Transgenerational epigenetic alterations on male germ cells caused by bisphenol S

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PROJECT SUMMARY/ABSTRACT Following extensive work examining the adverse effects of bisphenol A (BPA) as an endocrine-disrupting chemical (EDC), the usage of BPA has been restricted and/or banned in certain products such as baby bottles and sippy cups in Canada, the European Union and the US. As the result of restrictions on the use of BPA, a structurally similar analogue, BPS has become one of the major substitutes for BPA. BPS is found in numerous daily consumer products. BPS is the main analogue used to replace BPA in thermal papers. BPS levels in water, sediment, sludge and indoor dust have been continuously increasing and have already reached comparable or equal levels of BPA. BPS is detected in human urine, and its levels have been increasing in the US and are already higher than those of BPA in some other countries. However, it is still unclear how much of our toxicological understanding of BPA is applicable to BPS. Our recent studies have shown that mouse offspring exposed to BPS and BPA in utero exhibits extensive alterations in reproductive phenotypes in not only the F1 but also F3 offspring. These alterations include spermatogenic progression, altered gene expression in testes, and significantly reduced sperm counts and motility in males. Exposure to EDC insult during conception and/or embryonic development is thought to have an impact on subsequent generations. One potential mechanism is considered to be the altered epigenetic reprogramming in fetal germ cells of the F1 generation that persists into the later F2 and F3 generations. While BPA is able to induce epigenetic changes, limited transgenerational assessments have been conducted following BPA exposure. Global changes in epigenetic marks caused by BPS and even BPA in germ cells have not been reported. In addition, it is unclear whether and how these epimutations can be passed into subsequent generation. Therefore, we hypothesize that in utero exposure to two structurally similar EDC (BPA and BPS) will alter epigenetic reprogramming in germ cells, leading to disruption of DNA methylomes and transcriptomes to induce reproductive defects in adult. Certain epimutations sustained in cells of the germline can potentially be transmitted to subsequent generations. The objective of this application is to test this hypothesis by identifying specific classes of epigenetically and transgenerationally regulated genes. We will also determine how BPS affects DNA methylomes and transcriptomes in male germ cells to identify genes whose expression and DNA methylation status are altered in the subsequent generation. Due to the adverse effects of EDC on subsequent generations, understanding transgenerationally inherited epimutations by BPS in germ cells and comparing the differences of those by BPA will provide new insights for the toxicity of BPS and reveal the convergent and divergent mechanisms between similarly structured agents.