Jiang Jun-Tao, Xu Hong-Li, Zhu Yi-Ping, Wood Kristofer, Li En-Hui, Sun Wen-Lan, Yuan Quan, Xu Dong-Liang, Liu Zhi-Hong, Zhao Wei, Xia Shu-Jie
Department of Urology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Urology Surgery, Linyi People's Hospital, School of Medicine, Taishan Medical College, Linyi, Shangdong, China.
Toxicology. 2015 Dec 2;338:77-85. doi: 10.1016/j.tox.2015.10.006. Epub 2015 Oct 26.
Previous study have demonstrated that not only the anorectal development but also the general conditions of anorectal malformations (ARMs) male rats are severely affected by di-n-butyl phthalate (DBP) maternal exposure. However, the mechanisms underlying DBP-induced congenital defects remain elusive. Reportedly, Fgf10/Fgfr2 and androgen receptor (AR) are pivotal for the development of multiple organs. In this study, we therefore investigated the expression of Fgf10/Fgfr2 together with AR in the terminal rectum and multiple organs of ARM male rats induced by in utero exposure to DBP. DBP was administered to pregnant rats to establish the model and the incidence of ARMs in male offspring was 39.5%. On postnatal day(PND)1, the gross photograph and histopathological staining confirmed the abnormal manifestations in these organs of newborn ARMs. Decreased anogenital distance, body weight and serum testosterone level were observed in ARM male offspring. The reduced expression of Fgf10/Fgfr2 mRNA and protein was seen in terminal rectum and kidney, spleen, liver, heart in ARM male rats, whereas the reduced expression of AR was only observed in the kidney and terminal rectum. Our findings suggest the potential involvement of altered Fgf10/Fgfr2 signaling and AR in pathogenesis of local and systemic development defects in ARMs male rats induce by DBP.
先前的研究表明，孕期暴露于邻苯二甲酸二丁酯（DBP）不仅会严重影响雄性大鼠的肛门直肠发育，还会影响肛门直肠畸形（ARM）的总体状况。然而，DBP诱导先天性缺陷的潜在机制仍不清楚。据报道，Fgf10/Fgfr2和雄激素受体（AR）对多个器官的发育至关重要。因此，在本研究中，我们调查了子宫内暴露于DBP诱导的ARM雄性大鼠终末直肠和多个器官中Fgf10/Fgfr2与AR的表达。将DBP给予怀孕大鼠以建立模型，雄性后代中ARM的发生率为39.5%。在出生后第1天（PND1），大体照片和组织病理学染色证实了新生ARM这些器官中的异常表现。在ARM雄性后代中观察到肛门生殖距离、体重和血清睾酮水平降低。在ARM雄性大鼠的终末直肠以及肾脏、脾脏、肝脏、心脏中可见Fgf10/Fgfr2 mRNA和蛋白表达降低，而仅在肾脏和终末直肠中观察到AR表达降低。我们的研究结果表明，Fgf10/Fgfr2信号通路改变和AR可能参与了DBP诱导的ARM雄性大鼠局部和全身发育缺陷的发病机制。
