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.

项目概要/摘要 在对双酚 A (BPA) 作为内分泌干扰物的不利影响进行了大量研究之后 化学品 (EDC)，某些产品（例如婴儿奶瓶）中 BPA 的使用已受到限制和/或禁止 以及加拿大、欧盟和美国的吸管杯。由于 BPA 使用限制， 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 日常消费品。 BPS 是热敏纸中用于替代 BPA 的主要类似物。 BPS 水平 水、泥沙、污泥和室内粉尘不断增加，已达到 BPA 水平相当或相同。 BPS 在人类尿液中检测到，并且其水平在人体内不断增加 美国的 BPA 含量已经高于其他一些国家。但目前还不清楚有多少 我们对 BPA 的毒理学理解也适用于 BPS。我们最近的研究表明，小鼠 在子宫内接触 BPS 和 BPA 的后代在未接触过 BPS 和 BPA 的情况下表现出生殖表型的广泛改变 不仅有F1，还有F3后代。这些改变包括生精进展、基因改变 睾丸中的表达，并显着减少男性的精子数量和活力。遭受 EDC 侮辱 人们认为在受孕和/或胚胎发育期间对后代有影响。 一种潜在的机制被认为是胎儿生殖细胞中表观遗传重编程的改变。 F1 代持续到后来的 F2 和 F3 代。虽然 BPA 能够诱导表观遗传 变化，在 BPA 暴露后进行了有限的跨代评估。全球的 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， 目前还不清楚这些表观突变是否以及如何传递给下一代。因此，我们 假设在子宫内暴露于两种结构相似的 EDC（BPA 和 BPS）会改变表观遗传 生殖细胞中的重编程，导致 DNA 甲基化组和转录组的破坏，从而诱导 成人生殖缺陷。种系细胞中持续的某些表突变可能是 传承给后代。该应用程序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 甲基化组和转录组，以识别其表达和 DNA 的基因 甲基化状态在下一代中发生改变。由于EDC对后续的不良影响 几代人，了解生殖细胞中 BPS 的跨代遗传表突变，并比较 BPA 的差异将为 BPS 的毒性提供新的见解，并揭示收敛和 结构相似的代理之间存在不同的机制。