In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis.
In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis.
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DOI：
10.1210/en.2009-0847
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发表时间：
2009-11
期刊：
影响因子：
4.8
通讯作者：
D. B. Martinez-Arguelles;M. Culty;B. Zirkin;V. Papadopoulos
中科院分区：
文献类型：
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作者：
D. B. Martinez-Arguelles;M. Culty;B. Zirkin;V. Papadopoulos
在宫内暴露于邻苯二甲酸二(2-乙基己基)酯(DEHP)可导致胚胎和成年大鼠睾丸雄激素生成减少。在胎儿中，雄激素的减少伴随着类固醇生成酶的表达减少。然而，子宫内暴露导致成人雄激素形成减少的机制尚不清楚。我们假设，核类固醇受体的放松调控可能解释了宫内DEHP暴露对成人睾酮产生的影响。为了验证这一假设，从妊娠14-19天开始，给怀孕的SD大鼠每天每公斤灌胃100-950毫克DEHP，并在妊娠20天和出生后3天、21天和60天收集睾丸。在所研究的核受体中，PND60间质细胞中的盐皮质激素受体(MR)mRNA和蛋白水平降低，并伴随着MR调节基因的mRNA表达降低。甲基化敏感的聚合酶链式反应对核受体亚家族NR3A和-3C有影响，但只有MR在PND60受到影响。对MR基因启动子内的两个CpG岛进行焦磷酸测序显示，在DEHP处理的动物中，甲基化缺失与MR减少相关。由于已知MR激活刺激Leydig细胞睾酮的形成，而MR抑制是抑制的，我们的结果与以下假设一致：在宫内暴露于DEHP会导致MR功能障碍，从而抑制成年动物的睾酮生成。我们认为，MR降低，可能是表观遗传介导的，是邻苯二甲酸盐可能影响生命后期不同功能的一种新机制。
In utero exposure to di-(2-ethylhexyl) phthalate (DEHP) has been shown to result in decreased androgen formation by fetal and adult rat testes. In the fetus, decreased androgen is accompanied by the reduced expression of steroidogenic enzymes. The mechanism by which in utero exposure results in reduced androgen formation in the adult, however, is unknown. We hypothesized that deregulation of the nuclear steroid receptors might explain the effects of in utero DEHP exposure on adult testosterone production. To test this hypothesis, pregnant Sprague Dawley dams were gavaged with 100-950 mg DEHP per kilogram per day from gestational d 14-19, and testes were collected at gestational d 20 and postnatal days (PND) 3, 21, and 60. Among the nuclear receptors studied, the mineralocorticoid receptor (MR) mRNA and protein levels were reduced in PND60 interstitial Leydig cells, accompanied by reduced mRNA expression of MR-regulated genes. Methylation-sensitive PCR showed effects on the nuclear receptor subfamilies NR3A and -3C, but only MR was affected at PND60. Pyrosequencing of two CpG islands within the MR gene promoter revealed a loss of methylation in DEHP-treated animals that was correlated with reduced MR. Because MR activation is known to stimulate Leydig cell testosterone formation, and MR inhibition to be repressive, our results are consistent with the hypothesis that in utero exposure to DEHP leads to MR dysfunction and thus to depressed testosterone production in the adult. We suggest that decreased MR, possibly epigenetically mediated, is a novel mechanism by which phthalates may affect diverse functions later in life.