Activation of aryl hydrocarbon receptor protein promotes testosterone synthesis to alleviate abnormal spermatogenesis caused by cholestasis

Abstract

In this study, we have investigated potential roles of cholestasis played in spermatogenesis in the cholestatic animal model generated by giving the mice DDC diet. The data showed that cholestasis jeopardized the testicular structure and function by downregulating the expressions of genes related to the androgen's synthesis. Mechanistically, the cholestasis disturbers the liver's tryptophan metabolism and its metabolites. These tryptophan metabolites including serotonin, 5-Hydroxyindoleacetic acid, 4-(2-Aminophenyl)-2,4-dioxobutanoic acid and Quinoline-4,8-diol were significantly reduced in the cholestatic mice model compared to their controlled counterparts. These tryptophan metabolites are the endogenous ligands of AHR and their levels are positively correlated to the expressions of genes related to the androgen's synthesis and AHR. Notably, supplementation of AHR ligand ITE promoted the expression of genes related to the testosterone synthesis and alleviated abnormal spermatogenesis. In addition, the bacteria that disturbed the tryptophan metabolism in cholestatic mice were identified by 16S rDNA sequencing and Spearman correlation analysis. Briefly, we have identified a cholestasis associated gut microbiota-testis axis. This axis is responsible for the cholestasis induced abnormal spermatogenesis and male reproductive dysfunction. Breaking vicious cycle of this axis may be a suitable strategy to prevent and treat the cholestasis associated male infertility.

Keywords: Aryl hydrocarbon receptor; Cholestasis; Gut microbiota; Spermatogenesis; Testosterone; Tryptophan metabolites.