Bisphenol A, Phthalate, and Endometriosis: Mechanisms and Pathogenesis

描述（由申请人提供）：双酚A （BPA）和邻苯二甲酸二-2-乙基己基酯（DEHP）这两种广泛用于塑料制品的化学品的环境和职业暴露在女性生殖健康方面受到了大量关注，因为人类慢性暴露的风险很高。虽然BPA和DEHP对女性生殖功能有不利影响，但其对子宫生理功能调节的直接影响及其作用机制尚不清楚。我们实验室最近的研究表明，年轻雌性小鼠在一天内多次喂食长期暴露于低水平的BPA或DEHP时，子宫类固醇调节的生理功能会出现严重损害，主要是由于孕激素受体（PGR）和PGR靶点Hand2的表达水平降低导致对孕激素无反应。我们的研究还发现Hand2 DNA甲基化是人类子宫内膜早期表观遗传生物标志物，使女性易发生子宫内膜肿瘤。这些结果促使我们研究慢性双酚a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，年轻女性在青春期发育期间长期暴露于低水平双酚a或DEHP会导致成年子宫内膜细胞的表观遗传变化，导致PGR和Hand2表达沉默，从而导致黄体酮抵抗。暴露的子宫内膜碎片和驻留的免疫细胞之间的相互作用可能在子宫内膜碎片中创造一个雌激素优势的环境，促进它们在腹膜表面的建立。我们还提出，异位子宫内膜和异位病变中PGR和hand2表达的下调，作为对这些化学物质的慢性暴露的反应，可能通过激活FGFR对erk1 /2介导的MAPK信号通路，进一步推进黄体酮抵抗并加速疾病进展。我们设计了两个目的，探讨双酚a或DEHP在子宫内膜异位症的黄体酮抗性调控和发病机制中的影响及其潜在的分子机制。特异性Aim-1将研究年轻女性长期暴露于低水平双酚a或DEHP后子宫内膜的改变如何促进小鼠异位病变的建立和发展。特异性Aim-2将确定BPA和DEHP通过调节PGR和HAND2在异位子宫内膜和异位病变中的表达来增强孕酮抵抗的分子机制，最可能是通过DNA甲基化。这些实验的成功完成将有助于我们更好地了解慢性双酚a和DEHP调节子宫生理和病理功能的分子机制，并填补这些化学物质对子宫内膜异位症病因的贡献方面的实质性知识空白。

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.