Epigenetic Transgenerational Endocrine Disruptor Actions

表观遗传跨代内分泌干扰物作用

• 批准号: 9247187
• 负责人: MICHAEL K SKINNER
• 金额: $ 33.98万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247187
• 关键词: Adult; Copy Number Polymorphism; DNA Methylation; DNA Sequence Alteration; Development; Diagnostic; Dioxins; Disease; Dose; Embryonic Development; Endocrine Disruptors; Epigenetic Process; Etiology; Event; Fertilization; Generations; Genes; Genomic Instability; Genomics; Germ Cells; Grant; Heritability; Human; Hydrocarbons; Inbreeding; Industrial fungicide; Machine Learning; Male Infertility; Mediating; Mental Depression; Modeling; Molecular; Mutation; Onset of illness; Ovary; Pesticides; Phenotype; Plasticizers; Plastics; Rattus; Research; Safety; Somatic Cell; Spermatogenesis; Structure of primordial sex cell; Testing; Testis; Toxic Environmental Substances; Transcriptional Regulation; computerized; design; disease phenotype; epigenetic marker; epigenome; genome-wide; hazard; imprint; male; phthalates; prenatal exposure; promoter; public health relevance; sex determination; sperm cell; tool; transcriptome; transgenerational epigenetic inheritance; vinclozolin

DESCRIPTION (provided by applicant): A number of environmental toxicants were shown in the previous grant period to promote the epigenetic transgenerational inheritance of adult onset disease including the fungicide vinclozolin, pesticides, plastics (BPA and phthalates), dioxin, hydrocarbons, and DDT. The ability of environmental compounds (e.g. endocrine disruptors) to promote transgenerational disease phenotypes is anticipated to be a critical aspect of adult onset disease etiology. The transgenerational inheritance phenotype requires the heritable epigenetic alterations of the germline. The current proposal is designed to further investigate the molecular and developmental aspects of the epigenetic transgenerational inheritance phenomenon and assess the potential use of epigenetic biomarkers for exposure and disease. The general hypothesis tested is that "transient fetal exposure around the period of gonadal sex determination to environmental toxicants (i.e. vinclozolin) promotes the reprogramming of the epigenome (i.e. DNA methylation) of the male germline that then transmits an imprinted-like epigenome to subsequent generations to induce the epigenetic transgenerational inheritance of adult onset disease (e.g. male infertility)". The previous grant period focused on the analysis of the epigenetic alteration in the F3 generation sperm using promoter associated differential DNA methylation regions (epimutations), as well as documented the epigenetic and transcriptome changes in the F3 generation vinclozolin lineage primordial germ cells. The molecular etiology of somatic cell changes associated with ovary and testis disease was established. The current proposal further investigates the molecular and developmental aspects of the germline mediated epigenetic transgenerational inheritance of disease. The experimental approach to test the above hypothesis consists of the following specific aims: Aim 1) Determine the developmental and generational aspects of the genome-wide germline epimutations. Aim 2) Determine the genomic features associated with the epimutations and potential genetic alterations involved in the epigenetic transgenerational inheritance phenomenon. Aim 3) Determine the optimal exposure parameters of the environmental induced transgenerational model and correlate epigenetic biomarkers with exposure and disease. Completion of the proposed research will determine the cascade of epigenetic events involved in germ cell development that generates the sperm epimutations that transmit the epigenetic transgenerational inheritance of disease phenotypes. The protection of the sperm epimutations from DNA methylation erasure is anticipated in early embryonic development. The proposed research will further elucidate the molecular and developmental aspects of environmentally induced epigenetic transgenerational inheritance of disease and the potential use of epigenetic biomarkers for ancestral exposure and disease.

描述(由申请者提供)：在上一次赠款期间，有一些环境毒物被证明可以促进成人发病疾病的表观遗传遗传，包括杀菌剂长春新灵、杀虫剂、塑料(双酚A和邻苯二甲酸盐)、二恶英、碳氢化合物和滴滴涕。环境化合物(如内分泌干扰物)促进跨代疾病表型的能力预计是成人发病病因学的一个关键方面。跨代遗传表型要求生殖系发生可遗传的表观遗传改变。目前的提案旨在进一步调查 对表观遗传跨代遗传现象的分子和发育方面的研究，并评估表观遗传生物标记物在暴露和疾病方面的潜在用途。测试的一般假设是“胎儿在性腺性别决定期间短暂暴露于环境毒物(如长春新灵)会促进男性生殖系表观基因组的重新编程(即DNA甲基化)，然后将印迹状表观基因组传递给后代，从而诱导成人发病疾病(如男性不育)的表观遗传跨代遗传”。上一期的资助重点是利用启动子相关的差异DNA甲基化区域(表观突变)分析F3代精子的表观遗传学变化，并记录了F3代长春花碱谱系原始生殖细胞的表观遗传学和转录组的变化。建立了与卵巢和睾丸疾病相关的体细胞改变的分子病因学。目前的建议进一步研究了胚系介导的疾病表观遗传跨代遗传的分子和发育方面。检验上述假设的实验方法包括以下具体目标：目的1)确定全基因组生殖系上突变的发育和世代方面。目的2)确定与表观遗传跨代遗传现象有关的表观突变和潜在的遗传改变的基因组特征。目的3)确定环境诱导跨代模型的最佳暴露参数，并将表观遗传生物标志物与暴露和疾病联系起来。拟议研究的完成将确定生殖细胞发育中涉及的一系列表观遗传事件，这些事件产生精子表观突变，从而传递疾病表型的表观遗传跨代遗传。在早期胚胎发育中，预计精子表面突变不会受到DNA甲基化消除的影响。拟议的研究将进一步阐明环境诱导的表观遗传疾病跨代遗传的分子和发育方面，以及表观遗传生物标记物在祖先暴露和疾病方面的潜在用途。