Nitrophenols isolated from diesel exhaust particles regulate steroidogenic gene expression and steroid synthesis in the human H295R adrenocortical cell line
Nitrophenols isolated from diesel exhaust particles regulate steroidogenic gene expression and steroid synthesis in the human H295R adrenocortical cell line
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DOI：
10.1016/j.taap.2008.01.026
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发表时间：
2008-05-15
影响因子：
3.8
通讯作者：
Taya, Kazuyoshi
中科院分区：
文献类型：
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作者：
Furuta, Chie;Noda, Shiho;Taya, Kazuyoshi
从柴油尾气颗粒（DEPs）、3-甲基-4-硝基苯酚（PNMC）和4-硝基-3-苯基苯酚（PNMPP）中分离出的硝基酚类物质在体内体外均具有雌激素和抗雄激素活性，且PNMC在体内肾上腺中蓄积。然而，暴露于这些化合物对肾上腺内分泌干扰和类固醇生成的影响尚未调查。为了阐明PNMC和PNMPP的非受体介导作用，我们研究了在提供cAMP的人肾上腺H295R细胞中类固醇激素黄体酮、皮质醇、睾酮和雌二醇-17 β的产生以及参与合成类固醇激素（CYP11A、CYP11B1、CYP17、CYP19、17 β HSD1、17 β HSD4、CYP21、3 β HSD2、StAR）的9个主要酶基因的调节。暴露于10（-7）至10(-5)M PNMC和1 mM 8-Br-cAMP中48小时，睾酮、皮质醇和雌二醇-17 β水平降低，孕酮分泌增加。10-5 M时，含有1 mM 8-Br-cAMP的PNMC显著刺激17 β HSD4的表达，显著抑制3 β HSD2的表达。相比之下，10（-7）至2 × 10(-5) M PNMPP与1 mM 8-Br-cAMP作用48 h后，雌二醇-17 β浓度降低，孕酮水平升高，但不影响睾酮和皮质醇分泌，这是由于CYP17的显著抑制和CYP19的不显著但明显的抑制。我们的研究结果明确了甾体生成酶是抑制或刺激甾体生成途径中类固醇激素产生的候选物质，从而为这些硝基酚破坏内分泌途径的多种机制提供了第一个实验证据。(C) 2008爱思唯尔公司版权所有。
Studies of nitrophenols isolated from diesel exhaust particles (DEPs), 3-methyl-4-nitrophenol (PNMC) and 4-nitro-3-phenylphenol (PNMPP) have revealed that these chemicals possess estrogenic and anti-androgenic activity in vitro and in vivo and that PNMC accumulate in adrenal glands in vivo. However, the impacts of exposure to these compounds on adrenal endocrine disruption and steroidogenesis have not been investigated. To elucidate the non-receptor mediated effects of PNMC and PNMPP, we investigated the production of the steroid hormones progesterone, cortisol, testosterone, and estradiol-17 beta and modulation of nine major enzyme genes involved in the synthesis of steroid hormones (CYP11A, CYP11B1, CYP17, CYP19, 17 beta HSD1, 17 beta HSD4, CYP21, 3 beta HSD2, StAR) in human adrenal H295R cells supplied with cAMP. Exposure to 10(-7) to 10(-5) M PNMC and 1 mM 8-Br-cAMP for 48 h decreased testosterone, cortisol, and estradiol-17 beta levels and increased progesterone secretion. At 10-5 M, PNMC with 1 mM 8-Br-cAMP significantly stimulated expression of the 17 beta HSD4 and significantly suppressed expression of 3 beta HSD2. In comparison, 10(-7) to 2 x 10(-5) M PNMPP with 1 mM 8-Br-cAMP for 48 h decreased concentrations of estradiol-17 beta, increased progesterone levels, but did not affect testosterone and cortisol secretion due to the significant suppression of CYP17 and the non-significant but obvious suppression of CYP19. Our results clarified steroidogenic enzymes as candidates responsible for the inhibition or stimulation for the production of steroid hormones in the steroidogenic pathway, thus providing the first experimental evidence for multiple mechanisms of disruption of endocrine pathways by these nitrophenols. (C) 2008 Elsevier Inc. All rights reserved.