小剂量氟他胺对大鼠性分化影响的实验研究

Impact of Flutamide on Sex Differentiation in Rats

目的探讨低剂量抗雄激素药物氟他胺对大鼠性分化的影响,以及氟他胺诱导建立SD大鼠尿道下裂动物模型的可行性。方法60只孕鼠,随机分为5个实验组及1个对照组,从孕12～17d连续6d实验组每天腹部皮下注射用生理盐水配制的氟他胺4882.8、5078.1、5273.4、5468.7、6250.0μg/kg,对照组注射同量生理盐水。于孕18d每组解剖两只孕鼠,提取子代雄性胎鼠尿生殖结节做病理切片,同时观察睾丸位置和前列腺发育情况。并于出生后第2、13、28d观察雄性仔鼠性分化与性发育的指标。结果氟他胺染毒组雄性子一代肛殖距各组均明显小于对照组(P<0.05);尿道下裂的发生率依次为29.00%、40.00%、63.68%、78.72%、100%;单侧隐睾发生率分别为4.23%、6.23%、9.23%、11.52%、16.28%;乳晕延迟退化率均为100%;各组前列腺不发育或发育不全。结论小剂量氟他胺能够引起大鼠的性分化与性发育异常;并能诱导出稳定、直观的尿道下裂动物模型。

Objective To investigate the adverse effect of flutamide on the sex differentiation of F1 generation male rats and to establish a rat model of hypospadis. Methods Sixty pregnant SD rats were divided randomly into one control group and five treatment groups. Flutamide was injected subcutaneously （so） with normal salin （NS） at a dose of 0, 4882. 8, 5078. 1, 5273.4, 5468.7, and 6250. 0 μg/kg· d to the rats in the above groups respectively during the period of gestation day （GD） 12 to 17. The fetuses of two rats from each group were anatomized on GD18 to extract genital tubercle （GT） to make pathological sections. Meanwhile, the position of testes and the development of prostates were examined. The position of urethral opening and testes were examined on GD2, 13 and 28. Results The incidence of hypospadias increased with the dose of flutamide （0, 29.00%, 40. 00%, 63.68%, 78. 72%, and 100% for the above groups respectively）. The incidence of single cryptorchidism also increased with the dose of flutamide （0, 4.23%, 6.23%, 9. 23%, 11.52%, and 16. 28% for the above groups respectively）. Flutamide led to 100% incidence of prostate agenesis, 100% incidence of femalelike areola of nipple, and 100% incidence of female-like anogenital distance （AGD）. Conclusion Flutamide can cause abnormal sex differentiation and sex development and induce the experimental model of hypospa-ias in rats.