Molecular mechanisms for induction of DNA methylation by testosterone overdose in the rat prostate

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Aberrant DNA methylation is deeply involved in prostate carcinogenesis. However, inducers of aberrant methylation in the prostate are almost unknown. Here, we investigated whether androgen excess can induce aberrant methylation or not, using a rat prostate cancer model. We first identified two marker genes, methylated in testosterone/DMAB-induced invasive adenocarcinomas, in addition to three genes previously isolated. Next, we analyzed temporal profiles of methylation levels in the dorsolateral lobe of rats, and found that aberrant methylation of two genes (Amn1, Mmp23) was induced during the testosterone treatment. Androgen excess did not induce mRNA expression of DNA methyltransferases in the rat prostrate. In contrast, it induced infiltration of lymphocytes and neutrophils in the prostate. These results demonstrated that androgen excess can induce aberrant DNA methylation in the prostate, and suggested that inflammatory response underlies aberrant methylation induction.