ResearchPad - endocrine-disrupting-chemicals https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-713 Novel Estrogenic Gene Regulation Induced by OTC Medications Containing Paraben Preservatives Is Dependent on Concentration that Varies Between Products and Batches]]> https://www.researchpad.co/article/elastic_article_8792 Methylparaben, ethylparaben, and propylparaben are widely used as preservatives in food products, cosmetics, and pharmaceuticals. Parabens have been shown to be weak estrogens and this laboratory has described that extracts of some over the counter (OTC) medications with paraben preservatives can induce estrogen activity in tissue culture-based bioassays. At the same time, this laboratory determined that extracts from OTC medications containing the laxative bisacodyl induce estrogen activity regardless of parabens present and that bisacodyl is estrogenic. The current report describes the use of paraben standards and LC-MS analysis to determine paraben concentrations in extracts from OTC medications (Calcium Carbonate, Bisacodyl, Ibuprofen, Diphenhydramine, and Benzoyl Peroxide) used in previous studies. Also described is the application of the Qiagen RT2 Profiler PCR Array for Human Estrogen Receptor Signalling to determine gene induction profiles in MCF-7 cells treated with methyl, ethyl or proplyparaben, or each of the five pairs of OTC medication extracts (with or without parabens) relative to estradiol treatment. LC-MS analysis of extracts confirmed that five of six OTC medications labeled as paraben-free contain no detectable parabens, while one “paraben free” extract included measurable levels of parabens. At the same time, all of the extracts of OTC medications with paraben ingredients, some of which induce estrogen activity, were found to contain a wide range of paraben concentrations. A threshold range of paraben concentration in OTC medications is required to induce estrogen activity in bioassays. Analysis of paraben concentrations of extracts from different product lots of the same OTC medication identified discrepancies in the amount of paraben between batches. PCR Array profiles of the three paraben standards and the OTC medication extracts share some gene induction characteristics induced by estradiol. At the same time, methyl, ethyl and propylparabens induced unique gene array profiles that are shared by the OTC medication extracts containing parabens. The extracts of OTC medications containing bisacodyl stimulated a distinct gene induction profile that has some features of the profiles of estradiol and paraben treatment. This study highlights both the capacity for paraben preservatives in OTC medications to induce novel estrogen activity (gene induction) and the importance of determining the paraben concentration in OTC medications to determine estrogen potential. While the capacity for OTC medications containing parabens or other estrogenic substances to induce estrogen activity in individuals using the medications is unclear, consumers may want to know the potential for estrogen activity in these products.

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<![CDATA[SAT-717 Region-Specific Effects of the Exposome on Brain Monoamine Levels in Female Rats]]> https://www.researchpad.co/article/elastic_article_8726 Prenatal programming with endocrine disrupting chemicals (EDCs), in particular the ubiquitous plasticizers bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP), can induce long-lasting behavioral changes in rats. Additionally, changes in estrogen are correlated with the development of mood disorders in women; however, the underlying neurobiological mechanisms are unclear. This study was conducted to determine the cumulative effects of prenatal exposure to EDCs followed by chronic estradiol treatment in adult female rats on monoamine levels in the prefrontal cortex (PFC) and hippocampus (HC). Dams were orally administered saline (control; 10 µL/kg), BPA (B; 5 µg/kg), DEHP (D; 7.5 mg/kg) or a combination of BPA+DEHP (B+D) during days 6 through 21 of pregnancy. Adult female offspring were sham-implanted or implanted with pellets that release 17β-estradiol (E2) for 90 days (20 ng/day; Innovative Research America). The offspring then underwent a battery of behavioral tests at the end of treatment. Brains collected from the offspring were sectioned and the PFC and HC were microdissected and analyzed for levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT), using High-Performance Liquid Chromatography (HPLC). Significant reductions in monoamine levels were observed in the PFC while NE and 5-HT levels were markedly reduced in the HC after prenatal exposure to D or BD. BPA’s effects on monoamines were comparatively modest. E2 exposure increased DA but decreased 5-HT levels in the PFC of control animals. Prenatal exposure to EDCs made the offspring non-responsive to E2. The marked reduction in monoamine levels could have implications for learning and memory.

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<![CDATA[SAT-724 Endocrine Disruption by Phthalate Exposure in the Pediatric Intensive Care Unit]]> https://www.researchpad.co/article/elastic_article_8707 Aim: Pediatric intensive care relies on plastic indwelling medical devices softened by phthalates. Phthalates leach into the circulation and concerns about toxicity were raised. Exceeding a certain threshold of di(2-ethylhexyl)phthalate (DEHP) exposure in the pediatric intensive care unit (PICU) has been associated with an attention deficit 4 years later (1). Moreover, DEHP and its metabolites have endocrine disrupting properties. Critically ill children reveal the non-thyroidal illness syndrome (2) and unexplained relatively low cortisol (3). Whether DEHP exposure in PICU has endocrine disruptive effects is unknown. We investigated whether DEHP exposure in the PICU, exceeding the previously identified “toxic” threshold for attention, is independently associated with thyroid- and HPA-axis alterations upon PICU discharge. Methods: In this preplanned secondary analysis of the PEPaNIC RCT (N=1440) (4), plasma DEHP metabolite concentrations (MEHP, 5OH-MEHP, 5cx-MEPP, 5oxo-MEHP) were quantified for all patients with a last PICU day sample (N=920). Minimal DEHP exposure was defined as the product of the total DEHP metabolite concentrations on the last PICU day and duration of PICU stay, with 0.551 µmol/L.days identified as “toxic” threshold (1). Serum TSH, total T4, total T3 and rT3 concentrations were quantified for patients with an available last day sample (N=913). For patients with a last day plasma sample and who did not receive corticosteroids (N=391), plasma ACTH, total cortisol, albumin and CBG concentrations were quantified and free cortisol calculated. Multivariable linear regression analyses, adjusted for baseline risk factors and for duration of PICU stay, assessed whether exceeding the previously determined threshold of toxic DEHP exposure was independently associated with the hormone levels on the last PICU day. Main results: Median total DEHP metabolite concentration was 0.101 (IQR 0.049 - 0.279) µmol/L on the last PICU day. Minimal DEHP exposure was 0.337 (IQR 0.161 - 0.880) µmol/l.days, and 328 patients (35.7%) exceeded the toxic threshold. Exceeding this threshold was independently associated with lower total T4 (P=0.002), total T3 (P=0.02) and total cortisol (P=0.001), and higher rT3 (P=0.01) concentrations on the last PICU day, but not with TSH, ACTH or free cortisol. Conclusion: Critically ill children had DHEP metabolites in plasma upon PICU discharge and more than a third were exposed to toxic levels. Toxic DEHP exposure was an independent contributor to the severity of the non-thyroidal illness phenotype and to lower cortisol upon PICU discharge. Future research should assess whether such endocrine-disruptive impact of DHEP exposure in the PICU plays a role in the long-term developmental legacy of critical illness in children. 1 Verstraete et al Intensive Care Med 2016 2 Jacobs et al Thyroid 2019 3 Jacobs et al Intensive Care Med 2019 4 Fivez et al N Engl J Med 2016

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<![CDATA[SAT-715 Bisphenol-A Alters Pancreatic B-Cell Proliferation and Mass in an Estrogen Receptor Beta-Dependent Manner]]> https://www.researchpad.co/article/elastic_article_8659 Bisphenol-A (BPA) is one of the highest volume chemicals produced worldwide. It is used as the base compound in the manufacture of polycarbonate plastics, epoxies and resins. Humans are consistently exposed to BPA and consistently it has been detected in the majority of individuals examined. Experimental research in animals, as well as human epidemiological studies, converge to conclude that BPA is a risk factor for the development of type 2 diabetes. In previous studies we have demonstrated that the exposure to BPA during embryonic development promote an increment of pancreatic β-cell mass. This was correlated with increased β-cell division and altered global gene expression in pancreatic β-cells. The aim of this work was to determinate whether ERβ was involved in the in the β-cell mass and proliferation increment observed in male mice offspring. ERβ+/- pregnant mice were treated with vehicle or BPA (10 μg/kg/day) from day 9 to 16 of gestation. Offspring pancreatic β-cell mass was measured at postnatal day 0 (P0) and 30 (P30). For ex vivo experiments Wild-type (WT) and ERβ-/- neonates as well as adult male and female mice were used. For in vitro, single islets cells were cultured for 48 h in the presence of 10 μmol/L BrdU, and vehicle, BPA (1, 10, 100 nM) or the specific ERβ agonist WAY200070 (1, 10, 100 nM). β-cell proliferation rate was quantified as the percentage of BrdU-positive pancreatic β-cells. In vivo exposure to BPA during pregnancy promoted an increment of pancreatic β-cell mass and proliferation in WT mice at P30 which was absent in ERβ -/- mice. In order to explore if these changes were related to a direct action of BPA on pancreatic β-cell division we performed a series of ex vivo experiments. Augmented β-cell proliferation rate was observed in BPA-exposed β-cells isolated from both adult male and female WT animals in comparison to controls. The increment was significant at all BPA doses tested. The effect was imitated by the selective ERβ agonist, WAY200070, and was abolished in cells from ERβ-/- mice. We also explored the effects of BPA in pancreatic β-cells from neonates and found an increment in BPA-exposed cells compared to controls, although the difference was only significant at the dose of 1 nM. A similar effect was observed in neonate cells treated with WAY200070 (10 nM). The effects on β-cell replication were abolished in cells from ERβ-/- neonate mice treated either with BPA or WAY200070. Our findings suggest that BPA modulate pancreatic β-cell growth and mass in an ERβ-dependent manner. This could have important implications for metabolic programming of T2DM. Ministerio de Economía y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) grants BPU2017-86579-R (AN) and BFU2016-77125-R (IQ); Generalitat Valenciana PROMETEO II/2015/016 (AN). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

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<![CDATA[SAT-LB132 3-Generation Study of Metabolic Disruption by Pregnancy Serum PFASs: Associations With Abdominal and Whole-Body Obesity in Granddaughters in a 60-Year Follow-Up of the Child Health and Development Studies Cohort]]> https://www.researchpad.co/article/elastic_article_8558 Introduction. We previously found a 3.6-fold increased risk of breast cancer in daughters associated with high maternal (F0) early postpartum serum EtFOSAA combined with high F0 cholesterol (https://doi.org/10.1016/j.reprotox.2019.06.012). Here we test the hypothesis that F0 early postpartum EtFOSAA, in combination with F0 serum cholesterol predicts abdominal obesity (waist circumference > 88cm) and/or whole-body overweight or obesity (body mass index > 25 kg/m2) in daughters (F1) at age 30 and granddaughters (F2) at age 20. Methods. We measured F1 and F2 weight, height, waist circumference and blood pressure when F1 were an average age of 50 years and adult F2 were an average age of 20 years (N=213 triads). F1 also reported their weight at age 30, near the mean age of their pregnancies with their daughters (F2) to allow control for obesity during F2 gestation. EtFOSAA, PFOS, and cholesterol were assayed in archived early postpartum F0 serum samples collected within 3 days of delivery. Results. F0 cholesterol significantly (p<0.05) modified the association of F0 EtFOSAA with self-reported obesity at age 30 in F1 and measured abdominal and whole-body obesity, and blood pressure at age 20 in F2. Association patterns were similar for all outcomes: F0 EtFOSAA was associated with high metabolic risk when F0 serum cholesterol was low (Quartile 1): e.g. 20-year-old F2 had an estimated 2.3 fold increase in the joint risk of abdominal and whole-body obesity over the inter-quartile range of F0 ETFOSAA, 95% Confidence Interval= 1.1, 4.8. F0 EtFOSAA associations with F2 metabolic risk were independent of F0 race, early pregnancy overweight (BMI >25 kg/m2), and serum PFOS. F1 obesity at age 30 did not mediate F0 EtFOSAA associations with F2 outcomes, but additionally predicted high metabolic F2 risk. Conclusions. Findings support the hypothesis that in utero exposure to EtFOSAA impacts metabolic risk factors in female F2 exposed as germline and also independently via promotion of overweight in F1 (their mothers) during F2 gestation.

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<![CDATA[SAT-728 The Regulation of Tumor Suppressor Genes P53, BRCA-2, and Cell Cycle Protein p21 by Bisphenol S (BPS) in MCF-7 and T47-D Breast Cancer Cells]]> https://www.researchpad.co/article/elastic_article_6729 Bisphenol A (BPA) is considered to be an endocrine disrupting chemical (EDC), which mimics endogenous hormones and is linked to various cancers. Bisphenol S (BPS) is a BPA analogue, often used in plastics. BPS can leach into food and drink products, exposing humans to these chemicals. Evidence suggests BPS is also an EDC with similar endocrine disrupting effects. Despite hopes for a safer alternative, research has shown BPS possesses estrogenic activity due to its structural similarities with its analogue BPA. Previously we have shown the effects of BPS on estrogen receptor-alpha (ERα) and BRCA-1 in both MCF-7 and T-47D breast cancer cells. The wild-type p53 and BRCA-2 work to prevent cancer by monitoring and repairing DNA damage; however, in breast cancer patients these genes are often mutated. Mutated p53 will induce the cell cycle protein p21 to act as an oncogenic transcription factor. In the present study, we have examined the effects of BPS, alone and in combination with hormones and anti-hormones, on p53, BRCA-2, and p21 in both MCF-7 and T-47D cell lines by utilizing western blot analyses, cellular viability assays, confocal microscopy, apoptosis assay, and RT-qPCR analyses. Western blot studies revealed alterations in the expression of p53, BRCA-2, and p21 related with varying concentrations of BPS (4-20 µM). In comparison to the control, p53 expression increased (65-95%) in the presence of BPS in both MCF-7 and T-47D cells. In addition, BRCA-2 expression revealed a similar increase in both cell lines when treated with BPS. However, p21 expression decreased (approximately 50%) with increasing concentrations in both cell lines. For further evaluation, an optimal concentration of 8 µM BPS was then used in combination with various hormones and anti-hormones. Compared to the control, BPS and E2 were up regulated in a similar fashion to p53. A similar trend in the effects on BRCA-2 expression was depicted in T-47D and MCF-7 cells. However, in p21, BPS and E2 were down regulated in both MCF-7 and T-47D breast cancer cells. In order to determine the influence of BPS on the growth of breast cancer cells, image cytometric analysis with propidium iodide staining was utilized to quantify alterations in T-47D and MCF-7 cell numbers and viability. Upon treatment of BPS concentrations (4-20 µM), an increase in cellular proliferation (12-60% increase) occurred in both cell lines. These cellular proliferative effects of BPS and E2 were sensitive to combination treatments with anti-estrogens. Confocal microscopy was utilized to examine the cytolocalization of p53 upon exposure to BPS alone and in combination with hormones and anti-hormones. The results from this study will yield a greater understanding of the molecular regulation of BPS action via the p53, BRCA-2, and p21 signaling pathways linked with breast cancer.

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<![CDATA[SAT-726 Estrogen Receptor Alpha as a Potential Target for Bisphenol A-Mediated Epigenetic Reprogramming: An in Vitro Analysis]]> https://www.researchpad.co/article/elastic_article_6545 Perinatal exposure to bisphenol A (BPA) has been shown to reprogram the hepatic epigenome of rodents and may promote the development of various metabolic diseases later in life, such as nonalcoholic fatty liver disease (NAFLD). This developmental reprogramming is characterized by the creation of “super promoters” at target genes implicated in metabolic pathways. While it is unclear how these “super promoters” are created, their creation is potentially mediated through BPA and estrogen receptor (ER) interaction. In order to test this potential mechanism, in vitro methods were used to examine ER target gene expression via RT-qPCR in 2 human hepatic cell lines transiently transfected with the ER isoform, ER alpha, prior to BPA exposure for various lengths of time. Within individual time points, there were no significant differences in target gene expression levels between cells that had been transfected with ER alpha and the vector control. Gene expression levels in the target genes were visibly increased at the 24-hour exposure mark in both transfection groups in comparison to the 0- and 6-hour time points, however only a fraction of these increases were found to be statistically significant. These gene expression patterns are not only consistent with previous studies examining target gene expression in BPA-treated hepatic cell lines, but more importantly, suggest BPA does not act via ER alpha to orchestrate the epigenetic changes seen in vitro. BPA may interact with a different ER isoform or an unknown target to create the observed “super promoters” at target genes, reinforcing the promiscuity of BPA and other xenoestrogens in facilitating epigenetic modifications, and ultimately, disease phenotypes.

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<![CDATA[SAT-719 Prenatal Exposure to Bisphenol A, S and F Increases Blood Pressure in Female Rats]]> https://www.researchpad.co/article/N548b963f-23c9-4a04-afd5-24b37c41b1c4 Cardiovascular diseases are the leading causes of mortality among men and women. With the new blood pressure guidelines from the American Heart Association, almost half of the United States population has hypertension (45.6%). The reasons for this high prevalence of hypertension in our population could be several, but the effect of emerging contaminants are overlooked and understudied. Bisphenol-A (BPA) is a widely used plasticizing agent that contaminates the environment. Most humans are exposed to BPA on a daily basis and urine levels of this endocrine disrupting chemical (EDC) are positively correlated with hypertension. The FDA banned the use of BPA in baby bottles in 2012, however, it is still being used in food containers and plastics. Currently, several BPA analogs such as bisphenol-S (BPS) and bisphenol-F (BPF) are used to replace BPA in the plastic industry. But their physiological effects are not clear. In order to study the effects of these EDCs on the development of hypertension, we exposed pregnant Sprague Dawley (SD) rats to saline, 5 µg/Kg BW of BPA, BPS or 1µg/kg BW of BPF. The offspring were allowed to reach adulthood before implantation with a radiotelemeter (Data Sciences International; HD-S10) in the femoral artery for undisturbed monitoring of systolic, diastolic and mean arterial blood pressure and heart rate. Recordings were measured once a week for 11 weeks over 24 hours to establish day and night readings. Night-time systolic BP was significantly elevated in BPA, BPF and BPS exposed rats compared to control. During the day, systolic BP was significantly higher in the BPA group compared to control. Diastolic BP was elevated in the BPS and BPF groups. Heart rate was elevated the most in the BPS group. These results indicate that prenatal exposure to low levels of BPA analogs has a profound effect on hypertension.

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<![CDATA[SAT-725 Alterations in the Phenotype and Epigenomic Landscape of Luminal Breast Cancer Following Long-Term Nanomolar Exposure to Bisphenol a (BPA)]]> https://www.researchpad.co/article/N184cd5c8-6665-4833-8204-cebd7650578a AbstractBreast cancer (BCa) is the leading cause of female cancer-related death worldwide. Luminal BCa accounts for at least 70% of all BCa and is characterized by its hormone dependence, particularly to estrogen. Endocrine disruptors may function to exert the pro-tumorigenic effects of estrogen in proxy following environmental exposure. Bisphenol A (BPA) is a ubiquitous endocrine disruptor shown to increase risk towards developing BCa in multiple in vivo mammalian models and in vitro human breast models. Despite this, there is limited information on the phenotypic and epigenetic effects of nanomolar BPA following long-term exposure particularly in the context of BCa stem cell population, which accumulate the ‘cellular insult’ and are likely to pass such information down through epigenetic mechanisms. We hypothesize that BPA affects the epigenome, in part, by altering the regulation of DNA methyltransferases (DNMTs) since BPA disrupts transcriptional and translational regulation of DNMTs in various other tissue types such as the brain, testis and prostate. In this study, MCF7 cells were chronically (>4 weeks) cultured with nanomolar doses of BPA, and subsequently subjected to phenotypic assays and gene expression analysis in monolayer or mammosphere culture. Gene expression analysis revealed a downregulation of DNMT3A and ESR1 following long-term exposure to BPA in mammosphere culture of MCF7 cells, but not in monolayer culture. This is accompanied by alterations in mammosphere morphology, reduction in mammosphere size, an increase in the mammosphere number, and an increase in the CD49f+ population, indicating a positive contribution of BPA to stemness. However, there are no significant changes in proliferation, apoptotic rate, and metastasis in both monolayer and mammosphere culture. Future analysis includes assessment of genome-wide alterations in DNA methylation patterns in these chronically exposed MCF7 mammospheres, as well as identifying estrogen responsiveness, chemotherapeutic response, and self-renewal properties of these cancer cells. ]]> <![CDATA[SAT-712 Computational Study of the Effect of Androgen Receptor BF 3 Site Mutations on DDE Binding]]> https://www.researchpad.co/article/Ndf1bc3f4-7615-4c64-9f9c-41c43c0ba89f

Abstract

Exposure to endocrine disrupting chemicals (EDCs) affects the function of the androgen receptor (AR) causing reproductive system problems such as reduced sperm counts, increased infertility, testicular dysgenesis syndrome, and testicular and prostate cancers, as well as reduced bone mass and diabetes mellitus in males. Experimental results have shown that the presence of EDCs such as the diphenyl compound DDT and its analogue DDE, allosterically cause the release of the stably bound dihydrotestosterone (DHT) from the steroid binding site of the AR ligand binding domain. It was hypothesized that EDCs mediate this effect via binding to the Binding Function 3 (BF 3) surface binding site. Five mutations of three BF 3 amino acids (F673K, F673W, G724R, G724M, and L830D) showed that the ability of DDE to inhibit AR activity was reduced, suggesting that DDE binds to the BF 3 site and allosterically regulates AR activity. In this study, the Induced Fit Docking protocol of the Schrodinger software was used to dock DDE into the BF 3 site of the wild type AR ligand binding domain as well as the five mutant BF 3 sites. The docking poses generated for each receptor were clustered and representative structures were selected. The receptor-ligand complexes were energy minimized using the Schrodinger module Macromodel. Finally, the energy of interaction between DDE and the BF 3 site amino acids was evaluated for each of the selected docks of the wild type and mutant receptors. The relationship between the energies of interaction and the experimental results for DDE inhibition of the mutant AR activities will be discussed.

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<![CDATA[SAT-723 Effects of Organohalogenated Endocrine Disrupting Chemicals on Cell Proliferation and Gene Expression in GH3 Somatolactotropes]]> https://www.researchpad.co/article/N46b96287-48e8-4bca-92e1-b05574de6bfe <![CDATA[SAT-708 The Effect of Soybean Isoflavones in Developing Cerebellum]]> https://www.researchpad.co/article/Ne3a8910e-42ea-459b-91a8-29af8a369726 <![CDATA[SAT-718 Inhibition of Androgen Receptor Activity by DDE Is Affected by Mutations in the BF3 Site]]> https://www.researchpad.co/article/N118b3ffa-6d0d-4ba0-8373-b9a89b8917a0 <![CDATA[SAT-722 Structure-Based Discovery of Hydraulic Fracturing Chemicals as Novel Androgen Receptor Antagonists]]> https://www.researchpad.co/article/Ne31bedd3-cb07-4440-81ef-47844ca6e7e6 <![CDATA[SAT-710 Comparative Histopathology of Endocrine Glands in Phthalate Exposed Male Wistar Rats Unveil the Vulnerability of Adrenal Gland and Augmented by Molecular Docking]]> https://www.researchpad.co/article/Nb66cdb61-88ee-4d16-8b1c-c64cf24e6d0c <![CDATA[SAT-LB131 Examination of Hepatic Gene Expression Following Developmental Exposure to Dieldrin in Trachemys Scripta and Discovery of a Novel Hepacivirus]]> https://www.researchpad.co/article/N67aa5478-4dce-462c-bb1c-4cddfb80626d <![CDATA[SAT-LB130 Tamoxifen Affects MiRNA Expression in Uterus and Breast Tamoxifen Affects MiRNA Expression in Uterus and Breast Tamoxifen Affects MiRNA Expression in Uterus and Breast]]> https://www.researchpad.co/article/Nc30615d7-22a1-42b3-be64-f2792ec4aff7 <![CDATA[SAT-714 Cadmium, an Endocrine Disruptor of the Reproductive Axis in Mice]]> https://www.researchpad.co/article/Neb2f5506-1625-41b8-a64e-2777c23207c8 <![CDATA[SAT-732 Historical Occurrence of Intersex in Largemouth Bass (Micropterus Salmoides) and Smallmouth Bass (Micropterus Dolomieu)]]> https://www.researchpad.co/article/N9807d177-2f88-4fd4-bd8c-adff38d8828b <![CDATA[MON-LB131 Perfluoroalkyl Substance Exposure Was Negatively Associated With Cortisone Levels in Pregnancy]]> https://www.researchpad.co/article/N7e208944-ad5a-4aa6-a14b-7dfd008484de