The intersection of stress and environmental chemicals in germ cell reprogramming

生殖细胞重编程中压力和环境化学物质的交叉点

• 批准号: 10245162
• 负责人: Diana J Laird
• 金额: $ 28.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245162
• 关键词: Adult; Agrochemicals; Biological; California; Chemical Exposure; Chemicals; Consumer Participation; DNA Methylation; DNA Sequence Alteration; DNA Transposable Elements; Defect; Development; Disease; Dose; Elderly; Elements; Environmental Risk Factor; Epigenetic Process; Exposure to; Female; Fertility; Fetal Growth; Fetus; Future; Future Generations; Gene Expression Profile; Generations; Genetic; Genetic Transcription; Genome; Germ Cells; Goals; Health; High-Risk Pregnancy; House Dust; Individual; L1 Elements; Lead; Link; Malignant Neoplasms; Meiosis; Mobile Genetic Elements; Molecular; Mus; Oral; Pathway interactions; Pharmacology; Pharmacotherapy; Phenotype; Plastics; Predisposition; Pregnancy; Pregnant Women; Prevention; Protein Family; Proteins; Regimen; Reporter; Repression; Research; Retrotransposon; Risk; Stress; Testing; Time; Viral; Woman; Zidovudine; biological adaptation to stress; environmental chemical; epigenome; fetal; genome integrity; insight; metabolic phenotype; mouse model; next generation; novel; personal care products; phthalates; piRNA; pregnant; prenatal exposure; prenatal stress; public health relevance; reproductive; reproductive development; reproductive senescence

PROJECT ABSTRACT The goal of this proposal is to establish how exposures to ubiquitous plastics and prenatal stress interact to confer epigenetic changes to developing germ cells, and how such changes lead to reproductive and metabolic phenotypes in later life and potentially in subsequent generations. Numerous studies involving consumer and agricultural chemicals demonstrate effects that appear in the progeny and even grandchildren of individuals exposed in utero. Correspondence between period of susceptibility and epigenetic reprogramming suggest that epigenetic changes to germ cells are involved. However, as the majority of studies utilize oral gavage for dosing, the effects of the chemical and prenatal stress are difficult to resolve. Phthalates are the major chemical in household dust and have been detected in 100% of pregnant women in California. Our preliminary studies in mice find that prenatal exposures to two different phthalates during the period of germ cell epigenetic programming leads in each case to decreased repression of retrotransposons and germ cell developmental defects; evidence from our lab suggests that this occurs through disruption of the piRNA pathway, which silences endogenous transposable elements through epigenetic and post-translational mechanisms. In this proposal, we will interrogate the combined and separate effects of biologically relevant doses of phthalate and early gestational stress on the epigenetic state of mouse germ cells and relate these changes to the extent of retrotransposon activity and reproductive phenotypes in the progeny. Studies in Aim 1 will determine how early gestational stress and phthalate exposure interact to alter the epigenetic state of fetal germ cells and the potential for inheritance of that state. This will disentangle the effects of stress and chemical exposure that accompany oral gavage in many prior studies with quantifiable, molecular readouts as well as testing potential mechanisms of direct and multigenerational epigenetic dysregulation. Aim 2 will examine phenotypic consequences of early gestational stress and phthalate exposure on germ cells and female reproductive aging in the next generation. By connecting adult reproductive phenotypes to fetal exposures, this will begin to disentangle the effects of plastics versus prenatal stress. Pharmacologic modulation of key nodes in the stress response pathway will potentially provide insight on appropriate therapies for women in high-risk pregnancies. Aim 3 will determine the extent of genetic disruptions via transposon insertions induced by early gestational stress and phthalates in directly exposed germ cells and subsequent generations. These studies will identify environmental factors that pose greatest risk to genomic integrity and potentially a drug therapy to mitigate those effects.

项目摘要 该提案的目标是确定接触无处不在的塑料和产前压力如何相互作用 赋予发育中的生殖细胞表观遗传变化，以及这些变化如何导致生殖和代谢 晚年的表型以及可能在后代中的表型。许多研究涉及消费者和 农业化学品显示出对个体后代甚至孙辈的影响 暴露在子宫内。易感期和表观遗传重编程之间的对应关系表明 涉及生殖细胞的表观遗传变化。然而，由于大多数研究采用口服强饲法 剂量、化学物质和产前应激的影响很难解决。邻苯二甲酸盐是主要 家庭灰尘中含有这种化学物质，并且在加利福尼亚州 100% 的孕妇中都检测到了这种化学物质。我们的初步 对小鼠的研究发现，在生殖细胞表观遗传期间，产前接触两种不同的邻苯二甲酸盐 在每种情况下，编程都会导致逆转录转座子和生殖细胞发育的抑制减少 缺陷；我们实验室的证据表明，这是通过破坏 piRNA 途径而发生的，该途径 通过表观遗传和翻译后机制沉默内源转座元件。在这个 提案中，我们将探讨生物相关剂量的邻苯二甲酸盐和 妊娠早期应激对小鼠生殖细胞表观遗传状态的影响，并将这些变化与 后代中的逆转录转座子活性和生殖表型。目标 1 的研究将确定多久 妊娠应激和邻苯二甲酸盐暴露相互作用，改变胎儿生殖细胞的表观遗传状态和 该状态的继承潜力。这将消除压力和化学暴露的影响 在许多先前的研究中伴随口服强饲，具有可量化的分子读数以及测试潜力 直接和多代表观遗传失调的机制。目标 2 将检查表型 妊娠早期应激和邻苯二甲酸盐暴露对生殖细胞和女性生殖衰老的影响 在下一代。通过将成人生殖表型与胎儿暴露联系起来，这将开始 理清塑料与产前压力的影响。应激关键节点的药物调节 反应途径可能会为高危妊娠女性提供适当的治疗方法。 目标 3 将确定妊娠早期诱导的转座子插入造成的遗传破坏程度 直接暴露的生殖细胞及其后代中的应激和邻苯二甲酸盐。这些研究将确定 对基因组完整性构成最大风险的环境因素以及可能缓解的药物治疗 那些影响。