Molecular Mechanisms Of Hypospadias In Male Rats Exposed To Di-n-butyl Phthalate During Late Gestation

Objective: The objective of this study was to investigate molecularmechanisms of hypospadias in male rats exposed to di-n-butyl phthalate(DBP) during late gestation.Methods: Timed pregnant Sprague-Dawley (SD) rats were givenDBP by gastric intubation at a dose of 0, 500 or 800 mg/kg/day fromgestation day (GD) 14 to 18 after maternal body weight was recordeddaily. On postnatal day (PND) 1, male offspring were allocated to threegroups: control male offspring (group A), 500 mg/kg/day (H) (group B)and 800 mg/kg/day (H) (group C) after identifying control male offspringnot exposed to DBP and hypospadiac male offspring exposed to DBP.Real-time quantitative RT-PCR and Western blotting were used toquantify mRNA of sonic hedgehog (Shh), bone morphogenetic protein 4(Bmp4) and androgen receptor (Ar) and protein of Ar expression in ratpenises of above three groups on PND 1. Serum testosterone (T)concentration of male offspring in above three groups on PND 1 wasdetermined by using T radioimmunoassay (RIA) kit. Results: mRNA (Shh, Ar) expression in rat penises and serum Tlevel in group B were significantly decreased compared with those incontrol group (P＜0.05). mRNA (Shh, Bmp4, Ar), protein (Ar) expressionin rat penises and serum T level in group C were significantly decreasedcompared with those in control group (P＜0.05).Conclusions: DBP affects the development of the genital tubercle(GT) by regulating Shh signaling in early development of GT andandrogen signaling in late development of GT, inducing the occurrence ofhypospadias in male rats.