Endocrine Disruptors Exposure Research Articles

Characterizing the effect of endocrine disruptors on human health: The role of epidemiological cohorts

Research on endocrine disruptors (EDs) developed from numerous disciplines. In this concert of disciplines, epidemiology is central to inform on the relevance for humans of mechanisms and dose-response functions identified in animals, to characterize the health impact (number of attributable disease cases), the cost associated with ED exposure, and the efficiency of the measures taken to limit exposure. Here, we present epidemiological tools to draw valid inference regarding effects of potential EDs. Epidemiology is generally observational, requiring care to control confounding bias. Many potential EDs have a short biological half-life; approaches relying on repeated biospecimens sampling allow limiting exposure misclassification and the resulting bias. For non-persistent compounds, couple–child cohorts are a central study design. Cohorts can now rely on molecular biology approaches to characterize exposures and intermediate pathways, which corresponds to the advent of molecular epidemiology and allows stronger interactions between epidemiology, toxicology, and molecular epidemiology to characterize the health effects of EDs.

Do environmental factors affect male fathead minnow (Pimephales promelas) response to estrone? Part 2. Temperature and food availability

Fish are subject to constantly changing environmental conditions and food availability, factors that may impact their response to endocrine disruptors (EDs). This may, in part, explain outcome discrepancies between field studies and laboratory exposures to EDs. This study assessed whether standard laboratory conditions for fish exposures adequately represent effects of ED exposure at two environmentally realistic temperatures. The impact of temperature and food availability on male fathead minnow response to estrone (E1) exposure was studied in two experiments (3×2×2 factorial design) with three E1 concentrations (range 0–135ng/L); two temperatures (18°C and 26°C, the latter the prescribed laboratory temperature), and two feeding treatments (full fed vs. 25% of full fed) in a 21-day flow-through system. Morphometric endpoints [including body condition factor, somatic index of gonad (GSI) and liver (HSI), and secondary sex characteristics (SSC)], blood parameters [hematocrit (HCT), blood glucose, cortisol, and vitellogenin (VTG) concentrations], and histology of liver and testis were determined on day 22. High E1 consistently increased VTG, though interactions among E1, temperature and/or food on liver weight, HSI, and HCT were inconsistent between experiments. High temperature impacted the greatest number of parameters, independent of E1 treatment. Three sex-linked parameters were lower at high temperature (testis weight, GSI and VTG), and in Exp. 2SSC and gonad maturity rating were lower. At 26°C, in Exp. 1 HSI and HCT decreased, and in Exp. 2 length, body and liver weight, and body condition factor were lower. Food restriction decreased GSI in Exp. 1, and blood glucose and liver weight in Exp. 2. At 26°C several parameters were altered independent of E1 exposure, including three out of four measurements of sperm differentiation. Concordance between laboratory and field investigations of the biological effects of EDs may improve if environmentally-relevant exposure conditions, especially temperature, are employed.

Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences.

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the worlds leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

Endocrine Disrupting Chemicals and Endometrial Cancer: An Overview of Recent Laboratory Evidence and Epidemiological Studies.

Background: Although exposure to endocrine disruptor compounds (EDCs) has been suggested as a contributing factor to a range of women’s health disorders including infertility, polycystic ovaries and the early onset of puberty, considerable challenges remain in attributing cause and effect on gynaecological cancer. Until recently, there were relatively few epidemiological studies examining the relationship between EDCs and endometrial cancer, however, in the last years the number of these studies has increased. Methods: A systematic MEDLINE (PubMed) search was performed and relevant articles published in the last 23 years (from 1992 to 2016) were selected. Results: Human studies and animal experiments are confirming a carcinogenic effect due to the EDC exposure and its carcinogenesis process result to be complex, multifactorial and long standing, thus, it is extremely difficult to obtain the epidemiological proof of a carcinogenic effect of EDCs for the high number of confusing factors. Conclusions: The carcinogenic effects of endocrine disruptors are plausible, although additional studies are needed to clarify their mechanisms and responsible entities. Neverthless, to reduce endocrine disruptors (ED) exposure is mandatory to implement necessary measures to limit exposure, particularly during those periods of life most vulnerable to the impact of oncogenic environmental causes, such as embryonic period and puberty.

Early endocrine disruptors exposure acts on 3T3-L1 differentiation and endocrine activity.

Introduction: Data from last years suggested that early exposure to endocrine disruptors (EDs) can predispose newborns to endocrine dysfunction of adipocytes, obesity, and associated disorders. The implication of EDs at low doses on adipocyte development has been poorly investigated. For instance, vinclozolin (V) is a dicarboximide fungicide widely used in agriculture since the 90's, alone or in mixture with genistein (G), an isoflavonoid from Leguminosae. This study aims to identify the effect of vinclozolin alone or with genistein, on adipose tissue properties using cell culture. Methods: In steroid-free conditions, 3T3-L1 pre-adipocytes were induced to differentiate in the presence of EDs, singularly or in mixtures, for 2 days. DNA and triglyceride (TG) levels were measured on days 0, 2 and 8 of differentiation. Leptin secretion was measured only on the eighth day. Results: We show that low doses of G (25 µM) and V (0.1 µM) inhibit pre-adipocytes differentiation. This inhibition has been represented by a decreasing in DNA content (µg/well) and decreasing in TG accumulation (mg/mL) in 3T3-L1 cells. Nevertheless, V increased the anti-adipogenic properties of G. Conclusion: This study confirms that EDs singularly or in mixtures, introduced during early stages of life, could affect the differentiation and the endocrine activity of adipocytes, and can act as potential factors for obesity.

Effect of environmental endocrine disruptor's exposure on sperm quality and aneuploidy rates in fertile sperm donors

Effect of environmental endocrine disruptor's exposure on sperm quality and aneuploidy rates in fertile sperm donors

Association between Exposure to Endocrine Disruptors in Drinking Water and Preterm Birth, Taking Neighborhood Deprivation into Account: A Historic Cohort Study.

Background: The relationship between preterm birth (PTB) and endocrine disruptor exposure in drinking-water has only occasionally been studied. The objective of this work was to investigate the relation between exposure to atrazine metabolites, or atrazine/nitrate mixtures, in drinking-water during pregnancy and prevalence of PTB neonates, while taking neighborhood deprivation into account. Method: A historic cohort study in Deux-Sèvres, France, between 2005 and 2010 with a multiple imputation model for data of exposure to atrazine metabolites and a logistic regression were carried out. Results: We included 13,654 mother/neonate pairs living in 279 different census districts. The prevalence of PTB was 4%. Average atrazine metabolite concentration was 0.019 ± 0.009 (0.014–0.080) µg/L and 39% of mothers lived in less deprived areas. The individual data were associated with risk of PTB. The risk of PTB when exposed to highest concentration of atrazine metabolite adjusted for confounders, was ORa 1.625 95% CI [0.975; 2.710]. Taking, or not, neighborhood deprivation into account did not change the result. Exposure to atrazine/nitrate mixtures remained non-significant. Conclusions: Even if we took neighborhood deprivation into account, we could not show a significant relationship between exposure to atrazine metabolites, or mixtures, in drinking-water during the second trimester of pregnancy and PTB.

Preparation of High-quality Hematoxylin and Eosin-stained Sections from Rodent Mammary Gland Whole Mounts for Histopathologic Review.

Identifying environmental exposures that cause adverse mammary gland outcomes in rodents is a first step in disease prevention in humans and domestic pets. "Whole mounts" are an easy and inexpensive tissue preparation method that can elucidate typical or abnormal mammary gland morphology in rodent studies. Here, we propose procedures to facilitate the use of whole mounts for histological identification of grossly noted tissue alterations. We noted lesions in mammary whole mounts from 14-month-old CD-1 mice that were not found in the contralateral gland hematoxylin and eosin (H&E)-stained section. Whole mounts were removed from the slide and carefully processed to produce high-quality histological sections that mirrored the quality of the original H&E-stained section in order to properly diagnose the unidentified gross abnormalities. Incorporation of this method into testing protocols that focus on human relevant chemical and endocrine disruptors exposure will increase the chances of identifying lesions in the gland and reduce the risk of false negative findings. This method can be especially invaluable when lesions are not always palpable during the course of the study or visible at necropsy, or when a single cross section of the mammary gland is otherwise used for detecting lesions.

Carcinogenetic mechanisms of endocrine disruptors in female cancers (Review).

Endocrine disruptors (EDs) are pollutants that alter the endocrine system and are involved in carcinogenesis. EDs have multiple and complex levels of action. They can affect the synthesis, release and transport of natural hormones. In target tissues, EDs can reduce or increase the effects of natural hormones on their receptors and change signaling cascades. When ED exposure happens at critical periods of life, from embryo to puberty, they can act at doses considered safe for an adult. Furthermore, their epigenetic effects can also influence the cancer risk of future generations. The cancer mechanisms of known EDs are hereby reviewed, There are thousands of newly introduced substances whose potential endocrine-disrupting and cancer effects are completely unknown. Although there are still gaps in our knowledge, these data support the urgent need for health and environmental policies aimed at protecting the public and in particular, the developing fetus and women of reproductive age.

Association of bisphenol A exposure with dietary quality indices in Spanish schoolchildren

Young children, whose growth and development are highly dependent on the endocrine system, are particularly vulnerable to endocrine disruptor exposure. The main objectives of this study were to measure BPA migration levels from cans, fruit juice bottles/packs, and microwave containers used for food/drinks consumed by a sample of 6- to 8-year old schoolchildren in Spain and to estimate the relationship between their resulting BPA exposure and diet quality index scores (Mediterranean Diet Score and Breakfast Quality Index). The mean BPA concentration was 11.8 ng/mL for vegetable cans, 22.1 ng/mL for pulse cans, 3.6 ng/mL for juice bottles/packs, and 1.2 ng/mL for microwave containers. Results revealed a significant association between the Mediterranean Diet Score and low BPA exposure of the children. BPA exposure below the median level was significantly associated with a higher score in both the first-grade (P = 0.030) and second-grade (p = 0.0001) groups. However, no association was found between BPA exposure and the Breakfast Quality Index. In conclusion, children with a stronger adherence to a Mediterranean-like diet appear to be less exposed to BPA migrating from food packaging and microwave containers. Further research is warranted on the inadvertent exposure of children to endocrinedisrupting chemicals from these sources.

Bisphenol A (BPA) and Bisphenol S (BPS) increase Coxsackievirus B3 myocarditis in female and male BALB/c mice by activating mast cells, increasing immune cell infiltrate and activating the inflammasome

Abstract Myocarditis is an inflammatory heart disease that is the leading cause of heart failure in young adults. Sex hormones play a vital role in development of myocarditis with testosterone driving disease in males. Whereas, estrogen, via Estrogen Receptor α (ERα) mediates cardioprotection in females. Since myocarditis is influenced by sex hormones, it is highly probable that endocrine disruptors (EDs); which interfere with natural hormones, will play a part in the progression of the disease. The human population is exposed to Bisphenol A (BPA), a known ED that binds the ER, from plastics, such as water bottles and plastic food containers. BPA could increase myocarditis through deleterious actions of the ERβ rather than beneficial effects via ERα. To our knowledge no one has examined the role of EDs like BPA on myocarditis. We found that clinically relevant doses (25 μg/L and 250 μg/L) of BPA increased acute myocarditis compared to control water in females. In females we found BPA significantly decreased ERα, while ERβ was significantly increased. We found that mast cells (cKit) are largely responsible for the increase in inflammation along with CD4 Thelper cells, IL-1β, IFN-γ, TLR4, Caspase-1, Mmp9, and ST2. In male mice, we found that at the high dose of BPA increased myocarditis and increased all immune cell markers and the inflammasome. We also investigated the compound Bisphenol S (BPS) which has replaced BPA in a number of products and found that BPS also increases myocarditis. Interestingly this effect was only seen in Balb/c mice and not BL/6 suggesting that race could be a factor in evaluating ED role in disease. We have found that ED exposure is having a significant effect on myocarditis and could potentially influence a number of human diseases.

In vitro steroid profiling system for the evaluation of endocrine disruptors

Endocrine disruptors (ED) are chemicals that affect various aspects of the endocrine system, often leading to the inhibition of steroidogenesis. Current chemical safety policies that restrict human exposure to such chemicals describe often time-consuming and costly methods for the evaluation of ED effects. We aimed to develop an effective tool for accurate phenotypic chemical toxicology studies. We developed an invitro ED evaluation system using gas chromatography/mass spectrometry (GC/MS/MS) methods for metabolomic analysis of multi-marker profiles. Accounting for sample preparation and GC/MS/MS conditions, we established a screening method that allowed the simultaneous analysis of 17 steroids with good reproducibility and a linear calibration curve. Moreover, we applied the developed system to H295R human adrenocortical cells exposed to forskolin and prochloraz in accordance with the Organization for Economic Cooperation and Development (OECD) guidelines and observed dose-dependent variations in steroid profiles. While the OECD guidelines include only testosterone and 17β-estradiol, our system enabled a comprehensive and highly sensitive analysis of steroid profile alteration due to ED exposure. The application of our ED evaluation screen could be economical and provide novel insights into the hazards of ED exposure to the endocrine system.

AB159. Endocrine disrupting chemicals: toxicological risk assessment in vivo and in vitro models

In several studies, scientists asserted that many of endocrine disruptors (EDs), which have been involved in developmental, reproductive, neural, immunological, and other problems in wildlife and laboratory animals. Some environmental EDs, such as di-(2-ethylhexyl) phthalate (DEHP), flutamide (Flu), parabens, are used in many products in life and environment. However, the adverse effects caused by EDs can be temporary or permanent and the mechanism(s) through which these chemicals elicit their effects on biological systems of human and animal health is not clearly understood. The specific aim of this study is to evaluate endocrine disrupting chemicals-induced impact on the male or female reproductive system. An attempt is also made to elucidate the impact of these EDs in an in vitro model, i.e., GH3 rat pituitary cell line. A great deal of work has been carried out on the toxicity of phthalate, Flu, parabens in vivo and in vitro models. In brief, studies have been indicated that long-term and short-term exposure to various endocrine disrupting compounds (i.e., DEHP, Flu, parabens) during development stage (i.e., gestation, neonatal, immature, peripubertal) were done to find alternative dysfunctions later in animal life. The development and function of male or female reproductive tract showed many abnormalities, e.g., menstrual cycle irregularities; impaired fertility, endometriosis, and polycystic ovarian syndrome in female or morphological and functional gonadal dysfunction, e.g., infertility and decreased libido, congenital malformations (altered embryonic and fetal intrauterine development) and testicular dysgenesis syndrome in male. In addition, the differential gene expression patterns by microarray analysis following EDs exposure were found, particularly in steroid hormone synthesis, androgen and/or estrogen synthesis, and sex determination-related gene. On the other hand, studies revealed that parabens, a weak estrogenic chemical, exerted their actions on the stimulation of CaBP-9k gene, an estrogenic biomarker, via binding to estrogen receptor and/or progesterone receptor in immature female rat and GH3 cell line. An increasing number of chemical compounds in the environment have been identified as endocrine disruptor in vivo and in vitro bioassay. A future challenge is required to confirm a theoretical toxicology and risk assessment of EDs for human and animal health.

Abstract LB-089: Defining windows of susceptibility for low-dose exposure to endocrine disruptors in rat mammary development by microRNA profiling

Abstract BACKGROUND: Endocrine disruptors (EDs) constitute a class of chemicals that can interfere with the endocrine system, possibly influencing breast cancer risk. EDs exposure has been associated with changes in the epigenome such as methylation; their ability to modify other epigenetic processes, such as microRNA, has not been thoroughly investigated, especially in the context of mammary development. METHODS: We investigated the influence on microRNA of three EDs widely used in personal care products: diethyl phthalate (DEP), methyl paraben (MPB) and triclosan (TCS). Sprague-Dawley rats were treated with these EDs at six windows of susceptibility (prenatal, neonatal, prepubertal and pubertal, parous, and nulliparous) from in utero to young adulthood. Oral treatment doses were selected to produce urinary metabolite levels comparable to those found in the US population. MicroRNAs were profiled using the NanoString platform. RESULTS: Of 420 microRNAs analyzed, 90 were stably detected in >90% samples across all windows, with let-7 family members showing the highest expression. In the meantime, 132 microRNA species were expressed below the detection level in >90% of the samples; other miRNAs were expressed at different levels in some but not all samples. Principal component analysis revealed that different developmental windows displayed markedly different microRNA profiles. Importantly, we found that ED exposure, TCS in particular, resulted in measurable difference in rat mammary microRNAs, and the changes were window-specific. More specifically, the TCS-related changes were mainly present in prenatal, neonatal and pubertal windows; among these the neonatal period appeared to be the most susceptible window to EDs with the largest number of differentially expressed microRNAs (7 microRNA species with adjusted p<0.05). CONCLUSIONS: Low-dose ED exposure, even at levels comparable to human exposure, was able to modify microRNA expression in rat mammary tissues in a window-specific fashion. The study also demonstrates dynamic changes of microRNA profiles in developing mammary glands and highlights the importance of taking the normal developmental gene signal into account when searching for environment-induced gene signatures. Citation Format: Vasily N. Aushev, Maya Kappil, Kalpana Gopalakrishnan, Qian Li, Yula Ma, Luca Lambertini, Fabiana Manservisi, Laura Falcioni, Luciano Bua, Fiorella Belpoggi, Susan L. Teitelbaum, Jia Chen. Defining windows of susceptibility for low-dose exposure to endocrine disruptors in rat mammary development by microRNA profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-089. doi:10.1158/1538-7445.AM2015-LB-089

Abstract 5573: Effects of endocrine disruptors on rat mammary transcriptome at critical developmental windows

Abstract Background: Endocrine disruptors (EDs) are environmental chemicals that may disrupt endogenous hormones and have been linked to many adverse health outcomes including breast cancer. EDs have been shown to modulate the risk for mammary tumors in animal models, but their mechanisms at biologically relevant doses and during critical developmental windows remain poorly understood. Methods: We examined the individual and combinatorial (MIX) effects of three EDs commonly found in personal care products - diethyl phthalate (DEP), methyl paraben (MPB) and triclosan (TCS). Sprague-Dawley rats were exposed at four developmental windows - prenatal, neonatal, prepubertal and pubertal - at doses comparable to human exposure based on urinary levels reported in NHANES. Whole-transcriptome profiling was done using Affymetrix rat gene 2.0 st arrays. Results: Differential gene expression analysis by limma revealed that there were no substantial differences between the transcriptomes of prenatal and neonatal rats, so they were combined into a ‘perinatal’ group. Control rats: Expression levels of 702 transcripts significantly differed between the prepubertal and perinatal periods; gene ontology (GO) enrichment showed that GO terms related to development and response to estrogen stimuli were up-regulated and immune signaling pathways were down-regulated. Upstream analysis using Ingenuity Pathway Analysis showed that β-estradiol and estrogen receptor were among the top regulators up-regulated in the prepubertal window, and T-cell receptor and interleukins were among the top regulators down-regulated. The difference between later windows, i.e., between puberty and prepuberty was much less pronounced, with only 39 differentially expressed transcripts. ED-exposed rats: Large scale changes in mammary transcriptome were driven by developmental stage, while changes due to ED exposure appeared to be more subtle. One-way ANOVA among developmental windows demonstrated that only ∼3000 transcripts were significantly changed in DEP and MPB and ∼4000 transcripts changed in TCS and MIX compared to ∼6000 differentially expressed transcripts in control rats. Importantly, distinct signatures of genes were associated with each individual ED as well as MIX, suggesting distinctive mechanisms. Additionally, our data suggested that the pubertal window was the most susceptible; for example, 440 transcripts were differentially expressed in the MPB group relative to control only at the pubertal window and GO terms related to DNA damage and ion transport were up- and down-regulated, respectively. Conclusions: Exposure to common EDs at levels comparable to human exposure resulted in measurable changes in mammary transcriptome and reveal novel mechanisms of ED action in mammary development. Findings from our study highlight the importance of taking into account the timing of exposure when studying the relationship between environment and disease. Citation Format: Kalpana Gopalakrishnan, Qian Li, Yula Ma, Luca Lambertini, Jia Chen, Susan Teitelbaum, Fabiana Manservisi, Laura Falcioni, Luciano Bua, Fiorella Belpoggi. Effects of endocrine disruptors on rat mammary transcriptome at critical developmental windows. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5573. doi:10.1158/1538-7445.AM2015-5573

Endocrine disruptors and female cancer: Informing the patients (Review).

Pollutants altering the endocrine system, known as endocrine disruptors (ED), may modify the risk of female cancers. The carcinogenic effect of ED on humans has been confirmed by experimental studies for various substances including pesticides, DDT, dioxins, phthalates, bisphenol A, diethylstilbestrol, as well as heavy metals, but it is difficult to quantify precisely for several reasons hereby reviewed. Carcinogenesis is a complex and multifactorial mechanism that manifests itself over a long period of time, making difficult the detection of the specific contribution of the pollutants, whose absorbed dose is often unknown. The combined effect of various substances leads to complex interactions whose outcome is difficult to predict. These substances may accumulate and carry out their harmful effect on critical periods of life, probably also at doses considered harmless to an adult. ED can also have epigenetic adverse effects on the health of future generations. In conclusion, the carcinogenic effects of endocrine disruptors on female cancer types is plausible although additional studies are needed to clarify their mechanisms and entities. In the last part of the review we suggest ways to reduce ED exposure as it is mandatory to implement necessary measures to limit exposure, particularly during those periods of life most vulnerable to the impact of oncogenic environmental causes, such as the embryonic period and puberty.

Heat Stress Alters Ovarian Insulin-Mediated Phosphatidylinositol-3 Kinase and Steroidogenic Signaling in Gilt Ovaries.

Heat stress (HS) compromises a variety of reproductive functions in several mammalian species. Inexplicably, HS animals are frequently hyperinsulinemic despite marked hyperthermia-induced hypophagia. Our objectives were to determine the effects of HS on insulin signaling and components essential to steroid biosynthesis in the pig ovary. Female pigs (35 ± 4 kg) were exposed to constant thermoneutral (20°C; 35%-50% humidity; n = 6) or HS conditions (35°C; 20%-35% humidity; n = 6) for either 7 (n = 10) or 35 days (n = 12). After 7 days, HS increased (P < 0.05) ovarian mRNA abundance of the insulin receptor (INSR), insulin receptor substrate 1 (IRS1), protein kinase B subunit 1 (AKT1), low-density lipoprotein receptor (LDLR), luteinizing hormone receptor (LHCGR), and aromatase (CYP19a). After 35 days, HS increased INSR, IRS1, AKT1, LDLR, LHCGR, CYP19a, and steroidogenic acute regulatory protein (STAR) ovarian mRNA abundance. In addition, after 35 days, HS increased ovarian phosphorylated IRS1 (pIRS1), phosphorylated AKT (pAKT), STAR, and CYP19a protein abundance. Immunostaining analysis revealed similar localization of INSR and pAKT1 in the cytoplasmic membrane and oocyte cytoplasm, respectively, of all stage follicles, and in theca and granulosa cells. Collectively, these results demonstrate that HS alters ovarian insulin-mediated PI3K signaling pathway members, which likely impacts follicle activation and viability. In summary, environmentally induced HS is an endocrine-disrupting exposure that modifies ovarian physiology and potentially compromises production of ovarian hormones essential for fertility and pregnancy maintenance.

Phenotypic malignant changes and untargeted lipidomic analysis of long-term exposed prostate cancer cells to endocrine disruptors

Endocrine disruptors (EDs) are a class of environmental toxic molecules able to interfere with the normal hormone metabolism. Numerous studies involve EDs exposure to initiation and development of cancers, including prostate cancer. In this work, three different EDs (aldrin, aroclor 1254 and chlorpyrifos (CPF)) were investigated as potential inducers of a malignant phenotype in DU145 prostate cancer cells after a chronic exposure. Epithelial to mesenchymal transition (EMT) induction, proliferation, migration, colony formation and release of metalloproteinase 2 (MMP-2) were analyzed in 50-day exposed cells to the selected EDs. As a result, aldrin and CPF exposure led to an EMT induction (loss of 16% and 14% of E-cadherin levels, respectively, compared to the unexposed cells). Aroclor and CPF presented an increased migration (134% and 126%, respectively), colony formation (204% and 144%, respectively) and MMP-2 release (137% in both cases) compared to the unexposed cells. An untargeted lipidomic analysis was performed to decipher the lipids involved in the observed transformations. As general results, aldrin exposure showed a global decrease in phospholipids and sphingolipids, and aroclor and CPF showed an increase of certain phospholipids, glycosphingolipids as well as a remarkable increase of some cardiolipin species. Furthermore, the three exposures resulted in an increase of some triglyceride species. In conclusion, some significant changes in lipids were identified and thus we postulate that some lipid compounds and lipid metabolic pathways could be involved in the acquisition of the malignant phenotype in exposed prostate cancer cells to the selected EDs.

Mechanisms mediating environmental chemical-induced endocrine disruption in the adrenal gland.

Humans are continuously exposed to hundreds of man-made chemicals that pollute the environment in addition to multiple therapeutic drug treatments administered throughout life. Some of these chemicals, known as endocrine disruptors (EDs), mimic endogenous signals, thereby altering gene expression, influencing development, and promoting disease. Although EDs are eventually removed from the market or replaced with safer alternatives, new evidence suggests that early-life exposure leaves a fingerprint on the epigenome, which may increase the risk of disease later in life. Epigenetic changes occurring in early life in response to environmental toxicants have been shown to affect behavior, increase cancer risk, and modify the physiology of the cardiovascular system. Thus, exposure to an ED or combination of EDs may represent a first hit to the epigenome. Only limited information is available regarding the effect of ED exposure on adrenal function. The adrenal gland controls the stress response, blood pressure, and electrolyte homeostasis. This endocrine organ therefore has an important role in physiology and is a sensitive target of EDs. We review herein the effect of ED exposure on the adrenal gland with particular focus on in utero exposure to the plasticizer di(2-ethylehyl) phthalate. We discuss the challenges associated with identifying the mechanism mediating the epigenetic origins of disease and availability of biomarkers that may identify individual or population risks.

Parental Occupational Exposures to Endocrine Disruptors and the Risk of Simple Isolated Congenital Heart Defects

This study aims to explore the associations between parental occupational exposures to endocrine disruptors (EDs) and simple isolated congenital heart defects (CHDs). A case-control study with standardized data collection involving 761 children with isolated CHDs and 609 children without any congenital malformations was conducted in Sichuan Province of China from March in 2012 to August in 2013. An adjusted job exposure matrix was used for occupational EDs exposure assessment. Logistic regression analysis was performed to assess the associations between parental occupational EDs exposures and CHDs. Maternal age at births, maternal education level, gravity, parity, induced abortion, folic acid use, medication use, drinking capacity and area of residence periconceptionally were selected as confounding factors for mothers. For fathers, we selected the following confounding factors: paternal education level, smoking, drinking frequencies and drinking capacity periconceptionally. Maternal occupational exposures to phthalates are associated with perimembranous ventricular septal defect (PmVSD) (P = 0.001, adjusted OR 3.7, 95 % CI 1.7-8.0), patent ductus arteriosus (PDA) (P = 0.002, adjusted OR 3.8, 95 % CI 1.6-8.9), secundum atrial septal defect (s-ASD) (P = 0.008, adjusted OR 3.5, 95 % CI 1.4-8.7) and pulmonary valve stenosis (PS) (P = 0.035, adjusted OR 4.2, 95 % CI 1.1-16.0), to alkylphenolic compounds and PmVSD (P = 0.003, adjusted OR 2.2, 95 % CI 1.3-3.6), PDA (P = 0.005, adjusted OR 2.0, 95 % CI 1.1-3.5) and PS (P = 0.004, adjusted OR 3.8, 95 % CI 1.5-9.4), to heavy metals with PmVSD (P = 0.003, adjusted OR 7.3, 95 % CI 2.0-27.6) and s-ASD (P = 0.034, adjusted OR 6.5, 95 % CI 1.1-36.7). Paternal occupational exposures to phthalates are associated with PmVSD (P = 0.035, adjusted OR 1.6, 95 % CI 1.0-2.4) and PS (P = 0.026, adjusted OR 2.4, 95 % CI 1.1-5.2), to alkylphenolic compounds (P = 0.027, adjusted OR 1.5, 95 % CI 1.0-2.2) with PmVSD. In conclusion, parental occupational exposures to some specific EDs, in particular phthalates and alkylphenolic compounds, are associated with an increased risk of some CHD phenotypes. However, the findings need to be considered more circumspectly regarding a crude measure of exposure probabilities and small numbers.