Estrogen signaling in livers of male mice with hepatocellular carcinoma induced by exposure to arsenic in utero

Abstract

Background: Exposure of pregnant mice to inorganic arsenic induces a spectrum of tumors, including hepatocellular carcinoma (HCC), in their adult offspring similar to that induced by exposing adult mice to estrogenic compounds. To investigate whether arsenic exposure in utero causes altered estrogen signaling, we examined expression of estrogen receptor-α (ER-α), cyclin D1 (an estrogen-responsive hepatic oncogene), and several cytochrome P450 genes (with sexually dimorphic liver expression patterns) in livers from adult male mice with in utero arsenic-induced HCC. Methods: Quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate gene expression in livers of adult male mice that had (i.e., exposed mice; n = 8) or had not (i.e., control mice; n = 5) been exposed to arsenic in utero. DNA methylation status of portions of the ER-α and cyclin D1 gene promoters in liver tissue was measured using methylation-specific polymerase chain reaction. Statistical tests were two-sided. Results: ER-α mRNA levels were 3.1-fold (95% confidence interval [CI] = 2.0-fold to 4.3-fold) higher in livers of exposed mice than in those of control mice, and cyclin D1 levels were 3.0-fold (95% CI = 1.7-fold to 4.3-fold) higher. Exposed mice showed a feminized expression pattern of several cytochrome P450 genes, expressing the female-dominant CYP2A4 (P = .017 versus control) and CYP2B9 (P