In a previous study, researchers found that estrogen and arsenic together accelerated the neoplastic transformation of human prostate epithelial cells. DNA-reactive estrogen metabolites have also been demonstrated to have a significant role in mutagenicity and carcinogenicity in addition to receptor-mediated mechanisms. Arsenic and estrogen are both recognized prostate carcinogens. However, it was unknown how exposure to both of these substances simultaneously would affect the genes involved in estrogen metabolism. Therefore, for a study, they sought to assess how estrogen receptors and genes related to estrogen metabolism were expressed in response to estrogen and arsenic coexposure. They previously discussed the synergistic effect of estrogen and arsenic on the reduced expression of MBD4 genes, which were crucial for DNA repair due to their DNA glycosylase activity. This gene’s promoter methylation was also investigated to comprehend the process in greater detail.

Human prostate epithelial cells RWPE-1 that had been chronically exposed (6 months) to arsenic and estrogen were extracted for their total RNA and protein. Quantitative reverse transcriptase-polymerase chain reaction or western blotting was used to evaluate the expression of estrogen receptors, the phase I genes (CYP 1A1, 1A2, 3A4, and 1B1) and phase II gene catechol-O-methyltransferase (COMT), as well as the antioxidant MnSOD. By using pyrosequencing, the promoter methylation of MBD4 was examined.

In arsenic and estrogen coexposed cells, the expression of MnSOD and phase I genes, which transform E2 into the genotoxic metabolites 2-OH-E2 and 4-OH-E2, was dramatically elevated, but the expression of phase II gene COMT, which detoxifies estrogen metabolites, was significantly lowered. In cells exposed to both estrogen and arsenic, the MBD4 promoter was hypermethylated. Arsenic and estrogen coexposure affected these genes’ expression as well as MBD4 promoter hypermethylation in a synergistic manner.

The new findings implied that estrogen and arsenic co-exposure synergistically activated genes involved in genotoxic estrogen metabolism as well as genes involved in DNA glycosylase MBD4 inactivation and estrogen receptor activation. The molecular foundation for the potentiation of the carcinogenicity of estrogen and arsenic coexposure in prostate epithelial cells is provided by these genetic and epigenetic abnormalities taken together.

Reference: onlinelibrary.wiley.com/doi/10.1002/pros.24401