title: Chronic high dose intraperitoneal bisphenol A (BPA) induces substantial histological and gene expression alterations in rat penile tissue without impairing erectile function.
abstract: BACKGROUND
  Bisphenol A (BPA), released from plastics and dental sealants, is a suspected endocrine disruptor and reproductive toxicant. In occupationally exposed workers, BPA has been associated with erectile dysfunction (ED).
  
  
  OBJECTIVE
  To determine whether long-term exposure to high doses of BPA in the rat affects serum levels of testosterone (T) and estradiol (E2), and induces corporal histopathology and resultant ED.
  
  
  METHODS
  Young rats were injected intraperitoneal (IP) injection daily with BPA at 25 mg/kg/day or vehicle (n = 8/group). Erectile function was measured at 3 months by cavernosometry and electrical field stimulation (EFS). BPA was assayed in serum, urine, and penile tissue, and serum T and E2 were determined. Quantitative Masson trichrome, terminal deoxynucleotidyl transferase dUTP nick end labeling, Oil Red O, immunohistochemistry for calponin, α-smooth muscle actin, and Oct 4 were applied to penile tissue sections. Protein markers were assessed by Western blots and 2-D minigels, and RNA by DNA microarrays.
  
  
  METHODS
  Erectile function, histological, and biochemical markers in corporal tissue.
  
  
  RESULTS
  In the BPA-treated rats, total and free BPA levels were increased in the serum, urine, and penile tissue while serum T and E2 levels were reduced. In addition, the corpora cavernosa demonstrated a reduction in smooth muscle (SM) content, SM/collagen ratio, together with an increase in myofibroblasts, fat deposits, and apoptosis, but no significant change in collagen content or stem cells (nuclear/perinuclear Oct 4). In the penile shaft, BPA induced a downregulation of Nanog (stem cells), neuronal nitric oxide synthase (nitrergic terminals), and vascular endothelial growth factor (angiogenesis), with genes related to SM tone and cytoskeleton upregulated 5- to 50-fold, accompanied by changes in the multiple protein profile. However, both cavernosometry and EFS were unaltered by BPA.
  
  
  CONCLUSIONS
  While rats treated chronically with a high IP dose of BPA developed hypogonadism and a corporal histo- and molecular-pathology usually associated with ED, no changes were detected in erectile function as measured by EFS and cavernosometry. Further studies using alternate routes of BPA administration with various doses and length of exposure are needed to expand these findings.
authors.affiliation: Department of Surgery, Division of Urology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Kovanecz
authors.forename: Robert
authors.initials: R
authors.lastname: Gelfand
authors.forename: Maryam
authors.initials: M
authors.lastname: Masouminia
authors.forename: Sahir
authors.initials: S
authors.lastname: Gharib
authors.forename: Denesse
authors.initials: D
authors.lastname: Segura
authors.forename: Dolores
authors.initials: D
authors.lastname: Vernet
authors.forename: Jacob
authors.initials: J
authors.lastname: Rajfer
authors.forename: De-Kun
authors.initials: DK
authors.lastname: Li
authors.forename: Chun Yang
authors.initials: CY
authors.lastname: Liao
authors.forename: Kurunthachalam
authors.initials: K
authors.lastname: Kannan
authors.forename: Nestor F
authors.initials: NF
authors.lastname: Gonzalez-Cadavid
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D007150:Immunohistochemistry; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D000071317:Nanog Homeobox Protein; D052248:Nitric Oxide Synthase Type I; D010636:Phenols; D014157:Transcription Factors; C547030:Nanog protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Corporal Veno-Occlusive Dysfunction; Erectile Dysfunction; Fibrosis; Penis