ABSTRACT

Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR < 0.05). These CpGs were enriched in active promoter and transcription associated regions (p < 0.05), and in regions around the binding sites for transcription factors involved in xenobiotic metabolism and immune function (FDR < 0.05). PCB exposure also associated with proportions of CD4T, NK, and granulocyte cell types, and with the neutrophil to lymphocyte ratio (NLR) (p < 0.05), and the estimated effect sizes of PCB on the epigenome were correlated with the effect sizes previously reported in an epigenome-wide study of C-reactive protein (r = 0.29; p = 2.22e-5), supporting previous studies on the association between PCB and immune dysfunction. These results indicate that PCB exposure is associated with differences in epigenetic marks in active regions of the genome, and future work should investigate whether these may mediate the association between PCB and health consequences.

摘要

尽管几十年来一直禁止制造和使用 PCB，但多氯联苯 (PCB) 是一种内分泌干扰化合物，但仍无处不在。多氯联苯暴露的增加与一生的不良健康后果有关，包括 2 型糖尿病和癌症。PCB 暴露还与表观遗传标记和基因转录的改变有关，这可能导致不良的健康结果，但其中许多是特定于人群的。为了进一步研究 PCB 和表观遗传标记之间的关联，我们在密歇根多溴联苯 (PBB) 登记处的 641 个外周血样本中测量了 787,684 个 CpG 位点的 DNA 甲基化。在控制年龄、性别和 24 个替代变量（FDR < 0.05）后，1345 个 CpG 与总 PCB 水平升高相关。这些 CpG 富含活性启动子和转录相关区域 (p < 0.05)，以及参与外源代谢和免疫功能的转录因子结合位点周围的区域 (FDR < 0.05)。PCB 暴露还与 CD4T、NK 和粒细胞类型的比例以及中性粒细胞与淋巴细胞的比率 (NLR) 相关（p < 0.05），PCB 对表观基因组的估计效应大小与先前报道的效应大小相关在 C 反应蛋白的表观基因组研究中（r = 0.29；p = 2.22e-5），支持先前关于 PCB 与免疫功能障碍之间关联的研究。这些结果表明，PCB 暴露与基因组活动区域的表观遗传标记的差异有关，