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

• 批准号: 10422452
• 负责人: Allison Kupsco
• 金额: $ 14.07万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10422452
• 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

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 治疗努力。环境暴露可能会通过改变来促进儿童肥胖的发生 发展性编程。多溴二苯醚 (PBDE) 阻燃剂可在 子宫内导致产前暴露升高。实验证据表明 PBDE 具有脂肪生成作用， 然而，对人群的研究有限，其机制仍不清楚。 PBDEs可能会诱发 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 消耗。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 曝光度和效果。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，特别是线粒体组学、环境健康、流行病学、 和统计数据。作为持久性内分泌干扰物，多溴联苯醚是解决这一问题的绝佳范例。 研究/培训计划。在这项提案中，我们将利用纵向出生队列，哥伦比亚中心 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）。这些端点 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 努力。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 她著名的博士导师团队的指导。安德里亚·巴卡莱利、朱莉·赫布斯特曼、安德鲁·兰德尔、杰夫 戈德史密斯和迪姆纳·加拉格尔。具体来说，库普斯科博士将接受以下方面的培训： 1) 线粒体标记 巴卡莱利博士； 2) 与 Herbstman 博士一起探讨产前暴露和儿童环境健康； 3）中的方法 Rundle 博士的环境流行病学和因果调解； 4) 高级纵向数据分析 戈德史密斯博士； 5) 由 Gallagher 博士指导的肥胖/MRI 临床标志物。这将为库普斯科博士做好准备 作为一名独立的分子环境流行病学家，调查产前暴露， 线粒体毒性和儿童肥胖。这项工作的成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。