Transcriptomic and metabolomic insights into the enantioselective effects of chiral fungicide penflufen and its enantiomers on multi-endpoints in the liver for mice.

Succinate dehydrogenase inhibitors (SDHIs) have been increasingly used as fungicides in agriculture for decades. Penflufen (PEN) is a widely used chiral fungicide and the acute toxic concentration of S-(+)-PEN was 54 times higher than R-(-)-PEN in zebrafish. However, the toxic effects of rac-PEN and its enantiomers on mammals remain unclear. Here, 7-week-old C57BL/6 mice were exposed to 30 mg/kg bw/d or 100 mg/kg bw/d of rac-PEN and enantiomers for 28 days. Compared with R-(-)-PEN, S-(+)- and rac-PEN significantly decreased the relative weights of the kidney, spleen and testis. The integrated hepatic transcriptomic and non-target metabolomic results suggested that PEN exposure induced oxidation stress, caused glucose metabolism disorder, and disrupted steroid hormones. The specific binding modes in CYP450s might be related to the higher residue and toxic effects of S-(+)-PEN than R-(-)-PEN. Moreover, PEN exposure disrupted hepatic hormones including fibroblast growth factor 21 (Fgf21) and steroid hormone. The changed levels of hepatic pregnenolone, cortisol, and cortisone might be also associated with kidney function. Overall, these results indicated that S-(+)-PEN caused more toxic effects on different endpoints than R-(-)-PEN. These findings would be significant in providing novel insights for understanding the potential health risk of rac-PEN and its enantiomers in mammals.