Gender differences in dictamnin-induced liver injury in mice based on transcriptome and DNA methylation

Background Dictamnine is the main component of cortex dictamni and has hepatotoxicity, and the incidence of liver injury induced by dictamnine in female is higher than that in male.

Objective To explore the mechanism of DNA methylation and transcriptional regulation of dictamnine-induced liver injury in different genders by drawing DNA methylation and transcriptome profiles.

Methods The male and female mouse models of dictamnine-induced liver injury were constructed. The transcriptome sequencing (RNA-seq) and whole genome bisulfite sequencing (WGBS) of mouse liver were performed to explore the changes of differential signaling pathways and DNA methylation regulation after dictamnine-induced liver injury in male and female mice.

Results Dictamnine additionally activated exogenous drug catabolism and fatty acid metabolism in the liver of female mice, while caused global DNA hypermethylation in the liver of female mice. The core genes Cyp2d9 and Cyp2c67 that exercised exogenous drug catabolism and fatty acid metabolism were promoted (log₂FC=4.247, P＜0.001; log₂FC=3.331, P＜0.001) by DNA hypermethylation (diff.Methy=0.326, diff.Methy=0.355) in the gene body region.

Conclusion Dictamnine causes global DNA hypermethylation in the liver of female mice, which up-regulates the liver to perform exogenous drug catabolism, fatty acid metabolism and other functions, which may be the reason why dictamnine causes more liver injury in female mice.