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Objective: To assess the genetic and epigenetic effects promoted by Bisphenol A (BPA) exposure in adolescent males from the Spanish INMA-Granada birth cohort, and in human cells. Methods: DNA methylation was analysed using MEDIP. Repeat number variation in genomic DNA was evaluated, along with the analysis of H3K4me3 by using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq). Analyses were performed with material extracted from whole blood of the adolescents, complemented by in vitro assessments of human (HeLa) cells exposed to 10 nM BPA, specifically, immunofluorescence evaluation of protein levels, gene expression analysis and ChIP‒qPCR analysis. Results: Adolescents in the high urinary BPA levels group presented a higher level of Satellite A (SATA) repetitive region copy numbers compared to those in the low BPA group and a tendency towards increase in telomere length. We also observed decreased DNA methylation at the promoters of the imprinted genes H19, KCNQ1, and IGF2; at LINE1 retroelements; and at the ARID2, EGFR and ESRRA and TERT genes. Genome-wide sequencing revealed increased H3K4me3 occupancy at the promoters of genes encoding histone acetyltransferases, telomeric DNA binding factors and DNA repair genes. Results were supported in HeLa cells exposed to 10 nM BPA in vitro. In accordance with the data obtained in blood samples, we observed higher H3K4me3 occupancy and lower DNA methylation at some specific targets in HeLa cells. In exposed cells, changes in the expression of genes encoding DNA repair factors (ATM, ARID2, TRP53) were observed, and increased expression of several genes encoding telomeric DNA binding factors (SMG7, TERT, TEN1, UPF1, ZBTB48) were also found. Furthermore, an increase in ESR1/ERa was observed in the nuclei of HeLa cells along with increased binding of ESR1 to KAT5, KMT2E and TERF2IP promoters and decreased ESR1 binding at the RARA promoter. The DNA damage marker p53/TP53 was also increased. Conclusion: In this pilot study, genome-wide analysis of histone trimethylation in adolescent males exposed to BPA revealed a global impact on the expression of genes encoding telomeric binding proteins and histone acetyltransferase factors with similar results in HeLa cells. Nevertheless, larger studies should confirm our findings. [ABSTRACT FROM AUTHOR]

ABSTRACT In the past few decades, there has been much concern about the adverse health effects of environmental contaminants in general and Crude Oil in particular around the Niger Delta region of Nigeria where all the crude Oil exploration is taking place. Studies have shown the repro-toxic effects of Bonny-light crude oil (BLCO). However, the insight into the mechanisms of gonadal toxicity induced by BLCO is not well known. In this study, we sought to elucidate the mechanism(s) underpinning the gonadal effects within hours of exposure to BLCO. Experimental rats were divided into five groups of four each. Animals were orally administered with a single dose of BLCO (800 mg/kg body weight) and killed at 0, 6, 12, 24, and 72 h post-treatment. The levels and time-course of induction of stress response proteins and apoptosis-related proteins like cytochorome C, caspase 3 and procaspase 9, Fas-FasL, NF-kB and TNF-α were determined to assess sequential induction of apoptosis in the rat testis. DNA damage was assessed by TUNEL assay. Administration of BLCO resulted in a significant increase in the levels of stress response proteins and apoptotis- related proteins as early as 6 h following exposure. Time-dependent elevations in the levels of the proteins were observed. The DNA damage was measured and showed time-dependent increase in the TUNEL positive cells of testicular cells. The study demonstrates induction of testicular apoptosis in adult rats following exposure to a single dose of BLCO. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 242-252, 2015. [ABSTRACT FROM AUTHOR]

Background: Chlordecone (CD), also known as Kepone, is an organochlorine insecticide that has been used in banana crops in the French West Indies. Due to long-term contamination of soils and water, the population is still exposed to CD. Exposure to CD in adulthood is associated with an increased risk of prostate cancer (PCa)., Objectives: We examined the transgenerational effects of CD on murine prostate tissue., Methods: We exposed pregnant Swiss mice to CD. The prostates from directly exposed (F1) and non-exposed (F3) male progeny were analyzed. We used immunofluorescence, RNA-seq and ChIP-seq techniques for the comprehensive analyses of chromatin states in prostate., Results: We observed an increased prostatic intraepithelial neoplasia phenotype (PIN) in both F1 and F3 generations. Transcriptomic analysis in CD-derived F1 and F3 prostate using RNA-seq revealed that 970 genes in F1 and 218 in F3 genes were differentially expressed. The differentially expressed genes in both datasets could be clustered accordingly to common biological processes, "cell differentiation", "developmental process", "regulating of signaling", suggesting that in both generations similar processes were perturbed. We detected that in both datasets several Hox genes were upregulated; in F1, the expression was detected mainly in Hoxb and Hoxd, and in F3, in Hoxa family genes. Using a larger number of biological replicates and RT-qPCR we showed that genes implicated in testosterone synthesis (Akr1b3, Cyp11a1, Cyp17a1, Srd5a1) were dramatically upregulated in PIN samples; Cyp19a1, converting testosterone to estradiol was elevated as well. We found a dramatic increase in Esr2 expression both in F1 and F3 prostates containing PIN. The PIN-containing samples have a strong increase in expression of self-renewal-related genes (Nanog, Tbx3, Sox2, Sox3, Rb1). We observed changes in liver, F1 CD-exposed males have an increased expression of genes related to DNA repair, matrix collagen and inflammation related pathways in F1 but not in F3 adult CD-derived liver. The changes in RNA transcription were associated with epigenetic changes. Specifically, we found a global increase in H3K4 trimethylation (H3K4me3) and a decrease in H3K27 trimethylation (H3K27me3) in prostate of F1 mice. ChIP-seq analysis showed that 129 regions in F1 and 240 in F3 acquired altered H3K4me3 occupancy in CD-derived prostate, including highest increase at several promoters of Hoxa family genes in both datasets. The alteration in H3K4me3 in both generations overlap 73 genes including genes involved in proliferation regulation, Tbx2, Stat3, Stat5a, Pou2f3 and homeobox genes Hoxa13, Hoxa9., Conclusions: Our data suggest that developmental exposure to CD leads to epigenetic changes in prostate tissue. The PIN containing samples showed evidence of implication in hormonal pathway and self-renewal gene expression that have the capacity to promote neoplasia in CD-exposed mice., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bisphenol A (BPA) and nonylphenol (NP) are phenolic compounds used widely by the industries. BPA and NP are endocrine disruptors possessing estrogenic properties. Several studies have reported that BPA and NP induce oxidative stress in various organs or cell types in animals, by inhibiting the activities of antioxidant enzymes like catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. However, it is not understood how BPA and NP interact with these enzymes and inhibit their functions. Hence, it would be significant to check, whether binding sites are available for NP and BPA in antioxidant enzymes. In the present study three-dimensional structures of antioxidant enzymes, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase were modeled and docked with BPA and NP. Docking studies revealed that BPA and NP have binding pockets in the antioxidant enzymes. Among the antioxidant enzymes, Catalase was maximally inhibited by BPA and superoxide was maximally inhibited by NP.

Bisphenol A (BPA) is a potential endocrine disruptor and testicular toxicant. Recently, we have reported that exposure to BPA increases plasma insulin and glucose levels and decreases the levels of glycolytic enzymes, glucose transporter-8 (GLUT-8) and insulin receptor substrate-2 (IRS-2) in rat testis. In the present study we sought to investigate the effects of low doses of BPA on insulin signaling molecules, glucose transporter-2 (GLUT-2) and steroidogenesis in rat testis. BPA was administered to rats by oral gavage at doses of 0.005, 0.5, 50 and 500 μg/kg body weight/day for 45 days. A positive control was maintained by administering 17-β-estradiol (50 μg/kg body weight/day). Decreased levels of insulin, insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI-3 kinase) and GLUT-2 were observed in rat testis following BPA administration. Dose-dependent decrease in the activities of antioxidant enzymes, 3-β-hydroxysteroid dehydrogenase (3β-HSD), 17-β-hydroxysteroid dehydrogenase (17β-HSD), Steroidogenic Acute Regulatory Protein (StAR) and testosterone were also observed. Molecular docking of BPA, 17-β-estradiol, cytochalasin B and glucose with GLUT-2 and GLUT-8 revealed the higher binding affinity of BPA with GLUT-2 and GLUT-8. Thus, BPA impairs insulin signaling and glucose transport in rat testis which could consequently lead to impairment of testicular functions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)