来曲唑对幼龄SD大鼠发育毒性的考察

Investigation on Developmental Toxicity of Letrozole to Juvenile SD Rats

来曲唑(1)属于第三代非甾体类芳香化酶抑制剂,可用于治疗周围性性早熟、先天性肾上腺皮质增生症和身材矮小症,但1在儿科人群中的安全性评估尚有欠缺。该研究采用幼龄SD大鼠为模型评估1的发育毒性,考察了1连续灌胃给药28 d后幼龄SD大鼠的临床体征、体质量、学习和记忆功能、组织病理学、生殖功能、性激素以及骨代谢指标的变化。结果表明,与对照组(用0.5%羧甲纤维素溶液处理)相比,1对幼龄大鼠的临床体征、体质量、学习和记忆功能及Ⅰ型胶原C末端肽均无明显影响。但1高剂量(135 mg/kg)雄鼠试验组睾丸中睾酮的含量显著升高;1中、高剂量(1.5和15 mg/kg)雌鼠试验组卵巢中的雌二醇含量、子宫器官系数显著降低,且子宫可见萎缩。不同剂量(0.15、1.5和15 mg/kg)1作用下,雌鼠均出现闭锁卵泡显著增多的现象,而且各剂量组雌鼠卵母细胞中的Ⅲ型受体酪氨酸蛋白激酶(c-Kit)表达减少。综上所述,1会影响雌性幼龄大鼠生殖功能和雄性幼龄大鼠雄激素水平,主要与1的作用机制有关。

Letrozole(1),a third-generation nonsteroidal aromatase inhibitor,has been widely used to treat peripheral precocious puberty,congenital adrenal hyperplasia,and short stature.However,the safety assessment of 1 in the pediatric population need to be improved.In this study,juvenile SD rats were used as models to evaluate the developmental toxicity of 1.Juvenile SD rats were intragastrically administrated of 1 for 28 days,and the changes in clinical signs,body weight,learning and memory function,histopathology,reproductive function,sex hormones,and bone metabolism indexes were evaluated.The results showed that compared with the control group(treated with 0.5%of carboxymethylcellulose solution),there were no significant influences in clinical signs,body weight,learning and memory function,and C-terminal telopeptides of typeⅠcollagen of jurenile rats treated with 1.However,the testosterone level in testicular tissue of male rats treated with 1 at high dosage of 135 mg/kg was significantly increased.The estradiol level in the ovary,organ coefficient of the uterus in female rats treated with medium-and high-dose(1.5 and 15 mg/kg)of 1 were significantly decreased,and uterine atrophy was observed.Moreover,the significant increase of atresia follicles and decrease of c-Kit level in oocytes were observed in all groups of female rats treated with different doses(0.15,1.5 and 15 mg/kg)of 1.In conclusion,1 could affect the reproductive function of female juvenile rats and the androgen level of male juvenile rats,which was mainly related to the action mechanism of 1.