Transgenerational epigenetic alterations on male germ cells caused by bisphenol S

项目摘要/摘要 在广泛研究双酚A(BPA)作为内分泌干扰物的不良影响之后 化学品(EDC)，双酚A的使用已被限制和/或禁止在某些产品中，如婴儿奶瓶 在加拿大、欧盟和美国也有吸管杯。由于对双酚A使用的限制， 结构相似的类似物，BPS已成为BPA的主要替代品之一。BPS存在于许多 日用消费品。BPS是用来替代热敏纸中双酚A的主要类似物。中的bps级别 水、泥沙、污泥和室内粉尘不断增加，已经达到 类似或同等水平的双酚A。在人的尿液中检测到苯系物，其水平在 而且已经高于其他一些国家的双酚A。然而，目前仍不清楚有多少 我们对BPA的毒理学理解适用于BPS。我们最近的研究表明，老鼠 子宫内暴露于BPS和BPA的子代在NOT中表现出广泛的生殖表型变化 不仅是F1，还有F3的后代。这些改变包括生精进展、基因改变 在睾丸中的表达，并显著减少男性的精子数量和活动率。暴露在EDC侮辱中 在受孕和/或胚胎发育期间，被认为会对后代产生影响。 一种可能的机制被认为是在胎儿生殖细胞中改变的表观遗传重编程 延续到F2和F3世代的F1代。而双酚A能够诱导表观遗传学 在双酚A暴露后，进行了有限的跨代评估。全球 BPS甚至BPA在生殖细胞中引起的表观遗传标记的变化尚未见报道。此外, 目前尚不清楚这些表型突变是否以及如何传递给后代。因此，我们 假设子宫内暴露于两种结构相似的EDC(BPA和BPS)会改变表观遗传学 生殖细胞中的重新编程，导致DNA甲基体和转录体的破坏，从而诱导 成人的生殖缺陷。在生殖系的细胞中维持的某些表型突变可能是 传给后代。这个应用程序的目标是通过识别 特定类别的表观遗传和跨代调控基因。我们还将确定BPS如何 影响男性生殖细胞中的DNA甲基组和转录组，以确定其表达和DNA的基因 甲基化状态在随后的世代中会发生变化。由于EDC对后续工作的不利影响 世代，了解生殖细胞中BPS的跨代遗传表观突变，并比较 BPA的差异将为BPS的毒性提供新的见解，并揭示BPA与BPA的趋同 结构相似的代理之间的不同机制。

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.