孕期双酚类化合物暴露对胆汁酸代谢轮廓的影响及与妊娠期糖尿病的关联

Bisphenols, as a kind of typical environmental endocrine disruptors, have been shown to be related to metabolic disease. Animal studies have indicated that exposure of bisphenols during gestation can induce glucose metabolic disturbance and gestational diabetes mellitus (GDM). However, the relationship between maternal bisphenols exposure and GDM in human being is not clear. In the present study, based on the Guangxi Zhuang nationality birth cohort, we will measure the urinary bisphenols to explore the relationship between maternal bisphenols exposure and the risk of GDM in pregnant women, and then determine the critical window of exposure. Subsequently, we will explore the key role of metabolic profile of serum bile acids which are involved in the process of bisphenols-associated GDM using a two-phase study design: (1) select key serum metabolites (bile acids) in glucose metabolic pathway whose levels were altered by bisphenols exposure using metabolomics techniques in a relatively small population; (2) determine the concentration of these key metabolites in the serum samples in the large population of this cohort, and analyze the causal relationship of maternal bisphenols exposure - altered metabolic profile of serum bile acids - GDM using mediation analysis. The present project will be able to provide direct evidence on the increased risk of GDM resulted from maternal bisphenols exposure, and clarify the role of altered metabolic profile of serum bile acids in the effect of bisphenols exposure on GDM. Moreover, these findings will provide scientific basis for the prevention of GDM.

双酚类化合物是一类常见环境内分泌干扰物，研究发现双酚类化合物暴露与糖代谢疾病相关。动物实验表明孕期双酚类化合物暴露可破坏母体血糖稳态导致妊娠期糖尿病，而人类孕期暴露这类物质是否会增加妊娠糖尿病风险并不清楚。本项目拟基于进行中的广西壮族出生队列，随访确定孕妇妊娠期糖尿病发病情况，分析孕妇在孕期不同阶段的双酚类化合物内暴露水平与妊娠期糖尿病之间的关联，确定作用敏感期。在此基础上，检测孕妇血清胆汁酸代谢轮廓改变，筛选与双酚类化合物暴露相关的糖代谢调控关键胆汁酸代谢物并定量检测，分析其在双酚类化合物暴露与妊娠期糖尿病中的介导作用，最终阐明这些胆汁酸代谢物浓度改变与双酚类化合物暴露和妊娠期糖尿病发病间的因果关系。本项目将为明确孕期双酚类化合物暴露对胆汁酸代谢轮廓的影响及与妊娠期糖尿病的关联提供直接证据，并为妊娠期糖尿病的危险因素防控提供科学依据。

双酚类化合物作为一类常见环境内分泌干扰物，其与妊娠期糖尿病之间的研究有限且结论不一致。胆汁酸作为重要的代谢信号分子参与糖脂代谢，其在妊娠期糖尿病发病过程中的作用也尚未有研究报道。本项目检测了广西壮族出生队列822例孕妇孕早期血清的双酚A（BPA）、双酚B（BPB）、双酚F（BPF）、双酚S（BPS）和四溴双酚A（TBBPA）浓度，分析其与妊娠期糖尿病之间的关联，发现孕妇双酚类化合物暴露以BPA为主，低水平双酚混合暴露会增加孕妇患妊娠期糖尿病的风险。在此基础上，我们从研究人群中选取了141例妊娠期糖尿病病例并1:1匹配健康对照，对血清胆汁酸（BAs）进行了代谢组学检测，中介效应分析探讨双酚类化合物暴露-胆汁酸代谢轮廓改变-妊娠期糖尿病的关联。研究发现：在病例-对照人群所检测到的37种胆汁酸中，甘氨胆酸等12种与妊娠期糖尿病发生风险相关联，且总胆汁酸、总初级胆汁酸和总结合胆汁酸水平，以及4种主要结合型与游离型胆汁酸的浓度比值均与妊娠期糖尿病风险呈显著正相关。BPA暴露与3种胆汁酸以及甘氨胆酸/胆酸、牛磺胆酸/胆酸水平呈显著正相关；BPB暴露与6种胆汁酸水平呈正相关，与猪脱氧胆酸水平呈负相关；TBBPA暴露与甘氨鹅脱氧胆酸/鹅脱氧胆酸和牛磺鹅脱氧胆酸/鹅脱氧胆酸存在正相关关系。通过中介效应分析，发现甘氨胆酸、牛磺胆酸、甘氨胆酸/胆酸和牛磺鹅脱氧胆酸/鹅脱氧胆酸在双酚类化合物暴露与妊娠期糖尿病风险的关联性中起显著中介效应，提示双酚类化合物暴露对胆汁酸代谢轮廓的干扰作用是其导致妊娠期糖尿病风险升高的重要通路。研究结果为双酚类化合物的健康风险评价，妊娠期糖尿病的发病机制探查和危险因素防控提供了科学依据。