Abstract
Simple SummaryAflatoxin B1 (AFB1) 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 N6-methyladenosine (m6A) 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 B1 induced toxicity is unclear. Here, we found that AFB1-induced reactive oxygen species (ROS) accumulation changed m6A modification, and the role of resveratrol in alleviating the effect on hepatic disorder induced by aflatoxin B1 may be due to the removal of ROS, followed by the decreased abundance of m6A modification, and ultimately exerting its protective role in the liver. Together, this work provides key insights into the potential avenues for the treatment of AFB1-induced hepatotoxicity and other relevant liver diseases.Aflatoxin B1 (AFB1) is one of the most dangerous mycotoxins in both humans and animals. Regulation of resveratrol is essential for the inhibition of AFB1-induced oxidative stress and liver injury. Whether N6-methyladenosine (m6A) mRNA methylation participates in the crosstalk between resveratrol and AFB1 is unclear. The objective of this study was to investigate the effects of AFB1 and resveratrol in m6A 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), AFB1 (basal diet + 600 μg/kg aflatoxin B1), and ARE (basal diet + 500 mg/kg resveratrol and 600 μg/kg aflatoxin B1) group for 4 weeks of feeding (n = 8/group). Briefly, redox status, apoptosis, and m6A modification in the liver were assessed. Compared to the CON group, the AFB1 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 m6A modification. Compared to the CON group, the AFB1 group elevated the ROS accumulation, which led to the augment in m6A modification, whereas dietary resveratrol supplementation decreased ROS, followed by the reduction of m6A levels. In conclusion, our findings indicated that resveratrol decreased AFB1-induced ROS accumulation, consequently contributing to the alterations of m6A modification, and eventually impacting on the hepatic function.
Highlights
Aflatoxins (AF) are naturally produced by Aspergillus flavus and Aspergillus parasiticus, contaminating a wide range of agricultural products, including corn, peanuts, and soybeans, due to poor storage conditions or natural disasters, and thereby harming animal and human health [1].Among about twenty aflatoxins found, Aflatoxin B1 (AFB1) is listed as a first-grade carcinogen because of its violent toxicity, intensive harm, and widespread distribution [2]
Growing evidence shows that DNA methylation and histone modification, in part, controls AFB1 -induced liver injury [7], whereas few investigations have uncovered the relationship between RNA methylation and AFB1 -induced liver damage
We suggested that can6 reverse m6 A level in the liver, regulate the expression of hepatic antioxidant and apoptosis m A RNA methylation may involve in AFB1-induced hepatotoxicity, and dietary resveratrol genes, and eventually repair hepatic function
Summary
Aflatoxins (AF) are naturally produced by Aspergillus flavus and Aspergillus parasiticus, contaminating a wide range of agricultural products, including corn, peanuts, and soybeans, due to poor storage conditions or natural disasters, and thereby harming animal and human health [1].Among about twenty aflatoxins found, AFB1 is listed as a first-grade carcinogen because of its violent toxicity, intensive harm, and widespread distribution [2]. Aflatoxins (AF) are naturally produced by Aspergillus flavus and Aspergillus parasiticus, contaminating a wide range of agricultural products, including corn, peanuts, and soybeans, due to poor storage conditions or natural disasters, and thereby harming animal and human health [1]. AFB1 is metabolized by the cytochrome P-450 enzyme system to produce AFB1 -exo-8,9-epoxide (AFBO) in the liver, which covalently binds biomacromolecules such as DNA, RNA, and proteins in hepatocytes [3,4,5], inducing oxidative stress and hepatocyte apoptosis [6], eventually leading to liver damage and even cancer. The hepatic toxicity of AFB1 to humans, poultry, and livestock and the resulting degradation of quality in animal husbandry products has drawn great attention. RNA methyltransferases, known as ‘writers’, are primarily composed of methyltransferase-like 3 (METTL3), methyltransferase-like 14
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