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

 描述(申请人提供)：在过去的几十年里，妊娠期糖尿病(GDM)的患病率增加了3倍，这意味着在有这种病史的妇女中，2型糖尿病(T2 DM)的流行日益严重。越来越多的文献表明，邻苯二甲酸盐，一种内分泌干扰化学物质，与非怀孕女性T2 DM风险增加有关。这些化学品用于塑料、食品包装、化妆品和其他消费品。邻苯二甲酸盐与核受体、过氧化物酶体增殖物激活受体(PPAR)α和伽马结合，这些受体可能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怀孕妇女中的T2 DM风险有关，但目前尚不清楚这些化学物质是否与GDM风险相关。我们研究的初步数据表明，在参与正在进行的4,000名女性怀孕队列研究的一组女性(n=350)中，邻苯二甲酸单苄酯(MBzP)和单(3-羧丙基)(MCPP)邻苯二甲酸单酯(MBZP)和单(3-羧丙基)邻苯二甲酸单酯(MCPP)的尿液水平与妊娠期糖尿病的妊娠相关风险因素之间存在关联，如孕前体重增加、妊娠体重过度增加和妊娠期血糖水平升高。然而，还没有研究评估邻苯二甲酸盐水平和妊娠期糖尿病风险之间的关系。此外，已知妊娠期糖尿病会显著增加T2 DM的未来发展，有妊娠期糖尿病病史的女性中有50%以上会继续发展为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未来患T2 DM的风险明显更高。然而，还没有研究评估怀孕期间和怀孕后邻苯二甲酸盐水平之间的联系，以确定这些化学物质是否会增加怀孕后持续血糖调节失调的风险。为此，我们建议在已建立的妊娠队列中进行一项嵌套式病例对照研究，以评估560名妇女妊娠1、2周尿中邻苯二甲酸单苄酯和邻苯二甲酸单(3-羧丙基)酯代谢产物水平与妊娠期糖尿病风险的关系，以及与GDM风险相关的生物标记物(即血糖水平)。我们还将对866名新招募的妇女进行孕后随访研究，包括妊娠期糖尿病、糖耐量受损和血糖正常的妇女，以评估较高的孕期和孕后MBZP和MCPP水平与产后6周的血糖、胰岛素、血红蛋白A1c和HOMA-IR水平之间的关系，作为妊娠后持续血糖调节异常的衡量标准。通过评估怀孕和产后这两个敏感时间点邻苯二甲酸盐水平和糖尿病风险的作用，这项研究将更好地了解这些高度普遍的内分泌干扰化学物质对妊娠期糖尿病和未来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.