title: Aryl-hydrocarbon receptor activity modulates prolactin expression in the pituitary.
abstract: Pituitary tumors account for 15% of intracranial neoplasms, however the extent to which environmental toxicants contribute to the proliferation and hormone expression of pituitary cells is unknown. Aryl-hydrocarbon receptor (AhR) interacting protein (AIP) loss of function mutations cause somatotrope and lactotrope adenomas in humans. AIP sequesters AhR and inhibits its transcriptional function. Because of the link between AIP and pituitary tumors, we hypothesize that exposure to dioxins, potent exogenous ligands for AhR that are persistent in the environment, may predispose to pituitary dysfunction through activation of AhR. In the present study, we examined the effect of AhR activation on proliferation and endogenous pituitary hormone expression in the GH3 rat somatolactotrope tumor cell line and the effect of loss of AhR action in knockout mice. GH3 cells respond to nM doses of the reversible AhR agonist β-naphthoflavone with a robust induction of Cyp1a1. Although mRNA levels of the anti-proliferative signaling cytokine TGFbeta1 are suppressed upon β-naphthoflavone treatment, we did not observe an alteration in cell proliferation. AhR activation with β-naphthoflavone suppresses Ahr expression and impairs expression of prolactin (PRL), but not growth hormone (GH) mRNA in GH3 cells. In mice, loss of Ahr similarly leads to a reduction in Prl mRNA at P3, while Gh is unaffected. Additionally, there is a significant reduction in pituitary hormones Lhb and Fshb in the absence of Ahr. Overall, these results demonstrate that AhR is important for pituitary hormone expression and suggest that environmental dioxins can exert endocrine disrupting effects at the pituitary.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Moran
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Brannick
authors.forename: Lori T
authors.initials: LT
authors.lastname: Raetzman
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity; D052244:Endocrine Disruptors / Q000633:toxicity; D013006:Growth Hormone / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011388:Prolactin / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D004147:Dioxins; D052244:Endocrine Disruptors; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D053773:Transforming Growth Factor beta1; D019324:beta-Naphthoflavone; D011388:Prolactin; D013006:Growth Hormone; D019363:Cytochrome P-450 CYP1A1