Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes
Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes
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DOI：
10.1530/rep-07-0460
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发表时间：
2008-05-01
期刊：
影响因子：
3.8
通讯作者：
Selstam, Gunnar
中科院分区：
文献类型：
--
作者：
Gunnarsson, David;Leffler, Per;Selstam, Gunnar
邻苯二甲酸酯广泛用作许多日常产品中的增塑剂。在这项研究中，我们研究了邻苯二甲酸单（2-乙基己基）酯（MEHP），常用的增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）的活性代谢产物，在体外对性腺类固醇生成的影响。MEHP（25-100 μ M）以浓度依赖性方式刺激永生化小鼠Leydig肿瘤细胞（MLTC-1）的基础类固醇合成。在KK-1颗粒瘤细胞中也检测到刺激作用。MEHP暴露不影响cAMP或星星蛋白水平，并诱导关键类固醇生成蛋白的基因表达谱不同于人绒毛膜促性腺激素（hCG）诱导的基因表达谱。MEW和p450 SCC抑制剂（氨鲁米特）的同时治疗表明，MEHP发挥其主要的刺激作用之前，去甲烯醇酮形成。MEHP（10-100 μ M）上调对胆固醇敏感的脂肪酶和3-羟基-3-甲基戊二酰辅酶A还原酶，表明MEHP增加了可用于类固醇生成的胆固醇的量。我们的数据表明，MEHP，除了其已知的hCG作用的抑制作用，可以直接刺激性腺类固醇激素在两种性别通过cAMP和星独立的机制。DEHP的抗类固醇生成作用被认为会导致发育障碍，如尿道下裂和隐睾症，而刺激类固醇合成可能会过早启动青春期的开始，理论上会影响下丘脑-垂体-性腺轴。
Phthalates are widely used as plasticizers in a number of daily-life products. In this study, we investigated the influence of mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of the frequently used plasticizer di-(2-ethylhexyl) phthalate (DEHP), on gonadal steroidogenesis in vitro. MEHP (25-100 mu M) stimulated basal steroid synthesis in a concentration-dependent manner in immortalized mouse Leydig tumor cells (MLTC-1). The stimulatory effect was also detected in KK-1 granulosa tumor cells. MEHP exposure did not influence cAMP or StAR protein levels and induced a gene expression profile of key steroidogenic proteins different from the one induced by human chorionic gonadotropin (hCG). Simultaneous treatment with MEW and a p450scc inhibitor (aminoglutethimide) indicated that MEHP exerts its main stimulatory effect prior to pregnenolone formation. MEHP (10-100 mu M) up-regulated hormone-sensitive lipase and 3-hydroxy-3-methylglutaryl coenzyme A reductase, suggesting that MEHP increases the amount of cholesterol available for steroidogenesis. Our data suggest that MEHP, besides its known inhibitory effect on hCG action, can directly stimulate gonadal steroidogenesis in both sexes through a cAMP- and StAR-independent mechanism. The anti-steroidogenic effect of DEHP has been proposed to cause developmental disorders such as hypospadias and cryptorchidism, whereas a stimulation of steroid synthesis may prematurely initiate the onset of puberty and theoretically affect the hypothalamic-pituitary-gonadal axis.