Mechanisms of transgenerational epigenetic alterations induced by polybrominated biphenyls

多溴联苯诱导的跨代表观遗传改变机制

• 批准号: 10622320
• 负责人: Daniel Ruiz
• 金额: $ 7.81万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-05-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622320
• 关键词: ATAC-seq; Address; Adipose tissue; Adult; Affect; Androgen Receptor; Animals; Binding; Binding Sites; Cells; ChIP-seq; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Methylation; Daughter; Development; Disease; Ectoderm; Embryo; Enhancers; Environment; Epiblast; Epigenetic Process; Exposure to; Female; Fertilization; Fetal Development; Flame Retardants; Functional disorder; Gene Expression; Generations; Genes; Genomic Segment; Genomics; Germ Cells; Goals; Health; Histones; Human; Individual; Inherited; Knowledge; Livestock; Mammals; Mediator; Michigan; Modeling; Modification; Molecular; Mothers; Mus; Neurons; Nuclear Hormone Receptors; Nucleosomes; Obesity; Oocytes; Outcome; Persons; Phenotype; Polybrominated Biphenyls; Population; Pregnancy; Preventive care; Process; Proteins; Puberty; Registries; Rural; Rural Population; Site; Specific qualifier value; Structure of primordial sex cell; Testing; Time; Variant; Work; bisphenol A; bisulfite sequencing; blastomere structure; cancer type; disorder prevention; early experience; embryo cell; environmental chemical; epigenome; experimental study; genome-wide; girls; histone modification; in utero; mouse model; natural Blastocyst Implantation; neuronal cell body; novel; offspring; prenatal exposure; prevent; reproductive; reproductive outcome; rural area; rural dwellers; single cell technology; sperm cell; transcription factor; transgenerational epigenetic inheritance; transmission process; zygote

PROJECT SUMMARY/ABSTRACT Knowing how environmentally-induced epigenetic alterations are established in the mammalian germline, transgenerationally inherited, and contribute to disease in the adult, can lead to a more complete understanding of pathophysiology as well as novel preventive care opportunities. However, the mechanisms underlying the transgenerational inheritance of epiphenotypes remain perplexing due to the extensive epigenetic remodeling that happens in the germline during germ cell development and after fertilization. Work from the Corces lab suggests that aberrant transcription factor (TFs) occupancy due to environmental perturbations during primordial germ cell (PGC) development shields regions from DNA-methylation remodeling and results in lasting changes in chromatin accessibility. Understanding the protein makeup, genomic distribution, and fate of environmentally induced TF binding sites from the gametes to the post-implantation embryo is essential to understand how germline epimutations can withstand epigenetic remodeling, and how these alterations can influence the health of later generations. To address these issues, we propose to examine the transgenerational effects of polybrominated biphenyls (PBBs). Rural populations in Michigan were highly exposed to PBBs in contaminated livestock in the 1970s, resulting in numerous adverse health outcomes in individuals exposed in utero, including earlier puberty and other reproductive alterations by mechanisms that remain unknown. Whether this mass exposure could have transgenerational effects is also unknown. My preliminary mouse studies show that PBB exposure during PGC development leads to differentially accessible sites in sperm chromatin containing binding sites for the androgen receptor (Ar) that persist transgenerationally. This mouse exposure results in similar maternal adipose PBB levels as directly exposed Michigan residents, and leads to early puberty in female F1 mouse offspring, as observed in daughters of directly exposed mothers from the Michigan PBB registry. Importantly, early puberty is also observed in the unexposed F3 generation in mice. The goal of the proposed project is to use this mouse model reflecting the Michigan PBB exposure to increase our basic understanding of the transmission of epimutations with direct relevance to the exposed Michigan population. Aim 1 will test the hypothesis that transgenerationally persistent Ar footprints in sperm chromatin are hypomethylated, bound by Ar, and are flanked by nucleosomes possessing histone variants and modifications indicative of enhancers. Further, this aim will test the hypothesis that ancestral PBB exposure also results in differential Ar footprints in oocytes that overlap with those observed in sperm. Aim 2 will test the hypothesis that TF sites induced by PBB exposure are transmitted from the gametes to the embryo after fertilization. These experiments will generate highly significant results that will fill a critical gap in our understanding of the mechanisms governing transgenerational phenomena in mammals that will be directly applicable to the understanding of the health problems affecting thousands of exposed Michigan residents and their descendants.

项目摘要/摘要 知道如何在哺乳动物种系中建立环境引起的表观遗传改变， 跨他遗传的跨成年人遗传并为疾病做出贡献，可能会导致更完整的理解 病理生理学以及新型的预防保健机会。但是， 由于广泛的表观遗传重塑，表观型的转基因遗传仍然令人困惑 这在生殖细胞发育和受精后的种系中发生。来自Corces Lab的工作 表明由于原始过程中的环境扰动而引起的异常转录因子（TFS） 生殖细胞（PGC）开发屏蔽DNA-甲基化重塑，并导致持久变化 在染色质访问性中。了解环境的蛋白质构成，基因组分布和命运 从配子到植入后胚胎的诱导TF结合位点对于了解如何了解如何了解 种系的表述可以承受表观遗传重塑，以及这些改变如何影响健康 后来的。为了解决这些问题，我们建议检查 多溴双苯基（PBB）。密歇根州的农村人口在受污染中高度暴露于PBB 牲畜在1970年代，导致子宫内暴露的个体的不良健康结果，包括 较早的青春期和其他生殖改变是通过未知的机制进行的。是否质量 暴露可能会产生转世效应。我的初步鼠标研究表明PBB PGC开发期间的暴露导致含有结合的精子染色质中可及可访问的位点 持续转变的雄激素受体（AR）的位点。这种鼠标的暴露导致类似 母体脂肪PBB水平直接暴露于密歇根州居民，并导致女性F1的早期青春期 老鼠后代，正如密歇根州PBB注册表的直接暴露母亲的女儿所观察到的那样。 重要的是，在暴露的小鼠F3产生中也观察到早期青春期。提议的目标 项目是使用反映密歇根州PBB暴露的鼠标模型来增加我们对 与裸露的密歇根州人口直接相关的播种的传播。 AIM 1将测试 假设精子染色质中的跨世代持续AR足迹是低甲基化的，受 AR，侧面是具有组蛋白变体的核小体和指示增强子的修饰。 此外，该目标将检验以下假设： 与精子中观察到的卵母细胞重叠的卵母细胞。 AIM 2将测试PBB诱导的TF位点的假设 受精后，暴露于配子从配子传播到胚胎。这些实验将产生 高度显着的结果将填补我们对管理机制的理解的关键空白 哺乳动物中的跨代现象将直接适用于对健康的理解 影响成千上万的密歇根州居民及其后代的问题。