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

Abstract

Fumonisin B₁ (FB₁) poses a risk to animal and human health. Although the effects of FB₁ on sphingolipid metabolism are well documented, there are limited studies covering the epigenetic modifications and early molecular alterations associated with carcinogenesis pathways caused by FB₁ nephrotoxicity. The present study investigates the effects of FB₁ 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 FB₁. Dose-dependent downregulation of chromatin-modifying genes was observed after FB₁ exposure. In addition, chromatin immunoprecipitation results showed that 10 µmol/L of FB₁ induced a significant decrease in H3K9ac, H3K9me3 and H3K27me3 modifications of p16, while 100 µmol/L of FB₁ caused a significant increase in H3K27me3 levels of p16. Taken together, the results suggest that epigenetic mechanisms might play a role in FB₁ carcinogenesis through DNA methylation, and histone and chromatin modifications.