Zhu Ying-Jian, Jiang Jun-Tao, Ma Long, Zhang Jie, Hong Yan, Liao Kai, Liu Qiang, Liu Guo-Hua
Department of Urology, Shanghai First People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China.
Toxicology. 2009 Jun 16;260(1-3):120-5. doi: 10.1016/j.tox.2009.03.017. Epub 2009 Apr 5.
The objective of this study was to first evaluate the developmental abnormalities and carry out the molecular analysis of external genitalia in newborn hypospadiac male rats induced by maternal exposure to di-n-butyl phthalate (DBP). Timed-pregnant rats were given DBP by gastric intubation at dose of 750 mg/kg body weight (bw)/day from gestation day (GD) 14 to GD18 to establish a hypospadiac rat model. The incidence of hypospadias was 46.67% in male offsprings. On postnatal day (PND) 7, at the newborn stage, decreased body weight and anogenital distance (AGD)/body weight ratio were observed in newborn hypospadiac male rats. The general image and transverse serial histological analysis of genitalia of newborn hypospadiac male rats confirmed the malformation. Autopsy analysis revealed development of reproductive organs (testes, genital tubercle (GT)), hollow organs (stomach, bladder), and solid organs (brain, heart, liver, spleen, lung, kidney, pancreas) in newborn hypospadiac male rats affected by DBP. Moreover, significantly decreased gene expression of important signaling molecules necessary for GT formation including sonic hedgehog signaling molecules (Shh and Ptched 1), bone morphogenetic proteins signaling molecules (Bmp4 and Bmp7), fibroblast growth factor signaling molecules (Fgf8, Fgf10 and Fgfr2), and the transforming growth factor-beta superfamily signaling molecules (TGF-beta1 and TGF-beta receptor III) were observed, for the first time, in the GT of newborn hypospadias induced by DBP. These results showed that the reproductive system and development conditions of newborn hypospadiac rats were damaged by DBP. These disturbed signaling pathways which orchestrating genital development might play an important role in the toxic process of DBP induced hypospadias.
本研究的目的是首先评估发育异常情况，并对母体暴露于邻苯二甲酸二丁酯（DBP）诱导的新生尿道下裂雄性大鼠的外生殖器进行分子分析。从妊娠第14天（GD）至GD18，对定时受孕的大鼠进行胃插管给予剂量为750 mg/kg体重（bw）/天的DBP，以建立尿道下裂大鼠模型。雄性后代中尿道下裂的发生率为46.67%。在出生后第7天（PND）的新生阶段，观察到新生尿道下裂雄性大鼠体重下降，肛门生殖器距离（AGD）/体重比降低。新生尿道下裂雄性大鼠生殖器的整体图像和横向连续组织学分析证实了畸形。尸检分析显示，受DBP影响的新生尿道下裂雄性大鼠的生殖器官（睾丸、生殖结节（GT））、中空器官（胃、膀胱）和实体器官（脑、心脏、肝脏、脾脏、肺、肾、胰腺）发育情况。此外，首次在DBP诱导的新生尿道下裂的GT中观察到GT形成所需的重要信号分子的基因表达显著降低，包括音猬因子信号分子（Shh和Ptched 1）、骨形态发生蛋白信号分子（Bmp4和Bmp7）、成纤维细胞生长因子信号分子（Fgf8、Fgf10和Fgfr2）以及转化生长因子-β超家族信号分子（TGF-β1和TGF-β受体III）。这些结果表明，DBP损害了新生尿道下裂大鼠的生殖系统和发育状况。这些协调生殖器发育的信号通路紊乱可能在DBP诱导尿道下裂的毒性过程中起重要作用。
