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

项目总结：儿童肥胖是一个主要的公共卫生风险，迫切需要新的预防措施， 治疗的努力。环境暴露可能通过改变儿童肥胖症的发病率， 发展规划。多溴联苯醚（PBDE）阻燃剂可在 导致产前暴露增加。实验证据表明，多溴联苯醚具有脂肪形成作用， 然而，在人群中的研究有限，其机制仍不清楚。多溴联苯醚可能导致 线粒体功能障碍，这是进一步牵连肥胖，反映了线粒体的关键作用，在能源 消费我们建议调查产前多溴联苯醚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的机制， 曝光和效果。在这个K99/R 00中，Allison Kupsco博士将补充她在实验毒理学方面的技能 在人口研究，特别是生物学，环境卫生，流行病学， 和统计数据。作为持久性的内分泌干扰化学品，多溴二苯醚是这方面的一个很好的范例 研究/培训计划。在本提案中，我们将利用一个纵向出生队列，即哥伦比亚研究中心， 儿童环境健康（CCCEH），脐带血多溴联苯醚数据，肥胖纵向数据（BMI和 脂肪量），并在18岁时进行创新的腹部磁共振成像（MRI） 来识别脂肪的次级储存库。在K99阶段，现有的肥胖数据将提供以下方面的精确信息： 纵向和脂肪组织的具体影响的多溴二苯醚，单独和混合物（目标1），我们将 产生线粒体DNA含量的纵向标记，这是线粒体健康的一个很好的一般指标（目标2）。 在R 00阶段，Kupsco博士将完成mtDNA含量数据分析，并启动一项新的研究， 使用新型深度测序方法评估线粒体DNA氧化损伤和突变（异质性） 多溴二苯醚对线粒体DNA的特殊影响，并阐明肥胖症的线粒体基础（目标3）。这些终点 可以作为早期生物标志物，以识别具有高肥胖风险的儿童，这对预防至关重要 努力为了完成这些目标，Kupsco博士将接受正式课程和专家培训 她的著名指导团队Andrea Baccarelli博士，Julie Herbstman，Andrew Rundle，Jeff 金匠和丁普娜·加拉格尔。具体来说，Kupsco博士将接受以下方面的培训：1）线粒体标记物， 博士Baccarelli; 2）产前暴露和儿童环境健康与Herbstman博士; 3）方法， 环境流行病学和因果调解与博士Rundle; 4）先进的纵向数据分析与 博士金匠;和5）肥胖症的临床标志物/Gallagher博士的MRI。这会让库普斯科博士 职业生涯作为一个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。这项工作的结果将推动儿童环境领域的发展。 健康和有助于对肥胖的驱动因素和机制的新假设。

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.