Zearalenone, produced by various Fusarium species, is a non-steroidal estrogenic
mycotoxin that contaminates cereals, resulting in adverse effects on human health. We investigated the effects of
zearalenone and its metabolite
alpha zearalenol on epigenetic modifications and its relationship with metabolic pathways in human
hepatocellular carcinoma cells following 24 h of exposure.
Zearalenone and
alpha zearalenol at the concentrations of 1, 10 and 50 μM significantly increased global levels of DNA methylation and global histone modifications (H3K27me3, H3K9me3, H3K9ac). Expression levels of the
chromatin modifying
enzymes EHMT2, ESCO1, HAT1, KAT2B, PRMT6 and SETD8 were upregulated by 50 μM of
zearalenone exposure using PCR arrays, consistent with the results of global histone modifications.
Zearalenone and
alpha zearalenol also changed expression levels of the AhR, LXRα, PPARα, PPARɣ, L-fabp, LDLR, Glut2, Akt1 and HK2 genes, which are related to
nuclear receptors and metabolic pathways. PPARɣ, a key regulator of lipid metabolism, was selected from among these genes for further analysis. The PPARɣ promoter reduced methylation significantly following
zearalenone exposure. Taken together, the epigenetic mechanisms of DNA methylation and histone modifications may be key mechanisms in
zearalenone toxicity. Furthermore, effects of
zearalenone in metabolic pathways could be mediated by epigenetic modifications.