The involvement of m6A RNA methylation in the transgenerational inheritance of hepatotoxicity induced by paternal cadmium exposure

Cadmium (Cd), a widespread environmental pollutant, has linked with various adverse health effects. However, the paternally inherited transgenerational effects of cadmium exposure on hepatotoxicity in offspring and the underlying mechanism remained undefined. To address this issue, male mice (F0) were administrated with 100 mg/L cadmium chloride (CdCl₂) in drinking water for 3 months. Then, F0 males were mated with healthy female mice to produce F1 and F2 offspring. Liver function was assessed at age of 6 weeks and 6 months, respectively. Herein, we showed ancestral cadmium exposure led to liver injury in F1 male and F2 mice, characterized by hepatic steatosis and impaired glucose homeostasis. These results suggest that ancestral exposure to cadmium could induce the transgenerational inheritance of cadmium-induced liver injury, which was more profound in male offspring. Furthermore, methylated RNA immunoprecipitation (MeRIP) sequencing analysis identified 285 and 734 differentially methylation expressed genes in mice liver tissue treated with CdCl₂ for 3 months and 9 months, respectively. Among them, suppression of Irs1 and Il6st led to enhanced cytotoxicity induced by CdCl₂, indicating that Irs1 and Il6st might be involved in CdCl₂-induced liver injury. More importantly, the alteration of Irs1 and Il6st RNA methylation was also observed in F1 males and F2 mice, consistent with the phenotypes. Further analysis suggested the involvement of Irs1 methylation in the transgenerational inheritance of cadmium-induced hepatotoxicity, possibly mediated by METTL3. Collectively, these findings uncover the novel role of RNA methylation in the transgenerational inheritance of adverse effects and deepen the understanding of the etiology of disease.