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T-2 毒素通过 cAMP-PKA 途径调节大鼠卵巢颗粒细胞甾体激素的分泌。

T-2 toxin regulates steroid hormone secretion of rat ovarian granulosa cells through cAMP-PKA pathway.

机构信息

College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan 410128, PR China.

College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan 410128, PR China.

出版信息

Toxicol Lett. 2015 Feb 3;232(3):573-9. doi: 10.1016/j.toxlet.2014.12.016. Epub 2014 Dec 24.

Abstract

T-2 toxin is a secondary metabolite produced by Fusarium genus and is a common contaminant in food and feedstuffs of cereal origin. In porcine granulosa cells(GC), T-2 toxin has been shown to inhibit the steroidogenesis; however, the mechanism has not been well understood. Gonadotropin-stimulated steroidogenesis is regulated by the cAMP-PKA pathway. In this study, we investigated potential mechanisms for T-2 toxin-induced reproductive toxicity focusing on the critical steps of the cAMP-PKA pathway affected by T-2 toxin. We first analyzed the effects of T-2 toxin on progesterone and estrogen production in rat granulosa cells. For this purpose the granulosa cells were cultured for 48 h in 10% fetal bovine serum-containing medium followed by 24h in serum-free medium containing FSH (10 ng/ml) and androstenedione (3 ng/ml), both are required for normal steroidogenesis. Treatment of these cells with T-2 toxin dose-dependently inhibited the growth of cells and the steroid hormone production. Cellular cyclic AMP levels were dose-dependently inhibited by T-2 toxin (0, 1, 10 and 100 nM, 24 h). Furthermore, we found that although the induction of progesterone by 8-Br-cAMP (a FSH mimetic) and 22R-HC (substrate for progesterone) could both be inhibited by T-2 toxin treatment, the T-2-imposed inhibitory effects could be reversed by increasing doses of 22R-HC, while increasing 8-Br-cAMP had no effects, suggesting that T2 toxin targeted at distinct mechanisms. cAMP-stimulated steroidogenic acute regulatory protein (StAR) is a rate limiting protein in progesterone synthesis. Exposure to T2 toxin caused significant suppression of StAR expression as determined by Western blotting and semi-quantitative RT-PCR suggesting StAR is a sensitive target for T-2 toxin. Taken together, our results strongly suggest that T2 toxin inhibits steroidogenesis by suppressing cAMP-PKA pathway and StAR is a target for T-2-toxin. The antisteroidogenesis effects were observable at low T-2 dose (1 ng/ml) suggesting T-2 toxin has an endocrine disruptive effect.

摘要

T-2 毒素是真菌属产生的一种次生代谢物,是谷物来源的食物和饲料的常见污染物。在猪的颗粒细胞(GC)中,T-2 毒素已被证明抑制类固醇生成;然而,其机制尚未得到很好的理解。促性腺激素刺激的类固醇生成受 cAMP-PKA 途径调节。在这项研究中,我们研究了 T-2 毒素诱导生殖毒性的潜在机制,重点关注 T-2 毒素影响的 cAMP-PKA 途径的关键步骤。我们首先分析了 T-2 毒素对大鼠颗粒细胞孕激素和雌激素产生的影响。为此,将颗粒细胞在含有 10%胎牛血清的培养基中培养 48 小时,然后在不含血清的培养基中培养 24 小时,其中含有 FSH(10ng/ml)和雄烯二酮(3ng/ml),这两者都是正常类固醇生成所必需的。用 T-2 毒素处理这些细胞可剂量依赖性地抑制细胞生长和类固醇激素产生。T-2 毒素(0、1、10 和 100 nM,24 小时)可剂量依赖性地抑制细胞内环腺苷酸水平。此外,我们发现,尽管 8-Br-cAMP(FSH 模拟物)和 22R-HC(孕激素的底物)诱导的孕激素产生均可被 T-2 毒素处理抑制,但 T-2 毒素施加的抑制作用可通过增加 22R-HC 的剂量来逆转,而增加 8-Br-cAMP 则没有效果,这表明 T2 毒素针对不同的机制。cAMP 刺激的类固醇急性调节蛋白(StAR)是孕激素合成中的限速蛋白。Western blot 和半定量 RT-PCR 分析表明,暴露于 T2 毒素会导致 StAR 表达显著抑制,这表明 StAR 是 T-2 毒素的敏感靶点。总之,我们的结果强烈表明,T2 毒素通过抑制 cAMP-PKA 途径抑制类固醇生成,StAR 是 T-2 毒素的靶点。低剂量(1ng/ml)的 T-2 毒素就具有抗类固醇生成作用,表明 T-2 毒素具有内分泌干扰作用。

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