邻苯二甲酸二丁酯影响泄殖腔发育致雄性子鼠尿道下裂合并肛门直肠畸形的机制及干预研究

前期课题通过孕晚期补充人绒毛膜促性腺激素（HCG）降低了邻苯二甲酸二丁酯（DBP）致尿道下裂的发生率；同时发现部分尿道下裂雄性子鼠并发肛门直肠畸形（ARMs），且孕早期DBP染毒能增加这种合并畸形的发生。胚胎期泄殖腔发育对泌尿生殖系统和肛门直肠的形成起着重要作用。在此基础上，本研究拟：①建立DBP致畸大鼠模型，用病理学方法观察孕(GD)12-18天畸形雄性胎鼠泄殖腔的发育。②用基因芯片筛选GD18天畸形雄性胎鼠泄殖腔组织中异常表达基因并验证。在出生后1天的尿道下裂合并ARMs雄性子鼠生殖结节、膀胱和末端直肠组织中进一步检测这些基因的变化，探讨DBP对泄殖腔发育信号通路网络的影响。③进一步探讨孕早期使用HCG能否更有效的降低DBP的生殖发育毒性，并对其机制进行研究。本研究有助于我们加深对DBP毒性机制的理解，为寻找防治方法提供新的线索，同时对DBP与ARMs发生相关性提供了确实依据。

In previous works, we injected human chorionic gonadotropin (HCG) into pregnant rats in late pregnancy，which successfully reduced the incidence of hypospadias induced by di-n-butyl phthalate（DBP）. In addition, we found that part of the hypospadias male offspring were complicated by anorectal malformations(ARMs) and DBP exposure in early pregnancy can increase this malformation. The embryonic development of cloaca plays an important role in the formation of urogenital and anorectal system. On the basis of previous works, in this project, we intend to: ①establish DBP-induced rat models and study the development of cloaca in male rat offspring from gestational day(GD) 12 to 18 by histological observation; ②use the gene array to detect the cloaca of the male rat offspring on GD 18 and verify the differential genes, further validate these gene changes in genital tubercle, bladder and terminal rectum of the hypospadias male offspring complicated by ARMs on postnatal day（PND） 1. We will clarify the effects of DBP to signaling pathways of cloacal development; ③Further investigate whether use of HCG in early pregnancy can more effectively reduce the reproductive and developmental toxicity of DBP and study the mechanisms. This project will deepen our understandings of the toxicological mechanisms of DBP, and provide new clues to find the preventions and treatments, at the same time provide the exact basis that DBP can induce ARMs.