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

项目摘要：儿童肥胖是一个重大的公共健康风险，迫切需要新的预防和治疗方法 治疗方面的努力。环境暴露可能通过改变环境而促进儿童肥胖的发生 发展规划。多溴联苯醚(PBDE)阻燃剂可在 宫内感染会导致产前暴露增加。实验证据表明，多溴二苯醚是成脂的， 然而，在人类群体中进行的研究有限，其机制仍不清楚。多溴联苯醚可能会导致 线粒体功能障碍，这进一步与肥胖有关，反映了线粒体在能量中的关键作用 消费。我们建议调查产前接触多溴二苯醚与儿童肥胖症的关系， 检测线粒体DNA(MtDNA)含量、氧化损伤和突变作为潜在的机制 曝光和效果。在K99/R00中，艾莉森·库普斯科博士将补充她在实验毒物学方面的技能 接受过人类人口研究方面的培训，特别是在线粒体、环境健康、流行病学、 和统计数据。作为持久的、干扰内分泌的化学物质，多溴二苯醚是这方面的极佳范例暴露。 研究/培训计划。在这项提案中，我们将利用纵向出生队列，哥伦比亚大学中心 儿童环境健康(CCCEH)和脐带血多溴联苯醚数据、肥胖纵向数据(BMI和 5至18岁)和18岁的创新腹部磁共振成像(MRI) 以确定脂肪储存库。在K99阶段，现有的肥胖症数据将提供关于 多溴二苯醚的纵向和脂肪组织特异性效应，单独和混合(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R00阶段，Kupsco博士将完成mtDNA含量数据分析，并启动对 用一种新的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的特定影响，并阐明肥胖的线粒体基础(目标3)。这些终端 可以作为早期生物标记物来识别高肥胖风险的儿童，这对预防至关重要 努力。为了实现这些目标，库普斯科博士将接受正规课程和专家相结合的培训 由安德里亚·巴卡雷利博士、朱莉·赫布斯特曼博士、安德鲁·朗德尔博士、杰夫博士组成的著名指导团队提供指导 戈德史密斯和丁普娜·加拉格尔。具体地说，库普斯科博士将接受以下方面的培训：1)线粒体标记 Baccarelli博士；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Rundle博士的因果调解；4)高级纵向数据分析 戈德史密斯博士；5)肥胖的临床标记物/加拉格尔博士的磁共振成像。这将为Kupsco博士准备一个 作为一名独立的分子环境流行病学家，调查产前暴露， 线粒体毒性与儿童肥胖。这项工作的成果将推动儿童环境领域的发展 并有助于提出关于肥胖的驱动因素和机制的新假说。

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.