Robitaille Christina N, Rivest Patricia, Sanderson J Thomas
INRS-Institut Armand-Frappier, Université du Québec, 531 boulevard des Prairies, Laval, Quebec, Canada H7V 1B7.
INRS-Institut Armand-Frappier, Université du Québec, 531 boulevard des Prairies, Laval, Quebec, Canada H7V 1B7
Toxicol Sci. 2015 Jan;143(1):126-35. doi: 10.1093/toxsci/kfu212. Epub 2014 Oct 15.
Several pesticides suspected or known to have endocrine disrupting effects were screened for pro- or antiandrogenic properties by determining their effects on proliferation, prostatic-specific antigen (PSA) secretion and androgen receptor (AR) expression, and AR phosphorylation in androgen-dependent LNCaP human prostate cancer cells, as well as on the expression and catalytic activity of the enzyme CYP17 in H295R human adrenocortical carcinoma cells, an in vitro model of steroidogenesis. Effects on SRD5A gene expression were determined in both cell lines. Benomyl, vinclozolin, and prochloraz, but not atrazine, concentration dependently (1-30 μM) decreased dihydrotestosterone (DHT)-stimulated proliferation of LNCaP cells. All pesticides except atrazine decreased DHT-stimulated PSA secretion, AR nuclear accumulation, and AR phosphorylation on serines 81 and 213 in LNCaP cells. Benomyl and prochloraz, but not vinclozolin or atrazine, decreased levels of CYP17 gene and protein expression, as well as catalytic activity in H295R cells. In the case of prochloraz, some of these effects corresponded with cytotoxicity. H295R cells expressed AR protein and SRD5A1, but not SRD5A2 transcripts. SRD5A1 gene expression in H295R cells was increased by 10 nM DHT, whereas in LNCaP cells significant induction was observed by 0.1 nM DHT. AR protein expression in H295R cells was not increased by DHT. Vinclozolin decreased DHT-induced SRD5A1 gene expression in LNCaP, but not H295R cells, indicating a functional difference of AR between the cell lines. In conclusion, pesticides may exert antiandrogenic effects through several mechanisms that are cell type-specific, including AR antagonism and down-regulation or catalytic inhibition of androgen biosynthetic enzymes, such as CYP17 and SRD5A1.
通过测定几种疑似或已知具有内分泌干扰作用的农药对雄激素依赖性LNCaP人前列腺癌细胞的增殖、前列腺特异性抗原（PSA）分泌、雄激素受体（AR）表达及AR磷酸化的影响，以及对H295R人肾上腺皮质癌细胞（类固醇生成的体外模型）中细胞色素P450 17α酶（CYP17）的表达和催化活性的影响，来筛选这些农药的促雄激素或抗雄激素特性。同时测定了这两种细胞系中5α-还原酶（SRD5A）基因的表达。苯菌灵、乙烯菌核利和咪鲜胺（但莠去津未表现出此作用）浓度依赖性地（1 - 30 μM）降低了双氢睾酮（DHT）刺激的LNCaP细胞增殖。除莠去津外的所有农药均降低了DHT刺激的LNCaP细胞中PSA分泌、AR核积累以及丝氨酸81和213位点的AR磷酸化。苯菌灵和咪鲜胺（但乙烯菌核利或莠去津未表现出此作用）降低了H295R细胞中CYP17基因和蛋白表达水平以及催化活性。就咪鲜胺而言，其中一些作用与细胞毒性相关。H295R细胞表达AR蛋白和SRD5A1转录本，但不表达SRD5A2转录本。10 nM DHT可增加H295R细胞中SRD5A1基因表达，而在LNCaP细胞中，0.1 nM DHT可显著诱导该基因表达。DHT未增加H295R细胞中AR蛋白表达。乙烯菌核利降低了DHT诱导的LNCaP细胞中SRD5A1基因表达，但未降低H295R细胞中的该基因表达，表明这两种细胞系中AR存在功能差异。总之，农药可能通过多种细胞类型特异性机制发挥抗雄激素作用，包括AR拮抗以及对雄激素生物合成酶（如CYP17和SRD5A1）的下调或催化抑制。
