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 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. Hypotheses. 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 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. Approach: 1) measurements of erectile function; 2) cellular profile 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 through BPA effects on the PPARgamma /ERRgamma modulation of corporal smooth muscle changes and stem cell lineage commitment

U01ES020887

2011-09-19

2016-05-31