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Bisphenol A, Phthalate, and Endometriosis: Mechanisms and Pathogenesis

双酚 A、邻苯二甲酸盐和子宫内膜异位症：机制和发病机制

基本信息

批准号：
8878261
负责人：
Quanxi Li
金额：
$ 23.79万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878261
关键词：
Address Adult Affect Age Attention Biological Blood Vessels Cell Proliferation Cells Chemicals Child Chronic DNA Methylation Development Disease Disease Progression Dose Down-Regulation Endocrine Endometrial Endometrium Environment Environmental and Occupational Exposure Epigenetic Process Estrogens Etiology Exhibits Exposure to Female Fibroblast Growth Factor Receptors Gene Expression Genes Goals Greater sac of peritoneum Growth Growth Factor Health Human Immune Immunosuppressive Agents Impairment Infertility Inflammatory Knowledge Laboratories Lead Lesion Life Link MAPK Signaling Pathway Pathway MAPK3 gene Mediating Mediator of activation protein Methylation Mitotic Activity Molecular Mus Oral Organ Outcome Pathogenesis Pathway interactions Pelvis Perinatal Exposure Peritoneal Physiological Plastics Play Population Preschool Child Production Progesterone Progesterone Receptors Reaction Receptor Signaling Recruitment Activity Regulation Reproductive Health Resistance Risk Role Severities Steroids Surface Time Tissues Toxic Environmental Substances Uterus Woman attenuation bisphenol A chemokine chronic pelvic pain cytokine design endometriosis environmental chemical exposure epigenetic marker exposed human population feeding high risk immune clearance insight neonatal exposure phthalates receptor receptor-mediated signaling reproductive reproductive function research study response toxicant tumorigenesis

项目摘要

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.

描述(由申请人提供)：环境和职业接触双酚A(BPA)和邻苯二甲酸二乙基己酯(DEHP)这两种广泛用于塑料产品的化学品，由于人类长期接触的高风险，在女性生殖健康方面受到极大关注。尽管双酚A和DEHP显然会对女性生殖功能产生不利影响，但在调节子宫生理功能方面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，当年轻雌性小鼠在一天内通过多次喂养长期暴露于低水平的BPA或DEHP时，子宫激素调节的生理功能表现出严重的损害，主要是由于孕酮受体(PGR)和PGR靶标Hand2的表达水平降低而对孕酮无反应。我们的研究还发现，在人类子宫内膜中，Hand2 DNA甲基化是一个早期的表观遗传生物标记物，使女性更容易发生子宫内膜肿瘤。这些结果促使我们调查慢性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型生殖障碍，其特征是子宫外子宫内膜组织的生长。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的BPA或DEHP将导致成年子宫内膜细胞的表观遗传学变化，通过沉默PGR和Hand2的表达而导致孕酮抵抗。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创造一个雌激素主导的环境，促进它们在腹膜表面的建立。我们还认为，在位内膜和异位病变中PGR和Hand2的表达下调，可能通过激活FGFR到ERK1/2介导的MAPK信号通路，进一步增强孕酮抵抗，加速疾病进展。我们设计了两个目的，旨在探讨BPA或DEHP在调节孕激素抵抗和子宫内膜异位症发病机制中的作用及其潜在的分子机制。SPICAL AIM-1将研究年轻女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。特异的AIM-2将确定BPA和DEHP通过调节PGR和HAND2在在位内膜和异位病变中的表达来增强孕激素抵抗的分子机制，最可能的是通过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BPA和DEHP调节子宫功能的生理和病理方面的分子机制，并填补这些化学物质在子宫内膜异位症病因方面的实质性知识空白。