Phthalates, Gestational Diabetes, and Markers of Type 2 Diabetes Risk in Women

 描述（由申请人提供）：在过去的几十年中，妊娠期糖尿病（GDM）的患病率增加了3倍，这意味着有此病史的女性中2型糖尿病（T2 DM）的流行率不断增加。越来越多的文献表明，邻苯二甲酸酯（一种内分泌干扰化学物质）与非妊娠女性T2 DM风险增加相关。这些化学品用于塑料，食品包装，化妆品和其他消费品。邻苯二甲酸酯结合核受体，过氧化物酶体增殖物激活受体（PPAR）α和γ，其可以调节调节葡萄糖代谢的靶基因。虽然邻苯二甲酸酯已被发现与非孕妇的T2 DM风险有关，但目前尚不清楚这些化学物质是否与GDM风险有关。我们研究的初步数据表明，在参与一项正在进行的4,000名女性妊娠队列研究的一部分女性（n=350）中，邻苯二甲酸单苄基酯（MBzP）和邻苯二甲酸单（3-羧基丙基）酯（MCPP）的尿液水平与妊娠相关的GDM风险因素（如孕前体重增加、妊娠期体重过度增加和妊娠期间血糖水平升高）之间存在相关性。然而，没有研究评估邻苯二甲酸酯水平和GDM风险之间的关联。此外，已知GDM会大幅增加T2 DM的未来发展，超过50%的有GDM病史的女性会发展为T2 DM。这种增加的风险早在产后6周就可以看到，空腹和2小时血糖水平较高的女性将来患T2 DM的风险显著较高。然而，没有研究评估妊娠期间和妊娠后邻苯二甲酸酯水平之间的相关性，以确定这些化学物质是否会导致妊娠后持续葡萄糖失调的风险增加。为此，我们建议在一个已建立的妊娠队列中进行巢式病例对照研究，以评估560名女性的妊娠早期和妊娠中期尿中邻苯二甲酸单苄酯和邻苯二甲酸单（3-羧丙基）酯代谢物水平与GDM风险之间的关系，以及与GDM风险相关的生物标志物（即血糖水平）。我们还将在866名新招募的女性中进行一项妊娠后随访研究，包括GDM、葡萄糖耐量受损和正常妊娠的女性，以评估妊娠和妊娠后较高的MBzP和MCPP水平与产后6周的妊娠后血糖、胰岛素、血红蛋白A1 c和HOMA-IR水平之间的相关性，作为妊娠后持续血糖失调的指标。通过评估邻苯二甲酸酯水平和糖尿病风险在两个敏感时间点-怀孕和产后的作用，这项研究将更好地了解这些高度流行的内分泌干扰物对GDM和未来T2 DM风险的作用，并对识别可改变的风险因素产生影响。

 DESCRIPTION (provided by applicant): Over the past several decades, the prevalence of gestational diabetes (GDM) has increased 3-fold, with implications for the growing type 2 diabetes (T2DM) epidemic among women with a history of this condition. An increasing body of literature suggests that phthalates, an endocrine disrupting chemical, are associated with increased T2DM risk in non-pregnant women. These chemicals are used in plastics, food packaging, cosmetics, and other consumer products. Phthalates bind to the nuclear receptors, peroxisome proliferator activated receptors (PPAR) alpha and gamma, which may modulate target genes that regulate glucose metabolism. While phthalates have been found to be associated with T2DM risk among non-pregnant women, it remains unclear whether these chemicals are associated with GDM risk. Preliminary data from our research suggest associations between urinary levels of mono-benzyl (MBzP) and mono-(3-carboxypropyl) (MCPP) phthalates and pregnancy-related risk factors of GDM, such as increased pre-pregnancy weight, excessive gestational weight gain, and elevated blood glucose levels during pregnancy among a subset of women (n=350) participating in an ongoing pregnancy cohort study of 4,000 women. Yet, no studies have assessed the association between phthalate levels and GDM risk. In addition, GDM is known to substantially increase future development of T2DM, with over 50% of women with a history of GDM going on to develop T2DM. This increased risk can be seen as early as 6-weeks postpartum, with women with higher fasting and 2-hour blood glucose levels being at substantially higher risk of developing T2DM in the future. However, no studies have evaluated the association between phthalate levels during and after pregnancy to determine whether these chemicals contribute to an increased risk of sustained glucose dysregulation after pregnancy. To this end, we propose conducting a nested case-control study in an established pregnancy cohort to assess the association between 1st and 2nd trimester urinary metabolite levels of mono-benzyl phthalate and mono-(3-carboxypropyl) phthalate and GDM risk, as well as biomarkers associated with GDM risk (i.e. blood glucose levels) among 560 women. We will also conduct a post-pregnancy follow-up study in 866 newly recruited women, including those with GDM, impaired glucose tolerance, and normal glycemia, to evaluate the association of higher pregnancy and post-pregnancy levels of MBzP and MCPP and post-pregnancy glucose, insulin, hemoglobin A1c, and HOMA-IR levels at 6-weeks postpartum as measures of sustained glucose dysregulation after pregnancy. By evaluating the role of phthalate levels and diabetes risk at two sensitive time points-pregnancy and the postpartum, this research will give better understanding for the role of these highly-prevalent endocrine disrupting chemicals on GDM and future T2DM risk, with implications for identifying modifiable risk factors.