SOCS3基因DNA甲基化在联结农村人群双酚类暴露与2型糖尿病发病中作用的巣式病例对照研究

Bisphenol A (BPA) and BPA substitutes (bisphenol S and bisphenol F) are widespread environmental endocrine disruptors. A number of experimental studies have shown that bisphenols exposure can affect the occurrence of diabetes. Nevertheless, available epidemiology surveys such as cohort studies or prospective nested case-control studies which could provide causal evidence of the relationship between bisphenols exposure and diabetes are lacked. Type 2 diabetes mellitus (T2DM) is an endocrine disease that is influenced by epigenetic and environmental factors. The DNA methylation level of SOCS3 gene is significantly associated with T2DM, and bisphenols exposure has the ability to alter SOCS3 protein levels, suggesting the change of DNA methylation may play a role in the pathway of bisphenol exposure resulting in T2DM. However, it is unclear whether SOCS3 DNA methylation has an interaction or mediation effect on the relationship between bisphenols exposure and T2DM. Therefore, we propose to design a prospective nested case-control study in Henan rural population to determine the dose-effect relationship between bisphenols exposure and T2DM. Together with the detection of SOCS3 DNA methylation, we will further study the effects of bisphenols exposure on epigenetic modification which might be a potential mechanism, as well as the interaction between environmental exposure and epigenetics on T2DM. The results will provide meaningful information on the health risk assessment of bisphenols, and uncover the etiology, epigenetic mechanism as well as rational prevention of T2DM.

双酚A（BPA）及典型BPA替代物双酚S、双酚F是一类广泛存在的环境内分泌干扰物，实验研究发现双酚类暴露可影响糖尿病发生，但现有流行病调查缺乏可提供暴露-效应时间先后及因果关联证据的人群研究。2型糖尿病（T2DM）是一种受环境暴露及表观遗传等多因素影响的内分泌疾病，SOCS3基因DNA甲基化水平与T2DM易感性有关，且双酚类暴露会影响SOCS3蛋白水平，然而该基因甲基化修饰是否介导双酚类暴露致T2DM发病及其与暴露对T2DM的影响是否存在交互作用尚不清楚。因此本项目拟采用巣式病例对照研究，明确农村人群典型双酚类暴露与T2DM的因果关联及剂量-效应关系；结合SOCS3基因DNA甲基化检测结果，阐明双酚类暴露对SOCS3基因甲基化的影响，进一步探索暴露与表观遗传对T2DM的交互作用及SOCS3基因DNA甲基化的中介效应。研究结果将为双酚类物质的健康风险评价，T2DM病因探查及预防提供科学依据。

双酚类作为一类广泛存在于环境中的典型内分泌干扰物，人群处于双酚类普遍暴露中，而对于双酚类暴露与2型糖尿病关联的流行病学研究结论并不一致。SOCS3基因DNA甲基化与2型糖尿病密切相关，然而该基因DNA甲基化在双酚类暴露致2型糖尿病过程中的作用尚不清楚。因此本项目以河南农村人群（n = 1057）尿液中双酚类浓度为个体内暴露水平，以SCOS3基因DNA甲基化为表观遗传标志物，探讨影响人群双酚类暴露水平的因素和双酚类暴露-SOCS3基因DNA甲基化-2型糖尿病的关联。研究结果发现（1）河南农村人群典型双酚类暴露以双酚A为主要污染物，两种可控的人口特征因素（饮酒和身体质量指数）可影响双酚A暴露水平；农村人群双酚A暴露与2型糖尿病风险升高相关，且其与空腹血糖升高，糖化血红蛋白升高和胰岛β细胞功能下降相关（所有P < 0.05）；（2）SOCS3基因DNA有2个甲基化位点（Chr17:76356190 和 Chr17:76356199）与2型糖尿病风险负相关，且其与空腹血糖、胰岛素水平和胰岛素抵抗下降相关（所有P < 0.05）；（3）人群双酚A暴露和SOCS3基因 DNA甲基化对2型糖尿病的影响具有显著的联合作用，低甲基化和双酚A高暴露人群患2型糖尿病风险显著高于高甲基化和双酚A低暴露人群；（4）并未发现SOCS3基因DNA甲基化在双酚A暴露致2型糖尿病中起显著的中介效应。此外本项目在原定基础上，还探讨了人体性激素-SOCS3基因DNA甲基化-2型糖尿病的关联，发现睾酮与SOCS3基因DNA甲基化与2型糖尿病呈负相关关联，且SOCS3基因DNA甲基化在睾酮对2型糖尿病的影响中起显著的中介效应（中介作用达8.20%）；黄体酮与2型糖尿病呈正相关关联，黄体酮和SOCS3基因DNA甲基化对2型糖尿病的影响存在交互作用（P-interaction = 0.029）。研究结果已形成6篇SCI在国际知名杂志上发表，为双酚类物质的健康风险评价、2型糖尿病病因探查及预防提供科学依据。