In vivo endocrine regulation of rat hepatic aryl hydrocarbon receptor expression and function

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of aromatic hydrocarbons (AHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHR-mediated transcriptional regulation has been extensively studied, as exemplified by the prototypical induction of cytochrome P450 1A1 (CYP1A1) following AH exposure. However, the in vivo regulation of the expression of the hepatic AHR itself is poorly understood and the impact of changes in AHR expression on AH responsiveness is unclear. With respect to hormonal regulation of the AHR, our laboratory showed that hypophysectomy decreases hepatic AHR protein and TCDD-binding in male rats. This suggested that the AHR is positively regulated by pituitary-dependent factors in vivo. We initially focused on adrenal glucocorticoids (GCs) as candidate pituitary-dependent hormones in this response, since GCs can increase AHR expression and AH responsiveness in vitro. We hypothesized that GCs elevate AHR expression in rat liver, sensitizing rats to the diverse effects of AHs. Male rats were either adrenalectomized (ADX) or underwent sham surgery, and then rats were treated with either dexamethasone (DEX) or vehicle. Neither ADX nor DEX treatment had a significant effect on hepatic AHR expression, as assessed at the mRNA, protein and TCDD-binding levels. Thus, GCs are not important regulators of rat hepatic AHR expression in vivo. Other pituitary-dependent regulators of AHR expression and function will be studied in vivo to better understand the hormonal regulation of the AHR and how different hormonal states influence sensitivity to AHs. [Support: NSERC, CIHR]