Food, Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Environ Pollut. 2021 Mar 1;272:116397. doi: 10.1016/j.envpol.2020.116397. Epub 2021 Jan 2.
Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and β-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and β-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.
环境内分泌干扰化学物质（EDCs）的暴露被高度怀疑与前列腺癌的发生有关。虽然雌激素是 EDCs 研究最多的行为，但大多数 EDCs 的雄激素潜力仍然难以捉摸。本研究调查了一些常见 EDCs 的雄激素模拟潜力及其对雄激素依赖性前列腺癌（LNCaP）细胞的影响。基于计算机模拟相互作用研究，发现所有 8 种测试的 EDCs 均与雄激素受体以不同的结合能相互作用。此外，荧光素酶报告基因活性证实了 4 种 EDCs（苯并[a]芘、敌敌畏、染料木黄酮和β-硫丹）具有雄激素模拟潜力。而 aldrin、马拉硫磷、tebuconazole 和 DDT 在荧光素酶报告基因活性测定中被报道为抗雄激素。接下来，雄激素模拟 EDCs（苯并[a]芘、敌敌畏、染料木黄酮和β-硫丹）的纳摩尔浓度显著增强了 LNCaP 细胞中 AR 蛋白的表达和随后的核转位。我们的计算机模拟研究进一步表明，雄激素性 EDCs 也与表观遗传调节酶（即 DNMT1 和 HDAC1）结合。此外，暴露于这些 EDCs 增强了 LNCaP 细胞中 DNMT1 和 HDAC1 的蛋白表达。这些观察结果表明，EDCs 可能通过作为 AR 信号的雄激素模拟配体以及调节表观遗传机制来调节雄激素敏感的 LNCaP 细胞的增殖。EDCs 的雄激素潜力和表观遗传调节作用可能是前列腺癌发展和生长的基础。
