Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances
Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances
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DOI：
10.1073/pnas.0305977101
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发表时间：
2004-01-20
影响因子：
11.1
通讯作者：
Hardy, MP
中科院分区：
文献类型：
--
作者：
Akingbemi, BT;Ge, RS;Hardy, MP
暴露于环境因子与人类生殖障碍有关的可能性最近引起了公众的极大兴趣。邻苯二甲酸酯在食品和建筑行业中最常用作增塑剂，邻苯二甲酸二（2-乙基己基）酯（DEHP）是环境中含量最丰富的邻苯二甲酸酯。在美国，人体每日暴露于DEHP的量很大，职业和临床暴露于DEHP增塑的医疗器械，例如，血袋、血液透析管和鼻饲管增加了身体负担水平。我们研究了长期暴露于低环境相关DEHP水平对睾丸功能的影响。我们的数据表明，长期暴露于这种药物诱导高水平的促性腺激素促黄体生成激素和性激素[睾酮和17 β-雌二醇（E2）]的血清浓度增加> 50%。通过RT-PCR测定，细胞周期蛋白的表达增强证明了间质细胞增殖活性的增加。DEHP处理组大鼠睾丸间质细胞数量比对照组大鼠高40-60%，表明诱导了间质细胞增生。DEHP诱导的血清睾酮和E2水平升高表明雄激素、雌激素和类固醇激素受体之间可能存在多种串扰，而非生殖组织中雌激素受体的存在，例如，心血管系统和骨骼，意味着血清E2水平的增加具有生殖以外的影响，包括全身生理学。邻苯二甲酸酯暴露对促性腺激素和类固醇激素水平影响的分析应构成人群总体风险评估的一部分。
The possibility that exposures to environmental agents are associated with reproductive disorders in human populations has generated much public interest recently. Phthalate esters are used most commonly as plasticizers in the food and construction industry, and di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate in the environment. Daily human exposure to DEHP in the U.S. is significant, and occupational and clinical exposures from DEHP-plasticized medical devices, e.g., blood bags, hemodialysis tubing, and nasogastric feeding tubes, increase body burden levels. We investigated the effects of chronic exposures to low environmentally relevant DEHP levels on testicular function. Our data show that prolonged exposures to this agent induced high levels of the gonadotropin luteinizing hormone and increased the serum concentrations of sex hormones [testosterone and 17beta-estradiol (E2)] by >50%. Increased proliferative activity in Leydig cells was evidenced by enhanced expression of cell cycle proteins, as determined by RT-PCR. The numbers of Leydig cells in the testis of DEHP-treated rats were 40-60% higher than in control rats, indicating induction of Leydig cell hyperplasia. DEHP-induced elevations in serum testosterone and E2 levels suggest the possibility of multiple crosstalks between androgen, estrogen, and steroid hormone receptors, whereas the presence of estrogen receptors in nonreproductive tissues, e.g., cardiovascular system and bones, implies that the increases in serum E2 levels have implications beyond reproduction, including systemic physiology. Analysis of the effects of phthalate exposures on gonadotropin and steroid hormone levels should form part of overall risk assessment in human populations.