邻苯二甲酸二丁酯宫内和哺乳期染毒对F_1代雄性大鼠的生殖发育毒性

Reproductive and developmental toxicity of F_1 male rats treated with DBP in utero and during lactation

目的 观察邻苯二甲酸二丁酯 (DBP)对F1代仔鼠的发育状况及性成熟期雄性仔鼠生殖系统损害情况 ,并期望得到现有文献中缺如的DBP对F1代仔鼠生殖发育毒性的最大无作用剂量 (NOAEL)。方法 选择在宫内暴露期和哺乳期 (受孕第 2天至仔鼠 2 1天断奶 ) ,通过灌胃方式给母鼠染毒 (DBP终浓度分别为 0、5 0、2 5 0和 5 0 0mg (kg·d) ,观察对仔鼠的影响。结果 DBP对母鼠无明显影响 ,中高剂量组 [2 5 0、5 0 0mg (kg·d) ]对F1代雄性仔鼠的出生体重、每窝活产数、体重增长及雄性仔鼠肛殖距有明显影响 ,对性成熟期雄性仔鼠生殖系统损害尤为严重 ,可观察到小睾丸、附睾发育不全甚至缺失、睾丸未降等现象 ,附睾尾精子参数和睾丸精子头计数及附睾、肝、肾、前列腺的脏器系数明显降低 ,而与激素合成相关的垂体系数却略有上升。低剂量组未观察到有害影响。结论 雄性生殖系统是DBP作用的主要靶器官 ,幼年敏感期所受的损害部分不可逆 ,并得到DBP经口染毒对F1代仔鼠生殖发育毒性的NOAEL为 5 0mg (kg·d)。据此 ,进一步提出DBP经口摄入的参考剂量 (RfD)为 5 0 0 μg (kg·d)。

Objective To observe the effects of Di-n-butyl phthalate (DBP) on the developmental condition of F 1 rats and on the reproductive system of mature F 1 male rats and to establish the NOAEL of DBP. Methods In this study, pregnant rats were treated with different dose of DBP (0, 50, 250 and 500mg per kg per day) by gavage in utero and during lactation (from GD1 to PND21). The effects of DBP on F 1 rats were observed. Results DBP had no obvious effect on pregnant rats but could decline pups' born weight, live pups per litter, body weight gain and male pups' anogenital distance obviously. Severe damages on the reproductive system of mature F 1 male rats (testicular atrophy, underdevelopmental epididymis, absent of epididymis, undescended testes, obvious decline of epididymal sperm parameters, total sperm heads per g testis, decrease of organ/body weight ratio of epididymis, liver, kidney and prostate, etc.) were observed in the group of 250mg per kg per day and higher. Conclusion These results showed that male reproductive system was the target organ of DBP and the damages on pups were partly irreversible. According to these results, the NOAEL of DBP, which was not available in the current database, was established based on the outcomes of this study, i.e., 50mg per kg per day. Accordingly, the RfD for human exposure to DBP through oral intake was recommended as 500μg per kg per day.