The role of chromatin-modifying enzymes and histone modifications in the modulation of p16 gene in fumonisin B1-induced toxicity in human kidney cells

Fumonisin B 1 (FB 1 ) poses a risk to animal and human health. Although the effects of FB 1 on sphingolipid metabolism are well documented, there are limited studies covering the epigenetic modifications and early molecular alterations associated with carcinogenesis pathways caused by FB 1 nephrotoxicity. The present study investigates the effects of FB 1 on global DNA methylation, chromatin-modifying enzymes, and histone modification levels of the p16 gene in human kidney cells (HK-2) after 24 h exposure. An increase (2.23-fold) in the levels of 5-methylcytosine (5-mC) at 100 µmol/L was observed, a change independent from the decrease in gene expression levels of DNA methyltransferase 1 ( DNMT1 ) at 50 and 100 µmol/L; however, DNMT3a and DNMT3b were significantly upregulated at 100 µmol/L of FB 1 . Dose-dependent downregulation of chromatin-modifying genes was observed after FB 1 exposure. In addition, chromatin immunoprecipitation results showed that 10 µmol/L of FB 1 induced a significant decrease in H3K9ac, H3K9me3 and H3K27me3 modifications of p16 , while 100 µmol/L of FB 1 caused a significant increase in H3K27me3 levels of p16 . Taken together, the results suggest that epigenetic mechanisms might play a role in FB 1 carcinogenesis through DNA methylation, and histone and chromatin modifications.