Project 2: Metabolic Consequences of In Utero and Peripubertal Toxicant-Diet E

发育起源假说将早期接触内分泌干扰物(EDCs)与 慢性疾病的发展，包括代谢综合征，一种影响多达25%的美国人的疾病 成年人和30%的肥胖青少年。有限的人类研究已经考虑了这种机制， 接触EDCs混合物会与饮食相互作用，改变母婴代谢的动态平衡，也不 考虑青春期的后续暴露是否会加剧代谢综合征的风险。 来自我们正在形成的CEHC的试验性人类和动物数据：围产期暴露、表观遗传学、儿童肥胖和 性成熟“(P20 ESDI 8171/RD834800，PL：Peterson)表明， 代谢性和表观遗传学标志物上具有代表性的母体内皮细胞在不同的敏感期可能有所不同 儿童发展。利用无与伦比的机构资源，包括UM NIEHS中心 卓越表观遗传学实验室(P30 ES017885)和密歇根营养与肥胖研究 中心(MNORC，P30 DK089503)，这个项目将检验EDC混合物(双酚A，邻苯二甲酸盐， 铅、镉)通过表观遗传机制诱导氧化应激(酪氨酸氧化产物)，破坏 代谢稳态(游离脂肪酸、氨基酸、酰基肉碱)并导致基因变化 转录和代谢功能。我们进一步假设膳食中大量和微量营养素的摄入量 孕期和青春期的饮食模式将改变EDC混合物对这些因素的影响 结果。研究参与者包括密歇根州母婴配对(MMIP)队列(n=80)(扩展 R01 ES017005，PI：Padmanabhan)和400名儿童从怀孕到8-15岁 我们在墨西哥18年的早期接触环境毒物(元素)与 墨西哥国家萨鲁德公共研究院(INSP)。调查结果将：1)提供EDC的概念证据 混合物扰乱代谢动态平衡，2)阐明饮食在放大或否定这种影响方面的作用，3) 说明所涉及的表观遗传和转录变化，并为未来干预措施的设计提供信息 改变子宫内和青春期过渡期间EDC暴露的代谢后果。

The developmental origins hypothesis relates early exposures to endocrine disrupting chemicals (EDCs) to the development of chronic diseases, including metabolic syndrome, a condition affecting up to 25% of US adults and 30% of obese adolescents. Limited research in humans has considered the mechanisms by which exposures to EDCs mixtures interact with diet to alter maternal and child metabolic homeostasis, nor considered whether subsequent exposures during adolescence exacerbate risk of metabolic syndrome. Pilot human and animal data from our Formative CEHC: 'Perinatal exposures, epigenetics, child obesity and sexual maturation" (P20 ESDI 8171/ RD834800, Pl: Peterson) suggest that the disruptive effects of representative maternal EDCs on metabolic and epigenetic markers may differ across sensitive periods of child development. Drawing on unparalleled institutional resources including the UM NIEHS Center of Excellence Epigenetics Laboratory (P30 ES017885) and the Michigan Nutrition and Obesity Research Center (MNORC, P30 DK089503), this project will test the hypothesis that EDC mixtures (BPA, phthalates, lead, cadmium) via epigenetic mechanisms induce oxidative stress (tyrosine oxidation products), disrupt metabolic homeostasis (free fatty acids, amino acids, Acyl-carnitine) and lead to changes in gene transcription and metabolic function. We further hypothesize that dietary macro- and micronutrient intake and dietary patterns during pregnancy and adolescence will modify the impact of EDC mixtures on these outcomes. Study participants include the Michigan Mother-Infant Pairs (MMIP) cohort (n=80) (extension of R01 ES017005, PI: Padmanabhan) and 400 children followed from pregnancy to 8-15 years of age through our 18-yr Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) collaboration with Mexico's Instituto Nacional de Salud Publica (INSP). Findings will: 1) provide proof of concept that EDC mixtures perturb metabolic homeostasis, 2) clarify the role of diet in amplifying or negating such effects, 3) illustrate the epigenetic and transcriptional changes involved and 4) inform the design of future interventions to modify metabolic consequences of EDC exposures both in utero and during the pubertal transition.