Resveratrol Attenuates Aflatoxin B(1)-Induced ROS Formation and Increase of m(6)A RNA Methylation

SIMPLE SUMMARY: Aflatoxin B(1) (AFB(1)) is highly hepatotoxic in both animals and humans. Resveratrol, a naturally-occurring polyphenolic compound, has antioxidative, anti-inflammatory, antiapoptotic, and immunomodulatory functions and plays a critical role in preventing liver damage. However, whether N(6)-methyladenosine (m(6)A) mRNA methylation, which plays critical roles in regulating gene expression for fundamental cellular processes, is associated with the protective effects of resveratrol in attenuating aflatoxin B(1) induced toxicity is unclear. Here, we found that AFB(1)-induced reactive oxygen species (ROS) accumulation changed m(6)A modification, and the role of resveratrol in alleviating the effect on hepatic disorder induced by aflatoxin B(1) may be due to the removal of ROS, followed by the decreased abundance of m(6)A modification, and ultimately exerting its protective role in the liver. Together, this work provides key insights into the potential avenues for the treatment of AFB(1)-induced hepatotoxicity and other relevant liver diseases. ABSTRACT: Aflatoxin B(1) (AFB(1)) is one of the most dangerous mycotoxins in both humans and animals. Regulation of resveratrol is essential for the inhibition of AFB(1)-induced oxidative stress and liver injury. Whether N(6)-methyladenosine (m(6)A) mRNA methylation participates in the crosstalk between resveratrol and AFB(1) is unclear. The objective of this study was to investigate the effects of AFB(1) and resveratrol in m(6)A RNA methylation and their crosstalk in the regulation of hepatic function in mice. Thirty-two C57BL/6J male mice were randomly assigned to a CON (basal diet), RES (basal diet + 500 mg/kg resveratrol), AFB(1) (basal diet + 600 μg/kg aflatoxin B(1)), and ARE (basal diet + 500 mg/kg resveratrol and 600 μg/kg aflatoxin B(1)) group for 4 weeks of feeding (n = 8/group). Briefly, redox status, apoptosis, and m(6)A modification in the liver were assessed. Compared to the CON group, the AFB(1) group showed increased activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), prevalent vacuolization and cell edema, abnormal redox status, imbalance apoptosis, and especially, the higher expression of cleaved-caspase-3 protein. On the contrary, resveratrol ameliorated adverse hepatic function, via increasing hepatic antioxidative capacity and inhibiting the expression of cleaved-caspase-3 protein. Importantly, we noted that reactive oxygen species (ROS) content could be responsible for the alterations of m(6)A modification. Compared to the CON group, the AFB(1) group elevated the ROS accumulation, which led to the augment in m(6)A modification, whereas dietary resveratrol supplementation decreased ROS, followed by the reduction of m(6)A levels. In conclusion, our findings indicated that resveratrol decreased AFB(1)-induced ROS accumulation, consequently contributing to the alterations of m(6)A modification, and eventually impacting on the hepatic function.