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Multigenerational adverse effects from the environment such as nutrition and chemicals are among important concerns in environmental health issues. Previously, we have found that arsenite exposure of only F0 females during their pregnancy increases hepatic tumors in the F2 males in C3H mice. In the current study, we investigated the association of DNA methylation with the hepatic tumor increase in the F2 males of the arsenite group. Reduced‐representation bisulfite sequencing analysis newly identified that DNA methylation levels of regions around the transcriptional start sites of  Tmem54  and  Cd74  were decreased and the expression of these genes were significantly increased in the hepatic tumors of F2 males of the arsenite group. The associations between DNA methylation in these regions and gene expression changes were confirmed by treatment of murine hepatoma cell lines and hepatic stellate cell line with 5‐aza‐2′‐deoxycytidine. Overexpression of  Cd74  in Hepa1c1c7 cells increased  Trib3  expression and suppressed the expression of tumor suppressor genes  Id3  and  Atoh8 . Human database analysis using the Cancer Genome Atlas indicated that  TMEM54 ,  CD74 , and  TRIB3  were significantly increased and that  ATOH8  was decreased in hepatocellular carcinoma. The data also showed that high expression of  TMEM54  and  TRIB3  and low expression of  ATOH8  were associated with poor survival. These results suggested that an increase in  Tmem54  and  Cd74  expression via DNA methylation reduction was involved in the tumor increase in the F2 male offspring by gestational arsenite exposure of F0 females. This study also suggested that genes downstream of  Cd74  were involved in tumorigenesis.

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice