Mitochondrial epigenetics, traffic-related pollution and neonatal health

线粒体表观遗传学、交通相关污染和新生儿健康

基本信息

批准号：
9096794
负责人：
Carrie Van Doren Breton
金额：
$ 20.54万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096794
关键词：
Address Adenosine Triphosphate Affect Air Pollutants Air Pollution Apoptotic Aromatic Polycyclic Hydrocarbons Automobile Driving Basal metabolic rate Benzo(a)pyrene Biological Biological Markers Burn injury CASP3 gene California Carbon Black Cell division Cells Cessation of life Childhood Cognitive County County Hospitals Coupling DNA Damage DNA Methylation DNA Sequence DNA Sequence Alteration DNA copy number Diet Disease Disease susceptibility Environmental Exposure Environmental Pollutants Epigenetic Process Exposure to Gene Rearrangement Genetic Genetic Polymorphism Genome Growth Haplogroup Health Hospitals Human Impaired cognition Individual Infant Inflammation Life Lipid Peroxidation Literature Longevity Los Angeles Low Birth Weight Infant Lymphocyte Medical center Metabolic Metabolic Diseases Metabolism Methylation Mitochondria Mitochondrial DNA Modification Mothers Mutation Neonatal Neurons Newborn Infant Organelles Organic Synthesis Outcome Oxidative Stress Particulate Matter Play Point Mutation Pollution Population Predisposition Reactive Oxygen Species Recruitment Activity Risk Risk Factors Role Specificity Structure Thermogenesis Time Umbilical Cord Blood Universities Weight Gain adduct cell injury cohort cytochrome c disorder risk driving force energy balance environmental stressor fetal mitochondrial genome monocyte oxidation physical inactivity pollutant prenatal prenatal exposure response traffic-related air pollution trafficking

项目摘要

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.

描述（由申请人提供）：越来越多的科学证据表明，空气污染可能是代谢疾病的一个危险因素，但推动这种关联的生物学机制尚不清楚，代谢中的关键参与者之一是线粒体。事实上，功能失调的线粒体与多种疾病有关，包括代谢疾病。线粒体 DNA (mtDNA) 对外源性活性氧的损伤也很敏感，例如已知会产生的与交通相关的空气污染 (TRP)。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，已知线粒体DNA序列的多态性，特别是某些单倍群，可以改变TRP暴露与疾病之间的关系。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也含有表观遗传修饰 mtDNA 表达所需的机制，这表明表观遗传修饰也可能。在我们自己的初步研究中，产前接触非高速公路氮氧化物和苯并[a]芘与线粒体DNA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环境暴露敏感的证据，考虑到线粒体在新陈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联系（产前接触空气污染物可能会导致这种疾病），生命周期中哪些时期最容易受到影响是非常有限的。线粒体 DNA 损伤和改变会影响新生儿 mtDNA，以应对暴露引起的全身氧化，这可能会导致与代谢疾病相关的早期生命健康结果，我们将进一步研究 mtDNA 单倍群可能会改变对空气污染物的健康影响的易感性。对 300 名母亲进行的详细假设在 LAC + USC 县医院分娩时招募的婴儿对。