Zhu Yi-Ping, Li En-Hui, Sun Wen-Lan, Xu Dong-Liang, Liu Zhi-Hong, Zhao Wei, Wood Kristofer, Xia Shu-Jie, Jiang Jun-Tao
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
Department of Urology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China.
Reprod Toxicol. 2016 Jun;61:169-76. doi: 10.1016/j.reprotox.2016.04.007. Epub 2016 Apr 11.
Anorectal malformations in combination with hypospadias (ARMs & hypospadias) are a type of complex congenital malformations. The underlying mechanisms of this deformity are largely unknown. In this study, we comprehensively characterized the dysplasia, histological malformations, and genetic changes of ARMs & hypospadias in male rats after maternal exposure to di-n-butyl phthalate (DBP) by gastric intubation at doses of 850mg/kg bw/day during GD11-15. On postnatal day 1, anatomical and histopathological analysis confirmed combined malformations of the genital tubercle (GT), terminal rectum (TR) and testes. DBP-induced dysplasia was also seen in the kidney, lung, spleen, heart and liver of ARMs & hypospadias male rats. Moreover, decreased levels of serum testosterone, as well as reduced expression of genes related to the androgen signaling pathway (Cyp11a1, Hsd3b, Scarb1, Star, AR, Srd5a2) were found in the testes of ARMs & hypospadias male rats after DBP exposure as compared to untreated controls. Further, decreased mRNA levels of Shh, Fgf10, Gli2, Gli3, Bmp4, Wnt5a, Hoxa13, Hoxd13, Fgfr2 and AR were observed in TR and GT in the ARMs & hypospadias group. These results provide evidence that prenatal exposure to DBP can lead to combined anorectal and urogenital malformations as well as dysplasia of the testes.
肛门直肠畸形合并尿道下裂（ARMs & 尿道下裂）是一种复杂的先天性畸形。这种畸形的潜在机制在很大程度上尚不清楚。在本研究中，我们全面表征了孕鼠在妊娠第11 - 15天经胃插管给予850mg/kg体重/天剂量的邻苯二甲酸二丁酯（DBP）后，雄性大鼠ARMs & 尿道下裂的发育异常、组织学畸形和基因变化。出生后第1天，解剖学和组织病理学分析证实了生殖结节（GT）、直肠末端（TR）和睾丸的联合畸形。在ARMs & 尿道下裂雄性大鼠的肾脏、肺、脾脏、心脏和肝脏中也观察到DBP诱导的发育异常。此外，与未处理的对照组相比，DBP暴露后ARMs & 尿道下裂雄性大鼠睾丸中的血清睾酮水平降低，以及与雄激素信号通路相关的基因（Cyp11a1、Hsd3b、Scarb1、Star、AR、Srd5a2）表达减少。此外，在ARMs & 尿道下裂组的TR和GT中观察到Shh、Fgf10、Gli2、Gli3、Bmp4、Wnt5a、Hoxa13、Hoxd13、Fgfr2和AR的mRNA水平降低。这些结果提供了证据，表明产前暴露于DBP可导致肛门直肠和泌尿生殖系统联合畸形以及睾丸发育异常。
