Transgenerational epigenetic alterations on male germ cells caused by bisphenol S

双酚S引起的雄性生殖细胞的跨代表观遗传改变

• 批准号: 10183252
• 负责人: KANAKO HAYASHI
• 金额: $ 22.34万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183252
• 关键词: Adult; Adverse effects; Affect; Canada; Canned Foods; Cells; Conceptions; Country; DNA; DNA Methylation; Data Analyses; Defect; Dose; Dust; Embryonic Development; Endocrine Disruptors; Environmental sludge; Epididymis; Epigenetic Process; European Union; Exhibits; Exposure to; Female; Gene Expression; Generations; Genes; Germ Cells; Global Change; Human; Inherited; Label; Maintenance; Mus; Neonatal; Nucleic Acid Regulatory Sequences; Outcome; Paper; Partner in relationship; Phenotype; Regulator Genes; Reporting; Sperm Count Procedure; Sperm Motility; Spermatocytes; Spermatogonia; Structure; Testing; Testis; Toxic effect; Toxicology; Toy; Urine; Water; Work; analog; base; bisphenol A; consumer product; epigenetic regulation; fetal; histone modification; in utero; insight; male; methylome; offspring; personal care products; pregnant; prenatal exposure; reproductive; sperm cell; transcriptome; transmission process

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.

项目摘要/摘要 经过大量工作，研究了双酚A（BPA）作为内分泌干扰的不良影响 化学（EDC），BPA的使用已被限制和/或在某些产品（例如婴儿瓶）中被禁止 以及加拿大，欧盟和美国的吸管杯。由于限制了使用BPA， 在结构上相似的类似物，BPS已成为BPA的主要替代品之一。 BPS在许多人中发现 每日消费产品。 BPS是用于替代热纸中BPA的主要类似物。 BPS水平在 水，沉积物，污泥和室内灰尘一直在不断增加，已经到达 BPA的比较或相等水平。 BPS在人类尿液中检测到，其水平一直在增加 美国，已经比其他一些国家的BPA高。但是，目前尚不清楚多少 我们对BPA的毒理学理解适用于BPS。我们最近的研究表明鼠标 在子宫内暴露于BPS和BPA的后代在非生殖表型中表现出广泛的变化 只有F1，也只有F3后代。这些改变包括精子进展，基因改变 睾丸中的表达，并显着降低了男性的精子计数和运动性。暴露于EDC侮辱 在构思和/或胚胎期间，被认为会对后代产生影响。 一种潜在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 F1一代一直持续到后来的F2和F3代中。而BPA能够诱导表观遗传 BPA暴露后，已经进行了有限的转世评估。全球的 尚未报道由BPS甚至BPA在生殖细胞中引起的表观遗传标记的变化。此外， 目前尚不清楚这些表述是否以及如何传递到随后的一代中。因此，我们 假设在子宫内暴露于两个结构相似的EDC（BPA和BPS）将改变表观遗传学 在生殖细胞中重新编程，导致DNA甲基甲基和转录组的破坏以诱导 成人生殖缺陷。在种系细胞中持续的某些表现可能是 传输到后代。该应用的目的是通过识别来检验该假设 特定类别的表观遗传和跨代调节基因。我们还将确定bps如何 影响雄性生殖细胞中的DNA甲基组和转录组，以鉴定其表达和DNA的基因 甲基化状态在随后的一代中发生了变化。由于EDC对随后的不利影响 几代人，理解BPS在生殖细胞中通过BPS的经胎遗传遗传的表述，并比较 BPA的差异将为BP的毒性提供新的见解，并揭示收敛性和 类似结构化药物之间的不同机制。