Sen Anushna, Goforth Madison, Cooper Kerry K, Anakk Sayeepriyadarshini
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Toxicology Training Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
J Endocr Soc. 2022 Sep 21;6(12):bvac145. doi: 10.1210/jendso/bvac145. eCollection 2022 Oct 26.
Imidacloprid (IMI) is the most frequently detected neonicotinoid pesticide in the environment. Despite typically low toxicity in vertebrates, 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, such as the 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 and wild-type (WT) mice were orally administered imidacloprid (50 mg/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 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 α-diversity in mice while decreased α-diversity in WT mice. We observed 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 that IMI is not overtly toxic. However, the absence of xenobiotic nuclear receptor CAR allows increased accumulation of IMI in the liver and disrupts the villi structure and gene expression in the intestine.
吡虫啉（IMI）是环境中最常检测到的新烟碱类杀虫剂。尽管在脊椎动物中通常毒性较低，但接触IMI与肝脏和胃肠道毒性有关。IMI对哺乳动物毒性的潜在机制尚不清楚。农药暴露经常激活外源性核受体，如组成型雄烷受体（CAR），以诱导解毒I期和II期基因。本研究考察了CAR在介导IMI脱靶毒性中的作用。对雌性野生型（WT）小鼠口服吡虫啉（50mg/kg，每日两次），持续21天，之后收集血清、肝脏和肠道组织。肝脏组织分析表明，暴露于IMI的WT小鼠有轻度炎症和解毒基因的诱导。CAR的缺失增加了肝脏中IMI的积累。回肠样本的微生物组分析显示，IMI以基因型特异性方式改变了微生物多样性，在CAR基因敲除小鼠中α多样性增加，而在WT小鼠中α多样性降低。我们观察到，CAR基因敲除小鼠表现出肠道改变，CYP-P450表达降低、绒毛高度变钝，且小肠长度和重量增加，这与IMI暴露无关。我们的结果表明，IMI没有明显毒性。然而，外源性核受体CAR的缺失会使IMI在肝脏中的积累增加，并破坏肠道中的绒毛结构和基因表达。
