Title | Molecular effects of genistein on male urethral development. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Ross AE, Marchionni L, Phillips TM, Miller RM, Hurley PJ, Simons BW, Salmasi AH, Schaeffer AJ, Gearhart JP, Schaeffer EM |
Journal | J Urol |
Volume | 185 |
Issue | 5 |
Pagination | 1894-8 |
Date Published | 2011 May |
ISSN | 1527-3792 |
Keywords | Animals, Animals, Newborn, Blotting, Western, Cell Proliferation, Cell Survival, Extracellular Signal-Regulated MAP Kinases, Female, Fetus, Forkhead Box Protein O1, Forkhead Transcription Factors, Genistein, Homeodomain Proteins, Hypospadias, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase Kinases, Neoplasm Proteins, Phytoestrogens, Pregnancy, Prenatal Exposure Delayed Effects, Signal Transduction, Transforming Growth Factor beta, Urethra |
Abstract | PURPOSE: The increasing incidence of hypospadias is partly attributed to increased gestational exposure to endocrine disruptors. We investigated the effects of genistein, the primary phytoestrogen in soy, on the molecular program of male urethral development. MATERIALS AND METHODS: Female mice were fed diets supplemented with genistein (500 mg/kg diet) or control diets before breeding and throughout gestation. Urethras from embryonic day 17.5 male fetuses were harvested, and RNA was prepared, amplified, labeled and hybridized on whole genome microarrays. Data were analyzed using packages from the R/Bioconductor project. Immunohistochemical analysis and immunoblotting were used to confirm the activity of MAPK and the presence of Ntrk1 and Ntrk2 during urethral development. RESULTS: Gestational exposure to genistein altered the urethral expression of 277 genes (p <0.008). Among the most affected were hormonally regulated genes, including IGFBP-1, Kap and Rhox5. Differentially expressed genes were grouped into functional pathways of cell proliferation, adhesion, apoptosis and tube morphogenesis (p <0.0001), and were enriched for members of the MAPK (p <0.00001) and TGF-β (p <0.01) signaling cascades. Differentially expressed genes preferentially contained ELK1, Myc/Max, FOXO, HOX and ER control elements. The MAPK pathway was active, and its upstream genistein affected tyrosine kinase receptors Ntrk1 and Ntrk2 were present in the developing male urethra. CONCLUSIONS: Gestational exposure to genistein contributes to hypospadias by altering pathways of tissue morphogenesis, cell proliferation and cell survival. In particular, genes in the MAPK and TGF-β signaling pathways and those controlled by FOXO, HOX and ER transcription factors are disrupted. |
DOI | 10.1016/j.juro.2010.12.095 |
Alternate Journal | J Urol |
PubMed ID | 21421236 |
Grant List | K08DK081019 / DK / NIDDK NIH HHS / United States T32DK007552 / DK / NIDDK NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States |
Related Faculty:
Luigi Marchionni, M.D., Ph.D.