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（由适用提供）：科学证据表明，空气污染可能是代谢疾病的危险因素一直在稳步增加，但是驱动这种关联的生物学机制尚不清楚。新陈代谢的主要参与者之一是线粒体。实际上，在包括代谢疾病在内的多种疾病中暗示了线粒体功能失调。线粒体DNA（mtDNA）也对外源活性氧的损伤敏感。环境污染物，例如与交通相关的空气污染（TRP），已知会产生氧化物胁迫，与各种形式的线粒体损伤有关。线粒体基因组的遗传和表观遗传改变也可能在疾病易感性中起关键作用。已知MTDNA序列中的多态性，特别是某些单倍率，可以改变TRP暴露与氧化应激诱导的感染的全身生物标志物之间的关系，以及黑色碳和认知障碍。线粒体还包含表观遗传修饰mtDNA表达所需的机械，这表明表观遗传修饰也可能影响疾病的风险。在我们自己的初步研究中，产前暴露于非自由向NOX和苯并[A] pyrene与mtDNA甲基化水平的改变有关。但是，有关线粒体表观遗传标记的证据是否对促氧化的环境暴露敏感，以及寿命最易感的时间段是非常有限的。鉴于线粒体在代谢中的重要作用以及童年时空气污染物与代谢性疾病之间的建议相关性，因此假设在空气污染物的产前暴露可能会导致线粒体DNA损害，并导致新生儿MTDNA对暴露于暴露诱导的早期氧化的新生MTDNA的改变可能会影响与系统氧化有关的与系统相关的健康。我们进一步假设mtDNA单倍群可能会改变对空气污染物健康影响的敏感性。我们将在300个母亲的队列中详细研究这些假设婴儿成对在Lac +USC县医院分娩时招募。