Early life organophosphate ester (OPE) exposures and adiposity and cardiometabolic health during adolescence

项目总结 近几十年来，儿童肥胖症患病率急剧上升，使肥胖症成为 现代世界最大的公共卫生挑战。据估计，到2030年，美国33%和50%的人口 6-11岁和12-19岁的儿童将分别超重或肥胖。中国的环境暴露 子宫和出生后易感性增加的时期可能会增加肥胖的风险，并对 影响心脏新陈代谢健康。有机磷酸酯(OPE)是一种添加剂阻燃剂和增塑剂 在逐步淘汰多溴二苯醚(PBDEs)后，这些物质在世界范围内得到广泛使用。这个 OPE的普遍使用导致几乎所有孕妇都有OPE暴露，儿童也有 与成年人相比，身体负担更重。OPEs干扰公认的生物学途径 肥胖和心脏代谢健康的发展，包括：1)甲状腺激素；2)性 类固醇激素；以及3)过氧化物酶体增殖物激活受体，以及4)诱导慢性低级别 发炎。毒理学研究表明，Opes增加脂质堆积，扰乱代谢功能，并 损害葡萄糖耐量，支持它们作为潜在的肥胖和代谢干扰化学物质的作用。 流行病学研究报告超重和肥胖以及腰围偏高的几率增加 周长、体重指数(BMI)、总胆固醇和甘油三酯。然而，在中国没有纵向研究 人类研究了在早期生活中重复的OPE测量及其与肥胖和 青春期心脏代谢健康，这是一个重大的数据缺口。这项拟议的应用程序将使 关于健康结果和环境措施(家庭)研究的资源将是非常重要的 首先检查早期生活操作员是否与肥胖和心脏代谢健康措施有关 青春期，包括BMI和腰围z分数，脂肪质量指数，体脂百分比，血压， 采用前瞻性研究设计的空腹血糖、血脂、脂联素和瘦素。我们还会另外 测量新的心脏代谢中间体，包括高分子脂联素、糖蛋白 乙酰(GlycA)、淫羊藿素、花生素和脂蛋白颗粒，以及炎症的生物标志物。我们将使用 用于复数检验的分位数g计算(Q-gcomp)和贝叶斯核机回归(BKMR) OPE混合物确定OPE对肥胖和心脏代谢特征的单独和联合影响 青春期。我们将使用母婴环境化学品研究(MIREC)的数据 一项泛加拿大队列研究，以验证家庭研究的结果。我们将在以下方面产生新的发现 早期生活中的OPE是否是青春期的肥胖和代谢紊乱的化学物质，并确定 潜在的易感窗口。鉴于OPE的普遍存在以及肥胖和2型的全球负担 这一发现将对环境政策的制定和减少暴露具有很高的价值。

PROJECT SUMMARY The dramatic increase in the prevalence of childhood obesity in recent decades has made obesity one of the greatest public health challenges of the modern world. It is estimated that by 2030, 33% and 50% of US children ages 6-11 and 12-19 years, respectively, will be overweight or obese. Environmental exposures in utero and during postnatal periods of heightened susceptibility may increase risk of obesity and adversely impact cardiometabolic health. Organophosphate esters (OPEs) are additive flame retardants and plasticizers that are extensively used worldwide after the phase-out of polybrominated diphenyl ethers (PBDEs). The ubiquitous use of OPEs has resulted in almost all pregnant women having OPE exposures and children having a higher body burden compared to adults. OPEs interfere with well-recognized biological pathways contributing to the development of obesity and cardiometabolic health, including disruption of: 1) thyroid hormones; 2) sex steroid hormones; and 3) peroxisome proliferator-activated receptors as well as inducing 4) chronic low-grade inflammation. Toxicological studies indicate OPEs increase lipid accumulation, disrupt metabolic function, and impair glucose tolerance, supporting their role as potential obesogenic and metabolism-disrupting chemicals. Epidemiological studies report increased odds of being overweight and obese as well as higher waist circumference, body mass index (BMI), total cholesterol, and triglycerides. However, no longitudinal study in humans has examined repeated OPE measures in early life and their association with adiposity and cardiometabolic health in adolescence, which is a significant data gap. This proposed application will capitalize on resources of the Health Outcomes and Measures of the Environment (HOME) Study to be among the very first to examine whether early life OPEs are associated with adiposity and cardiometabolic health measures in adolescence, including BMI and waist circumference z-scores, fat-mass index, body fat %, blood pressure, fasting glucose, serum lipids, adiponectin, and leptin, using a prospective study design. We will additionally measure novel cardiometabolic intermediates, including high molecular weight adiponectin, glycoprotein acetyls (GlycA), irisin, vaspin, and lipoprotein particles, as well as biomarkers of inflammation. We will use Quantile g-computation (Q-gcomp) and Bayesian Kernel Machine Regression (BKMR) to examine complex OPE mixtures to determine the individual and joint effects of OPEs on adiposity and cardiometabolic profiles in adolescence. We will use data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort, to validate findings from the HOME Study. We will generate novel findings on whether early life OPEs are obesogenic and metabolism-disrupting chemicals during adolescence and identify potential windows of susceptibility. Given the ubiquity of OPEs and the global burden of obesity and type 2 diabetes, the findings will be highly valuable for environmental policy making and exposure reduction.