Identification of common genetic variants associated with serum concentrations of p, p'-DDE in non-occupational populations in eastern China
Identification of common genetic variants associated with serum concentrations of p, p'-DDE in non-occupational populations in eastern China
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DOI：
10.1016/j.envint.2021.106507
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发表时间：
2021-03-20
影响因子：
11.8
通讯作者：
Wang, Shou-Lin
中科院分区：
文献类型：
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作者：
Li, Shushu;Shao, Wei;Wang, Shou-Lin
二氯二苯二氯乙烯（DDE）是二氯二苯三氯乙烷（DDT）的主要和最稳定的有毒代谢物，DDT是20世纪80年代在世界范围内被禁止的一种著名的有机氯农药。然而，它仍然很容易在人体中检测到，并且个体之间的内部水平差异很大。本研究在中国东部地区非职业人群中进行了全基因组关联研究（GWAS）（511名受试者）和2个重复（812名和1030名受试者）。通过食物频率问卷（FFQ）和195份食物和85份饮用水样品的测定，计算了p， p'-滴滴涕和p， p'-DDE的估计膳食摄入量（EDI）。此外，通过双荧光素酶报告基因、免疫印迹和体外代谢活性测定对易感基因座进行了功能验证。采用气相色谱-串联质谱法（GC-MS/MS）测定p， p′-DDT和p， p′-DDE。在19p13.2位点发现CYP2B6的一个共同位点rs3181842（与rs2279345高度连锁平衡）与GWAS人群中p， p'-DDE的低血清水平密切相关，并通过两次重复和2353例受试者的联合分析证实（p = 1.00 × 106(-22)）。此外，携带rs3181842 C等位基因的受试者的p， p'-DDE水平显著低于携带正常基因型的受试者，即使在具有相似的p， p' ddt EDIs的个体中也是如此。此外，rs3181842 C等位基因在功能上导致CYP2B6的低表达和活性，导致从p， p'-DDT形成p， p'-DDE的代谢能力较低。该研究强调CYP2B6变异比环境暴露与内部p， p'-DDE暴露更相关，这是DDT风险评估的重要信息。
Dichlorodiphenyldichloroethylene (DDE) is the major and most stable toxic metabolite of dichlorodiphenyltri-chloroethane (DDT), a well-known organochlorine pesticide banned worldwide in the 1980s. However, it remains easy to detect in humans, and internal levels vary widely among individuals. In the present study, a genome-wide association study (GWAS) (511 subjects) and two replications (812 and 1030 subjects) were performed in non-occupational populations in eastern China. An estimated dietary intake (EDI) of p, p'-DDT and p, p'-DDE was calculated by a food frequency questionnaire (FFQ) and the determination of 195 food and 85 drinking water samples. In addition, functional verifications of susceptible loci were performed by dualluciferase reporter, immunoblotting and metabolic activity assays in vitro. p, p'-DDT and p, p'-DDE were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). A common loci rs3181842 (high linkage equilibrium with rs2279345) in CYP2B6 at 19p13.2 were found to be strongly associated with low serum levels of p, p'-DDE in this population in GWAS and were verified by two replications and combined analysis of 2353 subjects (P = 1.00 x 106(-22)). In addition, p, p'-DDE levels were significantly lower in subjects with the rs3181842 C allele than in those carrying the normal genotype, even in individuals with similar EDIs of p, p'DDT. Furthermore, the rs3181842 C allele functionally led to low CYP2B6 expression and activity, resulting in a low metabolic capacity for the formation of p, p'-DDE from p, p'-DDT. The study highlighted that CYP2B6 variants were more relevant than environmental exposure to internal p, p'-DDE exposure, which is important information for DDT risk assessments.