Erectile dysfunction (ED) is a highly prevalent condition that severely impairs the quality of life of patients and their sexual partners, compounded by a partially ineffective therapy that leads to a heavy public health burden. ED is also considered to be a sentinel for the diagnosis of cardiovascular disease. It is unknown whether environmental or occupational factors have contributed to the increasing prevalence of ED detected by improved diagnosis. However, ED is one of the very few human conditions where a clinical correlation with exposure to Bisphenol A (BPA) has been reported, in this case as occupational risk. To demonstrate an ED/BPA link on an accepted model under GLP conditions both functionally and at the underlying cellular and molecular pathophysiological levels, as well as the compounding effects of aging, would help to assess and rationalize the epidemiological findings, and considerably impact ED prevention and the evaluation of BPA real risks. The hypotheses to be tested are: The assessment of ED in the rat will allow to define after 1 and 2 years of BPA exposure at several doses: a) whether ED is induced;b) the cellular and molecular damage underlying these effects and their putative mechanisms;c) the role of peripheral versus central damage of the penile erectile response, and d) the compounding effects of low serum testosterone (T) and aging, at BPA doses compatible with human exposure.
Specific aims : To determine in aim 1 the effects of a chronic exposure from gestation to BPA on penile erection and the related tissues that participate in this process under the compounding factor of aging, and to establish the cellular and molecular signatures of the pathophysiology that underlies the peripheral effects; and in aim 2 whether BPA induces in the penile corpora cavernosa a detrimental SI /1C phenotypic switch and abnormal stem cell lineage commitment, acting through the PPARgamma and/or EERgamma. The approach will involve: 1) measurements of erectile function;2) cellular profile(s) of the corporal, pelvic ganglion and hypothalamic histopathology for lipofibrotic degeneration of the corpora or neural toxicity;3) molecular profile by DNA microarrays and proteomics;and 4) putative mechanism(s) through BPA effects on the PPARgamma /ERRgamma modulation of corporal smooth muscle changes and stem cell lineage commitment
This project fits well into the RFA goals by proposing ED as a disease end-point within the area of reproductive male toxicity, and utilizing the rats exposed to BPA in the GLP study, without changing its basic study design. The project may detect the first environmental cause of ED, and spur a prevention campaign by defining the effects on erectile function and its relevant tissues of the gestational exposure to BPA at doses related tn human exposure. relating the results to the epidemiological data and aging as a risk factor..
|Gelfand, Robert; Vernet, Dolores; Bruhn, Kevin et al. (2016) Long-term exposure of MCF-12A normal human breast epithelial cells to ethanol induces epithelial mesenchymal transition and oncogenic features. Int J Oncol 48:2399-414|
|Kovanecz, I; Gelfand, R; Masouminia, M et al. (2014) Oral Bisphenol A (BPA) given to rats at moderate doses is associated with erectile dysfunction, cavernosal lipofibrosis and alterations of global gene transcription. Int J Impot Res 26:67-75|
|Kovanecz, Istvan; Gelfand, Robert; Masouminia, Maryam et al. (2013) Chronic high dose intraperitoneal bisphenol A (BPA) induces substantial histological and gene expression alterations in rat penile tissue without impairing erectile function. J Sex Med 10:2952-66|