Prenatal exposure to di-n-butyl phthalate (DBP) differentially alters androgen cascade in undeformed versus hypospadiac male rat offspring |
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| Affiliation: | 1. Department of Urology, Shanghai First People’s Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China;2. Department of Neurology, Barrow Neurological Institute, St. Joseph''s Hospital and Medical Center, 350 W Thomas Rd, Phoenix, AZ 85013, United States;3. Department of Geriatrics, Shanghai First People’s Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China;4. Department of Urology, Zhejiang Provincial People''s Hospital, 158 Shangtang Road, Hangzhou 310014, China;1. Department of Chemistry, Elizabeth City State University, Elizabeth City, NC 27909, United States;2. Research Institute of the McGill University, Health Centre and Departments of Medicine, Biochemistry, Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1A4, Canada;3. Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States;1. Instituto de Investigación Biosanitaria (ibs.GRANADA), University of Granada, San Cecilio University Hospital, 18071 Granada, Spain;2. CIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain;3. Research Group of Analytical Chemistry and Life Sciences, Department of Analytical Chemistry, University of Granada, Granada, Spain;4. Institute of the Environment, Health and Societies, Brunel University, Kingston Lane, Uxbridge, UB8 3PH, UK;1. Center for Endocrinology, Diabetes, and Metabolism, Children''s Hospital Los Angeles, 4650 Sunset Blvd, #61, Los Angeles, CA 90027, USA;2. Medical Genetics Institute, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA;1. Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China;2. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China;3. College of Nursing, Nanjing Medical University, Nanjing, Jiangsu 211166, China;4. The Affiliated Kezhou People’s Hospital of Nanjing Medical University, Kezhou, Xinjiang 845350, China |
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| Abstract: | This study was to compare the alterations of androgen cascades in di-n-butyl phthalate (DBP)-exposed male offspring without hypospadias (undeformed) versus those with hypospadias. To induce hypospadias in male offspring, pregnant rats received DBP via oral gavage at a dose of 750 mg/kg BW/day during gestational days 14–18. The mRNA expression levels of genes downstream of the androgen signaling pathway, such as androgen receptor (AR) and Srd5a2, in testes of undeformed rat pups were similar to those in controls; in hypospadiac rat pups these levels were significantly lower than those of control pups. In contrast, both undeformed and hypospadiac rats had decreased serum testosterone levels, reduced mRNA expression of key enzymes in the androgen synthetic pathway in the testes, and ablated genes of developmental pathways, such as Shh, Bmp4, Fgf8, Fgf10 and Fgfr2, in the genital tubercle (GT) as compared to those in DBP-unexposed controls, albeit hypospadiac rats had a more severe decrement than those of undeformed rats. Although other possibilities cannot be excluded, our findings suggest that the relatively normal levels of testosterone-AR-Srd5a2 may contribute to the resistance to DBP toxicity in undeformed rats. In conclusion, our results showed a potential correlation between decreased testosterone levels, reduced mRNA expression of AR and Srd5a2 and the occurrence of hypospadias in male rat offspring prenatally exposed to DBP. |
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| Keywords: | Undeformed rats Hypospadias Environmental endocrine disrupting compounds (EEDs) Androgen cascade |
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