Mitochondrial epigenetics, traffic-related pollution and neonatal health

 描述（由申请人提供）：空气污染可能是代谢疾病的危险因素的科学证据一直在稳步增加，但驱动这种关联的生物学机制尚不清楚。代谢的关键参与者之一是线粒体;事实上，功能障碍的线粒体与包括代谢疾病在内的多种疾病有关。线粒体DNA（mtDNA）也对外源性活性氧的损伤敏感。环境污染物，如交通相关的空气污染（TRP），已知会产生氧化应激，与各种形式的线粒体损伤有关。线粒体基因组中的遗传和表观遗传改变也可能在疾病易感性中发挥关键作用。线粒体DNA序列的多态性，特别是某些单倍型群，已知可以改变TRP暴露与氧化应激诱导的炎症以及黑碳和认知障碍的全身生物标志物之间的关系。线粒体还包含表观遗传修饰mtDNA表达所需的机制，这表明表观遗传修饰也可能影响疾病风险。在我们自己的初步研究中，产前暴露于非高速公路氮氧化物和苯并[a]芘与mtDNA甲基化水平的改变有关。然而，关于线粒体表观遗传标记是否对促氧化剂环境暴露敏感，以及生命周期中哪些时间段最敏感的证据非常有限。鉴于线粒体在代谢中的重要作用以及空气污染物与儿童期代谢紊乱之间的相关性，我们假设产前暴露于空气污染物可能导致线粒体DNA损伤和新生儿mtDNA改变，以响应呼吸道诱导的全身氧化，这可能影响与代谢疾病相关的早期生命健康结局。我们进一步假设mtDNA单倍型群可能会改变对空气污染物健康影响的易感性。我们将在300名母亲的队列中详细调查这些假设 在LAC +USC县医院分娩时招募的婴儿对。

 DESCRIPTION (provided by applicant): The scientific evidence that air pollution may be a risk factor for metabolic disease has been steadily increasing, yet the biological mechanisms driving such associations are not well understood. One of the key players in metabolism are the mitochondria; in fact, dysfunctional mitochondria have been implicated in a variety of diseases including metabolic disease. Mitochondrial DNA (mtDNA) is also sensitive to damage by exogenous reactive oxygen species. Environmental pollutants, such as traffic-related air pollution (TRP), known to generate oxidative stress, have been associated with various forms of mitochondrial damage. Genetic and epigenetic alterations in the mitochondrial genome may also play pivotal roles in disease susceptibility. Polymorphisms in the mtDNA sequence, specifically certain haplogroups, are known to modify the relationship between TRP exposure and systemic biomarkers of oxidative stress-induced inflammation as well as black carbon and cognitive impairment. Mitochondria also contain the machinery required to epigenetically modify mtDNA expression, suggesting that epigenetic modifications may also affect disease risk. In our own preliminary study, prenatal exposure to non-freeway NOx and Benzo[a]pyrene was associated with altered levels of mtDNA methylation. However, the evidence regarding whether mitochondrial epigenetic marks are sensitive to pro-oxidant environmental exposures, and what time periods in the lifespan are most susceptible, is very limited. Given the important role for mitochondria in metabolism and the suggested associations between air pollutants and metabolic disorders in childhood, w e hypothesize that prenatal exposure to air pollutants may cause mitochondrial DNA damage and alteration to newborn mtDNA in response to exposure-induced systemic oxidation, which may affect early life health outcomes related to metabolic disease. We further hypothesize the mtDNA haplogroups may alter susceptibility to the health effects of air pollutants. We will investigate these hypotheses in detail in a cohort of 300 mother infant pairs recruited at the time of delivery at LAC +USC County hospital.