Background and Rationale. Bisphenol A (BPA), a key ingredient of polycarbonate plastics and epoxi resins, is a major endocrine disrupting chemical (EDC) present in urine. BPA is noxious to the reproductive system of experimental animals at doses below the LOAEL (Lowest Observed Adverse Effect Level). A derivative, BADGE, is a peroxisome-proliferator-activated receptor gamma (PPAR3) antagonist. Recently, self-reported erectile dysfunction (ED) was described in male workers occupationally exposed to BPA, but this has not been evaluated measuring penile erection. ED in animal models is caused by a loss of penile corporal smooth muscle and nitrergic nerves, fibrosis and oxidative stress, counteracted in part by PPAR3 and putatively by tissue repair involving endogenous Oct-4+ stem cells. BPA at supra-LOAEL doses causes lipofibrotic degeneration and impairment of compliance of penile corporal tissue in a rat model. This requires confirmation at sub-LOAEL levels, and a mechanistic clarification. Hypotheses. Prolonged exposure of adult rats to BPA, at doses comparable to occupational exposures in men, and possibly at doses suggestive of environmental risk:: a) leads to its accumulation in tissues involved in the peripheral mechanism of penile erection;b) causes inflammation and oxidative stress, followed by fibro- adipogenic infiltration of the corporal smooth muscle responsible for erection, and also interferes with its nitrergic modulation, leading at certain doses to ED;and c) disrupts PPAR3-mediated pathways triggering the histopathology underlying ED, and impairing the differentiation of endogenous stem cells during tissue repair. Specific Aims. To determine whether: 1. Prolonged exposure of rats to low doses of BPA causes ED and an increase of systemic and local BPA levels, leading to histopathology of the corpora cavernosa due to fibrosis and fat infiltration, and eventually ED. 2. This is mediated by abnormal PPAR3 signaling that in addition disrupts tissue repair after corporal inflammation/ oxidative stress, by altering endogenous stem cell differentiation into key corporal cell lines and nitrergic nerve terminals. Design. Young rats will be exposed for 3 months to BPA at various doses and its effects on erectile function and the penile corporal and pelvic ganglion histology will be evaluated, using PPAR3 agonists and antagonists. The mechanism of action of BPA on smooth muscle cells and differentiation of penile Oct-4+ stem cells will also be studied in vitro, and by DNA microarray analysis of gene expression. Relevance. 1. ED affects seriously the quality of life of patients and public health care, and BPA may increase it by occupational exposure. 2. A proof of concept at low doses of BPA may justify future developmental studies. 3. A novel PPAR3 mechanism of action for BPA, may be described.

PUBLIC HEALTH RELEVANCE: Bisphenol A (BPA), a key ingredient of some plastics and resins, is an environmental and occupational contaminant present in urine, and an endocrine disrupting chemical that is assumed to pose a reproductive risk at certain levels of exposure. Recently, self- reported erectile dysfunction was described in male workers occupationally exposed to BPA, but has not yet been validated by direct measures of penile erection. The current proposal aims to validate and understand these findings by determining in animal and cell culture models whether BPA at various doses causes ED by altering the penile histology and biochemistry as well as the subsequent tissue repair involving endogenous stem cells, through a novel mechanism different from the well known estrogenic-like action of BPA.

R21ES019465

2010-08-10

2013-07-31