Bisphenol A, Phthalate, and Endometriosis: Mechanisms and Pathogenesis

描述（由申请方提供）：双酚A（BPA）和邻苯二甲酸二（2-乙基己基）酯（DEHP）的环境和职业暴露，这两种化学品广泛用于塑料产品，由于人类长期暴露的高风险，在女性生殖健康方面受到了极大的关注。虽然BPA和DEHP显然会对女性生殖功能产生不利影响，但对子宫生理功能调节的直接影响和潜在作用机制仍不清楚。我们实验室最近的研究表明，年轻的雌性小鼠，当长期暴露于低水平的BPA或DEHP，在一天内多次喂养，显示严重损害类固醇调节的子宫生理功能，主要是由于孕酮受体（PGR）和PGR-目标Hand 2的表达水平降低所施加的孕酮无反应。我们的研究还确定了Hand 2 DNA甲基化作为人类子宫内膜中易患子宫内膜肿瘤发生的妇女的早期表观遗传生物标志物。这些结果促使我们研究慢性BPA或DEHP暴露与子宫内膜异位症发病机制之间的生物学联系，子宫内膜异位症是一种雌激素依赖性生殖疾病，其特征是子宫内膜组织在子宫外生长。我们的中心假设是，在青春期发育期间，年轻女性长期暴露于低水平BPA或DEHP将导致成年子宫内膜细胞的表观遗传变化，由于PGR和Hand 2表达的沉默而导致孕酮抵抗。暴露的子宫内膜碎片和常驻免疫细胞之间的相互作用可能会在子宫内膜碎片中产生一个雌激素主导的环境，从而促进它们在腹膜表面的建立。我们还提出，PGR和Hand 2-表达在在位子宫内膜和异位病变的下调，在响应慢性暴露于这些化学品，可能会进一步推进孕酮抵抗，并通过激活FGFR到ERK 1/2介导的MAPK信号通路加速疾病进展。我们设计了两个目的来探讨BPA或DEHP作用在调节孕酮抵抗和子宫内膜异位症发病机制中的影响和潜在的分子机制。具体目标-1将研究年轻雌性长期暴露于低水平BPA或DEHP后子宫内膜的变化如何促进小鼠异位病变的建立和发展。特异性目标-2将确定BPA和DEHP通过调节PGR和HAND 2在在位子宫内膜和异位病变中的表达（最可能通过DNA甲基化）增强孕酮抵抗的分子机制。这些实验的成功完成将有助于我们更好地了解慢性BPA和DEHP调节子宫功能生理和病理方面的分子机制，并填补了有关这些化学物质对子宫内膜异位症病因学贡献的知识空白。

DESCRIPTION (provided by applicant): 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.