Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate
Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate
复制标题
DOI：
10.1016/s0890-6238(01)00201-5
复制
发表时间：
2002-01-01
影响因子：
3.3
通讯作者：
Foster, PMD
中科院分区：
文献类型：
--
作者：
Mylchreest, E;Sar, M;Foster, PMD
先前在妊娠第 12-21 天 (GD) 暴露于邻苯二甲酸二正丁酯 (DBP) 的成年雄性大鼠会出现生殖道畸形，特别是附睾发育不全、精子生成减少。间质细胞增生和腺瘤。尽管强效雄激素受体 (AR) 拮抗剂氟他胺也能产生类似的作用，并且表明通过抗雄激素机制破坏男性性分化，但 DBP 不是 AR 拮抗剂。该研究的目的是确定DBP是否会导致男性生殖道分化产前阶段的病理变化和睾丸雄激素状态的改变。怀孕的 CD 大鼠口服玉米油、DBP（500 mg/kg/天）或氟他胺（100 mg/kg/天）。 GD 12-21。在 GD 16-21，DBP 引起 Leydig 细胞增生，其中许多细胞呈 30-羟基类固醇脱氢酶和/或 AR 阳性。增生灶区域的增殖细胞核抗原 (PCNA) 阳性 Leydig 细胞数量增加。在 GD 21 时，睾丸萎缩明显，DBP 暴露胎儿的生精索增大，并含有多核生殖细胞，与对照组不同，其具有 PCNA 阳性。在 GD 18 和 21 时，DBP（而非氟他胺）显着降低了睾丸睾酮水平。DBP 治疗时，附睾导管减少，某些导管中 AR 染色减少，而在存在轻度间质细胞增生的情况下，使用氟他胺观察到总体 AR 染色减少。间质细胞增殖可能是增加睾酮不足引发的睾丸类固醇生成的补偿机制。雄激素浓度的总体下降未得到纠正并导致生殖道畸形。生殖细胞的多核性和增殖表明支持细胞功能障碍。 (C) 2002 Elsevier Science Inc. 保留所有权利。
Adult male rats previously exposed on gestation days (GD) 12-21 to di(n-butyl) phthalate (DBP) have reproductive tract malformations, particularly agenesis of the epididymis, decreased sperm production. and Leydig cell hyperplasia and adenomas. Although similar effects are produced by the potent androgen receptor (AR) antagonist flutamide and are indicative of disruption of male sexual differentiation via an antiandrogenic mechanism, DBP is not an AR antagonist. The purpose of the study was to determine whether DBP causes pathologic changes and alterations in androgen status in the testis during the prenatal period of male reproductive tract differentiation. Pregnant CD rats were given corn oil, DBP (500 mg/kg/day), or flutamide (100 mg/kg/day) p.o. on GD 12-21. At GD 16-21, DBP caused hyperplasia of Leydig cells, many of which were 30-hydroxysteroid dehydrogenase- and/or AR-positive. Focal areas of hyperplasia had increased numbers of Leydig cells positive for proliferating cell nuclear antigen (PCNA). At GD 21, testis atrophy was apparent, seminiferous cords in DBP-exposed fetuses were enlarged and contained multinucleated gonocytes that, unlike controls, were PCNA-poqitive. DBP, but not flutamide, markedly decreased testicular testosterone levels at GD 18 and 21. Fewer epididymal ducts and reduced AR staining in some ducts were evident with DBP treatment, whereas decreased overall AR staining was seen with flutamide in the presence of mild Leydig cell hyperplasia, Leydig cell proliferation is likely a compensatory mechanism to increase testicular steroidogenesis triggered by testosterone insufficiency. The overall decrease in androgen concentration is not corrected and results in reproductive tract malformations. The multinuclearity and proliferation of gonocytes suggests tin underlying Sertoli cell dysfunction. (C) 2002 Elsevier Science Inc. All rights reserved.