Prenatal Exposures to Flame-Retardants: Mitochondrial Signatures and Childhood Obesity

产前接触阻燃剂：线粒体特征和儿童肥胖

基本信息

批准号：
10162587
负责人：
Allison Kupsco
金额：
$ 10.27万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-11 至 2021-08-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10162587
关键词：
18 year old Abdomen Adipose tissue Adolescent Affect African American Age Biological Markers Birth Blood Body mass index Calories Cells Child Childhood Chronic Clinical Clinical Markers Complement Consumption DNA Damage DNA Repair Data Data Analyses Development Endocrine Disruptors Environment Environmental Epidemiology Environmental Exposure Environmental Health Epidemiologist Epidemiology Exposure to Fatty acid glycerol esters Flame Retardants Genome Goals Growth Health Hispanics Human Incidence Individual Investigation Lead Link Long-Term Effects Low income Magnetic Resonance Imaging Measures Mediating Mediation Mentors Metabolic Methods Mitochondria Mitochondrial DNA Modeling Molecular Mothers Mutation Obesity Pathogenesis Phase Ploidies Population Prevalence Prevention Prevention strategy Production Public Health Research Research Training Risk Role Sampling Source Specimen Stress Study models Testing Therapeutic Tissues Toxic effect Toxicant exposure Toxicology Training Training Programs Umbilical Cord Blood Work abdominal fat aged career cohort deep sequencing early detection biomarkers epidemiology study follow-up health data heteroplasmy human population study in utero indexing innovation mitochondrial DNA mutation mitochondrial dysfunction next generation sequencing novel novel marker obesity in children obesity prevention obesity risk oxidative DNA damage oxidative damage polybrominated diphenyl ether predictive marker prenatal prenatal exposure prospective racial and ethnic skills statistics treatment strategy

项目摘要

PROJECT SUMMARY: Childhood obesity is a major public health risk in critical need of novel prevention and therapeutic efforts. Environmental exposures may promote the onset of childhood obesity through altered developmental programming. Poly-brominated diphenyl ether (PBDE) flame-retardants can bioaccumulate in utero resulting in elevated prenatal exposure. Experimental evidence suggests that PBDEs are adipogenic, however, studies in human populations are limited and the mechanisms remain unclear. PBDEs may induce mitochondrial dysfunction, which is further implicated in obesity, reflecting the key role of mitochondria in energy consumption. We propose to investigate associations of prenatal PBDE exposure with childhood adiposity, examining mitochondrial DNA (mtDNA) content, oxidative damage, and mutations as potential mechanisms of exposure and effect. In this K99/R00, Dr. Allison Kupsco will complement her skills in experimental toxicology with training in human population studies, specifically in mitochondriomics, environmental health, epidemiology, and statistics. As persistent, endocrine disrupting chemicals, PBDEs are an excellent paradigm exposure for this research/training program. In this proposal, we will leverage a longitudinal birth cohort, the Columbia Center for Children’s Environmental Health (CCCEH) with cord blood PBDE data, longitudinal data on adiposity (BMI and fat mass) from 5 to 18 years of age, and innovative abdominal magnetic resonance imaging (MRI) at 18 years to identify adipose sub-depots. In the K99 phase, existing adiposity data will provide precise information on longitudinal and adipose-tissue specific effects of PBDEs, individually and in mixtures (Aim 1), and we will generate longitudinal markers of mtDNA content, an excellent general indicator of mitochondrial health (Aim 2). In the R00 phase, Dr. Kupsco will complete mtDNA content data analysis and initiate a new investigation of mtDNA oxidative damage and mutations (heteroplasmy) with a novel deep-sequencing method, to assess specific effects of PBDEs on mtDNA and elucidate the mitochondrial basis of adiposity (Aim 3). These endpoints may serve as early biomarkers to identify children with high obesity risk, which would be critical to prevention efforts. To complete these aims, Dr. Kupsco will undergo training as a mix of formal coursework and expert guidance from her renowned mentoring team of Drs. Andrea Baccarelli, Julie Herbstman, Andrew Rundle, Jeff Goldsmith and Dympna Gallagher. Specifically, Dr. Kupsco will receive training in; 1) Mitochondrial markers with Dr. Baccarelli; 2) Prenatal exposure and children’s environmental health with Dr. Herbstman; 3) Methods in environmental epidemiology and causal mediation with Dr. Rundle; 4) Advanced longitudinal data analysis with Dr. Goldsmith; and 5) Clinical markers of adiposity/MRI with Dr. Gallagher. This will prepare Dr. Kupsco for a career as an independent molecular environmental epidemiologist, investigating prenatal exposures, mitochondrial toxicity and child obesity. Results from this work will advance the field of children’s environmental health and contribute to new hypotheses on drivers and mechanisms of adiposity.

项目摘要：儿童肥胖是一个主要的公共卫生风险，迫切需要新的预防和治疗方法环境暴露可能会促进儿童肥胖的发生。多溴二苯醚 (PBDE) 阻燃剂可在体内生物累积。子宫内导致产前接触量增加实验证据表明 PBDE 具有致脂肪作用，然而，针对人群的研究有限，PBDEs 的诱发机制仍不清楚。线粒体功能障碍，进一步与肥胖有关，反映了线粒体在能量方面的关键作用我们建议调查产前 PBDE 暴露与儿童肥胖的关系，检查线粒体 DNA (mtDNA) 含量、氧化损伤和突变作为潜在机制在本 K99/R00 中，Allison Kupsco 博士将补充她在实验毒理学方面的技能。接受过人口研究方面的培训，特别是线粒体、环境健康、流行病学、作为持久性内分泌干扰物，多溴联苯醚是一个很好的范例。在本提案中，我们将利用哥伦比亚中心的纵向出生队列。儿童环境健康 (CCCEH) 包含脐带血 PBDE 数据、肥胖纵向数据（BMI 和脂肪量）从 5 岁到 18 岁，以及创新的腹部磁共振成像（MRI）在 18 岁识别脂肪子库在 K99 阶段，现有的肥胖数据将提供精确的信息。 PBDEs 的纵向和脂肪组织特异性影响，单独和混合物（目标 1），我们将生成线粒体 DNA 含量的纵向标记，这是线粒体健康的一个极好的一般指标（目标 2）。在R00阶段，Kupsco博士将完成mtDNA内容数据分析，并启动新的调查使用新型深度测序方法评估 mtDNA 氧化损伤和突变（异质性） PBDE 对 mtDNA 的具体影响并阐明肥胖的线粒体基础（目标 3）。可以作为早期生物标志物来识别具有高肥胖风险的儿童，这对于预防至关重要为了实现这些目标，库普斯科博士将接受正式课程和专家培训相结合的培训来自她著名的导师团队 Andrea Baccarelli、Julie Herbstman、Andrew Rundle、Jeff 的指导 Goldsmith 和 Dympna Gallagher 博士将接受以下方面的培训： 1) 线粒体标记 Baccarelli 博士；2) Herbstman 博士的产前暴露和儿童环境健康；3) 方法 Rundle 博士的环境流行病学和因果调解；4) 高级纵向数据分析 Goldsmith 博士；以及 5) Gallagher 博士的肥胖临床标记/MRI 这将为 Kupsco 博士做好准备。作为一名独立的分子环境流行病学家，调查产前暴露，这项工作的结果将推动儿童环境领域的发展。健康并为肥胖驱动因素和机制的新假设做出贡献。