Okazaki Kazushi, Okazaki Shuzo, Nakamura Hideaki, Kitamura Yasuki, Hatayama Kazuhisa, Wakabayashi Sachiko, Tsuda Toshiharu, Katsumata Tomoyoshi, Nishikawa Akiyoshi, Hirose Masao
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Arch Toxicol. 2002 Oct;76(10):553-9. doi: 10.1007/s00204-002-0376-0. Epub 2002 Jul 18.
In association with the international validation project to establish an OECD Enhanced Test Guideline 407, we performed a 28-day repeated-dose toxicity study of genistein, which is known as a phytoestrogen. Attention was paid to the sensitivity of certain additional parameters, such as histopathology observations and organ weights of endocrine related organs, sperm characteristics, serum hormone levels and estrous cycle, for detecting endocrine-related effects of endocrine-disrupting chemicals based on the existing TG 407. Seven-week-old Crj:CD(SD)IGS rats were assigned to one of four groups, each consisting of ten males and ten females, and genistein was administered once daily by gavage at doses of 0 (control), 120, 400 or 1000 mg/kg body weight per day. Male rats were killed on the day after the 28th administration. Female rats were killed on the day of the diestrus stage during the 4 days after the 28th administration. Endocrine-disrupting effects of genistein were detected in females by histopathology. The changes included vacuolation and mucinification of the vaginal epithelium in the 400 and 1000 mg/kg groups; however, the incidences of the lesion were very low. Although increased serum prolactin levels were recorded in the males of the 1000 mg/kg group, we could not determine whether this was indeed induced by genistein. General toxicological effects of genistein were detected in blood chemistry, such as increased triglycerides and total protein and a decreased albumin/globulin ratio, as well as increased liver weight and glycogen deposition in the periportal hepatocytes. Based on these results, the no-observed-adverse-effect level (NOAEL) in the present study was estimated to be 120 mg/kg per day. In particular, endocrine-related effects were most sensitively detected by histopathology examination of sexual organs. However, the findings indicate that chemicals with weak endocrine-disrupting potential like genistein must be evaluated taking into consideration the results of other test systems.
结合建立经合组织强化测试指南407的国际验证项目，我们对染料木黄酮进行了一项为期28天的重复剂量毒性研究，染料木黄酮是一种已知的植物雌激素。基于现有的测试指南407，我们关注某些额外参数的敏感性，如组织病理学观察、内分泌相关器官的器官重量、精子特征、血清激素水平和发情周期，以检测内分泌干扰化学物质的内分泌相关效应。将7周龄的Crj:CD(SD)IGS大鼠分为四组，每组由10只雄性和10只雌性组成，通过灌胃每天一次给予染料木黄酮，剂量分别为0（对照）、120、400或1000 mg/kg体重。在第28次给药后的第二天处死雄性大鼠。在第28次给药后的4天内，在动情后期处死雌性大鼠。通过组织病理学在雌性大鼠中检测到染料木黄酮的内分泌干扰效应。这些变化包括400和1000 mg/kg组阴道上皮的空泡化和粘液化；然而，病变的发生率非常低。虽然在1000 mg/kg组的雄性大鼠中记录到血清催乳素水平升高，但我们无法确定这是否确实是由染料木黄酮诱导的。在血液化学中检测到染料木黄酮的一般毒理学效应，如甘油三酯和总蛋白增加以及白蛋白/球蛋白比值降低，以及肝脏重量增加和门静脉周围肝细胞中的糖原沉积。基于这些结果，本研究中未观察到不良反应水平（NOAEL）估计为每天120 mg/kg。特别是，通过性器官的组织病理学检查最敏感地检测到内分泌相关效应。然而，研究结果表明，必须考虑其他测试系统的结果来评估像染料木黄酮这样具有弱内分泌干扰潜力的化学物质。
