Aromatic Hydrocarbon Receptor Regulates Chicken Cytochrome P450 1A5 Transcription: A Novel Insight into T-2 Toxin-induced Gene Expression and Cytotoxicity in LMH Cells.

T-2 toxin is a secondary metabolite produced by the Fusarium genus and is highly toxic to both farmed animals and humans. In our previous study, we found that chicken cytochrome P450 1A5 (CYP1A5) can be significantly induced by T-2 toxin in chicken primary hepatocytes and catalyze T-2 toxin into a more toxic product, 3'-OH-T-2. Here, we showed that T-2 toxin also induced the expression of CYP1A5 in LMH cells at both the mRNA and protein levels, and this can be strongly inhibited by both resveratrol and siRNA targeting the aryl hydrocarbon receptor (AhR), indicating the involvement of AhR in T-2 toxin-induced transcriptional activation of CYP1A5. We further showed that T-2 toxin induced the expression of AhR and promoted the translocation of AhR into the nucleus as well as its binding to the proximal xenobiotic-responsive element (XRE) in the 5'-flanking region of CYP1A5, which mediates both the basal expression and the transcriptional activation of CYP1A5. Interestingly, CYP1A5 induction mediated by AhR enhances the cytotoxicity of T-2 toxin by reducing cell viability, activating oxidative stress and inducing DNA damage as well as apoptosis. Our findings provide novel insight into T-2 toxin-induced gene expression and cytotoxicity and may provide a novel target to reduce latent harm to chickens.