The Long-term Influence of Persistent Organic Pollutants Exposure During and After Pregnancy on Metabolic Decline in Women After Pregnancies Complicated by Gestational Diabetes

妊娠期间和妊娠后持久性有机污染物暴露对妊娠合并妊娠糖尿病女性代谢下降的长期影响

• 批准号: 10256678
• 负责人: Zhanghua Chen
• 金额: $ 46.66万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256678
• 关键词: Adipose tissue; Affect; Aging; Amino Acids; Animal Model; Animals; Archives; Beta Cell; Biological; Biological Assay; Body Burden; Body Composition; Body fat; Breast Feeding; Cell physiology; Chemicals; Data; Defect; Development; Diabetes Mellitus; Diet; Elderly; Endocrine Disruptors; Environment; Epidemic; Exposure to; Fasting; Flame Retardants; Functional disorder; Future; General Population; Genetic Predisposition to Disease; Gestational Diabetes; Glucose; Goals; Gold; Health; Hispanics; Human; Incidence; Individual; Insulin Resistance; International; Investigation; Joints; Knowledge; Link; Long-Term Effects; Measures; Metabolic; Metabolic Pathway; Methods; Minority; Modeling; Mothers; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Parents; Pathogenesis; Physical activity; Plasma; Poison; Polychlorinated Biphenyls; Postpartum Period; Predisposition; Pregnancy; Pregnancy Trimesters; Pregnant Women; Prospective Studies; Prospective cohort; Public Health; Publishing; Recording of previous events; Regulation; Research; Risk Factors; Role; Sampling; Structure of beta Cell of islet; Third Pregnancy Trimester; Time; Visit; Weight Gain; Woman; cohort; diabetes pathogenesis; diabetes risk; diabetogenic; epidemiology study; follow-up; health disparity; high risk; insulin sensitivity; interest; intravenous glucose tolerance test; lifetime risk; lipid metabolism; lipophilicity; metabolomics; novel; organochlorine pesticide; persistent organic pollutants; predictive signature; prevent; preventive intervention; prospective; public health priorities; response; unhealthy lifestyle; young woman

ABSTRACT Preventing diabetes has become a national priority for public health. Women with gestational diabetes mellitus (GDM) history carry a significantly higher risk of developing type 2 diabetes (T2D) over their lifetime. Therefore, GDM has been used as a unique model to identify early metabolic defects such as insulin resistance and β-cell dysfunction that precede the development of diabetes in young women. Beyond well-known risk factors including unhealthy lifestyle and genetic susceptibility, there is a growing concern over exposures to endocrine disrupting chemicals, such as persistent organic pollutants (POPs), as novel risk factors for T2D. The goal of this study is to investigate long-term effects of exposure to POPs during a woman’s vulnerable time windows of pregnancy and the postpartum period on the metabolic trajectory that leads to T2D in women after GDM pregnancies. Mounting evidence from animal models and human studies suggests that POPs exposure can adversely affect insulin sensitivity and β-cell function thereby increasing T2D risk. However, previous epidemiological studies of POPs and diabetes were mostly cross-sectional and have limitations of only examining the effect of a single chemical compound or chemical class. Little is known about the joint effects of exposure to POPs mixture on the metabolic decline and T2D. Importantly, no studies have assessed the long-term effects of POPs exposure during pregnancy and postpartum period on metabolic decline and development of T2D in women’s later life, beyond the effects of other risk factors such as aging and weight gain. To fill these knowledge gaps, we propose to measure plasma concentrations of 60 priori-selected potentially diabetogenic POPs as the internal POPs exposure level in women during pregnancy and postpartum period. The broad objectives of this project are to investigate long-term effects of POPs exposure during and after pregnancy on the longitudinal decline of insulin sensitivity and β-cell function as well as diabetes incidence in women after delivery. The study will be built upon a unique prospective cohort of 102 women who had GDM during pregnancy and were followed from pregnancy to 12 years after delivery. Insulin sensitivity and β-cell function were assessed in the original cohort using the gold-standard method of intravenous glucose tolerance test at the 3rd trimester of pregnancy and every 15 months up to 12 years after delivery. To further investigate the biological mechanism linking POPs exposure and long-term metabolic decline, we will further investigate the longitudinal metabolomic profiles from fasting plasma samples collected at the 3rd trimester of pregnancy, postpartum and every 15-month visit up to 12 years. We propose to use these metabolomic profiles as signatures of the biological response to the POPs exposure during pregnancy and identify those that predict metabolic decline and T2D incidence. This project will advance our knowledge in the role of POPs exposure during critical exposure windows of pregnancy and the postpartum period in perturbing metabolic pathways and inducing diabetes pathophysiology and T2D incidence in women.

抽象的 预防糖尿病已成为公共卫生的国家优先事项。妊娠糖尿病的妇女 （GDM）历史在其一生中患有2型糖尿病（T2D）的风险明显更高。所以， GDM已被用作识别早期代谢缺陷的独特模型，例如胰岛素抵抗和β细胞 在年轻女性糖尿病发展之前的功能障碍。除了众所周知的风险因素，包括 不健康的生活方式和遗传敏感性，对内分泌的暴露越来越关注 化学物质，例如持续的有机污染物（POP），是T2D的新风险因素。这项研究的目的是 调查在女性脆弱的怀孕时间窗口中暴露于流行音乐的长期影响 以及GDM妊娠后女性T2D的代谢轨迹的产后时期。 来自动物模型和人类研究的越来越多的证据表明，流行暴露会对 胰岛素敏感性和β细胞功能，从而增加T2D风险。但是，以前的流行病学研究 流行音乐和糖尿病主要是横截面，只有检查单个效果的局限性 化合物或化学类别。关于暴露于Pops混合物的关节作用知之甚少 代谢下降和T2D。重要的是，没有研究评估POPS暴露的长期影响 在怀孕和产后期间，关于妇女后来的T2D代谢下降和发展的期间， 除了其他风险因素（例如衰老和体重增加）的影响。为了填补这些知识空白，我们建议 在内部流行中测量60个先验选择的潜在糖尿病性POP的血浆浓度 怀孕和产后期间女性的暴露水平。该项目的广泛目标是 研究妊娠期间和妊娠期间POP暴露对胰岛素纵向下降的长期影响 敏感性和β细胞功能以及分娩后女性的糖尿病发生率。该研究将建立在 在怀孕期间患有GDM的102名女性的独特前瞻性队列 交货后12年。使用胰岛素灵敏度和β细胞功能在原始队列中使用 静脉葡萄糖耐受性测试的金标准方法在怀孕的第三个早期和每15 交货后最多12年。为了进一步研究，将POP暴露的生物机制与 长期代谢下降，我们将进一步研究禁食等离子体的纵向代谢谱 在怀孕的第三个三个月，产后和每15个月的访问中收集的样本最多12年。我们 建议使用这些代谢组概况作为对POPS暴露的生物反应的特征 怀孕并确定那些预测代谢下降和T2D事件的人。这个项目将推动我们的 在关键暴露窗户和产后的关键暴露窗口中，POPS暴露的作用知识 女性的代谢途径和诱导糖尿病的病理生理学和T2D发病率的时期。