Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Toxicol Appl Pharmacol. 2012 Nov 15;265(1):139-45. doi: 10.1016/j.taap.2012.08.026. Epub 2012 Sep 6.
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.
垂体肿瘤占颅内肿瘤的 15%,然而,环境毒物在多大程度上促进垂体细胞的增殖和激素表达尚不清楚。芳烃受体(AhR)相互作用蛋白(AIP)功能丧失突变导致人类的生长激素和催乳素腺瘤。AIP 隔离 AhR 并抑制其转录功能。由于 AIP 与垂体肿瘤之间存在联系,我们假设暴露于二恶英(AhR 的强外源性配体,在环境中持久存在)可能通过激活 AhR 导致垂体功能障碍。在本研究中,我们研究了 AhR 激活对 GH3 大鼠生长激素催乳素肿瘤细胞系增殖和内源性垂体激素表达的影响,以及 AhR 作用缺失对敲除小鼠的影响。GH3 细胞对 nM 剂量的可逆 AhR 激动剂β-萘黄酮作出强烈的 Cyp1a1 诱导反应。尽管β-萘黄酮处理后抗增殖信号细胞因子 TGFβ1 的 mRNA 水平受到抑制,但我们没有观察到细胞增殖的改变。AhR 激活用β-萘黄酮抑制 Ahr 表达并损害 GH3 细胞中催乳素(PRL)但不影响生长激素(GH)mRNA 的表达。在小鼠中,Ahr 的缺失同样导致 P3 时 Prl mRNA 的减少,而 Gh 不受影响。此外,在没有 Ahr 的情况下,垂体激素 Lhb 和 Fshb 的含量显著降低。总的来说,这些结果表明 AhR 对于垂体激素表达很重要,并表明环境中二恶英可以对垂体发挥内分泌干扰作用。