Evaluation of human relevance of Nicofluprole-induced rat thyroid disruption.

Nicofluprole is a novel insecticide of the phenylpyrazole class conferring selective antagonistic activity on insect GABA receptors. After repeated daily dietary administration to Wistar rats for 28/90 days, Nicofluprole induced increases in thyroid (and liver) weight, associated with histopathology changes. Nicofluprole did not inhibit thyroid peroxydase nor sodium/iodide symporter, two key players in the biosynthesis of thyroid hormones, indicating the absence of a direct thyroid effect. The results seen in rats suggested a mode of action of Nicofluprole driven by the molecular initiating event of CAR/PXR nuclear receptor activation in livers, with key events of increases in liver weight and hypertrophy, decreasing circulatory thyroid hormones, a compensatory increase in TSH release and follicular cell hypertrophy. To explore the relevance of these changes to humans, well established in vitro rat and human sandwich-cultured hepatocytes were exposed to Nicofluprole up to 7 days. A concentration-dependent CYP3A induction (PXR-activation), an increase in T4-glucuronoconjugation accompanied by UGT1A/2B inductions was observed in rat but not in human hepatocytes. The inductions seen with Nicofluprole in rat (in vivo and in vitro in hepatocytes) that were absent in human hepatocytes represent another example of species-selectivity of nuclear CAR/PXR receptor activators. Importantly, the different pattern observed in rat and human models demonstrate that Nicofluprole-related thyroid effects observed in the rat are with no human relevance.