Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra
Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra
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DOI：
10.1073/pnas.0502544102
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发表时间：
2005-05-10
影响因子：
11.1
通讯作者：
Vom Saal, FS
中科院分区：
文献类型：
--
作者：
Timms, BG;Howdeshell, KL;Vom Saal, FS
人类胎儿可能通过多种来源接触人造雌激素化学物质。例如，胎儿会接触炔雌醇，因为每年大约有 3% 服用口服避孕药的妇女怀孕。由于聚碳酸酯塑料产品和罐内衬中的大量浸出，人们通过食品和饮料接触雌激素化学物质双酚 A。我们给怀孕的CD-1小鼠喂食炔雌醇（每天0.1μg/kg）和双酚A（每天10μg/kg），其剂量低于孕妇的暴露范围。在雄性小鼠胎儿中，炔雌醇和双酚 A 都会增加背外侧前列腺管的数量和大小，并导致前列腺管体积总体增加。用增殖细胞核抗原和小鼠角蛋白5的抗体对切片进行组织化学染色表明，这些增加是由于位于初级导管中的基底上皮细胞的增殖显着增加所致。尿道丘区畸形，进入膀胱的地方明显收缩，这可能导致尿流障碍。这些效应与相似剂量（每天 0.1 微克/千克）雌激素药物己烯雌酚 (DES) 所引起的效应相同，DES 是一种已知的人类发育致畸剂和致癌剂。相比之下，高 2,000 倍的 DES 剂量完全抑制背外侧前列腺管的形成，揭示了高剂量和低剂量雌激素的相反作用。胎儿时期少量雌激素化学物质会加速前列腺上皮的增殖速度，可能会永久性地破坏细胞控制系统，并使成年后的前列腺容易患病。
Exposure of human fetuses to man-made estrogenic chemicals can occur through several sources. For example, fetal exposure to ethinylestradiol occurs because each year approximate to 3% of women taking oral contraceptives become pregnant. Exposure to the estrogenic chemical bisphenol A occurs through food and beverages because of significant leaching from polycarbonate plastic products and the lining of cans. We fed pregnant CD-1 mice ethinylestradiol (0.1 mu g/kg per day) and bisphenol A (10 mu g/kg per day), which are doses below the range of exposure by pregnant women. In male mouse fetuses, both ethinylestradiol and bisphenol A produced an increase in the number and size of dorsolateral prostate ducts and an overall increase in prostate duct volume. Histochemical staining of sections with antibodies to proliferating cell nuclear antigen and mouse keratin 5 indicated that these increases were due to a marked increase in proliferation of basal epithelial cells located in the primary ducts. The urethra was malformed in the colliculus region and was significantly constricted where it enters the bladder, which could contribute to urine flow disorders. These effects were identical to those caused by a similar dose (0.1 mu g/kg per day) of the estrogenic drug diethylstilbestrol (DES), a known human developmental teratogen and carcinogen. In contrast, a 2,000-fold higher DES dose completely inhibited dorsolateral prostate duct formation, revealing opposite effects of high and low doses of estrogen. Acceleration in the rate of proliferation of prostate epithelium during fetal life by small amounts of estrogenic chemicals could permanently disrupt cellular control systems and predispose the prostate to disease in adulthood.