Deletion of Constitutive Androstane Receptor Led to Intestinal Alterations and Increased Imidacloprid in Murine Liver

Anushna Sen; Madison Goforth; Kerry K Cooper; Sayeepriyadarshini Anakk

doi:10.1210/jendso/bvac145

Deletion of Constitutive Androstane Receptor Led to Intestinal Alterations and Increased Imidacloprid in Murine Liver

J Endocr Soc. 2022 Sep 21;6(12):bvac145. doi: 10.1210/jendso/bvac145. eCollection 2022 Oct 26.

Authors

Anushna Sen^{1

2}, Madison Goforth^{2

3}, Kerry K Cooper³, Sayeepriyadarshini Anakk^{1

2

4

5}

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
² Toxicology Training Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
³ School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA.
⁴ Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
⁵ Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

Abstract

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 Car^-/- 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 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 α-diversity in Car^-/- mice while decreased α-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 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 Cyp gene expression in the intestine.

Keywords: gastrointestinal tract; imidacloprid; microbiome; neonicotinoids; nuclear receptor; toxicity.