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Molecular effects of genistein on male urethral development.

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-? (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-? signaling pathways and those controlled by FOXO, HOX and ER transcription factors are disrupted.

SUBMITTER: Ross AE

PROVIDER: S-EPMC6489447 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Molecular effects of genistein on male urethral development.

Ross Ashley E AE Marchionni Luigi L Phillips Timothy M TM Miller Rebecca M RM Hurley Paula J PJ Simons Brian W BW Salmasi Amirali H AH Schaeffer Anthony J AJ Gearhart John P JP Schaeffer Edward M EM

The Journal of urology 20110321 5

<h4>Purpose</h4>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.<h4>Materials and methods</h4>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 ...[more]

PMID: 21421236

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Project description:Urethral stricture is fundamentally a fibrosis of the urethral epithelial and associated corpus spongiosum, which in turn, causes obstruction of the urethral lumen. Patients with urethral stricture most commonly present with lower urinary tract symptoms, urinary retention or urinary tract infection but may also experience a broad spectrum of other signs and symptoms, including genitourinary pain, hematuria, abscess, ejaculatory dysfunction, or renal failure. When urethral stricture is initially suspected based on clinical assessment, cystoscopy is suggested as the modality that most accurately establishes the diagnosis. This recommendation is based on several factors, including the accuracy of cystoscopy, as well as its wide availability, lesser overall cost, and comfort of urologists with this technique. When recurrent urethral stricture is suspected, we suggest performing retrograde urethrography to further stage the length and location of the stricture or referring the patient to a physician with expertise in reconstructive urology. Ultimately, the treatment decision depends on several factors, including the type and acuity of patient symptoms, the presence of complications, prior interventions, and the overall impact of the urethral stricture on the patient's quality of life. Endoscopic treatment, either as dilation or internal urethrotomy, is suggested rather than urethroplasty for the initial treatment of urethral stricture. This recommendation applies to men with undifferentiated urethral stricture and does not apply to trauma-related urethral injuries, penile urethral strictures (hypospadias, lichen sclerosus), or suspected urethral malignancy. In the setting of recurrent urethral stricture, urethroplasty is suggested rather than repeat endoscopic management but this may vary depending on patient preference and impact of the symptoms on the patient.The purpose of this guideline is to provide a practical summary outlining the diagnosis and treatment of urethral stricture in the Canadian setting.

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Molecular effects of genistein on male urethral development.

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Molecular effects of genistein on male urethral development.

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