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Abstract
The role of epigenetic mechanisms in gene regulation is well studied in basic science and cancer pathology. However, our knowledge on toxicant-induced alterations of gene expression via epigenetic alterations is meager. Having this knowledge is key to estimating the risk of adverse and long-term effects of toxicants on human health and ecosystem. This series of studies tested the epigenetic effects of sub-chronic exposure to low-dose bromate (BrO3-) on human and rat renal cells. BrO3- is a drinking water disinfection byproduct regulated by the US EPA. Based on our previous data, we tested the hypothesis that BrO3--induced renal p21 expression is mediated by epigenetic mechanisms. Our data demonstrated that expression of rat renal p21 was regulated by histone acetylation and not DNA methylation of the regions analyzed, after sub-chronic exposure to BrO3-. These data also demonstrated that BrO3--induced p21 expression in human renal cells was neither regulated by DNA methylation nor histone acetylation. Finally, these data demonstrated species-specific differences in epigenetic regulation of p21 and suggested an uncertainty in extrapolating rat epigenetic data for assessing the risk of toxicants in humans. 17-ethynylestradiol (EE2), an orally active synthetic estradiol used in contraceptives, it is a water contaminant that presents concerns for both human and ecological health significance. Vitellogenin (Vtg) is an egg yolk precursor protein and can be a molecular marker of exposure to estrogenic endocrine disrupting chemicals (EDCs). Our data demonstrated that adult male zebrafish exposed to EE2 showed a significant increase in Vtg mRNA as early as 0.25 days and promoter hypomethylation at any CpG sites analyzed only after 4 days. These decreases brought the methylation of vtg1 in male zebrafish to same level as that of female controls, suggesting that it may lead to feminization. We also observed that EE2-induced decrease in DNA methylation persisted after EE2 removal, unlike mRNA levels which returned to baseline by 7 days. These data suggested a role for DNA methylation in Vtg induction and identified a novel epigenetic mark of feminization that may serve as an indicator of previous exposure to EE2, which will aid in ecological risk assessment of EDCs.