Disrupting effects of bifenthrin on ovulatory gene expression and prostaglandin synthesis in rat ovarian granulosa cells
Disrupting effects of bifenthrin on ovulatory gene expression and prostaglandin synthesis in rat ovarian granulosa cells
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联苯菊酯对大鼠卵巢颗粒细胞排卵基因表达和前列腺素合成的干扰作用
DOI：
10.1016/j.tox.2011.01.007
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发表时间：
2011-03-28
期刊：
影响因子：
4.5
通讯作者：
Liu, Weiping
中科院分区：
文献类型：
--
作者：
Liu, Jing;Yang, Ye;Liu, Weiping
合成拟除虫菊酯（SP）是最常用和最广泛使用的农药类别之一。虽然接触五氯苯酚与哺乳动物的生殖毒性有关，但关于五氯苯酚对雌性排卵功能的影响的信息有限。联苯菊酯（BF）是一种广谱的I型SP，已被广泛应用于害虫防治二十年。先前的研究表明，BF具有雌激素样活性作为一种内分泌干扰化学品。在这项工作中，我们显示了在体外抑制作用的BF对促黄体生成素（LH）诱导的排卵基因表达在大鼠卵巢颗粒细胞，包括基因P450 SCC，星星，PR，AREG，EREG，TGF-β 1，C/EBP β，RUNX 1，p21，细胞周期蛋白E1，CYP 19 a1，SULT 1 E1和PTGS 2。我们在体内的研究表明，短期管理BF促性腺激素引发的大鼠LH负责排卵基因的表达中断，这表明BF在体外和体内LH信号具有类似的干扰作用。由于野牡丹素及其关键合成酶PTGS 2在排卵过程中起关键作用，我们进一步研究了BF对PTGS 2的破坏作用的分子机制。重要的是，我们发现BF阻断LH诱导的颗粒细胞培养液中前列腺素E2（PGE 2）的积累。BF处理后，Forskolin刺激的PTGS 2表达降低，表明BF可能通过蛋白激酶A（PKA）介导的信号通路抑制LH诱导的PTGS 2表达。此外，BF降低了Forskolin刺激的PTGS 2启动子的转录活性，表明BF在转录水平上阻断了PTGS 2基因的表达。综上所述，我们目前的研究首次显示了BF对排卵基因表达模式网络以及前列腺素合成的系统性破坏作用，并表明暴露于BF可能会增加女性排卵功能障碍的风险。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Synthetic pyrethroids (SPs) are one of the most frequently and widely used classes of pesticides. Although exposure to SPs is associated with reproductive toxicity in mammals, limited information is available regarding the effects of SPs on female ovulatory function. Bifenthrin (BF), a broad-spectrum type I SP, has been widely used for pest control for two decades. Previous studies showed that BF had estrogen-like activity as an endocrine-disrupting chemical. In this work, we showed the in vitro inhibitory effects of BF on luteinizing hormone (LH)-inducible ovulatory gene expression in rat ovarian granulosa cells, including genes P450scc, StAR, PR, AREG, EREG, TGF-beta 1, C/EBP beta, RUNX1, p21, cyclin El, CYP19a1, SULT1E1 and PTGS2. Our in vivo studies demonstrated that short-term administration of BF to gonadotropin-primed rats disrupted the expression of LH-responsible ovulatory genes, suggesting that BF has similar disrupting effects on in vitro and in vivo LH signaling. Because prostaglandins and their key synthetic enzyme PTGS2 play pivotal roles in ovulatory process, we further investigated the molecular mechanism of disruption of PTGS2 by BF. Importantly, we found that BF blocked LH-inducible prostaglandin E2 (PGE2) accumulation in cultured medium of granulosa cells. Forskolin stimulated PTGS2 expression was decreased by treatment with BF, indicating that BF may inhibit LH-induced PTGS2 expression through the protein kinase A (PKA)-mediated signaling pathway. In addition, the reduction in transcriptional activity of forskolin-stimulated PTGS2 promoter by BF, indicates that BF blocks the expression of PTGS2 gene at the transcriptional level. Taken together, our present study firstly shows the systemic disrupting effects of BF on the network of ovulatory gene expression patterns as well as prostaglandin synthesis, and suggest that exposure to BF may increase the risk of ovulatory dysfunction in females. (C) 2011 Elsevier Ireland Ltd. All rights reserved.