Transgenerational Inheritance of Epigenetic Effects of Polychlorinated Biphenyls

多氯联苯表观遗传效应的跨代遗传

• 批准号: 8599612
• 负责人: Alvaro Puga
• 金额: $ 32.7万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-29 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599612
• 关键词: Address; Adult; Affect; Age; Attention deficit hyperactivity disorder; Behavior Disorders; Brain; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Caring; Child; Childhood; Chromatin; Cognitive deficits; Congenital Heart Defects; DNA Methylation; Development; Diet; Dioxins; Disease; Disease Outcome; Dose; Environmental Exposure; Environmental Pollutants; Epigenetic Process; Exposure to; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Germ Lines; Goals; Halogenated Hydrocarbons; Health; Health Care Costs; Heart Diseases; Incidence; Individual; Industrial fungicide; Infant; Lead; Learning; Life; Link; Mammals; Maternal Exposure; Molecular; Molecular Conformation; Molecular Profiling; Morbidity - disease rate; Mothers; Mus; Nervous System Physiology; Nutritional; Parents; Pattern; Perinatal Exposure; Phenotype; Physiological; Physiology; Pilot Projects; Polychlorinated Biphenyls; Population; Pregnancy; Primates; Recording of previous events; Reporting; Research; Rodent; Role; Simulate; Time; Tissues; Toxic Environmental Substances; Toxic effect; Work; cognitive function; cost; early life exposure; environmental chemical; epigenome; epigenomics; exposed human population; fetal; grandparent; in utero; maternal stress; morris water maze; neurobehavioral; neurodevelopment; novel; object recognition; offspring; pregnant; prenatal exposure; public health relevance; relating to nervous system; research study; response; trait; vinclozolin

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.

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（PCB）是否会导致表观遗传转世代作用。有广泛的证据表明，早期生命暴露于环境化学物质会导致成人生活中的疾病结果。这些暴露的负面影响被认为是每一代人重置的，因此随后的世代不受父母和祖父母的暴露历史的影响。但是，挑战这种观念的证据正在增长，表明在某些情况下，环境暴露会影响从原始侮辱中删除的多代，从而导致了巨大的后果。尽管暴露于特定的饮食或营养因素，孕产妇压力和某些环境化学物质，但据报道，这种现象是在哺乳动物中发生的这种现象，即被称为获得性状的跨代遗传而发生的现象，这仍然是有争议的。我们已经表明，在子宫内用共面和非旋转PCB的混合物治疗的大坝的后代，模拟人类暴露的后代表现出认知缺陷。啮齿动物和灵长类动物中的其他实验证据表明，子宫暴露在子宫内的跨代影响是胎儿神经发育异常的原因，后来又是儿童期认知功能。还有令人信服的证据表明，PCB暴露与婴儿和儿童神经功能的降低相关，包括注意力缺陷多动障碍。同样，怀孕期间对PCB和其他卤代碳氢化合物的暴露与后代和心脏不足的先天性心脏缺陷的发生率更高有关，与胎儿和成人心血管疾病联系起来。这些健康效应是否是由跨世代或直接毒性引起的，因为没有对F3发电进行研究。在此应用中，我们建议解决以下假设：在临界发育范围内暴露于PCB会导致CNS和心脏生理学的遗传转传表型变化与DNA甲基化模式的变化相关，导致染色质构象的变化以及可改变的基因表达失调，至少可检测到F3生成的基因表达失调。在三个具体目标中，我们将确定在种系规范期间的发育性PCB暴露是否会改变神经或心脏表型，以及这些变化是否与种系表观基因组和受影响的组织表观基因组和转录组的相应变化有关。成功地证明了跨代遗传响应子宫PCB暴露将改变我们对这些无处不在的环境污染物的健康影响的理解。