5-Aza-2＇-deoxycytidine暴露对新生大鼠精子发生的影响

目的]探讨暴露于DNA甲基化抑制剂5-Aza-2’-deoxycytidine（5-Aza-CdR）对新生SD大鼠生长发育和成年精子发生的影响。方法]新生大鼠随机分为3组，每组24只雄鼠。自出生第3天（postnatal day3，PND3）开始经口给予5-Aza-CdR 25、250μg／kg，对照组给予等量的溶剂。连续暴露5d，最后一次暴露结束后24h，处死半数雄鼠（幼鼠。剩余部分继续喂养至12周龄（成鼠），乙醚麻醉。取睾丸组织做病理学检查、精子头计数等，附睾做精子畸形检查。结果]随着剂量的增加，幼鼠体重出现下降趋势，与对照组比较差异有统计学意义（P〈0.05）。组织病理学发现幼鼠睾丸组织中出现空泡变性。检查发现染毒结束后继续喂养至12周的成鼠睾丸组织无明显形态和组织学变化；但每克睾丸组织精子头计数及每日精子生成量随幼年时暴露剂量增加呈现下降趋势（P〈0.05），而精子畸形率随剂量增加呈现上升趋势（P〈0.05）。结论]新生大鼠对DNA甲基化抑制制5-Aza-CdR生殖毒性作用敏感，低剂量短时间的暴露即可引起成年期生殖功能的异常。

Effects of 5-Aza-2'-deoxycytidine on Spermatogenesis of Rats

Objective ] To evaluate the effect of 5-Aza-2＇-deoxycytidine （ 5-Aza-CdR ） on the spermatogenesis of rats in vivo. Methods ] The neonatal male rats were randomly divided into 3 groups, 24 per group. The rats were received oral administrations of 5-Aza-CdR 25, 250μg/kg or vehicle control daily for 5 d from postnatal day 3 （ PND3 ）. Half male rats were killed 24 h after the last administration. The rest rats were fed until 12 weeks old. Testes were collected for histologic examination and sperm heads count, epididymis collected for sperm malformation assay. Results ] Body weight was lower in 5-Aza-CdR exposure groups than that in the control group（ P 〈 0.05 ）just after the final exposure. The histopathology of testes was examined on PND8 and vacuoles were found in 5-Aza-CdR exposure groups. When rats grew to 12 weeks of age, although no obvious defects in testes were observed with hematoxylin and eosin staining, but the number of sperm per gram of testis was significantly decreased （ P 〈 0.05 ） and the malformation rate of sperm was significantly increased （ P 〈 0.05 ）. Conclusion ] Neonatal exposure of DNA methylation inhibitor 5-Aza-CdR damaged tile spermatogenesis and reduced the sperm function in adult stage of rats. Neonatal stage may be the critical time point for reproductive toxicity of DNA methylation inhibitor.