Constitutive and TCDD-Induced Expression of Ah Receptor-Responsive Genes in the Pituitary

Abstract

The 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and related substances cause a wide variety of pathological alterations, with the most severe being progressive anorexia and body weight loss. These features suggest a possible involvement of the nervous system and endocrine organs, including the pituitary gland. TCDD-related toxicity is considered mainly to be mediated by the aryl hydrocarbon receptor (AHR) protein, which binds TCDD, and heterodimerizes with its partner protein, the aryl hydrocarbon receptor nuclear translocator (ARNT), and binds to xenobiotica responsive elements (XREs) in the promoter regions of biotransformation genes as well as genes involved in growth, differentiation and cellular homeostasis. In the present study, we have investigated the expression of AHR responsive genes in the pituitary of untreated and TCDD treated 129/SV/C57BL/6 mice in vivo and in pituitary cells in vitro. After TCDD or beta-naphthoflavone (βNF) treatment, the relative levels of cytochrome P4501A1 (CYP1A1) mRNA and protein were dramatically increased in pituitary cells. The AHR repressor (AHRR) mRNA level was induced 7–13-fold by TCDD and βNF. Furthermore, the expression of the adrenocorticotrophic hormone (ACTH) precursor, the proopiomelanocortin ( POMC) gene, was investigated. A three-fold increase in POMC mRNA was observed in the pituitary of TCDD treated mice. POMC mRNA level was also increased in the pituitary cell line AtT-20 after TCDD treatment. The proteins encoded by POMC translational products, ACTH and β-endorphin, were found with immunocytochemistry staining to be increased in AtT-20 cells after TCDD exposure. The presence of several XRE sequences in the promoter region and in the first intron of the human POMC gene suggest that the up-regulation of POMC expression in the pituitary may play a role in the endocrine alterations induced by TCDD. All together, the results point to the pituitary gland being a direct target for TCDD.