Transgenerational Inheritance of Epigenetic Effects of Polychlorinated Biphenyls

描述（由申请人提供）：我们申请的目的是确定暴露于多氯联苯（PCBs）是否会引起表观遗传跨代效应。有大量证据表明，生命早期接触环境化学物质可能导致成年后的疾病。这些暴露的负面影响被认为在每一代人中都是重置的，这样后代就不会受到父母和祖父母的暴露历史的影响。然而，挑战这一观念的证据越来越多，表明在某些情况下，环境暴露会影响到远离原始侮辱的多代人，造成深远的后果。这种被称为后天性状的跨代遗传的现象是否发生在哺乳动物身上仍存在争议，尽管据报道，暴露于特定的饮食或营养因素、母亲的压力和某些环境化学物质都会诱发至少两代后观察到的表型变化。我们已经证明，在子宫内与共面和非共面多氯联苯混合处理的后代，模拟人类接触，成年后表现出认知缺陷。啮齿类动物和灵长类动物的其他实验证据强烈表明，子宫内暴露的跨代影响是导致胎儿神经发育异常和儿童后期认知功能异常的原因。还有令人信服的证据表明，多氯联苯暴露与婴儿和儿童的神经功能下降有关，包括注意缺陷多动障碍。同样，孕妇在怀孕期间接触多氯联苯和其他卤化碳氢化合物与后代先天性心脏缺陷和晚年心脏功能不全的发生率较高有关，将胎儿和成人心血管疾病联系在一起。这些健康影响是由跨代毒性还是直接毒性引起的，还有待确定，因为尚未对F3代进行研究。在这个应用中，我们提出解决这样一个假设，即在发育的关键窗口期暴露于多氯联苯会导致CNS和心脏生理学的遗传跨代表型变化，这些变化与DNA甲基化模式的变化有关，这些变化导致染色质构象的改变和随后的基因表达失调，至少在F3代之前都可以检测到。在三个特定目标中，我们将确定在生殖系规范期间发育中的PCB暴露是否会改变神经或心脏表型，以及这些变化是否与生殖系表观基因组、受影响的组织表观基因组和转录组的相应变化有关。成功证明子宫内多氯联苯暴露的跨代遗传将改变我们对这些无处不在的环境污染物对健康影响的理解。

DESCRIPTION (provided by applicant): The objective of our application is to determine if exposure to polychlorinated biphenyls (PCBs) causes epigenetic transgenerational effects. There is extensive evidence that early life exposure to environmental chemicals can lead to disease outcomes in adult life. The negative effects of these exposures are believed to be reset in each generation, such that subsequent generations are unaffected by the exposure history of their parents and grandparents. However, evidence challenging this notion is growing, suggesting that in certain cases, environmental exposures affect multiple generations removed from the original insult, causing far- reaching consequences. It is still controversial whether thi phenomenon, known as transgenerational inheritance of acquired traits, occurs in mammals, though exposure to specific diets or nutritional factors, maternal stress, and certain environmental chemicals have all been reported to induce phenotypic changes observed at least two generations after exposure. We have shown that progeny of dams treated in utero with a mixture of coplanar and non-coplanar PCBs that simulates human exposure show cognitive deficits as adults. Other experimental evidence in rodents and primates strongly suggests a transgenerational impact of in utero exposure as the cause of abnormal fetal neurodevelopment and later childhood cognitive function. There is also compelling evidence of an association of PCB exposure with decreases in neurological function in infants and children, including Attention Deficit Hyperactivity Disorder. Similarly, maternal exposure during pregnancy to PCBs and other halogenated hydrocarbons has been associated with a higher incidence of congenital heart defects in the progeny and cardiac insufficiency later in life, linking fetal and adult cardiovascular disease. It remains to be determined if these health effects are caused by transgenerational or direct toxicity because studies have not been carried out to the F3 generation. In this application, we propose to address the hypothesis that exposure to PCBs during a critical window of development causes heritable transgenerational phenotypic changes in CNS and cardiac physiology associated with changes in DNA methylation patterns responsible for altered chromatin conformation and subsequent dysregulation of gene expression, detectable at least up to the F3 generation. In three Specific Aims, we will determine whether developmental PCB exposure during the time of germ-line specification will change neural or cardiac phenotypes transgenerationally and whether these changes will be associated with corresponding changes in the germ-line epigenome and affected tissue epigenomes and transcriptomes. Successful demonstration of transgenerational inheritance in response to in utero PCB exposure will transform our understanding of the health effects of these ubiquitous environmental pollutants.