Goto Kazunori, Koizumi Keiji, Takaori Hitoshi, Fujii Yoshinobu, Furuyama Yuko, Saika Osamu, Suzuki Hiroetsu, Saito Kenichi, Suzuki Katsushi
Department of Toxicology Research, Odawara Research Center Nippon Soda Co., Ltd., Kanagawa, Japan.
J Toxicol Sci. 2004 Dec;29(5):517-34. doi: 10.2131/jts.29.517.
Flutamide, when administered subcutaneously to female rats at doses of 3, 10, or 30 mg/kg/day during late pregnancy (gestational days 16-21), significantly and dose-dependently decreased anogenital distance (AGD) of the male offspring in each dose group compared to controls. Significant delays in preputial separation were found in males at a dose of 30 mg/kg, but body weight gain was not inhibited. Cryptorchidism and absence of the prostate gland and seminal vesicles were found in males at doses > or = 10 mg/kg, and testicular hypoplasia at a dose of 30 mg/kg. Hypospadias was noted in all dose groups and vaginal pouches at doses of > or =10 mg/kg. The effects on the accessory reproductive organs were severe, although the effects on the testes themselves were mild. However, those effects appeared to become more pronounced with growth, as evaluated on Days 30 and 42 and Weeks 16 to 18. Most of these affected animals displayed cryptorchidism. Male offspring exposed to flutamide in utero showed impairments of sexual behavior as adults in a dose-related manner. Number and frequency of mounts with intromissions was markedly decreased in all treated groups as compared to controls. At 10 mg/kg, no mounting with ejaculation was observed, and at a dose of 30 mg/kg, no mounting with intromission or ejaculation was observed. These changes in sexual behavior were closely associated with abnormalities of the external genitalia. Animals with hypospadias did not display mounts with ejaculation. However, F1 males that copulated at a dose of 3 mg/kg had a normal reproductive function. Histological examination of the reproductive organs revealed degeneration of the seminiferous tubules, hypospermatogenesis, and hypoplasia and inflammation of the seminal vesicles and prostate. Serum levels of FSH, LH, and testosterone in these animals were comparable between control and all dose groups. Therefore, the male reproductive dysfunction seen in the present study could not be attributed to abnormal sex hormone levels during maturation, but to possible demasculinization of the brain and progressively delayed dysmorphology of the male genitalia caused by fetal exposure to flutamide.
在妊娠后期（妊娠第16 - 21天），当以3、10或30毫克/千克/天的剂量对雌性大鼠皮下注射氟他胺时，与对照组相比，各剂量组雄性后代的肛门生殖器距离（AGD）均显著且呈剂量依赖性降低。在30毫克/千克的剂量下，雄性大鼠出现明显的包皮分离延迟，但体重增加未受抑制。在剂量≥10毫克/千克的雄性大鼠中发现隐睾、前列腺和精囊缺如，在30毫克/千克的剂量下出现睾丸发育不全。在所有剂量组均观察到尿道下裂，在剂量≥10毫克/千克时出现阴道袋。尽管对睾丸本身的影响较轻，但对附属生殖器官的影响较为严重。然而，从第30天和第42天以及第16至18周的评估来看，这些影响似乎随着生长而变得更加明显。这些受影响的动物大多表现为隐睾。子宫内接触氟他胺的雄性后代成年后性行为出现剂量相关的损害。与对照组相比，所有治疗组的爬跨并插入行为的次数和频率均显著降低。在10毫克/千克时，未观察到射精的爬跨行为，在30毫克/千克的剂量下，未观察到插入或射精的爬跨行为。性行为的这些变化与外生殖器异常密切相关。患有尿道下裂的动物未表现出射精的爬跨行为。然而，在3毫克/千克剂量下交配的F1雄性具有正常的生殖功能。生殖器官的组织学检查显示生精小管退化、精子发生减少、精囊和前列腺发育不全及炎症。这些动物的血清促卵泡激素（FSH）、促黄体生成素（LH）和睾酮水平在对照组和所有剂量组之间相当。因此，本研究中观察到的雄性生殖功能障碍并非归因于成熟过程中异常的性激素水平，而是由于胎儿接触氟他胺导致大脑可能的去男性化以及雄性生殖器逐渐延迟的畸形。
