Short term Imidacloprid exposure is not hepatotoxic but deletion of constitutive androstane receptor results in increased imidacloprid levels in the liver and intestinal alterations in female mice.

Imidacloprid (IMI) is the most frequently detected neonicotinoid pesticide in the environment. Despite typically low vertebrate toxicity, IMI exposure is associated with liver and gastrointestinal toxicity. The mechanism underlying IMI toxicity in mammals is unclear. Pesticide exposure frequently activates xenobiotic nuclear receptors, like constitutive androstane receptor (CAR), to induce detoxification phase I and phase II genes. This study examined the role of CAR in mediating IMI off-target toxicity. Female Car-/- and wild-type (WT) mice were orally administered imidacloprid (50mg/kg, twice daily) for 21 days, following which serum, liver, and intestinal tissues were collected. Liver tissue analysis indicated mild inflammation and induction of detoxification gene Cyp2b10 in IMI-exposed WT mice. The absence of CAR increased hepatic IMI accumulation. Microbiome analysis of ileal samples revealed IMI altered microbial diversity in a genotype-specific manner, with increased alpha-diversity in Car-/- mice while decreased alpha-diversity in WT mice. We observed Car-/- mice exhibit intestinal alterations with decreased CYP-P450 expression, blunted villi height, and increased small intestine length and weight independent of IMI-exposure. Our results suggest IMI is not overtly toxic. However, the absence of xenobiotic nuclear receptor CAR allows increased accumulation of IMI in the liver and disrupts the structure and Cyp gene expression in the intestine.