Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate
Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate
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DOI：
10.1093/toxsci/kfh169
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发表时间：
2004-09-01
影响因子：
3.8
通讯作者：
Gaido, KW
中科院分区：
文献类型：
--
作者：
Lehmann, KP;Phillips, S;Gaido, KW
在子宫内接触邻苯二甲酸二丁酯(DBP)会损害雄性大鼠生殖道的发育。不利的影响部分是由于参与胆固醇运输和类固醇生成的基因表达的协调减少，从而导致胎儿睾丸中睾酮的产生减少。为探讨DBP对胎鼠睾丸类固醇激素合成影响的量效关系，孕12~19天的SD大鼠每天灌胃给予玉米油(溶剂对照组)或DBP(0.1、1.0、10、50、100或500 mg/kg/d)。于孕19d分离睾丸，用RT-PCR和Western分析检测基因和蛋白表达的变化。用放射免疫法测定胎儿睾丸睾酮水平。DBP暴露导致清道夫受体、类固醇合成急性调节蛋白(STAR)、细胞色素P450侧链裂解、3β-羟基类固醇脱氢酶和细胞色素P450c17的mRNA和蛋白浓度显著降低。睾丸睾酮在50 mg/kg/d及以上剂量时降低。外周苯二氮卓类受体(PBR)mRNA与STAR一起作用于线粒体膜转运胆固醇，在DBP 500 mg/kg/d暴露后，其全睾丸表达上调。免疫细胞化学显示，PBR蛋白在间质细胞中减少，在性腺细胞中也表达，但不减少。我们的结果表明，在母亲暴露于DBP后，参与胆固醇运输和类固醇生成的关键基因和蛋白的表达呈剂量依赖性的协调减少，胎儿睾丸中的睾酮相应减少，低于该剂量水平，发育中的男性生殖道会检测到不良影响。基因和蛋白质表达以及睾酮合成的改变可能是睾丸对DBP反应的敏感指标。
Exposure to di (n-butyl) phthalate (DBP) in utero impairs the development of the male rat reproductive tract. The adverse effects are due in part to a coordinated decrease in expression of genes involved in cholesterol transport and steroidogenesis with a resultant reduction in testosterone production in the fetal testis. To determine the dose-response relationship for the effect of DBP on steroidogenesis in fetal rat testes, pregnant Sprague-Dawley rats received corn oil (vehicle control) or DBP (0.1, 1.0, 10, 50, 100, or 500 mg/kg/day) by gavage daily from gestation day (GD) 12 to 19. Testes were isolated on GD 19, and changes in gene and protein expression were quantified by RT-PCR and Western analysis. Fetal testicular testosterone concentration was determined by radioimmunoassay. DBP exposure resulted in significant dose-dependent reductions in mRNA and protein concentration of scavenger receptor, steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage, 3beta-hydroxysteroid dehydrogenase, and cytochrome P450c17. Testicular testosterone was reduced at doses of 50 mg/kg/day and above. Whole-testis expression of peripheral benzodiazepine receptor (PBR) mRNA, which functions with StAR to transport cholesterol across the mitochondrial membrane, was upregulated following exposure to DBP at 500 mg/kg/day. By immunocytochemistry, however, PBR protein was reduced in interstitial cells and also expressed but not reduced in gonocytes. Our results demonstrate a coordinate, dose-dependent reduction in the expression of key genes and proteins involved in cholesterol transport and steroidogenesis and a corresponding reduction in testosterone in fetal testes following maternal exposure to DBP, at dose levels below which adverse effects are detected in the developing male reproductive tract. Alterations in gene and protein expression and testosterone synthesis may serve as sensitive indicators of testicular response to DBP.