TET3-mediated DNA demethylation and chromatin remodeling regulate T-2 toxin-induced human CYP1A1 expression and cytotoxicity in HepG2 cells.

T-2 toxin is a hazardous environmental pollutant that poses a risk to both farm animals and humans. Our previous research has reported that T-2 toxin highly induced the expression of human cytochrome P450 1A1 (CYP1A1), which may be a representative inducible marker of T-2 toxin and mediate the toxicity of T-2 toxin. In this study, we found that T-2 toxin decreased the DNA methylation levels of the CpG islands on the CYP1A1 promoter by inducing the expression of eleven translocation family protein 3 (TET3) and facilitating its binding to the promoter. These DNA methylation changes then generated an activated chromatin structure on the CYP1A1 promoter by releasing the repressor complex methyl-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2), increasing the active histone modification markers, including H3K4ac, H3K9ac and H3K14ac, and facilitating RNA pol II and NRF1/Sp1 recruitment, which ultimately led to the transcriptional activation of CYP1A1. Interestingly, TET3-mediated CYP1A1 induction enhanced the cytotoxicity of T-2 toxin through inhibiting cell proliferation. Our results demonstrate that T-2 toxin-induced CYP1A1 expression is detrimental to cells and clearly show how T-2 toxin inhibits cell proliferation through regulating CYP1A1 expression from an epigenetic perspective. The findings broaden our current knowledge of the epigenetic mechanisms regulating environmental factors-induced CYP1A1 expression and cytotoxicity. TET3 may serve as a potential new target for toxicogenic detoxification.