Deletion of Nuclear Receptor Constitutive Androstane Receptor CAR Increases Anxiety and Lowers Androgen Levels

Abstract

The orphan nuclear receptor, Constitutive Androstane Receptor (CAR, NR1I3) is primarily known to regulate the transcriptional networks involved in detoxification. We have identified a novel extra-hepatic role of CAR in regulating androgen levels and modulating testis function. Previous data has revealed that CAR activation by estradiol and inactivation by androstanol suggests an intricate link between sex hormones and CAR. We investigated control wild type and CARKO mice and found that the serum testosterone and androstenedione levels were lower in the absence of CAR. As expected, we did not find any induction of the genes in the detoxification machinery including, Cyp3a, Cyp2b, Cyp2c family, Sult2a1 and Mrp. The decrease in the androgen levels in the CARKO mice is consistent with decrease in the anogenital distance, increased anxiety as measured by marble burying and elevated plus maze but no change in testis weight. H&E staining of CARKO mice shows accumulation of fat in the Leydig cells and lower numbers of Leydig cells which are in accordance with the loss of androgen levels. In addition, we will examine the consequence of reduced androgen and the hypothalamus-pituitary-gonadal axis in the CARKO mice.