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.

摘要 预防糖尿病已成为国家公共卫生的优先事项。妊娠期糖尿病孕妇 (GDM)糖尿病史携带着在其一生中发展为2型糖尿病（T2D）显著更高风险。因此，我们认为， 妊娠期糖尿病是一种独特的模型，可用于早期代谢缺陷如胰岛素抵抗和β细胞 年轻女性患糖尿病之前的功能障碍。除了众所周知的风险因素， 由于不健康的生活方式和遗传易感性，人们越来越关注内分泌干扰物的暴露。 化学品，如持久性有机污染物（POP），作为T2D的新风险因素。本研究的目的是 调查妇女在怀孕的脆弱时间窗内接触持久性有机污染物的长期影响 和产后期的代谢轨迹，导致2型糖尿病的妇女怀孕后。 动物模型和人类研究提供的越来越多的证据表明，接触持久性有机污染物会对环境产生不利影响， 胰岛素敏感性和β细胞功能，从而增加T2 D风险。然而，以前的流行病学研究， 持久性有机污染物和糖尿病大多是横截面的，并有局限性，只检查一个单一的影响， 化合物或化学类别。关于接触持久性有机污染物混合物对环境的联合影响， 代谢下降和T2D。重要的是，没有研究评估了持久性有机污染物暴露的长期影响 在怀孕期间和产后期间对代谢下降和女性晚年T2D的发展的影响， 超出了其他风险因素的影响，如衰老和体重增加。为了填补这些知识空白，我们建议 测量60种优先选择的潜在致糖尿病的持久性有机污染物作为体内持久性有机污染物的血浆浓度 妇女在怀孕和产后期间的接触水平。该项目的主要目标是 研究妊娠期间和妊娠后接触持久性有机污染物对胰岛素纵向下降的长期影响 敏感性和β细胞功能以及产后妇女糖尿病发病率。这项研究将建立在 一个独特的前瞻性队列，102名妇女在怀孕期间患有GDM，并从怀孕开始进行随访 到分娩后12年。胰岛素敏感性和β细胞功能在最初的队列中使用 金标准法静脉葡萄糖耐量试验在妊娠晚期和每15 分娩后12个月至12年。进一步调查持久性有机污染物接触与 长期代谢下降，我们将进一步研究空腹血浆中的纵向代谢组学特征， 在妊娠晚期、产后和12年内每15个月随访时采集样本。我们 建议使用这些代谢组学特征作为在以下情况下对持久性有机污染物接触的生物反应的特征： 妊娠，并确定那些预测代谢下降和T2D发病率。该项目将推动我们的 了解持久性有机污染物接触在怀孕和产后关键接触窗口期的作用 在扰乱代谢途径和诱导糖尿病病理生理学和女性T2D发病率的时期。