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

项目摘要 近几十年来，儿童肥胖症的患病率急剧增加，使肥胖症成为世界上最严重的疾病之一。 现代世界最大的公共卫生挑战。据估计，到2030年，33%和50%的美国 6-11岁和12-19岁的儿童将分别超重或肥胖。环境暴露 子宫内和出生后期间的易感性增加可能会增加肥胖的风险， 影响心脏代谢健康。有机磷酸酯（OPEs）是添加型阻燃剂和增塑剂 在多溴联苯醚（PBDEs）逐步淘汰后，在世界范围内广泛使用。的 OPE的普遍使用导致几乎所有孕妇都有OPE暴露， 与成年人相比，身体负担更重。OPEs干扰公认的生物途径， 肥胖和心脏代谢健康的发展，包括破坏：1）甲状腺激素; 2）性 类固醇激素;和3）过氧化物酶体增殖物激活受体以及诱导4）慢性低度恶性 炎症毒理学研究表明，OPEs增加脂质积累，破坏代谢功能， 降低葡萄糖耐量，支持其作为潜在致肥胖和代谢破坏化学物质的作用。 流行病学研究报告称，超重和肥胖以及腰围增大的几率增加 围度、体重指数（BMI）、总胆固醇和甘油三酯。然而，没有纵向研究， 人类已经研究了早期生命中重复的OPE测量及其与肥胖的关系， 青少年的心脏代谢健康，这是一个重大的数据缺口。本申请将利用 健康成果与环境措施研究的资源， 第一次检查早期生活OPEs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评分，脂肪质量指数，体脂%，血压， 空腹血糖、血脂、脂联素和瘦素，采用前瞻性研究设计。我们还将 测量新的心脏代谢中间体，包括高分子量脂联素、糖蛋白 乙酰基（GlycA）、鸢尾素、vaspin和脂蛋白颗粒，以及炎症的生物标志物。我们将使用 分位数g计算（Q-gcomp）和贝叶斯核机器回归（BKMR）来检查复杂的 OPE混合物，以确定OPE对肥胖和心脏代谢特征的个体和联合影响， 青春期我们将使用环境化学品母婴研究（MIREC）的数据 研究，一个泛加拿大的队列，以验证从家庭研究的结果。我们将在以下方面产生新的发现： 早期生活中的OPEs是否是致肥胖和青春期代谢紊乱的化学物质，并确定 敏感性的潜在窗口。考虑到OPEs的普遍存在以及肥胖和2型糖尿病的全球负担， 糖尿病，研究结果将是非常有价值的环境政策的制定和减少接触。

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.