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.

项目总结/摘要 在广泛研究双酚A（BPA）作为内分泌干扰物的不良影响后， 由于双酚A是一种化学品（EDC），BPA的使用已被限制和/或禁止在某些产品，如婴儿奶瓶 和吸管杯在加拿大，欧盟和美国。由于限制使用BPA， 结构类似物，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是热敏纸中用来取代BPA的主要类似物。BPS水平 水、沉积物、污泥和室内灰尘不断增加， 与BPA水平相当或相同。在人类尿液中检测到BPS，其水平在2009年一直在增加。 在美国，BPA的含量已经高于其他一些国家。然而，目前还不清楚有多少 我们对BPA毒理学的理解适用于BPS。我们最近的研究表明， 在子宫内暴露于BPS和BPA的后代在生殖表型上表现出广泛的改变， F1和F3的后代。这些改变包括精子发生进展，基因改变， 在睾丸中表达，并显着降低精子计数和运动力的男性。暴露于EDC损伤 在怀孕和/或胚胎发育期间，被认为对后代有影响。 一个潜在的机制被认为是胎儿生殖细胞中改变的表观遗传重编程。 F1代，持续到后来的F2和F3代。虽然BPA能够诱导表观遗传 由于环境变化，在BPA暴露后进行了有限的代际评估。全球 由BPS甚至BPA在生殖细胞中引起的表观遗传标记的变化尚未报道。此外，本发明还提供了一种方法， 尚不清楚这些表突变是否以及如何传递给后代。所以我们 假设在子宫内暴露于两种结构相似EDC（BPA和BPS）将改变表观遗传 生殖细胞中的重编程，导致DNA甲基化组和转录组的破坏， 成人生殖缺陷在生殖系细胞中持续的某些表突变可能是潜在的。 传给后代。本申请的目的是通过识别 表观遗传和转代调节基因的特定类别。我们还将确定BPS如何 影响雄性生殖细胞中的DNA甲基化组和转录组，以确定其表达和DNA 甲基化状态在下一代中发生改变。由于EDC对随后的 几代人，了解转代遗传表突变的BPS在生殖细胞和比较， 这些差异将为BPS的毒性提供新的见解，并揭示了BPS的收敛性， 类似结构的代理之间的分歧机制。