Environmental and occupational exposure to Bisphenol A (BPA) and di-2-ethylhexyl phthalate (DEHP), two chemicals widely used in plastic products, are receiving substantial attention in female reproductive health because of the high risk of chronic exposure in humans. Although it is clear that BPA and DEHP can adversely affect female reproductive functions, the direct impact and underlying mechanisms of action in regulation of physiological functions of the uterus remain unknown. Recent studies in our laboratory have shown that young female mice, when exposed chronically to low-levels of BPA or DEHP by multiple feedings in a day, display severe impairment in steroid-regulated physiological functions of the uterus, primarily due to unresponsiveness to progesterone that imposed by the reduced expression levels of progesterone receptor (PGR) and PGR- target Hand2. Our studies also identified Hand2 DNA methylation as an early epigenetic biomarker in human endometrium predisposing women to endometrial tumorigenesis. These results prompt us to investigate biological link between chronic BPA or DEHP exposure and pathogenesis of endometriosis, an estrogen- dependent reproductive disorder, characterized by growth of endometrial tissues outside the uterus. Our central hypothesis is that chronic exposure to low-level BPA or DEHP in young females during pubertal development period will result in epigenetic changes in adult endometrial cells, leading to progesterone resistance due to silencing of PGR and Hand2 expression. The interplay between the exposed-endometrial fragments and the resident immune cells may create an estrogen-dominant environment in endometrial fragments that facilitate their establishment on the peritoneal surface. We also propose that the down regulation of PGR and Hand2-expression in the eutopic endometrium and the ectopic lesions, in response to chronic exposure to these chemicals, may further advance progesterone resistance and accelerate disease progression by activating FGFR to ERK1/2-mediated MAPK signaling pathway. We designed two aims to explore the impact and the underlying molecular mechanism of BPA or DEHP action in regulation of progesterone resistance and pathogenesis of endometriosis.
Specific Aim -1 will investigate how the alteration in endometrium in response to chronic exposure to low-levels of BPA or DEHP in young females will promote the establishment and development of ectopic lesions in mice.
Specific Aim -2 will determine the molecular mechanisms by which BPA and DEHP enhance progesterone resistance by modulate PGR and HAND2 expression in the eutopic endometrium and the ectopic lesions, most likely through DNA methylation. Successful completion of these experiments will help us better understand the molecular mechanisms through which chronic BPA and DEHP regulate physiological and pathological aspects of the uterine functions and fill the substantial gap in knowledge about the contribution of these chemicals to the etiology of endometriosis.
The goal of this project is to explore the biological link between the exposure of environmental chemicals commonly used in plastics and pathogenesis of endometriosis, a gynecological disorder affecting many women of reproductive age. The proposal will also address the molecular mechanisms through which progesterone receptor and HAND2 expressions are regulated in the eutopic and ectopic endometrium that could potentially lead to progesterone- resistance and accelerate disease progression of endometriosis. The BPA exposure paradigm in this application reflects the real human exposure situation in which BPA is ingested orally, multiple times a day, at lower levels. The outcome of the proposed studies is expected to provide considerable insights into the potential risks of BPA and DEHP exposure on female reproductive health and the underlying mechanism in pathogenesis of female reproductive disorders that are associated with environmental toxicants.