile Pacific Chinook salmon were fed five environmentally relevant concentrations of either BDE-47 (0.3-552 ng total PBDEs/g food), BDE-99 (0.3-580 ng total PBDEs/g food), or nearly equal mixtures of both congeners (0.7-690 ng total PBDEs/g food) for 39-40 days. The concentrations of circulating total thyroid hormones, thyroxine (T 4 ) and 3,5,3'-triiodothyronine (T 3 ), were measured using a hormone-specific time-resolved fluoroimmunoassay to determine if PBDE exposure disrupts the hypothalamic-pituitary-thyroid endocrine axis. The concentrations of both circulating T 4 and T 3 were altered in juvenile salmon by dietary uptake of BDE-99. Exposure to BDE-47 did not alter either T 3 or T 4 circulating hormone concentrations. However, exposure to a mixture of BDE-47 and BDE-99 reduced T 3 in fish with lower concentrations of total whole body PBDEs than with either congener alone at equivalent PBDE whole body concentrations. Accordingly, the disruption of PBDEs on circulating thyroid hormone concentrations has the potential to impact a number of critical functions in juvenile salmon including growth, parr-smolt transformation, and immunological processes. Published by Elsevier Ltd.

Effects of endocrine disrupting chemicals from leather industry effluents on male reproductive system.

PubMed

Kumar, Vikas; Majumdar, Chandrajeetbalo; Roy, Partha

2008-09-01

The leather tanning industry is characterized by the production of different kinds of effluents, generated in each step of leather processing. These effluents have various chemical compounds which may cause toxicity and endocrine disruption and are thus known as endocrine disrupting chemicals (EDC). This study was aimed to examine the androgenic potential of leather industry effluents collected from northern region of India. Hershberger assay data showed a significant increase (p<0.05) in the weight and structure of sex accessory tissues of castrated rats. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis demonstrated a significant change (p<0.05) in the expression patterns of the major steroidogenic enzymes in adrenal and testes namely, cytochrome P450scc, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydorgenase in castrated and intact rats. This was further supported by increased enzymatic activities measured in vitro spectrophotometrically. Serum hormone profile demonstrated a dose dependent increase in testicular and adrenal testosterone productions in intact and castrated rats, respectively. This was further supported by decreased level of gonadotrophic hormones (LH and FSH) in treated groups of animals. Further, the effluent treatment resulted in the development of hyperplasia in seminiferous tubules of testes in treated rats as evident from histopathological studies and about two-fold increases in daily sperm production. On analysis of water samples using GC-MS, it was found to contain various aromatic compounds (nonylphenol, hexaclrobenzene and several azo dyes) some of which independently demonstrated similar effects as shown by water samples. Our data suggests that the effluents from leather industry have potential EDC demonstrating androgenic activities.

Alternatives to in vivo tests to detect endocrine disrupting chemicals (EDCs) in fish and amphibians – interactions with estrogens, androgens, and thyroid hormones

EPA Science Inventory

Endocrine disruption is considered a highly relevant endpoint for environmental risk assessment of chemicals, plant protection products, biocides and pharmaceuticals. Therefore, screening for endocrine disruption – with focus on vertebrates (fish and amphibians) and estrogen, and...

Girls' childhood trajectories of disruptive behavior predict adjustment problems in early adolescence.

PubMed

van der Molen, Elsa; Blokland, Arjan A J; Hipwell, Alison E; Vermeiren, Robert R J M; Doreleijers, Theo A H; Loeber, Rolf

2015-07-01

It is widely recognized that early onset of disruptive behavior is linked to a variety of detrimental outcomes in males, later in life. In contrast, little is known about the association between girls' childhood trajectories of disruptive behavior and adjustment problems in early adolescence. This study used nine waves of data from the ongoing Pittsburgh Girls Study. A semiparametric group-based model was used to identify trajectories of disruptive behavior in 1,513 girls from age 6 to 12 years. Adjustment problems were characterized by depression, self-harm, Post Traumatic Stress Disorder (PTSD), substance use, interpersonal aggression, sexual behavior, affiliation with delinquent peers, and academic achievement at ages 13 and 14. Three trajectories of childhood disruptive behavior were identified: low, medium, and high. Girls in the high group were at increased risk for depression, self-harm, PTSD, illegal substance use, interpersonal aggression, early and risky sexual behavior, and lower academic achievement. The likelihood of multiple adjustment problems increased with trajectories reflecting higher levels of disruptive behavior. Girls following the high childhood trajectory of disruptive behavior require early intervention programs to prevent multiple, adverse outcomes in adolescence and further escalation in adulthood. © 2014 Association for Child and Adolescent Mental Health.

Developmental programming: deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep.

PubMed

Veiga-Lopez, A; Ye, W; Phillips, D J; Herkimer, C; Knight, P G; Padmanabhan, V

2008-04-01

Prenatal testosterone excess leads to neuroendocrine, ovarian, and metabolic disruptions, culminating in reproductive phenotypes mimicking that of women with polycystic ovary syndrome (PCOS). The objective of this study was to determine the consequences of prenatal testosterone treatment on periovulatory hormonal dynamics and ovulatory outcomes. To generate prenatal testosterone-treated females, pregnant sheep were injected intramuscularly (days 30-90 of gestation, term=147 days) with 100 mg of testosterone-propionate in cottonseed oil semi-weekly. Female offspring born to untreated control females and prenatal testosterone-treated females were then studied during their first two breeding seasons. Sheep were given two injections of prostaglandin F2alpha 11 days apart, and blood samples were collected at 2-h intervals for 120 h, 10-min intervals for 8 h during the luteal phase (first breeding season only), and daily for an additional 15 days to characterize changes in reproductive hormonal dynamics. During the first breeding season, prenatal testosterone-treated females manifested disruptions in the timing and magnitude of primary gonadotropin surges, luteal defects, and reduced responsiveness to progesterone negative feedback. Disruptions in the periovulatory sequence of events during the second breeding season included: 1) delayed but increased preovulatory estradiol rise, 2) delayed and severely reduced primary gonadotropin surge in prenatal testosterone-treated females having an LH surge, 3) tendency for an amplified secondary FSH surge and a shift in the relative balance of FSH regulatory proteins, and 4) luteal responses that ranged from normal to anovulatory. These outcomes are likely to be of relevance to developmental origin of infertility disorders and suggest that differences in fetal exposure or fetal susceptibility to testosterone may account for the variability in reproductive phenotypes.

Age-Related Sleep Disruption and Reduction in the Circadian Rhythm of Urine Output: Contribution to Nocturia?

PubMed Central

Duffy, Jeanne F.; Scheuermaier, Karine; Loughlin, Kevin R.

2015-01-01

Aging is associated with a marked increase in sleep complaints, and one factor causing sleep disruption is waking to void (nocturia). Urological surveys have found that few young adults report nocturia symptoms, but about half of those in their 60’s and nearly 80% of older age groups are affected. Sleep surveys have found nocturia is a major cause of sleep disruption, with a majority of older adults with sleep disruption citing the need to void as the cause of their awakening. While much of the urological literature implies that nocturia causes sleep disruption, age-related changes in sleep depth and continuity may make it more likely that an older adult will wake in response to a filling bladder, or that an older adult will wake for another reason and then decide to void. There is also evidence that age-related changes in the amplitude of circadian rhythms contribute to nocturia. There is a well-described circadian rhythm in urine output, and evidence of circadian rhythmicity in some diuretic and anti-diuretic hormones. In this article we describe how age-related changes in sleep depth and continuity and age-related changes in circadian rhythm amplitude may contribute to nocturia, and how nocturia in turn leads to sleep disruption. Better understanding of how changes in sleep and circadian rhythmicity impact nocturia may lead to improved treatments and better quality of life for older adults. PMID:26632430

Microbial production of plant hormones: Opportunities and challenges.

PubMed

Shi, Tian-Qiong; Peng, Hui; Zeng, Si-Yu; Ji, Rong-Yu; Shi, Kun; Huang, He; Ji, Xiao-Jun

2017-03-04

Plant hormones are a class of organic substances which are synthesized during the plant metabolism. They have obvious physiological effect on plant growth at very low concentrations. Generally, plant hormones are mainly divided into 5 categories: auxins, cytokinins, ethylene, gibberellins (GAs) and abscisic acid (ABA). With the deepening of research, some novel plant hormones such as brassinosteroid and salicylates have been found and identified. The plant hormone products are mainly obtained through plant extraction, chemical synthesis as well as microbial fermentation. However, the extremely low yield in plants and relatively complex chemical structure limit the development of the former 2 approaches. Therefore, more attention has been paid into the microbial fermentative production. In this commentary, the developments and technological achievements of the 2 important plant hormones (GAs and ABA) have been discussed. The discovery, producing strains, fermentation technologies, and their accumulation mechanisms are first introduced. Furthermore, progresses in the industrial mass scale production are discussed. Finally, guidelines for future studies for GAs and ABA production are proposed in light of the current progress, challenges and trends in the field. With the widespread use of plant hormones in agriculture, we believe that the microbial production of plant hormones will have a bright future.

Thyroid Disruption in Zebrafish Larvae by Short-Term Exposure to Bisphenol AF

PubMed Central

Tang, Tianle; Yang, Yang; Chen, Yawen; Tang, Wenhao; Wang, Fuqiang; Diao, Xiaoping

2015-01-01

Bisphenol AF (BPAF) is extensively used as a raw material in industry, resulting in its widespread distribution in the aqueous environment. However, the effect of BPAF on the hypothalamic-pituitary-thyroidal (HPT) axis remains unknown. For elucidating the disruptive effects of BPAF on thyroid function and expression of the representative genes along the HPT axis in zebrafish (Danio rerio) embryos, whole-body total 3,3′,5-triiodothyronine (TT3), total 3,5,3′,5′-tetraiodothyronine (TT4), free 3,3′,5-triiodothyronine (FT3) and free 3,5,3′,5′-tetraiodothyronine (FT4) levels were examined following 168 h post-fertilization exposure to different BPAF concentrations (0, 5, 50 and 500 μg/L). The results showed that whole-body TT3, TT4, FT3 and FT4 contents decreased significantly with the BPAF treatment, indicating an endocrine disruption of thyroid. The expression of thyroid-stimulating hormone-β and thyroglobulin genes increased after exposing to 50 μg/L BPAF in seven-day-old larvae. The expressions of thyronine deiodinases type 1, type 2 and transthyretin mRNAs were also significantly up-regulated, which were possibly associated with a deterioration of thyroid function. However, slc5a5 gene transcription was significantly down-regulated at 50 μg/L and 500 μg/L BPAF exposure. Furthermore, trα and trβ genes were down-regulated transcriptionally after BPAF exposure. It demonstrates that BPAF exposure triggered thyroid endocrine toxicity by altering the whole-body contents of thyroid hormones and changing the transcription of the genes involved in the HPT axis in zebrafish larvae. PMID:26501309

Effects of polychlorinated biphenyls on metamorphosis of a marine fish Japanese flounder (Paralichthys olivaceus) in relation to thyroid disruption.

PubMed

Dong, Yifei; Zhang, Xiaona; Tian, Hua; Li, Xiang; Wang, Wei; Ru, Shaoguo

2017-06-15

This study examined the influence of environmental concentrations of Aroclor 1254 (10, 100, and 1000ng/L) on metamorphosis of Paralichthys olivaceus, and analyzed the mechanisms in relation to thyroid disruption. Results showed that 100 and 1000ng/L Aroclor 1254 delayed metamorphosis and that 1000ng/L Aroclor 1254 caused abnormal morphology. Thyroxine and triiodothyronine levels in the control group were significantly elevated at metamorphic climax, but treatment with 100 and 1000ng/L delayed the increase in thyroid hormones (THs) and retarded metamorphic processes. In larvae exposed to 1000ng/L Aroclor 1254, TH levels at metamorphic climax were significantly lower than those of the control group at the same metamorphic stage. We suggest that the effects of Aroclor 1254 on larval metamorphosis can be explained by disruption of thyroid homeostasis. These findings provide a new perspective and biological model for thyroid-disrupting chemicals (TDCs) screening and investigating interference of thyroid function by TDCs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Featured Article: Transcriptional landscape analysis identifies differently expressed genes involved in follicle-stimulating hormone induced postmenopausal osteoporosis.

PubMed

Maasalu, Katre; Laius, Ott; Zhytnik, Lidiia; Kõks, Sulev; Prans, Ele; Reimann, Ene; Märtson, Aare

2017-01-01

Osteoporosis is a disorder associated with bone tissue reorganization, bone mass, and mineral density. Osteoporosis can severely affect postmenopausal women, causing bone fragility and osteoporotic fractures. The aim of the current study was to compare blood mRNA profiles of postmenopausal women with and without osteoporosis, with the aim of finding different gene expressions and thus targets for future osteoporosis biomarker studies. Our study consisted of transcriptome analysis of whole blood serum from 12 elderly female osteoporotic patients and 12 non-osteoporotic elderly female controls. The transcriptome analysis was performed with RNA sequencing technology. For data analysis, the edgeR package of R Bioconductor was used. Two hundred and fourteen genes were expressed differently in osteoporotic compared with non-osteoporotic patients. Statistical analysis revealed 20 differently expressed genes with a false discovery rate of less than 1.47 × 10 -4 among osteoporotic patients. The expression of 10 genes were up-regulated and 10 down-regulated. Further statistical analysis identified a potential osteoporosis mRNA biomarker pattern consisting of six genes: CACNA1G, ALG13, SBK1, GGT7, MBNL3, and RIOK3. Functional ingenuity pathway analysis identified the strongest candidate genes with regard to potential involvement in a follicle-stimulating hormone activated network of increased osteoclast activity and hypogonadal bone loss. The differentially expressed genes identified in this study may contribute to future research of postmenopausal osteoporosis blood biomarkers.

Waterborne exposure to BPS causes thyroid endocrine disruption in zebrafish larvae

PubMed Central

Zhang, Dan-hua; Zhou, En-xiang; Yang, Zhu-lin

2017-01-01

Bisphenol S (BPS) is widely used as a raw material in industry, resulting in its ubiquitous distribution in natural environment, including the aqueous environment. However, the effect of BPS on the thyroid endocrine system is largely unknown. In this study, zebrafish (Danio rerio) embryos were exposed to BPS at 1, 3, 10, and 30 μg/L, from 2 h post-fertilization (hpf) to 168hpf. Bioconcentration of BPS and whole-body thyroid hormones (THs), thyroid-stimulating hormone (TSH) concentrations as well as transcriptional profiling of key genes related to the hypothalamic-pituitary-thyroid (HPT) axis were examined. Chemical analysis indicated that BPS was accumulated in zebrafish larvae. Thyroxine (T4) and triiodothyronine (T3) levels were significantly decreased at ≥ 10 and 30 μg/L of BPS, respectively. However, TSH concentration was significantly induced in the 10 and 30 μg/L BPS-treated groups. After exposure to BPS, the mRNA expression of corticotrophin releasing hormone (crh) and thyroglobulin (tg) genes were up-regulated at ≥10 μg/L of BPS, in a dose-response manner. The transcription of genes involved in thyroid development (pax8) and synthesis (sodium/iodide symporter, slc5a5) were also significantly increased in the 30 μg/L of BPS treatment group. Moreover, exposure to 10 μg/L or higher concentration of BPS significantly up-regulated genes related to thyroid hormone metabolism (deiodinases, dio1, dio2 and uridinediphosphate glucoronosyltransferases, ugt1ab), which might be responsible for the altered THs levels. However, the transcript of transthyretin (ttr) was significantly down-regulated at ≥ 3 μg/L of BPS, while the mRNA levels of thyroid hormone receptors (trα and trβ) and dio3 remained unchanged. All the results indicated that exposure to BPS altered the whole-body THs and TSH concentrations and changed the expression profiling of key genes related to HPT axis, thus triggering thyroid endocrine disruption. PMID:28467477

Application of Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for Interpretation of High-throughput Screening Assay for Thyroperoxidase Inhibition

EPA Science Inventory

In vitro based assays are used to identify potential endocrine disrupting chemicals. Thyroperoxidase (TPO), an enzyme essential for thyroid hormone (TH) synthesis, is a target site for disruption of the thyroid axis for which a high-throughput screening (HTPS) assay has recently ...

Hormones

MedlinePlus

Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...

Dimeric Arrangement of the Parathyroid Hormone Receptor and a Structural Mechanism for Ligand-induced Dissociation

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

Pioszak, Augen A.; Harikumar, Kaleeckal G.; Parker, Naomi R.

2010-06-25

The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an {alpha}-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure,more » PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein.« less

Mutations in PROP1 cause familial combined pituitary hormone deficiency.

PubMed

Wu, W; Cogan, J D; Pfäffle, R W; Dasen, J S; Frisch, H; O'Connell, S M; Flynn, S E; Brown, M R; Mullis, P E; Parks, J S; Phillips, J A; Rosenfeld, M G

1998-02-01

Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1, which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report, we have identified four CPHD families with homozygosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge.

PubMed

Surkin, P N; Di Rosso, M E; Correa, F; Elverdin, J C; Genaro, A M; De Laurentiis, A; Fernández-Solari, J

2017-08-01

Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 μL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor α and adenohypophyseal mRNA expression of Tnfα and Il1β increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS

A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

PubMed Central

Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Anderson, Richard A.; Ross, Alexander W.; Mercer, Julian G.

2014-01-01

Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms. Methods: Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA. Results: Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (±1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic

Liposome Disruption Assay to Examine Lytic Properties of Biomolecules.

PubMed

Jimah, John R; Schlesinger, Paul H; Tolia, Niraj H

2017-08-05

Proteins may have three dimensional structural or amino acid features that suggest a role in targeting and disrupting lipids within cell membranes. It is often necessary to experimentally investigate if these proteins and biomolecules are able to disrupt membranes in order to conclusively characterize the function of these biomolecules. Here, we describe an in vitro assay to evaluate the membrane lytic properties of proteins and biomolecules. Large unilamellar vesicles (liposomes) containing carboxyfluorescein at fluorescence-quenching concentrations are treated with the biomolecule of interest. A resulting increase in fluorescence due to leakage of the dye from liposomes and subsequent dilution in the buffer demonstrates that the biomolecule is sufficient for disrupting liposomes and membranes. Additionally, since liposome disruption may occur via pore-formation or via general solubilization of lipids similar to detergents, we provide a method to distinguish between these two mechanisms. Pore-formation can be identified and evaluated by examining the blockade of carboxyfluorescein release with dextran molecules that fit the pore. The methods described here were used to determine that the malaria vaccine candidate CelTOS and proapoptotic Bax disrupt liposomes by pore formation (Saito et al. , 2000; Jimah et al. , 2016). Since membrane lipid binding by a biomolecule precedes membrane disruption, we recommend the companion protocol: Jimah et al. , 2017.

hCG and Its Disruption by Environmental Contaminants during Human Pregnancy.

PubMed

Paulesu, Luana; Rao, Ch V; Ietta, Francesca; Pietropolli, Adalgisa; Ticconi, Carlo

2018-03-20

Human chorionic gonadotropin (hCG) is a hormone of considerable importance in the establishment, promotion and maintenance of human pregnancy. It has been clearly demonstrated that hCG exerts multiple endocrine, paracrine and autocrine actions on a variety of gestational and non-gestational cells and tissues. These actions are directed to promote trophoblast invasiveness and differentiation, placental growth, angiogenesis in uterine vasculature, hormone production, modulation of the immune system at the maternal-fetal interface, inhibition of myometrial contractility as well as fetal growth and differentiation. In recent years, considerable interest has been raised towards the biological effects of environmental contaminants, particularly endocrine disrupting chemicals (EDCs). Emerging evidence suggests that prenatal exposure to selected EDCs can have a deleterious impact on the fetus and long-lasting consequences also in adult life. The results of the in vitro effects of commonly found EDCs, particularly Bisphenol A (BPA) and para -Nonylphenol ( p -NP), indicate that these substances can alter hCG production and through this action could exert their fetal damage, suggesting that hCG could represent and become a potentially useful clinical biomarker of an inappropriate prenatal exposure to these substances.

hCG and Its Disruption by Environmental Contaminants during Human Pregnancy

PubMed Central

Paulesu, Luana; Rao, Ch.V.; Ietta, Francesca; Pietropolli, Adalgisa; Ticconi, Carlo

2018-01-01

Human chorionic gonadotropin (hCG) is a hormone of considerable importance in the establishment, promotion and maintenance of human pregnancy. It has been clearly demonstrated that hCG exerts multiple endocrine, paracrine and autocrine actions on a variety of gestational and non-gestational cells and tissues. These actions are directed to promote trophoblast invasiveness and differentiation, placental growth, angiogenesis in uterine vasculature, hormone production, modulation of the immune system at the maternal-fetal interface, inhibition of myometrial contractility as well as fetal growth and differentiation. In recent years, considerable interest has been raised towards the biological effects of environmental contaminants, particularly endocrine disrupting chemicals (EDCs). Emerging evidence suggests that prenatal exposure to selected EDCs can have a deleterious impact on the fetus and long-lasting consequences also in adult life. The results of the in vitro effects of commonly found EDCs, particularly Bisphenol A (BPA) and para-Nonylphenol (p-NP), indicate that these substances can alter hCG production and through this action could exert their fetal damage, suggesting that hCG could represent and become a potentially useful clinical biomarker of an inappropriate prenatal exposure to these substances. PMID:29558393

Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses.

PubMed

Goldstein, Jill M; Lancaster, Katie; Longenecker, Julia M; Abbs, Brandon; Holsen, Laura M; Cherkerzian, Sara; Whitfield-Gabrieli, Susan; Makris, Nicolas; Tsuang, Ming T; Buka, Stephen L; Seidman, Larry J; Klibanski, Anne

2015-06-30

Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The ITPA disruption database

DOE PAGES

Eidietis, N. W.; Gerhardt, S. P.; Granetz, R. S.; ...

2015-05-22

A multi-device database of disruption characteristics has been developed under the auspices of the International Tokamak Physics Activity magneto hydrodynamics topical group. The purpose of this ITPA Disruption Database (IDDB) is to find the commonalities between the disruption and disruption mitigation characteristics in a wide variety of tokamaks in order to elucidate the physics underlying tokamak disruptions and to extrapolate toward much larger devices, such as ITER and future burning plasma devices. Conversely, in order to previous smaller disruption data collation efforts, the IDDB aims to provide significant context for each shot provided, allowing exploration of a wide array ofmore » relationships between pre-disruption and disruption parameters. Furthermore, the IDDB presently includes contributions from nine tokamaks, including both conventional aspect ratio and spherical tokamaks. An initial parametric analysis of the available data is presented. Our analysis includes current quench rates, halo current fraction and peaking, and the effectiveness of massive impurity injection. The IDDB is publicly available, with instruction for access provided herein.« less

Mutations in the growth hormone releasing hormone receptor: a new form of dwarfism in humans.

PubMed

Baumann, G

1999-06-01

We describe a recently identified new form of dwarfism due to isolated growth hormone (GH) deficiency, secondary to inactivating mutations in the GH-releasing hormone receptor (GHRHR) gene. The identical nonsense mutations in the extracellular domain of the GHRHR (E72X or E50X, depending on whether the signal peptide is included in the numbering) has been independently described in three families residing on or originating from the Indian subcontinent (Pakistan, the Bombay region, and Delft near Sri Lanka). Another inactivating mutation, involving the donor splice site of intron 1, has been identified in a population in north-eastern Brazil. Genetic transmission is autosomal recessive; the gene is located on the short arm of chromosome 7. Affected subjects have severe isolated GH deficiency and postnatal growth failure, with a mean adult height of 130 cm for men and 114 cm for women (7-8 standard deviations below the norm). Dwarfism is proportional; a characteristic feature is relative microcephaly, which results in a 'miniaturized adult', eumorphic aspect. Bone age and puberty are delayed, but fertility appears normal. This new syndrome corresponds to the human homologue of the previously identified 'little mouse'.

New insights into the endocrine disrupting effects of brominated flame retardants.

PubMed

Legler, Juliette

2008-09-01

The objective of this review is to provide an overview of recent studies demonstrating the endocrine disrupting (ED) effects of brominated flame retardants (BFRs), while highlighting interesting data presented at the recent international BFR workshop in Amsterdam in April, 2007. A review written in 2002 was used as a starting point and about 60 publications published since 2003 were reviewed. New insights into the in vivo effects of BFRs on thyroid hormone, estrogen and androgen pathways in both mammalian and non-mammalian models are provided, and novel (in vitro) findings on the mechanisms underlying ED effects are highlighted. Special attention is also given to reports on neurotoxicological effects at relatively low doses of BFRs, although an endocrine-related mechanism is disputable. Convincing evidence has been published showing that BFRs and importantly, BFR metabolites, have the potential to disrupt endocrine systems at multiple target sites. While some studies suggest a wide margin of safety between effect concentrations in rodent models and levels encountered in humans and the environment, other studies demonstrate that exposure to low doses relevant for humans and wildlife at critical time points in development can result in profound effects on both endocrine pathways and (neuro)development.

Hormone therapy in acne.

PubMed

Lakshmi, Chembolli

2013-01-01

Underlying hormone imbalances may render acne unresponsive to conventional therapy. Relevant investigations followed by initiation of hormonal therapy in combination with regular anti-acne therapy may be necessary if signs of hyperandrogenism are present. In addition to other factors, androgen-stimulated sebum production plays an important role in the pathophysiology of acne in women. Sebum production is also regulated by other hormones, including estrogens, growth hormone, insulin, insulin-like growth factor-1, glucocorticoids, adrenocorticotropic hormone, and melanocortins. Hormonal therapy may also be beneficial in female acne patients with normal serum androgen levels. An understanding of the sebaceous gland and the hormonal influences in the pathogenesis of acne would be essential for optimizing hormonal therapy. Sebocytes form the sebaceous gland. Human sebocytes express a multitude of receptors, including receptors for peptide hormones, neurotransmitters and the receptors for steroid and thyroid hormones. Various hormones and mediators acting through the sebocyte receptors play a role in the orchestration of pathogenetic lesions of acne. Thus, the goal of hormonal treatment is a reduction in sebum production. This review shall focus on hormonal influences in the elicitation of acne via the sebocyte receptors, pathways of cutaneous androgen metabolism, various clinical scenarios and syndromes associated with acne, and the available therapeutic armamentarium of hormones and drugs having hormone-like actions in the treatment of acne.

Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems.

PubMed

Sifakis, Stavros; Androutsopoulos, Vasilis P; Tsatsakis, Aristeidis M; Spandidos, Demetrios A

2017-04-01

Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system. Copyright © 2017 Elsevier B.V. All rights reserved.

The interrelationships of thyroid and growth hormones: effect of growth hormone releasing hormone in hypo- and hyperthyroid male rats.

PubMed

Root, A W; Shulman, D; Root, J; Diamond, F

1986-01-01

Growth hormone (GH) and the thyroid hormones interact in the hypothalamus, pituitary and peripheral tissues. Thyroid hormone exerts a permissive effect upon the anabolic and metabolic effects of GH, and increases pituitary synthesis of this protein hormone. GH depresses the secretion of thyrotropin and the thyroid hormones and increases the peripheral conversion of thyroxine to triiodothyronine. In the adult male rat experimental hypothyroidism produced by ingestion of propylthiouracil depresses the GH secretory response to GH-releasing hormone in vivo and in vitro, reflecting the lowered pituitary stores of GH in the hypothyroid state. Short term administration of large amounts of thyroxine with induction of the hyperthyroid state does not affect the in vivo GH secretory response to GH-releasing hormone in this animal.

Disruption of the Aortic Elastic Lamina and Medial Calcification Share Genetic Determinants in Mice

PubMed Central

Wang, Susanna S.; Martin, Lisa J.; Schadt, Eric E.; Meng, Haijin; Wang, Xuping; Zhao, Wei; Ingram-Drake, Leslie; Nebohacova, Martina; Mehrabian, Margarete; Drake, Thomas A.; Lusis, Aldons J.

2010-01-01

Background Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans. Methods and Results We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F2 mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE−/−) null background. We identified 3 quantitative trait loci (QTLs) on chromosomes 6, 13, and 18, which are common to both traits, and 2 additional QTLs for medial calcification on chromosomes 3 and 7. Medial disruption, including severe disruptions leading to aneurysm formation, and medial calcification were highly correlated and occurred concomitantly in the cross. The chromosome 18 locus showed a striking male sex-specificity for both traits. To identify candidate genes, we integrated data from microarray analysis, genetic segregation, and clinical traits. The chromosome 7 locus contains the Abcc6 gene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification. Conclusions Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption and that in addition to aneurysm formation, medial disruption may be the precursor to calcification. PMID:20031637

New Jersey Grant Program To Reduce Student Disruption in Schools: Award Recipients.

ERIC Educational Resources Information Center

New Jersey State Dept. of Education, Trenton. Div. of General Academic Education.

New Jersey's $1 million Grant Program to Reduce Student Disruption in Schools is intended to provide resources to individual school districts or groups of cooperating districts for developing and implementing programs for chronically disruptive students, and thereby to identify models to make available to other districts throughout the state. Out…

ENDOCRINE DISRUPTERS: A REVIEW OF SOME SOURCES, EFFECTS, AND MECHANISMS OF ACTIONS ON BEHAVIOR AND NEUROENDOCRINE SYSTEMS

PubMed Central

Frye, C.; Bo, E.; Calamandrei, G.; Calzà, L.; Dessì-Fulgheri, F.; Fernández, M.; Fusani, L.; Kah, O.; Kajta, M.; Le Page, Y.; Patisaul, H.B.; Venerosi, A.; Wojtowicz, A.K.; Panzica, G.C.

2011-01-01

Some environmental contaminants interact with hormones and may exert adverse consequences due to their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically due to contamination of the food chain, inhalation of contaminated house dust, or occupational exposure. EDCs include pesticides and herbicides (such as diphenyl-dichloro-trichloroethane, DDT, or its metabolites), methoxychlor, biocides, heat stabilizers and chemical catalysts (such as tributyltin, TBT), plastic contaminants (e.g. bisphenol A, BPA), pharmaceuticals (i.e. diethylstilbestrol, DES; 17alpha-ethynilestradiol, EE2), or dietary components (such as phytoestrogens). The goal of this review is to address sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or non-reproductive, sexually-dimorphic behaviors. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific “critical periods” of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, than in other periods. However, exposure to EDCs in adulthood also can alter physiology. Several EDCs are xenoestrogens, may alter serum lipid concentrations, or metabolism enzymes that are necessary for converting cholesterol to steroid hormones, ultimately altering production of E2 and/or other steroids. Finally, many EDCs may have actions via, or independent of, classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor (AhR), the peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR), signal transduction pathways, calcium influx, and/or neurotransmitter receptors. Thus, EDCs, from varied

Thyroid hormone modulates offspring sex ratio in a turtle with temperature-dependent sex determination

PubMed Central

Li, Teng; Mu, Yi; McGlashan, Jessica K.; Georges, Arthur

2016-01-01

The adaptive significance of temperature-dependent sex determination (TSD) has attracted a great deal of research, but the underlying mechanisms by which temperature determines the sex of a developing embryo remain poorly understood. Here, we manipulated the level of a thyroid hormone (TH), triiodothyronine (T3), during embryonic development (by adding excess T3 to the eggs of the red-eared slider turtle Trachemys scripta, a reptile with TSD), to test two competing hypotheses on the proximate basis for TSD: the developmental rate hypothesis versus the hormone hypothesis. Exogenous TH accelerated embryonic heart rate (and hence metabolic rate), developmental rate, and rates of early post-hatching growth. More importantly, hyperthyroid conditions depressed expression of Cyp19a1 (the gene encoding for aromatase) and levels of oestradiol, and induced more male offspring. This result is contrary to the direction of sex-ratio shift predicted by the developmental rate hypothesis, but consistent with that predicted by the hormone hypothesis. Our results suggest an important role for THs in regulating sex steroid hormones, and therefore, in affecting gonadal sex differentiation in TSD reptiles. Our study has implications for the conservation of TSD reptiles in the context of global change because environmental contaminants may disrupt the activity of THs, and thereby affect offspring sex in TSD reptiles. PMID:27798296

Novel growth hormone receptor gene mutation in a patient with Laron syndrome.

PubMed

Arman, Ahmet; Yüksel, Bilgin; Coker, Ajda; Sarioz, Ozlem; Temiz, Fatih; Topaloglu, Ali Kemal

2010-04-01

Growth Hormone (GH) is a 22 kDa protein that has effects on growth and glucose and fat metabolisms. These effects are initiated by binding of growth hormone (GH) to growth hormone receptors (GHR) expressed in target cells. Mutations or deletions in the growth hormone receptor cause an autosomal disorder called Laron-type dwarfism (LS) characterized by high circulating levels of serum GH and low levels of insulin like growth factor-1 (IGF-1). We analyzed the GHR gene for genetic defect in seven patients identified as Laron type dwarfism. We identified two missense mutations (S40L and W104R), and four polymorphisms (S473S, L526I, G168G and exon 3 deletion). We are reporting a mutation (W104R) at exon 5 of GHR gene that is not previously reported, and it is a novel mutation.

Acetylcholine Modulates the Hormones of the Growth Hormone/Insulinlike Growth Factor-1 Axis During Development in Mice.

PubMed

Lecomte, Marie-José; Bertolus, Chloé; Ramanantsoa, Nélina; Saurini, Françoise; Callebert, Jacques; Sénamaud-Beaufort, Catherine; Ringot, Maud; Bourgeois, Thomas; Matrot, Boris; Collet, Corinne; Nardelli, Jeannette; Mallet, Jacques; Vodjdani, Guilan; Gallego, Jorge; Launay, Jean-Marie; Berrard, Sylvie

2018-04-01

Pituitary growth hormone (GH) and insulinlike growth factor (IGF)-1 are anabolic hormones whose physiological roles are particularly important during development. The activity of the GH/IGF-1 axis is controlled by complex neuroendocrine systems including two hypothalamic neuropeptides, GH-releasing hormone (GHRH) and somatostatin (SRIF), and a gastrointestinal hormone, ghrelin. The neurotransmitter acetylcholine (ACh) is involved in tuning GH secretion, and its GH-stimulatory action has mainly been shown in adults but is not clearly documented during development. ACh, together with these hormones and their receptors, is expressed before birth, and somatotroph cells are already responsive to GHRH, SRIF, and ghrelin. We thus hypothesized that ACh could contribute to the modulation of the main components of the somatotropic axis during development. In this study, we generated a choline acetyltransferase knockout mouse line and showed that heterozygous mice display a transient deficit in ACh from embryonic day 18.5 to postnatal day 10, and they recover normal ACh levels from the second postnatal week. This developmental ACh deficiency had no major impact on weight gain and cardiorespiratory status of newborn mice. Using this mouse model, we found that endogenous ACh levels determined the concentrations of circulating GH and IGF-1 at embryonic and postnatal stages. In particular, serum GH level was correlated with brain ACh content. ACh also modulated the levels of GHRH and SRIF in the hypothalamus and ghrelin in the stomach, and it affected the levels of these hormones in the circulation. This study identifies ACh as a potential regulator of the somatotropic axis during the developmental period.

Disruptive Civil Technologies: Six Technologies With Potential Impacts on US Interests Out to 2025

DTIC Science & Technology

2008-04-01

power (geopolitical, military, economic, or social cohesion). The six disruptive technologies were identified through a process carried out by...clustering, development of technology descriptors, screening, and prioritizing, analysts down-selected from 102 potentially disruptive technologies . They

Circadian Disruption Changes Gut Microbiome Taxa and Functional Gene Composition.

PubMed

Deaver, Jessica A; Eum, Sung Y; Toborek, Michal

2018-01-01

Disrupted circadian rhythms and alterations of the gut microbiome composition were proposed to affect host health. Therefore, the aim of this research was to identify whether these events are connected and if circadian rhythm disruption by abnormal light-dark (LD) cycles affects microbial community gene expression and host vulnerability to intestinal dysfunction. Mice were subjected to either a 4-week period of constant 24-h light or of normal 12-h LD cycles. Stool samples were collected at the beginning and after the circadian rhythm disruption. A metatranscriptomic analysis revealed an increase in Ruminococcus torques , a bacterial species known to decrease gut barrier integrity, and a decrease in Lactobacillus johnsonii , a bacterium that helps maintain the intestinal epithelial cell layer, after circadian rhythm disruption. In addition, genes involved in pathways promoting host beneficial immune responses were downregulated, while genes involved in the synthesis and transportation of the endotoxin lipopolysaccharide were upregulated in mice with disrupted circadian cycles. Importantly, these mice were also more prone to dysfunction of the intestinal barrier. These results further elucidate the impact of light-cycle disruption on the gut microbiome and its connection with increased incidence of disease in response to circadian rhythm disturbances.

Endotherapy is effective for pancreatic ductal disruption: A dual center experience.

PubMed

Das, Rohit; Papachristou, Georgios I; Slivka, Adam; Easler, Jeffrey J; Chennat, Jennifer; Malin, Jessica; Herman, Justin B; Laique, Sobia N; Hayat, Umar; Ooi, Yinn Shaung; Rabinovitz, Mordechai; Yadav, Dhiraj; Siddiqui, Ali A

2016-01-01

Pancreatic duct (PD) disruptions occur as a result of different etiologies and can be managed medically, endoscopically, or surgically. The aim of this study was to provide an evaluation on the efficacy of endotherapy for treatment of PD disruption in a large cohort of patients and identify factors that predict successful treatment outcome. We retrospectively evaluated consecutive patients who underwent endoscopic retrograde pancreatography (ERP) for transpapillary pancreatic stent placement for PD disruption from 2008 to 2013 at two tertiary referral institutions. PD disruption was defined as extravasation of contrast from the pancreatic duct as seen on ERP. Therapeutic success was defined by resolution of PD leak on ERP, clinical, and/or imaging evaluation. We evaluated 107 patients (58% male, mean age 53 years) with PD disruption. Etiologies of PD disruption were acute pancreatitis (36%), post-operative (31%), chronic pancreatitis (29%), and trauma (4%). PD disruption was successfully bridged by a stent in 45 (44%) patients. Two patients developed post-sphincterotomy bleeding, two had stent migration, and two patients died as a result of post-ERP related complications. Placement of a PD stent was successful in 103/107 (96%) patients. Therapeutic success was achieved in 80/107 (75%) patients. Non-acute pancreatitis etiologies and absence of complete duct disruption were independent predictors of therapeutic success. Endoscopic therapy using a transpapillary stent for PD disruption is safe and effective. Absence of complete duct disruption and non-AP etiologies determine a favorable endoscopic outcome. Published by Elsevier India Pvt Ltd.

Obesity Disrupts the Rhythmic Profiles of Maternal and Fetal Progesterone in Rat Pregnancy.

PubMed

Crew, Rachael C; Mark, Peter J; Clarke, Michael W; Waddell, Brendan J

2016-09-01

Maternal obesity increases the risk of abnormal fetal growth, but the underlying mechanisms remain unclear. Because steroid hormones regulate fetal growth, and both pregnancy and obesity markedly alter circadian biology, we hypothesized that maternal obesity disrupts the normal rhythmic profiles of steroid hormones in rat pregnancy. Obesity was established by cafeteria (CAF) feeding for 8 wk prior to mating and throughout pregnancy. Control (CON) animals had ad libitum access to chow. Daily profiles of plasma corticosterone, 11-dehydrocorticosterone, progesterone, and testosterone were measured at Days 15 and 21 of gestation (term = 23 days) in maternal (both days) and fetal (Day 21) plasma. CAF mothers exhibited increased adiposity relative to CON and showed fetal and placental growth restriction. There was no change, however, in total fetal or placental mass due to slightly larger litter sizes in CAF. Nocturnal declines in progesterone were observed in maternal (39% lower) and fetal (45% lower) plasma in CON animals, but these were absent in CAF animals. CAF mothers were hyperlipidemic at both days of gestation, but this effect was isolated to the dark period at Day 21. CAF maternal testosterone was slightly lower at Day 15 (8%) but increased above CON by Day 21 (16%). Despite elevated maternal testosterone, male fetal testosterone was suppressed by obesity on Day 21. Neither maternal nor fetal glucocorticoid profiles were affected by obesity. In conclusion, obesity disrupts rhythmic profiles of maternal and fetal progesterone, preventing the normal nocturnal decline. Obesity subtly changed testosterone profiles but did not alter maternal and fetal glucocorticoids. © 2016 by the Society for the Study of Reproduction, Inc.

Gene-environment interaction: Does fluoride influence the reproductive hormones in male farmers modified by ERα gene polymorphisms?

PubMed

Ma, Qiang; Huang, Hui; Sun, Long; Zhou, Tong; Zhu, Jingyuan; Cheng, Xuemin; Duan, Lijv; Li, Zhiyuan; Cui, Liuxin; Ba, Yue

2017-12-01

The occurrence of endemic fluorosis is derived from high fluoride levels in drinking water and industrial fumes or dust. Reproductive disruption is also a major harm caused by fluoride exposure besides dental and skeletal lesions. However, few studies focus on the mechanism of fluoride exposure on male reproductive function, especially the possible interaction of fluoride exposure and gene polymorphism on male reproductive hormones. Therefore, we conducted a cross-sectional study in rural areas of Henan province in China to explore the interaction between the estrogen receptor alpha (ERα) gene and fluoride exposure on reproductive hormone levels in male farmers living in the endemic fluorosis villages. The results showed that fluoride exposure significantly increased the serum level of estradiol in the hypothalamic-pituitary-testicular (HPT) axis in male farmers. Moreover, the observations indicated that fluoride exposure and genetic markers had an interaction on serum concentration of follicle-stimulating hormone and estradiol, and the interaction among different loci of the ERα gene could impact the serum testosterone level. Findings in the present work suggest that chronic fluoride exposure in drinking water could modulate the levels of reproductive hormones in males living in endemic fluorosis areas, and the interaction between fluoride exposure and ERα polymorphisms might affect the serum levels of hormones in the HPT axis in male farmers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sex hormones, aging, and Alzheimer’s disease

PubMed Central

Barron, Anna M.; Pike, Christian J.

2012-01-01

A promising strategy to delay and perhaps prevent Alzheimer’s disease (AD) is to identify the age-related changes that put the brain at risk for the disease. A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones. In women, menopause results in a relatively rapid loss of estradiol and progesterone. In men, aging is associated with a comparatively gradual yet significant decrease in testosterone. We review a broad literature that indicates age-related losses of estrogens in women and testosterone in men are risk factors for AD. Both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health, suggesting that hormone therapies have the potential to combat AD pathogenesis. However, translation of experimental findings into effective therapies has proven challenging. One emerging treatment option is the development of novel hormone mimetics termed selective estrogen and androgen receptor modulators. Continued research of sex hormones and their roles in the aging brain is expected to yield valuable approaches to reducing the risk of AD. PMID:22201929

Reprint of "In silico methods in the discovery of endocrine disrupting chemicals".

PubMed

Vuorinen, Anna; Odermatt, Alex; Schuster, Daniela

2015-09-01

The prevalence of sex hormone-dependent cancers, reproductive problems, obesity, and cardiovascular complications has risen especially in the Western world. It has been suggested, that the exposure to various endocrine disrupting chemicals (EDCs) contributes to the development and progression of these diseases. EDCs can interfere with various proteins: nuclear steroid hormone receptors, such as estrogen-, androgen-, glucocorticoid- and mineralocorticoid receptors (ER, AR, GR, MR), and enzymes that are involved in steroid hormone synthesis and metabolism, for example hydroxysteroid dehydrogenases (HSDs). Numerous chemicals are known as endocrine disruptors. However, the mechanism of action for most of these EDCs is still unknown. It is exhaustive and time consuming to test in vitro all chemicals - potential EDCs - used in industry, agriculture or as food preservatives against their effects on the endocrine system. Computational methods, such as virtual screening, quantitative structure activity relationships and docking, are already well recognized and used in drug development. The same methods could also aid the research on EDCs. So far, the computational methods in the search of EDCs have been retrospective. There are, however, some prospective studies reporting the use of in silico methods: five studies reporting the identification of previously unknown 17β-HSD3 inhibitors, MR agonists, and ER antagonists/agonists. This review provides an overview of case studies and in silico methods that are used in the search of EDCs. This article is part of a Special Issue entitled 'CSR 2013'. Copyright © 2015 Elsevier Ltd. All rights reserved.

White matter tract network disruption explains reduced conscientiousness in multiple sclerosis.

PubMed

Fuchs, Tom A; Dwyer, Michael G; Kuceyeski, Amy; Choudhery, Sanjeevani; Carolus, Keith; Li, Xian; Mallory, Matthew; Weinstock-Guttman, Bianca; Jakimovski, Dejan; Ramasamy, Deepa; Zivadinov, Robert; Benedict, Ralph H B

2018-05-08

Quantifying white matter (WM) tract disruption in people with multiple sclerosis (PwMS) provides a novel means for investigating the relationship between defective network connectivity and clinical markers. PwMS exhibit perturbations in personality, where decreased Conscientiousness is particularly prominent. This trait deficit influences disease trajectory and functional outcomes such as work capacity. We aimed to identify patterns of WM tract disruption related to decreased Conscientiousness in PwMS. Personality assessment and brain MRI were obtained in 133 PwMS and 49 age- and sex-matched healthy controls (HC). Lesion maps were applied to determine the severity of WM tract disruption between pairs of gray matter regions. Next, the Network-Based-Statistics tool was applied to identify structural networks whose disruption negatively correlates with Conscientiousness. Finally, to determine whether these networks explain unique variance above conventional MRI measures and cognition, regression models were applied controlling for age, sex, brain volume, T2-lesion volume, and cognition. Relative to HCs, PwMS exhibited lower Conscientiousness and slowed cognitive processing speed (p = .025, p = .006). Lower Conscientiousness in PwMS was significantly associated with WM tract disruption between frontal, frontal-parietal, and frontal-cingulate pathways in the left (p = .02) and right (p = .01) hemisphere. The mean disruption of these pathways explained unique additive variance in Conscientiousness, after accounting for conventional MRI markers of pathology and cognition (ΔR 2  = .049, p = .029). Damage to WM tracts between frontal, frontal-parietal, and frontal-cingulate cortical regions is significantly correlated with reduced Conscientiousness in PwMS. Tract disruption within these networks explains decreased Conscientiousness observed in PwMS as compared with HCs. © 2018 Wiley Periodicals, Inc.

Ovarian hormones and obesity.

PubMed

Leeners, Brigitte; Geary, Nori; Tobler, Philippe N; Asarian, Lori

2017-05-01

Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a

New Insights into Thyroid Hormone Action

PubMed Central

Mendoza, Arturo; Hollenberg, Anthony N.

2017-01-01

Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is exquisitely modulated to maintain nearly constant TH (T4 and T3) concentrations in circulation. However peripheral tissues and the CNS control the intracellular availability of TH, suggesting that circulating concentrations of TH are not fully representative of what each cell type sees. Indeed, recent work in the field has identified that TH transporters, deiodinases and thyroid hormone receptor coregulators can strongly control tissue-specific sensitivity to a set amount of TH. Furthermore, the mechanism by which the thyroid hormone receptors regulate target gene expression can vary by gene, tissue and cellular context. This review will highlight novel insights into the machinery that controls the cellular response to TH, which include unique signaling cascades. These findings shed new light into the pathophysiology of human diseases caused by abnormal TH signaling. PMID:28174093

Polybrominated diphenyl ether (PBDE) exposures and thyroid hormones in children at age 3 years.

PubMed

Vuong, Ann M; Braun, Joseph M; Webster, Glenys M; Thomas Zoeller, R; Hoofnagle, Andrew N; Sjödin, Andreas; Yolton, Kimberly; Lanphear, Bruce P; Chen, Aimin

2018-08-01

Polybrominated diphenyl ethers (PBDEs) reduce serum thyroid hormone concentrations in animal studies, but few studies have examined the impact of early-life PBDE exposures on thyroid hormone disruption in childhood. We used data from 162 mother-child pairs from the Health Outcomes and Measures of the Environment Study (2003-2006, Cincinnati, OH). We measured PBDEs in maternal serum at 16 ± 3 weeks gestation and in child serum at 1-3 years. Thyroid hormones were measured in serum at 3 years. We used multiple informant models to investigate associations between prenatal and early-life PBDE exposures and thyroid hormone levels at age 3 years. Prenatal PBDEs were associated with decreased thyroid stimulating hormone (TSH) levels at age 3 years. A 10-fold increase in prenatal ∑PBDEs (BDE-28, -47, -99, -100, and -153) was associated with a 27.6% decrease (95% CI -40.8%, -11.3%) in TSH. A ten-fold increase in prenatal ∑PBDEs was associated with a 0.25 pg/mL (0.07, 0.43) increase in free triiodothyronine (FT 3 ). Child sex modified associations between prenatal PBDEs and thyroid hormones, with significant decrements in TSH among females and decreased free T 4 (FT 4 ) in males. Prenatal ∑PBDEs were not associated with TT 4 , FT 4 , or total T 3 . These findings suggest an inverse relationship between prenatal ∑PBDEs and TSH at 3 years. Associations may be sexually dimorphic, with an inverse relationship between prenatal BDE-47 and -99 and TSH in females and null associations among males. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect-directed analysis to explore the polar bear exposome: identification of thyroid hormone disrupting compounds in plasma.

PubMed

Simon, Eszter; van Velzen, Martin; Brandsma, Sicco H; Lie, Elisabeth; Løken, Katharina; de Boer, Jacob; Bytingsvik, Jenny; Jenssen, Bjørn M; Aars, Jon; Hamers, Timo; Lamoree, Marja H

2013-08-06

Compounds with transthyretin (TTR)-binding potency in the blood plasma of polar bear cubs were identified with effect-directed analysis (EDA). This approach contributes to the understanding of the thyroid disrupting exposome of polar bears. The selection of these samples for in-depth EDA was based on the difference between the observed TTR-binding potency on the one hand and the calculated potency (based on known concentrations of TTR-binding compounds and their relative potencies) on the other. A library-based identification was applied to the liquid chromatography-time-of-flight-mass spectrometry (LC-ToF-MS) data by screening for matches between compound lists and the LC-ToF-MS data regarding accurate mass and isotope pattern. Then, isotope cluster analysis (ICA) was applied to the LC-ToF-MS data allowing specific screening for halogen isotope patterns. The presence of linear and branched nonylphenol (NP) was observed for the first time in polar bears. Furthermore, the presence of one di- and two monohydroxylated octachlorinated biphenyls (octaCBs) was revealed in the extracts. Linear and branched NP, 4'-OH-CB201 and 4,4'-OH-CB202 could be successfully confirmed with respect to their retention time in the analytical system. In addition, branched NP, mono- and dihydroxylated-octaCBs showed TTR-binding potencies and could explain another 32 ± 2% of the total measured activities in the extracts.

Progesterone: The neglected hormone in schizophrenia? A focus on progesterone-dopamine interactions.

PubMed

Sun, Jeehae; Walker, Adam J; Dean, Brian; van den Buuse, Maarten; Gogos, Andrea

2016-12-01

Sex differences appear to be an important factor in schizophrenia. Women with schizophrenia tend to exhibit less disease impairment than men, typically presenting with a later age-at-onset, lower overall incidence and less severe symptoms. These observations underpin the estrogen hypothesis of schizophrenia, which postulates a protective role of estrogen against the development and severity of the disorder. While there has been significant attention placed on the impact of estrogens in schizophrenia, less consideration has been afforded to the role of progesterone, the other main female gonadal hormone. This narrative review discusses the role of progesterone as a neuroactive steroid and how it may be dysregulated in schizophrenia. Preclinical and molecular studies relevant to schizophrenia are discussed with a particular focus on the interactions between progesterone and the dopaminergic system. Notably, existing data on progesterone in relation to schizophrenia is inconsistent, with some studies suggesting a neuroprotective role for the hormone (e.g. animal models of cognitive dysfunction and positive symptoms), while other studies posit a disruptive impact of the hormone (e.g. negative correlations with symptom modulation in patients). This review aims to thoroughly address these discrepancies, concluding that altogether the data suggest that progesterone is a key modulator of central systems implicated in schizophrenia. On this basis, we argue that a more inclusive, considered effort of future studies to understand the intricacies of the interactions between progesterone and estrogen. Such an effort may enhance our understanding of the roles of sex hormones in schizophrenia, thus leading to avenues for novel therapeutic approaches. Copyright © 2016 Elsevier Ltd. All rights reserved.

Current Concepts in Neuroendocrine Disruption

PubMed Central

2014-01-01

In the last few years, it has become clear that a wide variety of environmental contaminants have specific effects on neuroendocrine systems in fish, amphibians, birds and mammals. While it is beyond the scope of this review to provide a comprehensive examination of all of these neuroendocrine disruptors, we will focus on select representative examples. Organochlorine pesticides bioaccumulate in neuroendocrine areas of the brain that directly regulate GnRH neurons, thereby altering the expression of genes downstream of GnRH signaling. Organochlorine pesticides can also agonize or antagonize hormone receptors, adversely affecting crosstalk between neurotransmitter systems. The impacts of polychlorinated biphenyls are varied and in many cases subtle. This is particularly true for neuroedocrine and behavioral effects of exposure. These effects impact sexual differentiation of the hypothalamic-pituitary-gonadal axis, and other neuroendocrine systems regulating the thyroid, metabolic, and stress axes and their physiological responses. Weakly estrogenic and anti-androgenic pollutants such as bisphenol A, phthalates, phytochemicals, and the fungicide vinclozolin can lead to severe and widespread neuroendocrine disruptions in discrete brain regions, including the hippocampus, amygdala, and hypothalamus, resulting in behavioral changes in a wide range of species. Behavioral features that have been shown to be affected by one or more these chemicals include cognitive deficits, heightened anxiety or anxiety-like, sociosexual, locomotor, and appetitive behaviors. Neuroactive pharmaceuticals are now widely detected in aquatic environments and water supplies through the release of wastewater treatment plant effluents. The antidepressant fluoxetine is one such pharmaceutical neuroendocrine disruptor. Fluoxetine is a selective serotonin reuptake inhibitor that can affect multiple neuroendocrine pathways and behavioral circuits, including disruptive effects on reproduction and

Effects of TDCPP or TPP on gene transcriptions and hormones of HPG axis, and their consequences on reproduction in adult zebrafish (Danio rerio).

PubMed

Liu, Xiaoshan; Ji, Kyunghee; Jo, Areum; Moon, Hyo-Bang; Choi, Kyungho

2013-06-15

disruption of GnRH and GtHs could be further related to subsequent disruption in both sex steroid hormone balance and plasma VTG levels, as well as reproductive performance. Overall, our observation indicates that both TDCPP and TPP could disturb the sex hormone balance by altering regulatory mechanisms of the HPG axis, eventually leading to disruption of reproductive performance in fish. Copyright © 2013 Elsevier B.V. All rights reserved.

Inclusion of Endogenous Hormone Levels in Risk Prediction Models of Postmenopausal Breast Cancer

PubMed Central

Tworoger, Shelley S.; Zhang, Xuehong; Eliassen, A. Heather; Qian, Jing; Colditz, Graham A.; Willett, Walter C.; Rosner, Bernard A.; Kraft, Peter; Hankinson, Susan E.

2014-01-01

Purpose Endogenous hormones are risk factors for postmenopausal breast cancer, and their measurement may improve our ability to identify high-risk women. Therefore, we evaluated whether inclusion of plasma estradiol, estrone, estrone sulfate, testosterone, dehydroepiandrosterone sulfate, prolactin, and sex hormone–binding globulin (SHBG) improved risk prediction for postmenopausal invasive breast cancer (n = 437 patient cases and n = 775 controls not using postmenopausal hormones) in the Nurses' Health Study. Methods We evaluated improvement in the area under the curve (AUC) for 5-year risk of invasive breast cancer by adding each hormone to the Gail and Rosner-Colditz risk scores. We used stepwise regression to identify the subset of hormones most associated with risk and assessed AUC improvement; we used 10-fold cross validation to assess model overfitting. Results Each hormone was associated with breast cancer risk (odds ratio doubling, 0.82 [SHBG] to 1.37 [estrone sulfate]). Individual hormones improved the AUC by 1.3 to 5.2 units relative to the Gail score and 0.3 to 2.9 for the Rosner-Colditz score. Estrone sulfate, testosterone, and prolactin were selected by stepwise regression and increased the AUC by 5.9 units (P = .003) for the Gail score and 3.4 (P = .04) for the Rosner-Colditz score. In cross validation, the average AUC change across the validation data sets was 6.0 (P = .002) and 3.0 units (P = .03), respectively. Similar results were observed for estrogen receptor–positive disease (selected hormones: estrone sulfate, testosterone, prolactin, and SHBG; change in AUC, 8.8 [P < .001] for Gail score and 5.8 [P = .004] for Rosner-Colditz score). Conclusion Our results support that endogenous hormones improve risk prediction for invasive breast cancer and could help identify women who may benefit from chemoprevention or more screening. PMID:25135988

The optimal hormonal replacement modality selection for multiple organ procurement from brain-dead organ donors

PubMed Central

Mi, Zhibao; Novitzky, Dimitri; Collins, Joseph F; Cooper, David KC

2015-01-01

The management of brain-dead organ donors is complex. The use of inotropic agents and replacement of depleted hormones (hormonal replacement therapy) is crucial for successful multiple organ procurement, yet the optimal hormonal replacement has not been identified, and the statistical adjustment to determine the best selection is not trivial. Traditional pair-wise comparisons between every pair of treatments, and multiple comparisons to all (MCA), are statistically conservative. Hsu’s multiple comparisons with the best (MCB) – adapted from the Dunnett’s multiple comparisons with control (MCC) – has been used for selecting the best treatment based on continuous variables. We selected the best hormonal replacement modality for successful multiple organ procurement using a two-step approach. First, we estimated the predicted margins by constructing generalized linear models (GLM) or generalized linear mixed models (GLMM), and then we applied the multiple comparison methods to identify the best hormonal replacement modality given that the testing of hormonal replacement modalities is independent. Based on 10-year data from the United Network for Organ Sharing (UNOS), among 16 hormonal replacement modalities, and using the 95% simultaneous confidence intervals, we found that the combination of thyroid hormone, a corticosteroid, antidiuretic hormone, and insulin was the best modality for multiple organ procurement for transplantation. PMID:25565890

HormoneBase, a population-level database of steroid hormone levels across vertebrates

PubMed Central

Vitousek, Maren N.; Johnson, Michele A.; Donald, Jeremy W.; Francis, Clinton D.; Fuxjager, Matthew J.; Goymann, Wolfgang; Hau, Michaela; Husak, Jerry F.; Kircher, Bonnie K.; Knapp, Rosemary; Martin, Lynn B.; Miller, Eliot T.; Schoenle, Laura A.; Uehling, Jennifer J.; Williams, Tony D.

2018-01-01

Hormones are central regulators of organismal function and flexibility that mediate a diversity of phenotypic traits from early development through senescence. Yet despite these important roles, basic questions about how and why hormone systems vary within and across species remain unanswered. Here we describe HormoneBase, a database of circulating steroid hormone levels and their variation across vertebrates. This database aims to provide all available data on the mean, variation, and range of plasma glucocorticoids (both baseline and stress-induced) and androgens in free-living and un-manipulated adult vertebrates. HormoneBase (www.HormoneBase.org) currently includes >6,580 entries from 476 species, reported in 648 publications from 1967 to 2015, and unpublished datasets. Entries are associated with data on the species and population, sex, year and month of study, geographic coordinates, life history stage, method and latency of hormone sampling, and analysis technique. This novel resource could be used for analyses of the function and evolution of hormone systems, and the relationships between hormonal variation and a variety of processes including phenotypic variation, fitness, and species distributions. PMID:29786693

Immunocytochemistry and fluorescence imaging efficiently identify individual neurons with CRISPR/Cas9-mediated gene disruption in primary cortical cultures.

PubMed

Tsunematsu, Hiroto; Uyeda, Akiko; Yamamoto, Nobuhiko; Sugo, Noriyuki

2017-08-01

CRISPR/Cas9 system is a powerful method to investigate the role of genes by introducing a mutation selectively and efficiently to specific genome positions in cell and animal lines. However, in primary neuron cultures, this method is affected by the issue that the effectiveness of CRISPR/Cas9 is different in each neuron. Here, we report an easy, quick and reliable method to identify mutants induced by the CRISPR/Cas9 system at a single neuron level, using immunocytochemistry (ICC) and fluorescence imaging. Dissociated cortical cells were transfected with CRISPR/Cas9 plasmids targeting the transcription factor cAMP-response element binding protein (CREB). Fluorescence ICC with CREB antibody and quantitative analysis of fluorescence intensity demonstrated that CREB expression disappeared in a fraction of the transfected neurons. The downstream FOS expression was also decreased in accordance with suppressed CREB expression. Moreover, dendritic arborization was decreased in the transfected neurons which lacked CREB immunoreactivity. Detection of protein expression is efficient to identify individual postmitotic neurons with CRISPR/Cas9-mediated gene disruption in primary cortical cultures. The present method composed of CRISPR/Cas9 system, ICC and fluorescence imaging is applicable to study the function of various genes at a single-neuron level.

Adverse Outcome Pathway for Embryonic Vascular Disruption and Alternative Methods to Identify Chemical Vascular Disruptors During Development

EPA Science Inventory

Chemically induced vascular toxicity during embryonic development can result in a wide range of adverse prenatal outcomes. We used information from genetic mouse models linked to phenotypic outcomes and a vascular toxicity knowledge base to construct an embryonic vascular disrupt...

Spin Dependence in Tidal Disruption Events

NASA Astrophysics Data System (ADS)

Kesden, Michael; Stone, Nicholas; van Velzen, Sjoert

2018-01-01

A supermassive black hole (SBH) can tidally disrupt stars when its tidal field overwhelms the stars’ self-gravity. The stellar debris produced in such tidal disruption events (TDEs) evolves into tidal streams that can self-intersect. These inelastic stream collisions dissipate orbital energy, both circularizing the tidal stream and contributing to the emission observed during the TDE. Once circularized into a disk, the stellar debris can be viscously accreted by the SBH powering additional luminous emission. We explore how SBH spin can affect the tidal disruption process. Tidal forces are spin dependent, as is the minimum orbital angular momentum below which stars are directly captured by the SBH. This implies that the TDE rate will be spin dependent, particularly for more massive SBHs for which relativistic effects are more significant. SBH spin also affects TDE light curves through the initial debris orbits, the nature of the stream collisions, the viscous evolution of the accretion disk, and the possibility of launching jets. We explore the spin dependence of these phenomena to identify promising signatures for upcoming surveys expected to discover hundreds of TDE candidates in the next decade.

Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

PubMed Central

Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

2016-01-01

Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

Endocrine disrupting chemicals in Minnesota lakes - Water-quality and hydrological data from 2008 and 2010

USGS Publications Warehouse

Barber, Larry B.; Writer, Jeffrey H.; Keefe, Steffanie K.; Brown, Greg K.; Ferrey, Mark L.; Jahns, Nathan D.; Kiesling, Richard L.; Lundy, James R.; Poganski, Beth H.; Rosenberry, Donald O.; Taylor, Howard E.; Woodruff, Olivia P.; Schoenfuss, Heiko L.

2012-01-01

Understanding the sources, fate, and effects of endocrine disrupting chemicals in aquatic ecosystems is important for water-resource management. This study was conducted during 2008 and 2010 to establish a framework for assessing endocrine disrupting chemicals, and involved a statewide survey of their occurrence in 14 Minnesota lakes and a targeted study of different microhabitats on a single lake. The lakes ranged in size from about 0.1 to 100 square kilometers, varied in trophic status from oligotrophic to eutrophic, and spanned a range of land-uses from wetlands and forest to agricultural and urban use. Water and sediment samples were collected from the near-shore littoral environment and analyzed for endocrine disrupting chemicals, including trace elements, acidic organic compounds, neutral organic compounds, and steroidal hormones. In addition, polar organic compound integrative samplers were deployed for 21 days and analyzed for the same organic compounds. One lake was selected for a detailed microhabitat study of multiple near-shore environments. This report compiles the results from the field measurements and laboratory chemical analysis of water, sediment, and polar organic compound integrative sampler samples collected during 2008 and 2010. Most of the organic compounds measured were not detected in any of the water samples, although a few compounds were detected in several of the lakes.

Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4

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

Kucka, Marek; Pogrmic-Majkic, Kristina; Fa, Svetlana

2012-11-15

Atrazine, one of the most commonly used herbicides worldwide, acts as an endocrine disruptor, but the mechanism of its action has not been characterized. In this study, we show that atrazine rapidly increases cAMP levels in cultured rat pituitary and testicular Leydig cells in a concentration-dependent manner, but less effectively than 3-isobutyl-1-methylxanthine, a competitive non-specific inhibitor of phosphodiesterases (PDEs). In forskolin (an activator of adenylyl cyclase)- and probenecid (an inhibitor of cyclic nucleotide transporters)-treated cells, but not in 3-isobutyl-1-methylxanthine-treated cells, atrazine further increased cAMP levels, indicating that inhibition of PDEs accounts for accumulation of cAMP. In contrast to cAMP, atrazinemore » did not alter cGMP levels, further indicating that it inhibits cAMP-specific PDEs. Atrazine-induced changes in cAMP levels were sufficient to stimulate prolactin release in pituitary cells and androgen production in Leydig cells, indicating that it acts as an endocrine disrupter both in cells that secrete by exocytosis of prestored hormones and in cells that secrete by de novo hormone synthesis. Rolipram abolished the stimulatory effect of atrazine on cAMP release in both cell types, suggesting that it acts as an inhibitor of PDE4s, isoforms whose mRNA transcripts dominate in pituitary and Leydig cells together with mRNA for PDE8A. In contrast, immortalized lacto-somatotrophs showed low expression of these mRNA transcripts and several fold higher cAMP levels compared to normal pituitary cells, and atrazine was unable to further increase cAMP levels. These results indicate that atrazine acts as a general endocrine disrupter by inhibiting cAMP-specific PDE4s. -- Highlights: ► Atrazine stimulates cAMP accumulation in pituitary and Leydig cells. ► Atrazine also stimulates PRL and androgens secretion. ► Stimulatory effects of atrazine were abolished in cells with IBMX-inhibited PDEs. ► Atrazine specificity toward

A novel KAL1 mutation is associated with combined pituitary hormone deficiency.

PubMed

Takagi, Masaki; Narumi, Satoshi; Hamada, Riku; Hasegawa, Yukihiro; Hasegawa, Tomonobu

2014-01-01

Using a next-generation sequencing strategy, we identified a novel KAL1 missense mutation (p.His568Gln) in a patient with combined pituitary hormone deficiency, right microphthalmia, right renal aplasia and severe developmental delay. Our findings will provide additional evidence that KAL1 mutations are associated with hypopituitarism, in addition to luteinizing hormone, and follicle-stimulating hormone deficiencies, and improve our understanding of the phenotypic features and developmental course associated with KAL1 mutations.

Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorders

ERIC Educational Resources Information Center

Yau, Vincent M.; Lutsky, Marta; Yoshida, Cathleen K.; Lasley, Bill; Kharrazi, Martin; Windham, Gayle; Gee, Nancy; Croen, Lisa A.

2015-01-01

Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay…

Family members' experiences of driving disruption after acquired brain injury.

PubMed

Liang, Phyllis; Fleming, Jennifer; Gustafsson, Louise; Griffin, Janelle; Liddle, Jacki

2017-01-01

1) To explore family members' lived experiences of driving disruption at early and later stages of the recovery continuum following acquired brain injury (ABI). 2) To describe health-related quality of life of family members of individuals with ABI who are experiencing driving disruption. Mixed methods phenomenological research approach. Semi-structured interviews and health-related quality of life questionnaires were conducted with 15 family members of individuals with ABI (early group: 1-12 months post-injury, n = 6; later group: >1 year post-injury, n = 9). Two main themes were identified: Different for everyone: how driving disruption affects families, and Making it harder: context of driving disruption. The challenges of driving disruption were reported more frequently and with a more intense focus by family members who were caring for their relative for more than 1 year post-injury. This group also reported higher caregiver strain and poorer health-related quality of life. Reduced satisfaction with life, poor mental health and affected family functioning were reported by both groups. Driving disruption impacts on family members and has long-lasting consequences. It is important for clinicians to work with family members to manage these challenges even years after ABI and consider individual contextual factors.

Circadian Disruption Changes Gut Microbiome Taxa and Functional Gene Composition

PubMed Central

Deaver, Jessica A.; Eum, Sung Y.; Toborek, Michal

2018-01-01

Disrupted circadian rhythms and alterations of the gut microbiome composition were proposed to affect host health. Therefore, the aim of this research was to identify whether these events are connected and if circadian rhythm disruption by abnormal light–dark (LD) cycles affects microbial community gene expression and host vulnerability to intestinal dysfunction. Mice were subjected to either a 4-week period of constant 24-h light or of normal 12-h LD cycles. Stool samples were collected at the beginning and after the circadian rhythm disruption. A metatranscriptomic analysis revealed an increase in Ruminococcus torques, a bacterial species known to decrease gut barrier integrity, and a decrease in Lactobacillus johnsonii, a bacterium that helps maintain the intestinal epithelial cell layer, after circadian rhythm disruption. In addition, genes involved in pathways promoting host beneficial immune responses were downregulated, while genes involved in the synthesis and transportation of the endotoxin lipopolysaccharide were upregulated in mice with disrupted circadian cycles. Importantly, these mice were also more prone to dysfunction of the intestinal barrier. These results further elucidate the impact of light-cycle disruption on the gut microbiome and its connection with increased incidence of disease in response to circadian rhythm disturbances. PMID:29706947

Bioidentical Hormones and Menopause

MedlinePlus

... Endocrinologist Search Featured Resource Menopause Map™ View Bioidentical Hormones January 2012 Download PDFs English Espanol Editors Howard ... take HT for symptom relief. What are bioidentical hormones? Bioidentical hormones are identical to the hormones that ...

Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries

PubMed Central

Watt, Eric D.; Hornung, Michael W.; Hedge, Joan M.; Judson, Richard S.; Crofton, Kevin M.; Houck, Keith A.; Simmons, Steven O.

2016-01-01

High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the U.S. Environmental Protection Agency ToxCast screening assay portfolio. To fill 1 critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast phase I and II chemical libraries, comprised of 1074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single-concentration screen were retested in concentration-response. Due to high false-positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed 2 additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidation assay using guaiacol as a substrate to confirm the activity profiles of putative TPO inhibitors. This effort represents the most extensive TPO inhibition screening campaign to date and illustrates a tiered screening approach that focuses resources, maximizes assay throughput, and reduces animal use. PMID:26884060

Role of Thyroid Hormones in Skeletal Development and Bone Maintenance

PubMed Central

Bassett, J. H. Duncan

2016-01-01

The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art. PMID:26862888

CRISPR-mediated HDAC2 disruption identifies two distinct classes of target genes in human cells.

PubMed

Somanath, Priyanka; Herndon Klein, Rachel; Knoepfler, Paul S

2017-01-01

The transcriptional functions of the class I histone deacetylases (HDACs) HDAC1 and HDAC2 are mainly viewed as both repressive and redundant based on murine knockout studies, but they may have additional independent roles and their physiological functions in human cells are not as clearly defined. To address the individual epigenomic functions of HDAC2, here we utilized CRISPR-Cas9 to disrupt HDAC2 in human cells. We find that while HDAC2 null cells exhibited signs of cross-regulation between HDAC1 and HDAC2, specific epigenomic phenotypes were still apparent using RNA-seq and ChIP assays. We identified specific targets of HDAC2 repression, and defined a novel class of genes that are actively expressed in a partially HDAC2-dependent manner. While HDAC2 was required for the recruitment of HDAC1 to repressed HDAC2-gene targets, HDAC2 was dispensable for HDAC1 binding to HDAC2-activated targets, supporting the notion of distinct classes of targets. Both active and repressed classes of gene targets demonstrated enhanced histone acetylation and methylation in HDAC2-null cells. Binding of the HDAC1/2-associated SIN3A corepressor was altered at most HDAC2-targets, but without a clear pattern. Overall, our study defines two classes of HDAC2 targets in human cells, with a dependence of HDAC1 on HDAC2 at one class of targets, and distinguishes unique functions for HDAC2.

[Ghrelin: a gastric hormone at the crossroad between growth and appetite regulation].

PubMed

Labarthe, Alexandra; Tolle, Virginie

2016-01-01

Ghrelin is a 28 amino acid peptide hormone synthesized within the gastrointestinal tract. Initially identified as the endogenous ligand of the GHS-R1a (Growth Hormone Secretagogue Receptor 1a), ghrelin is a powerful stimulator of growth hormone (GH) secretion. At the crossroad between nutrition, growth and long-term energy metabolism, ghrelin also plays a unique role as the first identified gastric hormone increasing appetite and adiposity. However, the role of the ghrelin/GHS-R system in the physiology of growth, feeding behaviour and energy homeostasis needs to be better understood. Utilization of pharmacological tools and complementary animal models with deficiency in preproghrelin, ghrelin-O-acyl-transferase (GOAT - the enzyme that acylates ghrelin -) or GHS-R in situations of chronic undernutrition or high fat diet gives a more precise overview of the role of ghrelin in the pathophysiology of eating and metabolic disorders. © Société de Biologie, 2017.

Thyroid hormone is essential for pituitary somatotropes and lactotropes.

PubMed

Stahl, J H; Kendall, S K; Brinkmeier, M L; Greco, T L; Watkins-Chow, D E; Campos-Barros, A; Lloyd, R V; Camper, S A

1999-04-01

Mice homozygous for a disruption in the alpha-subunit essential for TSH, LH, and FSH activity (alphaGsu-/-) exhibit hypothyroidism and hypogonadism similar to that observed in TSH receptor-deficient hypothyroid mice (hyt) and GnRH-deficient hypogonadal mutants (hpg). Although the five major hormone-producing cells of the anterior pituitary are present in alphaGsu-/- mice, the relative proportions of each cell type are altered dramatically. Thyrotropes exhibit hypertrophy and hyperplasia, and somatotropes and lactotropes are underrepresented. The size and number of gonadotropes in alphaGsu mutants are not remarkable in contrast to the hypertrophy characteristic of gonadectomized animals. The reduction in lactotropes is more severe in alphaGsu mutants (13-fold relative to wild-type) than in hyt or hpg mutants (4.5- and 1.5-fold, respectively). In addition, T4 replacement therapy of alphaGsu mutants restores lactotropes to near-normal levels, illustrating the importance of T4, but not alpha-subunit, for lactotrope proliferation and function. T4 replacement is permissive for gonadotrope hypertrophy in alphaGsu mutants, consistent with the role for T4 in the function of gonadotropes. This study reveals the importance of thyroid hormone in developing the appropriate proportions of anterior pituitary cell types.

A novel KAL1 mutation is associated with combined pituitary hormone deficiency

PubMed Central

Takagi, Masaki; Narumi, Satoshi; Hamada, Riku; Hasegawa, Yukihiro; Hasegawa, Tomonobu

2014-01-01

Using a next-generation sequencing strategy, we identified a novel KAL1 missense mutation (p.His568Gln) in a patient with combined pituitary hormone deficiency, right microphthalmia, right renal aplasia and severe developmental delay. Our findings will provide additional evidence that KAL1 mutations are associated with hypopituitarism, in addition to luteinizing hormone, and follicle-stimulating hormone deficiencies, and improve our understanding of the phenotypic features and developmental course associated with KAL1 mutations. PMID:27081504

Pulp and paper mill effluent treatments have differential endocrine-disrupting effects on rainbow trout.

PubMed

Orrego, Rodrigo; Guchardi, John; Hernandez, Victor; Krause, Rachelle; Roti, Lucia; Armour, Jeffrey; Ganeshakumar, Mathumai; Holdway, Douglas

2009-01-01

Endocrine disruption (ED) effects due to pulp and paper mill effluents extracts involving different industrial procedures and effluent treatments (nontreated, primary, and secondary treated) were evaluated using immature triploid rainbow trout in a pulse-exposure toxicity experiment. The protocol involved the use of intraperitoneal injection of mill extracts (solid-phase extraction [SPE]) corrected for individual fish weight and included several laboratory standards (steroidal hormones and phytosterols). Biological endpoints at two different levels of biological organization were analyzed (molecular and individual organism). Results indicated that nonsignificant changes were observed in the individual physiological indices represented by condition factor, liver somatic index, and gonad somatic index during the experiment. Significant induction of liver ethoxyresorufin-O-deethylase activity was observed between different effluent treatments and experimental controls. Significant endocrine-disrupting effects at the reproductive level were observed in all effluent treatments involving significant increments in plasma vitellogenin (VTG) levels. Fish exposed to untreated effluent extracts had significantly higher VTG levels compared to fish exposed to primary and secondary treatment effluent extracts, indicating a decrease of the estrogenic effect due to the effluent treatment. The present study has shown that for the Chilean pulp and paper mill SPE extracts evaluated, an endocrine disruption effect was induced in immature triploid rainbow, reaffirming the significant estrogenic effects demonstrated previously in laboratory and field experiments.

Sleep disruption in hematopoietic cell transplantation recipients: prevalence, severity, and clinical management.

PubMed

Jim, Heather S L; Evans, Bryan; Jeong, Jiyeon M; Gonzalez, Brian D; Johnston, Laura; Nelson, Ashley M; Kesler, Shelli; Phillips, Kristin M; Barata, Anna; Pidala, Joseph; Palesh, Oxana

2014-10-01

Sleep disruption is common among hematopoietic cell transplant (HCT) recipients, with over 50% of recipients experiencing sleep disruption pre-transplant, with up to 82% of patients experiencing moderate to severe sleep disruption during hospitalization for transplant and up to 43% after transplant. These rates of sleep disruption are substantially higher than what we see in the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption and disorders (ie, insomnia, obstructive sleep apnea, restless legs syndrome) as a clinical problem in HCT in order to facilitate patient education, intervention, and research. We identified 35 observational studies published in the past decade that examined sleep disruption or disorders in HCT. Most studies utilized a single item measure of sleep, had small sample size, and included heterogeneous samples of patients. Six studies of the effects of psychosocial and exercise interventions on sleep in HCT have reported no significant improvements. These results highlight the need for rigorous observational and interventional studies of sleep disruption and disorders in HCT recipients.. Copyright © 2014 American Society for Blood and Marrow Transplantation. All rights reserved.

Diabetes Insipidus

MedlinePlus

... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... an Endocrinologist Clinical Trials Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ...

Tributyltin disrupts feeding and energy metabolism in the goldfish (Carassius auratus).

PubMed

Zhang, Jiliang; Sun, Ping; Yang, Fan; Kong, Tao; Zhang, Ruichen

2016-06-01

Tributyltin (TBT) can induce obesogen response. However, little is known about the adverse effects of TBT on food intake and energy metabolism. The present study was designed to investigate the effects of TBT, at environmental concentrations of 2.44 and 24.4 ng/L (1 and 10 ng/L as Sn), on feeding and energy metabolism in goldfish (Carassius auratus). After exposure for 54 d, TBT increased the weight gain and food intake in fish. The patterns of brain neuropeptide genes expression were in line with potential orexigenic effects, with increased expression of neuropeptide Y and apelin, and decreased expression of pro-opiomelanocortin, ghrelin, cocaine and amphetamine-regulated transcript, and corticotropin-releasing factor. Interestingly, the energy metabolism indicators (oxygen consumption, ammonia exertion and swimming activity) and the serum thyroid hormones were all significantly increased at the 2.44 ng/L TBT group in fish. However, no changes of energy metabolism indicators or a decrease of thyroid hormones was found at the 24.4 ng/L TBT group, which indicated a complex disrupting effect on metabolism of TBT. In short, TBT can alter feeding and energy metabolism in fish, which might promote the obesogenic responses. Copyright © 2016 Elsevier Ltd. All rights reserved.

Detection of immunotoxic effects of estrogenic and androgenic endocrine disrupting compounds using splenic immune cells of the female three-spined stickleback, Gasterosteus aculeatus (L.).

PubMed

Bado-Nilles, A; Techer, R; Porcher, J M; Geffard, A; Gagnaire, B; Betoulle, S; Sanchez, W

2014-09-01

Today, the list of endocrine disrupting compounds (EDCs) in freshwater and marine environments that mimic or block endogenous hormones is expanding at an alarming rate. As immune and reproductive systems may interact in a bidirectional way, some authors proposed the immune capacities as attractive markers to evaluate the hormonal potential of environmental samples. Thus, the present work proposed to gain more knowledge on direct biological effects of natural and EDCs on female fish splenic leucocyte non-specific immune activities by using ex vivo assays. After determining the optimal required conditions to analyze splenic immune responses, seven different EDCs were tested ex vivo at 0.01, 1 and 100nM over 12h on the leucocyte functions of female three-spined stickleback, Gasterosteus aculeatus. In summary, we found that natural hormones acted as immunostimulants, whilst EDCs were immunosuppressive. Copyright © 2014 Elsevier B.V. All rights reserved.

Ovarian hormones and obesity

PubMed Central

Leeners, Brigitte; Geary, Nori; Tobler, Philippe N.; Asarian, Lori

2017-01-01

Abstract BACKGROUND Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. OBJECTIVE AND RATIONALE We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. SEARCH METHODS Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. OUTCOMES We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates

THYROID HORMONE RECEPTOR BETA GENE MUTATION (P453A) IN A TURKISH FAMILY PRODUCING RESISTANCE TO THYROID HORMONE

PubMed Central

Bayraktaroglu, Taner; Noel, Janet; Mukaddes, Nahit Motavalli; Refetoff, Samuel

2018-01-01

Two members of a Turkish family, a mother and son, had thyroid function tests suggestive of resistance to thyroid hormone (RTH). The clinical presentation was, however, different. The mother (proposita) had palpitation, weakness, tiredness, nervousness, dry mouth and was misdiagnosed as having multinodular toxic goiter which was treated with antithyroid drugs and partial thyroidectomy. Her younger son had attention deficit hyperactivity disorder and primary encopresis, but normal intellectual quotient. Both had elevated serum iodothyronine levels with nonsuppressed thyrotropin. A mutation in one allele of the thyroid hormone receptor beta gene (P453A) was identified, providing a genetic confirmation for the diagnosis of RTH. PMID:18561095

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol A as a Case Study

PubMed Central

Vandenberg, Laura N.

2014-01-01

Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not ‘common enough’ to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where ‘safe’ low doses are predicted from high dose exposures. PMID:24910584

Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol a as a case study.

PubMed

Vandenberg, Laura N

2014-05-01

Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not 'common enough' to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where 'safe' low doses are predicted from high dose exposures.

Early Blood-Brain Barrier Disruption after Mechanical Thrombectomy in Acute Ischemic Stroke.

PubMed

Shi, Zhong-Song; Duckwiler, Gary R; Jahan, Reza; Tateshima, Satoshi; Szeder, Viktor; Saver, Jeffrey L; Kim, Doojin; Sharma, Latisha K; Vespa, Paul M; Salamon, Noriko; Villablanca, J Pablo; Viñuela, Fernando; Feng, Lei; Loh, Yince; Liebeskind, David S

2018-05-01

The impact of blood-brain barrier (BBB) disruption can be detected by intraparenchymal hyperdense lesion on the computed tomography (CT) scan after endovascular stroke therapy. The purpose of this study was to determine whether early BBB disruption predicts intracranial hemorrhage and poor outcome in patients with acute ischemic stroke treated with mechanical thrombectomy. We analyzed patients with anterior circulation stroke treated with mechanical thrombectomy and identified BBB disruption on the noncontrast CT images immediately after endovascular treatment. Follow-up CT or magnetic resonance imaging scan was performed at 24 hours to assess intracranial hemorrhage. We dichotomized patients into those with moderate BBB disruption versus those with minor BBB disruption and no BBB disruption. We evaluated the association of moderate BBB disruption after mechanical thrombectomy with intracranial hemorrhage and clinical outcomes. Moderate BBB disruption after mechanical thrombectomy was found in 56 of 210 patients (26.7%). Moderate BBB disruption was independently associated with higher rates of hemorrhagic transformation (OR 25.33; 95% CI 9.93-64.65; P < .001), parenchymal hematoma (OR 20.57; 95% CI 5.64-74.99; P < .001), and poor outcome at discharge (OR 2.35; 95% CI 1.09-5.07; P = .03). The association of BBB disruption with intracranial hemorrhage remained in patients with successful reperfusion after mechanical thrombectomy. The location of BBB disruption was not associated with intracranial hemorrhage and poor outcome. Moderate BBB disruption is common after mechanical thrombectomy in a quarter of patients with acute ischemic stroke and increases the risk of intracranial hemorrhage and poor outcome. Copyright © 2018 by the American Society of Neuroimaging.

Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure.

PubMed

Dulka, Eden A; Moenter, Suzanne M

2017-11-01

Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction though pulsatile hormone release. Disruption of GnRH release as measured via luteinizing hormone (LH) pulses occurs in polycystic ovary syndrome (PCOS), and in young hyperandrogenemic girls. In adult prenatally androgenized (PNA) mice, which exhibit many aspects of PCOS, increased LH is associated with increased GnRH neuron action potential firing. How GnRH neuron activity develops over the prepubertal period and whether this is altered by sex or prenatal androgen treatment are unknown. We hypothesized GnRH neurons are active before puberty and that this activity is sexually differentiated and altered by PNA. Dams were injected with dihydrotestosterone (DHT) on days 16 to 18 post copulation to generate PNA mice. Action potential firing of GFP-identified GnRH neurons in brain slices from 1-, 2-, 3-, and 4-week-old and adult mice was monitored. GnRH neurons were active at all ages tested. In control females, activity increased with age through 3 weeks, then decreased to adult levels. In contrast, activity did not change in PNA females and was reduced at 3 weeks. Activity was higher in control females than males from 2 to 3 weeks. PNA did not affect GnRH neuron firing rate in males at any age. Short-term action potential patterns were also affected by age and PNA treatment. GnRH neurons are thus typically more active during the prepubertal period than adulthood, and PNA reduces prepubertal activity in females. Prepubertal activity may play a role in establishing sexually differentiated neuronal networks upstream of GnRH neurons; androgen-induced changes during this time may contribute to the adult PNA, and possibly PCOS, phenotype. Copyright © 2017 Endocrine Society.

A Rat α-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals.

PubMed

Hong, Huixiao; Shen, Jie; Ng, Hui Wen; Sakkiah, Sugunadevi; Ye, Hao; Ge, Weigong; Gong, Ping; Xiao, Wenming; Tong, Weida

2016-03-25

Endocrine disruptors such as polychlorinated biphenyls (PCBs), diethylstilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT) are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. α-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for α-fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest) and the molecular descriptors calculated from two-dimensional structures by Mold² software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69%) and external validations using 22 chemicals (balanced accuracy of 71%). Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence) in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed.

Disrupted Nighttime Sleep in Narcolepsy

PubMed Central

Roth, Thomas; Dauvilliers, Yves; Mignot, Emmanuel; Montplaisir, Jacques; Paul, Josh; Swick, Todd; Zee, Phyllis

2013-01-01

Study Objectives: Characterize disrupted nighttime sleep (DNS) in narcolepsy, an important symptom of narcolepsy. Methods: A panel of international narcolepsy experts was convened in 2011 to build a consensus characterization of DNS in patients with narcolepsy. A literature search of the Medline (1965 to date), Medline In-Process (latest weeks), Embase (1974 to date), Embase Alert (latest 8 weeks), and Biosis (1965 to date) databases was conducted using the following search terms: narcolepsy and disrupted nighttime sleep, disturbed nighttime sleep, fragmented sleep, consolidated sleep, sleep disruption, and narcolepsy questionnaire. The purpose of the literature search was to identify publications characterizing the nighttime sleep of patients with narcolepsy. The panel reviewed the literature. Nocturnal sleep can also be disturbed by REM sleep abnormalities such as vivid dreaming and REM sleep behavior disorder; however, these were not reviewed in the current paper, as we were evaluating for idiopathic sleep disturbances. Results: The literature reviewed provide a consistent characterization of nighttime sleep in patients with narcolepsy as fragmented, with reports of frequent, brief nightly awakenings with difficulties returning to sleep and associated reports of poor sleep quality. Polysomnographic studies consistently report frequent awakenings/arousals after sleep onset, more stage 1 (S1) sleep, and more frequent shifts to S1 sleep or wake from deeper stages of sleep. The consensus of the International Experts' Panel on Narcolepsy was that DNS can be distressing for patients with narcolepsy and that treatment of DNS warrants consideration. Conclusions: Clinicians involved in the management of patients with narcolepsy should investigate patients' quality of nighttime sleep, give weight and consideration to patient reports of nighttime sleep experience, and consider DNS a target for treatment. Citation: Roth T; Dauvilliers Y; Mignot E; Montplaisir J; Paul J

Effects of endocrine disrupters on the expression of growth hormone and prolactin mRNA in the rainbow trout pituitary.

USDA-ARS?s Scientific Manuscript database

It is now widely accepted that chemical pollutants in the environment can interfere with the endocrine system of animals, thus affecting development and reproduction. Some of these endocrine disrupters (EDs) can have estrogenic or antiestrogenic effects. Most studies to date have focused on the ef...

Rapid Hypothesis Testing with Candida albicans through Gene Disruption with Short Homology Regions

PubMed Central

Wilson, R. Bryce; Davis, Dana; Mitchell, Aaron P.

1999-01-01

Disruption of newly identified genes in the pathogen Candida albicans is a vital step in determination of gene function. Several gene disruption methods described previously employ long regions of homology flanking a selectable marker. Here, we describe disruption of C. albicans genes with PCR products that have 50 to 60 bp of homology to a genomic sequence on each end of a selectable marker. We used the method to disrupt two known genes, ARG5 and ADE2, and two sequences newly identified through the Candida genome project, HRM101 and ENX3. HRM101 and ENX3 are homologous to genes in the conserved RIM101 (previously called RIM1) and PacC pathways of Saccharomyces cerevisiae and Aspergillus nidulans. We show that three independent hrm101/hrm101 mutants and two independent enx3/enx3 mutants are defective in filamentation on Spider medium. These observations argue that HRM101 and ENX3 sequences are indeed portions of genes and that the respective gene products have related functions. PMID:10074081

Polyamide 6/chitosan nanofibers as support for the immobilization of Trametes versicolor laccase for the elimination of endocrine disrupting chemicals.

PubMed

Maryšková, Milena; Ardao, Inés; García-González, Carlos A; Martinová, Lenka; Rotková, Jana; Ševců, Alena

2016-07-01

In recent years, there has been an increase in efforts to improve wastewater treatment as the concentration of dangerous pollutants, such as endocrine disrupting chemicals, in wastewater increases. These compounds, which mimic the effect of hormones, have a negative impact on human health and are not easily removed from water. One way to effectively eliminate these pollutants is to use enzymatically activated materials. In this study, we report on the use of laccase from the white rot fungus Trametes versicolor immobilized onto polyamide 6/chitosan (PA6/CHIT) nanofibers modified using two different spacers (bovine serum albumin and hexamethylenediamine). We then tested the ability of the PA6/CHIT-laccase biocatalysts to eliminate a mixture containing 50μM of two endocrine disrupting chemicals: bisphenol A and 17α-ethinylestradiol. The PA6/CHIT nanofiber matrix used in this study not only proved to be a suitable carrier for immobilized and modified laccase but was also efficient in the removal of a mixture of endocrine disrupting chemicals in three treatment cycles. Copyright © 2016 Elsevier Inc. All rights reserved.

Selective enhancement of NMDA receptor-mediated locomotor hyperactivity by male sex hormones in mice.

PubMed

van den Buuse, Maarten; Low, Jac Kee; Kwek, Perrin; Martin, Sally; Gogos, Andrea

2017-09-01

Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [ 3 H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.

Negative regulation of parathyroid hormone-related protein expression by steroid hormones

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

Kajitani, Takashi; Tamamori-Adachi, Mimi; Okinaga, Hiroko

Highlights: {yields} Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. {yields} Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. {yields} Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here wemore » studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor {alpha}, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.« less

Hormonal Aspects of Epilepsy

PubMed Central

Pennell, Page B.

2009-01-01

Synopsis The interactions between hormones, epilepsy, and the medications used to treat epilepsy are complex, with tridirectional interactions which affect both men and women in various ways. Abnormalities of baseline endocrine status occur more commonly in people with epilepsy, and are most often described for the sex steroid hormone axis. Common symptoms include sexual dysfunction, decreased fertility, premature menopause, and polycystic ovarian syndrome. Antiepileptic drugs and hormones have a bidirectional interaction, with a decrease in the efficacy of hormonal contraceptive agents with some AEDs and a decrease in the concentration and efficacy of other AEDs with hormonal contraceptives. Endogenous hormones can influence seizure severity and frequency, resulting in catamenial patterns of epilepsy. However, this knowledge can be used to develop hormonal strategies to improve seizure control in people with epilepsy. PMID:19853217

Short-term ingestion of deoxynivalenol in naturally contaminated feed alters piglet performance and gut hormone secretion.

PubMed

Li, Ruonan; Li, Yansen; Su, Yongteng; Shen, Dan; Dai, Pengyuan; Li, Chunmei

2018-05-28

The mycotoxin deoxynivalenol (DON) generally exists in cereals and affects human and animal health. The aim of this study is to analyze the impacts of DON in naturally contaminated feed on piglet growth performance and intestinal hormone secretion in the short term. We randomly divided 5-week-old piglets into four groups: Control, DON 1,000, DON 2,000 and DON 3,000 groups. Piglets received a feed naturally contaminated with DON (approximately 400, 1,000, 2,000 or 3,000 μg/kg) for 21 days. Body weight showed no significant difference following exposure to DON. The balance of anti-oxidation and oxidation was disrupted by DON after 21 days. The concentration of tumor necrosis factor-alpha (TNF-α) and cyclooxgenase-2 (COX-2) significantly increased (p < .001) in all DON-treated groups. Gut anorexigenic hormone secretion of peptide YY (PYY) and cholecystokinin (CCK) had a time- and dose-dependent relationship with DON exposure; however, there was no effect on orexigenic hormone ghrelin secretion. Changes of histomorphology in the jejunum were observed in DON-treated groups, including villi flattening and fusion, and apical necrosis of villi. These results indicated that DON could suppress piglet growth performance and alter gut hormone secretion in the short term. © 2018 Japanese Society of Animal Science.

Dim light at night disrupts the short-day response in Siberian hamsters.

PubMed

Ikeno, Tomoko; Weil, Zachary M; Nelson, Randy J

2014-02-01

Photoperiodic regulation of physiology, morphology, and behavior is crucial for many animals to survive seasonally variable conditions unfavorable for reproduction and survival. The photoperiodic response in mammals is mediated by nocturnal secretion of melatonin under the control of a circadian clock. However, artificial light at night caused by recent urbanization may disrupt the circadian clock, as well as the photoperiodic response by blunting melatonin secretion. Here we examined the effect of dim light at night (dLAN) (5lux of light during the dark phase) on locomotor activity rhythms and short-day regulation of reproduction, body mass, pelage properties, and immune responses of male Siberian hamsters. Short-day animals reduced gonadal and body mass, decreased spermatid nuclei and sperm numbers, molted to a whiter pelage, and increased pelage density compared to long-day animals. However, animals that experienced short days with dLAN did not show these short-day responses. Moreover, short-day specific immune responses were altered in dLAN conditions. The nocturnal activity pattern was blunted in dLAN hamsters, consistent with the observation that dLAN changed expression of the circadian clock gene, Period1. In addition, we demonstrated that expression levels of genes implicated in the photoperiodic response, Mel-1a melatonin receptor, Eyes absent 3, thyroid stimulating hormone receptor, gonadotropin-releasing hormone, and gonadotropin-inhibitory hormone, were higher in dLAN animals than those in short-day animals. These results suggest that dLAN disturbs the circadian clock function and affects the molecular mechanisms of the photoperiodic response. Copyright © 2013 Elsevier Inc. All rights reserved.

Disruption of Radiologist Workflow.

PubMed

Kansagra, Akash P; Liu, Kevin; Yu, John-Paul J

2016-01-01

The effect of disruptions has been studied extensively in surgery and emergency medicine, and a number of solutions-such as preoperative checklists-have been implemented to enforce the integrity of critical safety-related workflows. Disruptions of the highly complex and cognitively demanding workflow of modern clinical radiology have only recently attracted attention as a potential safety hazard. In this article, we describe the variety of disruptions that arise in the reading room environment, review approaches that other specialties have taken to mitigate workflow disruption, and suggest possible solutions for workflow improvement in radiology. Copyright © 2015 Mosby, Inc. All rights reserved.

Disruptive behaviour in the perioperative setting: a contemporary review.

PubMed

Villafranca, Alexander; Hamlin, Colin; Enns, Stephanie; Jacobsohn, Eric

2017-02-01

Disruptive behaviour, which we define as behaviour that does not show others an adequate level of respect and causes victims or witnesses to feel threatened, is a concern in the operating room. This review summarizes the current literature on disruptive behaviour as it applies to the perioperative domain. Searches of MEDLINE ® , Scopus™, and Google books identified articles and monographs of interest, with backreferencing used as a supplemental strategy. Much of the data comes from studies outside the operating room and has significant methodological limitations. Disruptive behaviour has intrapersonal, interpersonal, and organizational causes. While fewer than 10% of clinicians display disruptive behaviour, up to 98% of clinicians report witnessing disruptive behaviour in the last year, 70% report being treated with incivility, and 36% report being bullied. This type of conduct can have many negative ramifications for clinicians, students, and institutions. Although the evidence regarding patient outcomes is primarily based on clinician perceptions, anecdotes, and expert opinion, this evidence supports the contention of an increase in morbidity and mortality. The plausible mechanism for this increase is social undermining of teamwork, communication, clinical decision-making, and technical performance. The behavioural responses of those who are exposed to such conduct can positively or adversely moderate the consequences of disruptive behaviour. All operating room professions are involved, with the rank order (from high to low) being surgeons, nurses, anesthesiologists, and "others". The optimal approaches to the prevention and management of disruptive behaviour are uncertain, but they include preventative and professional development courses, training in soft skills and teamwork, institutional efforts to optimize the workplace, clinician contracts outlining the clinician's (and institution's) responsibilities, institutional policies that are monitored and

Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action.

PubMed

Ansar Ahmed, S; Penhale, W J; Talal, N

1985-12-01

Immune reactivity is greater in females than in males. In both experimental animals and in man there is a greater preponderance of autoimmune diseases in females, compared with males. Studies in many experimental models have established that the underlying basis for this sex-related susceptibility is the marked effects of sex hormones. Sex hormones influence the onset and severity of immune-mediated pathologic conditions by modulating lymphocytes at all stages of life, prenatal, prepubertal, and postpubertal. However, despite extensive studies, the mechanisms of sex hormone action are not precisely understood. Earlier evidence suggested that the sex hormones acted via the thymus gland. In recent years it has become apparent that sex hormones can also influence the immune system by acting on several nonclassic target sites such as the immune system itself (nonthymic lymphoid organs), the central nervous system, the macrophage-macrocyte system, and the skeletal system. Immunoregulatory T cells appear to be most sensitive to sex hormone action among lymphoid cells. Several mechanisms of action of sex hormones are discussed in this review. The possibility of using sex hormone modulation of immune responses for the treatment of autoimmune disorders is a promising area for future investigation.

Thyroid-stimulating hormone pituitary adenomas.

PubMed

Clarke, Michelle J; Erickson, Dana; Castro, M Regina; Atkinson, John L D

2008-07-01

Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas are rare, representing < 2% of all pituitary adenomas. The authors conducted a retrospective analysis of patients with TSH-secreting or clinically silent TSH-immunostaining pituitary tumors among all pituitary adenomas followed at their institution between 1987 and 2003. Patient records, including clinical, imaging, and pathological and surgical characteristics were reviewed. Twenty-one patients (6 women and 15 men; mean age 46 years, range 26-73 years) were identified. Of these, 10 patients had a history of clinical hyperthyroidism, of whom 7 had undergone ablative thyroid procedures (thyroid surgery/(131)I ablation) prior to the diagnosis of pituitary adenoma. Ten patients had elevated TSH preoperatively. Seven patients presented with headache, and 8 presented with visual field defects. All patients underwent imaging, of which 19 were available for imaging review. Sixteen patients had macroadenomas. Of the 21 patients, 18 underwent transsphenoidal surgery at the authors' institution, 2 patients underwent transsphenoidal surgery at another facility, and 1 was treated medically. Patients with TSH-secreting tumors were defined as in remission after surgery if they had no residual adenoma on imaging and had biochemical evidence of hypo-or euthyroidism. Patients with TSH-immunostaining tumors were considered in remission if they had no residual tumor. Of these 18 patients, 9 (50%) were in remission following surgery. Seven patients had residual tumor; 2 of these patients underwent further transsphenoidal resection, 1 underwent a craniotomy, and 4 underwent postoperative radiation therapy (2 conventional radiation therapy, 1 Gamma Knife surgery, and 1 had both types of radiation treatment). Two patients had persistently elevated TSH levels despite the lack of evidence of residual tumor. On pathological analysis and immunostaining of the surgical specimen, 17 patients had samples that stained positively for

Cortisol disrupts the neural correlates of extinction recall.

PubMed

Kinner, Valerie L; Merz, Christian J; Lissek, Silke; Wolf, Oliver T

2016-06-01

The renewal effect describes the recovery of extinguished responses that may occur after a change in context and indicates that extinction memory retrieval is sometimes prone to failure. Stress hormones have been implicated to modulate extinction processes, with mostly impairing effects on extinction retrieval. However, the neurobiological mechanisms mediating stress effects on extinction memory remain elusive. In this functional magnetic resonance imaging study, we investigated the effects of cortisol administration on the neural correlates of extinction memory retrieval in a predictive learning task. In this task, participants were required to predict whether certain food stimuli were associated with stomach trouble when presented in two different contexts. A two-day renewal paradigm was applied in which an association was acquired in context A and subsequently extinguished in context B. On the following day, participants received either cortisol or placebo 40min before extinction memory retrieval was tested in both contexts. Behaviorally, cortisol impaired the retrieval of extinguished associations when presented in the extinction context. On the neural level, this effect was characterized by a reduced context differentiation for the extinguished stimulus in the ventromedial prefrontal cortex, but only in men. In the placebo group, ventromedial prefrontal cortex was functionally connected to the left cerebellum, the anterior cingulate and the right anterior parahippocampal gyrus to express extinction memory. This functional crosstalk was reduced under cortisol. These findings illustrate that the stress hormone cortisol disrupts ventromedial prefrontal cortex functioning and its communication with other brain regions implicated in extinction memory. Copyright © 2016 Elsevier Inc. All rights reserved.

Luteinising hormone releasing hormone for incomplete descent of the testis.

PubMed Central

Klidjian, A M; Swift, P G; Johnstone, J M

1985-01-01

Forty boys with 54 incompletely descended testes took part in a double blind, controlled trial of intranasal luteinising hormone releasing hormone. In the control (placebo) group of 18 boys there was no significant change in testicular descent and all required orchidopexy; in the 22 treated boys, however, 12 of 29 testes (42%) were found in a lower position. This study supports the idea that a trial of intranasal luteinising hormone releasing hormone (1200 micrograms/day for 28 days) will help clarify the need for orchidopexy in at least 30% of boys with incomplete descent of the testis, particularly those in whom the testes have emerged from the inguinal canal. PMID:2861791

Luteinising hormone releasing hormone for incomplete descent of the testis.

PubMed

Klidjian, A M; Swift, P G; Johnstone, J M

1985-06-01

Forty boys with 54 incompletely descended testes took part in a double blind, controlled trial of intranasal luteinising hormone releasing hormone. In the control (placebo) group of 18 boys there was no significant change in testicular descent and all required orchidopexy; in the 22 treated boys, however, 12 of 29 testes (42%) were found in a lower position. This study supports the idea that a trial of intranasal luteinising hormone releasing hormone (1200 micrograms/day for 28 days) will help clarify the need for orchidopexy in at least 30% of boys with incomplete descent of the testis, particularly those in whom the testes have emerged from the inguinal canal.

Use of anti-Müllerian hormone testing during ovarian reserve screening to identify women at risk of polycystic ovary syndrome.

PubMed

Safier, Lauren Z; Grossman, Lisa C; Chan, Cariann W; Sauer, Mark V; Lobo, Rogerio A; Douglas, Nataki C

2016-10-01

To assess the applicability of anti-Müllerian hormone (AMH) testing in the identification of women at risk for polycystic ovary syndrome (PCOS) when AMH is used in ovarian reserve screening in the general population. A secondary analysis was undertaken of a large cross-sectional study. Women aged 27-37years, presently delaying childbearing but interested in future fertility, completed an online questionnaire to assess knowledge and attitudes about ovarian reserve testing, and underwent serum AMH testing between October 2014 and April 2015 in New York, NY, USA. For the secondary analysis, women considered to have elevated AMH levels (≥4.7ng/mL) were invited for physical examination and transvaginal ultrasonography. Among 97 women who underwent AMH testing, 32 (33.0%) had elevated AMH levels. Hyperandrogenism was reported by 8 (25.0%) women with elevated AMH and none with AMH concentrations lower than 4.7ng/mL (P<0.001). Irregular menstrual cycles before hormonal contraceptive use were reported by 16 (24.6%) of 65 women with AMH concentrations lower than 4.7ng/mL and 11 (34.4%) with elevated AMH (P=0.34). Of the 20 women with elevated AMH who returned for further evaluation, 16 (80.0%) had polycystic ovaries and 13 (65.0%) were diagnosed with PCOS (Rotterdam criteria). When AMH levels are used as a screening test for fertility, elevated concentrations can identify women at risk for PCOS. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Interactions between the thyroid hormones and the hormones of the growth hormone axis.

PubMed

Laron, Zvi

2003-12-01

The normal secretion and action of the thyroid hormones and the hormones of the GH/IGF-I (growth hormone/ insulin-like growth factor I) axis are interdependent. Their interactions often differ in man from animal studies in rodents and sheep. Thus neonates with congenital hypothyroidism are of normal length in humans but IUGR (intrauterine growth retardation) in sheep. Postnatally normal GH/IGF-I secretion and action depends on an euthyroid state. Present knowledge on the interactions between the two axes is reviewed in states of hypo- and hyperthyroidism, states of GH/IGF-I deprivation and hypersecretion, as well as the relationship between IGF-I and thyroid cancer. Emphasis is given to data in children and aspects of linear growth and skeletal maturation.

Plurihormonal pituitary adenoma immunoreactive for thyroid-stimulating hormone, growth hormone, follicle-stimulating hormone, and prolactin.

PubMed

Luk, Cynthia T; Kovacs, Kalman; Rotondo, Fabio; Horvath, Eva; Cusimano, Michael; Booth, Gillian L

2012-01-01

To describe the case of a patient with an unusual plurihormonal pituitary adenoma with immunoreactivity for thyroid-stimulating hormone (TSH), growth hormone, follicle-stimulating hormone, prolactin, and α-subunit. We report the clinical, laboratory, imaging, and pathology findings of a patient symptomatic from a plurihormonal pituitary adenoma and describe her outcome after surgical treatment. A 60-year-old woman presented to the emergency department with headaches, blurry vision, fatigue, palpitations, sweaty hands, and weight loss. Her medical history was notable for hyperthyroidism, treated intermittently with methimazole. Magnetic resonance imaging disclosed a pituitary macroadenoma (2.3 by 2.2 by 2.0 cm), and preoperative blood studies revealed elevated levels of TSH at 6.11 mIU/L, free thyroxine at 3.6 ng/dL, and free triiodothyronine at 6.0 pg/mL. She underwent an uncomplicated transsphenoidal resection of the pituitary adenoma. Immunostaining of tumor tissue demonstrated positivity for not only TSH but also growth hormone, follicle-stimulating hormone, prolactin, and α-subunit. The Ki-67 index of the tumor was estimated at 2% to 5%, and DNA repair enzyme O6-methylguanine-DNA methyltransferase immunostaining was mostly negative. Electron microscopy showed the ultrastructural phenotype of a glycoprotein-producing adenoma. Postoperatively, her symptoms and hyperthyroidism resolved. Thyrotropin-secreting pituitary adenomas are rare. Furthermore, recent reports suggest that 31% to 36% of adenomas may show evidence of secretion of multiple pituitary hormones. This case emphasizes the importance of considering pituitary causes of thyrotoxicosis and summarizes the clinical and pathology findings in a patient with a plurihormonal pituitary adenoma.

What is the role of metabolic hormones in taste buds of the tongue.

PubMed

Cai, Huan; Maudsley, Stuart; Martin, Bronwen

2014-01-01

Gustation is one of the important chemical senses that guides the organism to identify nutrition while avoiding toxic chemicals. An increasing number of metabolic hormones and/or hormone receptors have been identified in the taste buds of the tongue and are involved in modulating taste perception. The gustatory system constitutes an additional endocrine regulatory locus that affects food intake, and in turn whole-body energy homeostasis. Here we provide an overview of the main metabolic hormones known to be present in the taste buds of the tongue; discuss their potential functional roles in taste perception and energy homeostasis and how their functional integrity is altered in the metabolic imbalance status (obesity and diabetes) and aging process. Better understanding of the functional roles of metabolic hormones in flavor perception as well as the link between taste perception and peripheral metabolism may be vital for developing strategies to promote healthier eating and prevent obesity or lifestyle-related disorders. © 2014 S. Karger AG, Basel.

Thyroid Hormone Regulation of Metabolism

PubMed Central

Mullur, Rashmi; Liu, Yan-Yun

2014-01-01

Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets. PMID:24692351

NIH Common Fund - Disruptive Proteomics Technologies - Challenges and Opportunities | Office of Cancer Clinical Proteomics Research

Cancer.gov

This Request for Information (RFI) is directed toward determining how best to accelerate research in disruptive proteomics technologies. The Disruptive Proteomics Technologies (DPT) Working Group of the NIH Common Fund wishes to identify gaps and opportunities in current technologies and methodologies related to proteome-wide measurements.  For the purposes of this RFI, “disruptive” is defined as very rapid, very significant gains, similar to the "disruptive" technology development that occurred in DNA sequencing technology.

Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action.

PubMed Central

Ansar Ahmed, S.; Penhale, W. J.; Talal, N.

1985-01-01

Immune reactivity is greater in females than in males. In both experimental animals and in man there is a greater preponderance of autoimmune diseases in females, compared with males. Studies in many experimental models have established that the underlying basis for this sex-related susceptibility is the marked effects of sex hormones. Sex hormones influence the onset and severity of immune-mediated pathologic conditions by modulating lymphocytes at all stages of life, prenatal, prepubertal, and postpubertal. However, despite extensive studies, the mechanisms of sex hormone action are not precisely understood. Earlier evidence suggested that the sex hormones acted via the thymus gland. In recent years it has become apparent that sex hormones can also influence the immune system by acting on several nonclassic target sites such as the immune system itself (nonthymic lymphoid organs), the central nervous system, the macrophage-macrocyte system, and the skeletal system. Immunoregulatory T cells appear to be most sensitive to sex hormone action among lymphoid cells. Several mechanisms of action of sex hormones are discussed in this review. The possibility of using sex hormone modulation of immune responses for the treatment of autoimmune disorders is a promising area for future investigation. Images Figure 1 PMID:3907369

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1.

PubMed

Asakura, Yumi; Abe, Kiyomi; Muroya, Koji; Hanakawa, Junko; Oto, Yuji; Narumi, Satoshi; Hasegawa, Tomonobu; Adachi, Masanori

2015-01-01

Recent reports have indicated that loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1, OMIM 300888) cause congenital central hypothyroidism with macroorchidism. We conducted a next-generation sequencing-based comprehensive mutation screening for pituitary hormone deficiencies to elucidate molecular mechanisms other than anatomical abnormalities of the pituitary that might be responsible for multiple anterior hormone deficiency in a male patient who originally visited our institute complaining of short stature. He was born large for gestational age (4,370 g, +3.0 SD) after an obstructed labour. Endocrinological evaluation revealed growth hormone and thyroid-stimulating hormone deficiency. Magnetic resonance imaging showed a discontinuity of the pituitary stalk with an ectopic posterior lobe and a hypoplastic anterior lobe, likely explaining multiple anterior pituitary hormone deficiency. We identified a novel hemizygous IGSF1 mutation (c.1137_1138delCA, p.Asn380Glnfs*6) in the patient. In reviewing the literature, we noticed that all reported Japanese male IGSF1 mutation carriers were born larger than mean standards for gestational age (mean birth weight SD score of +2.0, 95% confidence interval 1.0-3.0). This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation. © 2015 S. Karger AG, Basel.

Impact of Sex Hormone Metabolism on the Vascular Effects of Menopausal Hormone Therapy in Cardiovascular Disease

PubMed Central

Masood, Durr-e-Nayab; Roach, Emir C.; Beauregard, Katie G.; Khalil, Raouf A.

2010-01-01

Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to age-related changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete

Alcohol disrupts sleep homeostasis.

PubMed

Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

2015-06-01

Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems.

PubMed

Frye, C A; Bo, E; Calamandrei, G; Calzà, L; Dessì-Fulgheri, F; Fernández, M; Fusani, L; Kah, O; Kajta, M; Le Page, Y; Patisaul, H B; Venerosi, A; Wojtowicz, A K; Panzica, G C

2012-01-01

Some environmental contaminants interact with hormones and may exert adverse consequences as a result of their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically a result of contamination of the food chain, inhalation of contaminated house dust or occupational exposure. EDCs include pesticides and herbicides (such as dichlorodiphenyl trichloroethane or its metabolites), methoxychlor, biocides, heat stabilisers and chemical catalysts (such as tributyltin), plastic contaminants (e.g. bisphenol A), pharmaceuticals (i.e. diethylstilbestrol; 17α-ethinylestradiol) or dietary components (such as phytoestrogens). The goal of this review is to address the sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or nonreproductive, sexually-dimorphic behaviours. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing the morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific 'critical periods' of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, compared to other periods. However, exposure to EDCs in adulthood can also alter physiology. Several EDCs are xenoestrogens, which can alter serum lipid concentrations or metabolism enzymes that are necessary for converting cholesterol to steroid hormones. This can ultimately alter the production of oestradiol and/or other steroids. Finally, many EDCs may have actions via (or independent of) classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor, the peroxisome proliferator-activated receptor and the retinoid X receptor, signal transduction pathways, calcium influx and/or neurotransmitter receptors. Thus, EDCs, from varied

EFFECTS OF 2,2′4,4′-TETRABROMODIPHENYL ETHER ON NUCLEAR RECEPTOR REGULATED GENES: IMPLICATIONS FOR THYROID HORMONE DISRUPTION

EPA Science Inventory

2,2′,4,4′-Tetrabromodiphenyl ether (BDE 47) is usually the most common polybrominated diphenyl ether (PBDE) congener found in human tissues and wildlife. Several studies demonstrate that PBDEs may act as endocrine disruptors through interference with thyroid hormone h...

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with isolated growth hormone deficiency due to organic causes.

PubMed

Child, Christopher J; Blum, Werner F; Deal, Cheri; Zimmermann, Alan G; Quigley, Charmian A; Drop, Stenvert L S; Cutler, Gordon B; Rosenfeld, Ron G

2016-05-01

To determine characteristics of children initially diagnosed with isolated growth hormone deficiency (IGHD) of organic aetiology, who later developed multiple pituitary hormone deficiencies (MPHD). Data were analysed for 716 growth hormone-treated children with organic IGHD, who were growth hormone-naïve at baseline in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. Development of MPHD was ascertained from investigator-provided diagnoses, adverse events and concomitant medications. Analyses were performed for all patients and separately for those who developed MPHD within 4.5 years or had >3.5 years follow-up and continued to have IGHD (4-year cohort). MPHD developed in 71/716 (9.9%) children overall, and in 60/290 (20.7%) in the 4-year cohort. The most frequent additional deficiencies were thyroid-stimulating hormone (47 patients) and gonadotropins (23 patients). Compared with those who remained with IGHD, children who developed MPHD had more severe GHD at study entry, significantly lower baseline insulin-like growth factor1, peak stimulated growth hormone, and more frequent diagnosis of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Multivariate logistic regression analyses identified female gender, longer follow-up, higher baseline age and lower peak stimulated growth hormone as predictors of MPHD development. MPHD is more likely to develop in patients with severe organic IGHD, especially those with history of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Older baseline age, female gender and longer follow-up duration were also associated with higher incidence of MPHD. Long-term monitoring of pituitary function is recommended, irrespective of the aetiology of GHD. © 2016 European Society of Endocrinology.

Cardiovascular actions of the ghrelin gene-derived peptides and growth hormone-releasing hormone.

PubMed

Granata, Riccarda; Isgaard, Jörgen; Alloatti, Giuseppe; Ghigo, Ezio

2011-05-01

In 1976, small peptide growth hormone secretagogues (GHSs) were discovered and found to promote growth hormone (GH) release from the pituitary. The GHS receptor (GHS-R) was subsequently cloned, and its endogenous ligand ghrelin was later isolated from the stomach. Ghrelin is a 28-amino acid peptide, whose acylation is essential for binding to GHS-R type 1a and for the endocrine functions, including stimulation of GH secretion and subsequent food intake. Unacylated ghrelin, the other ghrelin form, although devoid of GHS-R binding is an active peptide, sharing many peripheral effects with acylated ghrelin (AG). The ghrelin system is broadly expressed in myocardial tissues, where it exerts different functions. Indeed, ghrelin inhibits cardiomyocyte and endothelial cell apoptosis, and improves left ventricular (LV) function during ischemia-reperfusion (I/R) injury. In rats with heart failure (HF), ghrelin improves LV dysfunction and attenuates the development of cardiac cachexia. Similarly, ghrelin exerts vasodilatory effects in humans, improves cardiac function and decreases systemic vascular resistance in patients with chronic HF. Obestatin is a recently identified ghrelin gene peptide. The physiological role of obestatin and its binding to the putative GPR39 receptor are still unclear, although protective effects have been demonstrated in the pancreas and heart. Similarly to AG, the hypothalamic peptide growth hormone-releasing hormone (GHRH) stimulates GH release from the pituitary, through binding to the GHRH-receptor. Besides its proliferative effects in different cell types, at the cardiovascular level GHRH inhibits cardiomyocyte apoptosis, and reduces infarct size in both isolated rat heart after I/R and in vivo after myocardial infarction. Therefore, both ghrelin and GHRH exert cardioprotective effects, which make them candidate targets for therapeutic intervention in cardiovascular dysfunctions.

Growth hormone (GH)-releasing activity of chicken GH-releasing hormone (GHRH) in chickens.

PubMed

Harvey, S; Gineste, C; Gaylinn, B D

2014-08-01

Two peptides with sequence similarities to growth hormone releasing hormone (GHRH) have been identified by analysis of the chicken genome. One of these peptides, chicken (c) GHRH-LP (like peptide) was previously found to poorly bind to chicken pituitary membranes or to cloned and expressed chicken GHRH receptors and had little, if any, growth hormone (GH)-releasing activity in vivo or in vitro. In contrast, a second more recently discovered peptide, cGHRH, does bind to cloned and expressed cGHRH receptors and increases cAMP activity in transfected cells. The possibility that this peptide may have in vivo GH-releasing activity was therefore assessed. The intravenous (i.v.) administration of cGHRH to immature chickens, at doses of 3-100 μg/kg, significantly increased circulating GH concentrations within 10 min of injection and the plasma GH levels remained elevated for at least 30 min after the injection of maximally effective doses. The plasma GH responses to cGHRH were comparable with those induced by human (h) or porcine (p) GHRH preparations and to that induced by thyrotropin releasing hormone (TRH). In marked contrast, the i.v. injection of cGHRH-LP had no significant effect on circulating GH concentrations in immature chicks. GH release was also increased from slaughterhouse chicken pituitary glands perifused for 5 min with cGHRH at doses of 0.1 μg/ml or 1.0 μg/ml, comparable with GH responses to hGHRH1-44. In contrast, the perifusion of chicken pituitary glands with cGHRH-LP had no significant effect on GH release. In summary, these results demonstrate that cGHRH has GH-releasing activity in chickens and support the possibility that it is the endogenous ligand of the cGHRH receptor. Copyright © 2014 Elsevier Inc. All rights reserved.

Hormone Profiling in Plant Tissues.

PubMed

Müller, Maren; Munné-Bosch, Sergi

2017-01-01

Plant hormones are for a long time known to act as chemical messengers in the regulation of physiological processes during a plant's life cycle, from germination to senescence. Furthermore, plant hormones simultaneously coordinate physiological responses to biotic and abiotic stresses. To study the hormonal regulation of physiological processes, three main approaches have been used (1) exogenous application of hormones, (2) correlative studies through measurements of endogenous hormone levels, and (3) use of transgenic and/or mutant plants altered in hormone metabolism or signaling. A plant hormone profiling method is useful to unravel cross talk between hormones and help unravel the hormonal regulation of physiological processes in studies using any of the aforementioned approaches. However, hormone profiling is still particularly challenging due to their very low abundance in plant tissues. In this chapter, a sensitive, rapid, and accurate method to quantify all the five "classic" classes of plant hormones plus other plant growth regulators, such as jasmonates, salicylic acid, melatonin, and brassinosteroids is described. The method includes a fast and simple extraction procedure without time consuming steps as purification or derivatization, followed by optimized ultrahigh-performance liquid chromatography coupled to electrospray ionization-tandem mass spectrometry (UHPLC-MS/MS) analysis. This protocol facilitates the high-throughput analysis of hormone profiling and is applicable to different plant tissues.

Mechanical algal disruption for efficient biodiesel extraction

NASA Astrophysics Data System (ADS)

Krehbiel, Joel David

Biodiesel from algae provides several benefits over current biodiesel feedstocks, but the energy requirements of processing algae into a useable fuel are currently so high as to be prohibitive. One route to improving this is via disruption of the cells prior to lipid extraction, which can significantly increase energy recovery. Unfortunately, several obvious disruption techniques require more energy than can be gained. This dissertation examines the use of microbubbles to improve mechanical disruption of algal cells using experimental, theoretical, and computational methods. New laboratory experiments show that effective ultrasonic disruption of algae is achieved by adding microbubbles to an algal solution. The configuration studied flows the solution through a tube and insonifies a small section with a high-pressure ultrasound wave. Previous biomedical research has shown effective cell membrane damage on animal cells with similar methods, but the present research is the first to extend such study to algal cells. Results indicate that disruption increases with peak negative pressure between 1.90 and 3.07 MPa and with microbubble concentration up to 12.5 x 107 bubbles/ml. Energy estimates of this process suggest that it requires only one-fourth the currently most-efficient laboratory-scale disruption process. Estimates of the radius near each bubble that causes disruption (i.e. the disruption radius) suggest that it increases with peak negative pressure and is near 9--20 microm for all cases tested. It is anticipated that these procedures can be designed for better efficiency and efficacy, which will be facilitated by identifying the root mechanisms of the bubble-induced disruption. We therefore examine whether bubble expansion alone creates sufficient cell deformation for cell rupture. The spherically-symmetric Marmottant model for bubble dynamics allows estimation of the flow regime under experimental conditions. Bubble expansion is modeled as a point source of

Follicle stimulating hormone, its novel association with sex hormone binding globulin in men and postmenopausal women.

PubMed

Wang, Ningjian; Zhang, Kun; Han, Bing; Li, Qin; Chen, Yi; Zhu, Chunfang; Chen, Yingchao; Xia, Fangzhen; Zhai, Hualing; Jiang, Boren; Shen, Zhoujun; Lu, Yingli

2017-06-01

Follicle stimulating hormone plays direct roles in a variety of nongonadal tissues and sex hormone binding globulin is becoming the convergence of the crosstalk among metabolic diseases. However, no studies have explored the association between follicle stimulating hormone and sex hormone binding globulin. We aimed to study this association among men and women. SPECT-China is a population-based study conducted since 2014. This study included 4206 men and 2842 postmenopausal women. Collected serum was assayed for gonadotropins, sex hormone binding globulin, sex hormones etc. Regression analyses were performed to assess the relationship between sex hormone binding globulin and follicle stimulating hormone and other variables including metabolic factors, thyroid function and sex hormones. Treatment with follicle stimulating hormone at different concentrations of 0, 5, 50 and 100 IU/L for 24 h was performed in HepG2 cells. In Spearman correlation, sex hormone binding globulin was significantly correlated with FSH, triglycerides, thyroxins, body mass index and blood pressure in men and postmenopausal women (all P < 0.05). In regression analyses, follicle stimulating hormone was a significant predictor of sex hormone binding globulin in men and postmenopausal women (P < 0.05), independent of above variables. Follicle stimulating hormone induced sex hormone binding globulin expression in a dose-dependent fashion in HepG2 cells. Serum follicle stimulating hormone levels were positively associated with circulating sex hormone binding globulin levels in men and postmenopausal women. This association is independent of age, insulin resistance, hepatic function, lipid profile, thyroid function, adiposity, blood pressure, and endogenous sex hormones.

In Silico Identification and Pharmacological Evaluation of Novel Endocrine Disrupting Chemicals That Act via the Ligand-Binding Domain of the Estrogen Receptor α

PubMed Central

Kufareva, Irina; Abagyan, Ruben

2014-01-01

Endocrine disrupting chemicals (EDCs) pose a significant threat to human health, society, and the environment. Many EDCs elicit their toxic effects through nuclear hormone receptors, like the estrogen receptor α (ERα). In silico models can be used to prioritize chemicals for toxicological evaluation to reduce the amount of costly pharmacological testing and enable early alerts for newly designed compounds. However, many of the current computational models are overly dependent on the chemistry of known modulators and perform poorly for novel chemical scaffolds. Herein we describe the development of computational, three-dimensional multi-conformational pocket-field docking, and chemical-field docking models for the identification of novel EDCs that act via the ligand-binding domain of ERα. These models were highly accurate in the retrospective task of distinguishing known high-affinity ERα modulators from inactive or decoy molecules, with minimal training. To illustrate the utility of the models in prospective in silico compound screening, we screened a database of over 6000 environmental chemicals and evaluated the 24 top-ranked hits in an ERα transcriptional activation assay and a differential scanning fluorimetry-based ERα binding assay. Promisingly, six chemicals displayed ERα agonist activity (32nM–3.98μM) and two chemicals had moderately stabilizing effects on ERα. Two newly identified active compounds were chemically related β-adrenergic receptor (βAR) agonists, dobutamine, and ractopamine (a feed additive that promotes leanness in cattle and poultry), which are the first βAR agonists identified as activators of ERα-mediated gene transcription. This approach can be applied to other receptors implicated in endocrine disruption. PMID:24928891

Non-contraceptive benefits of hormonal and intrauterine reversible contraceptive methods.

PubMed

Bahamondes, Luis; Valeria Bahamondes, M; Shulman, Lee P

2015-01-01

Most contraceptive methods present benefits beyond contraception; however, despite a large body of evidence, many healthcare professionals (HCPs), users and potential users are unaware of those benefits. This review evaluates the evidence for non-contraceptive benefits of hormonal and non-hormonal contraceptive methods. We searched the medical publications in PubMed, POPLINE, CENTRAL, EMBASE and LILACS for relevant articles, on non-contraceptive benefits of the use of hormonal and intrauterine reversible contraceptive methods, which were published in English between 1980 and July 2014. Articles were identified using the following search terms: 'contraceptive methods', 'benefits', 'cancer', 'anaemia', 'heavy menstrual bleeding (HMB)', 'endometrial hyperplasia', 'endometriosis' and 'leiomyoma'. We identified, through the literature search, evidence that some combined oral contraceptives have benefits in controlling HMB and anaemia, reducing the rate of endometrial, ovarian and colorectal cancer and ectopic pregnancy as well as alleviating symptoms of premenstrual dysphoric disorder. Furthermore, the use of the levonorgestrel-releasing intrauterine system also controls HMB and anaemia and endometrial hyperplasia and cancer, reduces rates of endometrial polyps in users of tamoxifen and alleviates pain associated with endometriosis and adenomyosis. Depot medroxyprogesterone acetate controls crises of pain associated with sickle cell disease and endometriosis. Users of the etonogestrel-releasing contraceptive implant have the benefits of a reduction of pain associated with endometriosis, and users of the copper intrauterine device have reduced rates of endometrial and cervical cancer. Despite the high contraceptive effectiveness of many hormonal and intrauterine reversible contraceptive methods, many HCPs, users and potential users are concerned mainly about side effects and safety of both hormonal and non-hormonal contraceptive methods, and there is scarce information

Monitoring-induced disruption in skilled typewriting.

PubMed

Snyder, Kristy M; Logan, Gordon D

2013-10-01

It is often disruptive to attend to the details of one's expert performance. The current work presents four experiments that utilized a monitor to report protocol to evaluate the sufficiency of three accounts of monitoring-induced disruption. The inhibition hypothesis states that disruption results from costs associated with preparing to withhold inappropriate responses. The dual-task hypothesis states that disruption results from maintaining monitored information in working memory. The implicit-explicit hypothesis states that disruption results from explicitly monitoring details of performance that are normally implicit. The findings suggest that all three hypotheses are sufficient to produce disruption, but inhibition and dual-task costs are not necessary. Experiment 1 showed that monitoring to report was disruptive even when there was no requirement to inhibit. Experiment 2 showed that maintaining information in working memory caused some disruption but much less than monitoring to report. Experiment 4 showed that monitoring to inhibit was more disruptive than monitoring to report, suggesting that monitoring is more disruptive when it is combined with other task requirements, such as inhibition. PsycINFO Database Record (c) 2013 APA, all rights reserved.