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

发育起源假说将早期暴露于内分泌干扰物（EDCs）与 慢性疾病的发展，包括代谢综合征，一种影响美国25%的疾病 成年人和30%的肥胖青少年。对人类的有限研究认为， 暴露于EDCs混合物与饮食相互作用，改变母亲和儿童的代谢稳态， 考虑青春期的后续暴露是否会加剧代谢综合征的风险。 来自我们的形成性CEHC的试点人类和动物数据：“围产期暴露，表观遗传学，儿童肥胖和 性成熟”（P20 ESDI 8171/RD 834800，Pl：Peterson）表明， 代谢和表观遗传标记上的代表性母体内分泌干扰物可能在不同的敏感期不同， 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 ES 017885）和密歇根州营养和肥胖研究 中心（MNORC，P30 DK 089503），本项目将检验EDC混合物（BPA，邻苯二甲酸酯， 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-肉毒碱），并导致基因的变化 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 怀孕和青春期的饮食模式将改变EDC混合物对这些的影响， 结果。研究参与者包括密歇根州母婴配对（MMIP）队列（n=80）（扩展 R 01 ES 017005，PI：Padmanabhan）和400名儿童，从怀孕到8-15岁， 我们在墨西哥的18年早期生命暴露于环境毒物（ELEMENT）合作， 墨西哥国家公共卫生研究所。研究结果将：1）提供EDC 混合物扰乱代谢稳态，2）阐明饮食在放大或消除这种影响中的作用，3） 说明所涉及的表观遗传和转录变化，以及4）为未来干预措施的设计提供信息 以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.