title: Maternal exposure to di-n-butyl phthalate (DBP) induces combined anorectal and urogenital malformations in male rat offspring.
abstract: 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.
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Zhu
authors.affiliation: Department of Urology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China.
authors.forename: En-Hui
authors.initials: EH
authors.lastname: Li
authors.affiliation: Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
authors.forename: Wen-Lan
authors.initials: WL
authors.lastname: Sun
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
authors.forename: Dong-Liang
authors.initials: DL
authors.lastname: Xu
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Liu
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Kristofer
authors.initials: K
authors.lastname: Wood
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China. Electronic address: xsjurologist@126.com.
authors.forename: Shu-Jie
authors.initials: SJ
authors.lastname: Xia
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China. Electronic address: tianyi_xyz@163.com.
authors.forename: Jun-Tao
authors.initials: JT
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000071056:Anorectal Malformations / Q000139:chemically induced; D004268:DNA-Binding Proteins / Q000235:genetics; D003993:Dibutyl Phthalate / Q000633:toxicity*; D005260:Female; D007021:Hypospadias / Q000139:chemically induced; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D010968:Plasticizers / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017207:Rats, Sprague-Dawley; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics; D013737:Testis / Q000002:abnormalities / Q000187:drug effects; D013739:Testosterone / Q000097:blood
chemical_list: D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010968:Plasticizers; D011944:Receptors, Androgen; D003993:Dibutyl Phthalate; D013739:Testosterone; C496356:Fgfr2 protein, rat; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: Anorectal malformations; Di-n-butyl phthalate (DBP); Hypospadias