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

生命早期有机磷酸酯 (OPE) 暴露与青春期肥胖和心脏代谢健康

• 批准号: 10707932
• 负责人: Ann Vuong
• 金额: $ 49.52万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707932
• 关键词: 12 year old; Adipocytes; Adolescence; Adult; Affect; Age; Androgen Receptor; Biological; Biological Markers; Birth; Blood Pressure; Body Burden; Body fat; Body mass index; C-reactive protein; Canada; Chemicals; Child; Cholesterol; Chronic; Complex; Data; Development; Diet; Dyslipidemias; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Policy; Esters; Estrogen Receptors; Exposure to; Family; Fasting; Fatty acid glycerol esters; Flame Retardants; General Population; Genetic; Glucose; Glycoproteins; Gonadal Steroid Hormones; Growth; Health; Health Resources; Heart Diseases; Hip region structure; Homeostasis; Hormones; Human; Hypertension; Individual; Infant; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Joints; Leptin; Life; Lipids; Lipolysis; Lipoproteins; Longitudinal Studies; Measurement; Measures; Metabolic; Metabolic syndrome; Metabolism; Modeling; Modernization; Molecular Weight; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organophosphates; Outcome; Outcome Measure; Overweight; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Perinatal; Peroxisome Proliferator-Activated Receptors; Phase; Physical activity; Plasticizers; Play; Policy Making; Predisposition; Pregnancy; Pregnant Women; Prevalence; Prospective Studies; Public Health; Reporting; Research; Research Design; Risk Factors; Rodent; Role; Serum; Statistical Methods; TNF gene; Thermogenesis; Thyroid Hormones; Time; Tissues; Toxicology; Triglycerides; United States; adiponectin; cardiometabolism; cohort; early adolescence; early life exposure; environmental chemical; epidemiology study; fasting glucose; high risk; impaired glucose tolerance; indexing; inorganic phosphate; lipid biosynthesis; lipid metabolism; metabolic profile; novel; novel marker; obesity development; obesity in children; obesity risk; obesogen; obesogenic; particle; pollutant; polybrominated diphenyl ether; postnatal; postnatal period; prenatal; prenatal exposure; prospective; trait; transcription factor; tris(2-carboxyethyl)phosphine; urinary; waist circumference

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.

项目概要 近几十年来，儿童肥胖患病率急剧上升，使肥胖成为影响健康的问题之一。 现代世界最大的公共卫生挑战。预计到 2030 年，美国将分别有 33% 和 50% 6-11岁和12-19岁的儿童将分别超重或肥胖。环境暴露于 子宫内和产后易感性升高可能会增加肥胖风险，并产生不利影响 影响心脏代谢健康。有机磷酸酯 (OPE) 是添加型阻燃剂和增塑剂 多溴二苯醚 (PBDE) 淘汰后在全球范围内广泛使用。这 OPE 的普遍使用导致几乎所有孕妇都接触过 OPE，儿童也接触过 OPE 与成人相比，身体负担更高。 OPE 会干扰公认的生物途径，从而促进 导致肥胖和心脏代谢健康，包括破坏：1) 甲状腺激素； 2）性别 类固醇激素； 3) 过氧化物酶体增殖物激活受体以及诱导 4) 慢性低度 炎。毒理学研究表明 OPE 会增加脂质积累，扰乱代谢功能，并 损害葡萄糖耐量，支持其作为潜在致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较高的几率增加 周长、体重指数 (BMI)、总胆固醇和甘油三酯。然而，没有纵向研究 人类已经研究了生命早期重复的 OPE 测量及其与肥胖和肥胖的关系。 青春期的心脏代谢健康状况，这是一个重大的数据差距。该拟议申请将利用 健康成果和环境措施（HOME）研究的资源是最重要的 首先检查生命早期 OPE 是否与肥胖和心脏代谢健康指标相关 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，检测空腹血糖、血脂、脂联素和瘦素。我们还将另外 测量新型心脏代谢中间体，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，以及炎症生物标志物。我们将使用 用于检查复杂情况的分位数 g 计算 (Q-gcomp) 和贝叶斯核机器回归 (BKMR) OPE 混合物，用于确定 OPE 对肥胖和心脏代谢特征的个体和联合影响 青春期。我们将使用来自环境化学物质母婴研究 (MIREC) 的数据 这项研究是一项泛加拿大队列研究，旨在验证 HOME 研究的结果。我们将产生新的发现 生命早期 OPE 是否会导致青春期肥胖和代谢紊乱，并确定 潜在的易感性窗口。鉴于 OPE 的普遍存在以及肥胖和 2 型肥胖的全球负担 糖尿病，这些发现对于环境政策制定和减少接触非常有价值。