Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
Environ Res. 2023 Nov 15;237(Pt 2):117063. doi: 10.1016/j.envres.2023.117063. Epub 2023 Sep 1.
More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06-1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09-2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.
已有 200 多种遗传变异被独立证实与前列腺癌风险相关。在农民群体中的研究也观察到，接触特定有机磷（地虫磷、特丁磷、马拉硫磷、乐果）和有机氯（艾氏剂、氯丹）杀虫剂会增加前列腺癌风险。我们在农业健康研究队列中，对 1162 例病例（588 例侵袭性）和 2206 例频数匹配对照者进行了嵌套研究，以检验这些杀虫剂、已确定的前列腺癌基因座与前列腺癌风险之间的联合关联。终生使用杀虫剂史与使用 256 个已确定的前列腺癌风险变异构建的多基因风险评分（PRS）相结合。Logistic 回归模型估计了杀虫剂、PRS 和 256 个个体遗传变异与总前列腺癌和侵袭性前列腺癌风险的联合关联。似然比检验评估了乘法交互作用。我们观察到，曾用地虫磷与 PRS 与总前列腺癌和侵袭性前列腺癌风险之间存在交互作用。与参考组（从未使用，PRS<中位数）相比，曾用地虫磷与 PRS>中位数的男性总前列腺癌（OR 1.35[1.06-1.73]，p 交互作用=0.03）和侵袭性前列腺癌（OR 1.49[1.09-2.04]，p 交互作用=0.19）风险增加。还提示杀虫剂与 DNA 损伤反应相关区域的个体遗传变异（CDH3、EMSY 基因）和与改变雄激素受体驱动的关键前列腺癌转录程序相关的变异之间存在交互作用。本研究提供了证据，表明遗传易感性较高的男性如果接触杀虫剂，可能面临更高的前列腺癌风险，并提示了杀虫剂可能增加前列腺癌风险的潜在机制。
