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：
10670305
负责人：
Allison Kupsco
金额：
$ 24.9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
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/10670305
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 Markers Complement Consumption DNA Repair Data Data Analyses Development Endocrine Disruptors Energy consumption Environment Environmental Epidemiology Environmental Exposure Environmental Health Epidemiologist Epidemiology Ethnic Origin Exposure to Fatty acid glycerol esters Flame Retardants Genome Goals Growth Health Hispanic Human Incidence Individual Investigation Link Long-Term Effects Low income Magnetic Resonance Imaging Measures Mediating Mediation Mentors Metabolic Diseases Methods Mitochondria Mitochondrial DNA Modeling Molecular Mothers Mutation Obesity Oxidative Stress Oxidative Stress Induction Pathogenesis Phase Ploidies Population Predisposition Prevalence Prevention Prevention strategy Production Public Health Research Risk Role Sample Size Source Stress Study models Testing Therapeutic Tissues Toxic effect Toxicant exposure Toxicology Training Training Programs Umbilical Cord Blood Work abdominal fat aged bioaccumulation career clinical training cohort deep sequencing early detection biomarkers epidemiology study follow-up health data heteroplasmy human population study in utero indexing innovation lipid biosynthesis mitochondrial DNA mutation mitochondrial dysfunction next generation sequencing novel novel marker obesity in children obesity prevention obesity risk oxidative damage polybrominated diphenyl ether predictive marker prenatal prenatal exposure prospective racial minority 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：儿童肥胖是迫切需要新预防和的主要公共卫生风险治疗努力。环境暴露可能会通过改变来促进儿童对象的开始开发编程。多溴溴化的二苯基醚（PBDE）标志剂可以在子宫导致产前暴露升高。实验证据表明，PBDE是掺杂的，但是，人口的研究是有限的，机制尚不清楚。 PBDE可能会诱导线粒体功能障碍，进一步与肥胖有关，反映了线粒体在能量中的关键作用消耗。我们建议调查产前PBDE暴露与儿童肥胖的关联，检查线粒体DNA（mtDNA）含量，氧化损伤和突变作为潜在机制暴露和效果。在此K99/R00中，Allison Kupsco博士将补充她在实验毒理学方面的技能在人群研究中的培训，特别是线粒体，环境健康，流行病学方面的培训，和统计。作为持续的，内分泌干扰化学物质的PBDE，PBDE是一个极好的范式。研究/培训计划。在此提案中，我们将利用纵向出生队列，哥伦比亚中心儿童环境卫生（CCCEH），具有脐带血PBDE数据，有关肥胖的纵向数据（BMI和脂肪质量）从5至18岁，以及18岁时创新的腹部磁共振成像（MRI）识别脂肪sub-depots。在K99阶段，现有的肥胖数据将提供有关的精确信息 PBDE的纵向和脂肪组织特定效应，单独和混合物（AIM 1），我们将产生mtDNA含量的纵向标记，这是线粒体健康的出色一般指标（AIM 2）。在R00阶段，Kupsco博士将完成mtDNA内容数据分析，并开始对 mtDNA氧化损伤和突变（异质）采用新颖的深层测量方法来评估 PBDE对mtDNA的特定影响并阐明了肥胖的线粒体基础（AIM 3）。这些终点可以作为早期生物标志物来识别肥胖风险高的儿童，这对于预防至关重要努力。为了完成这些目标，Kupsco博士将接受培训，作为正式课程和专家她著名的DRS指导团队的指导。 Andrea Baccarelli，Julie Herbstman，Andrew Rundle，Jeff Goldsmith和Dympna Gallagher。具体来说，Kupsco博士将接受培训； 1）线粒体标记 Baccarelli博士； 2）与Herbstman博士一起产前暴露和儿童环境健康； 3）方法与Rundle博士一起环境流行病学和因果关系； 4）高级纵向数据分析戈德史密斯博士； 5）Gallagher博士的肥胖/MRI临床标记。这将为Kupsco博士准备作为独立分子环境流行病学家的职业，调查产前暴露，线粒体毒性和子对象。这项工作的结果将推动儿童环境领域健康并促进了有关驱动因素和肥胖机制的新假设。