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

• 批准号: 8753041
• 负责人: Quanxi Li
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753041
• 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; 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; public health relevance; receptor; receptor-mediated signaling; reproductive; reproductive function; research study; response; toxicant; tumorigenesis

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) 和邻苯二甲酸二-2-乙基己酯 (DEHP) 这两种广泛用于塑料制品的化学物质，由于人类长期接触的高风险，在女性生殖健康方面受到广泛关注。尽管BPA和DEHP显然会对女性生殖功能产生不利影响，但其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，当年轻雌性小鼠通过一天多次喂养而长期接触低水平的 BPA 或 DEHP 时，类固醇调节的子宫生理功能会受到严重损害，这主要是由于孕酮受体 (PGR) 和 PGR 靶点 Hand2 表达水平降低而导致对孕酮无反应。我们的研究还发现 Hand2 DNA 甲基化是人类子宫内膜的早期表观遗传生物标志物，使女性容易发生子宫内膜肿瘤。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，年轻女性在青春期发育期间长期接触低水平的 BPA 或 DEHP 将导致成年子宫内膜细胞发生表观遗传变化，由于 PGR 和 Hand2 表达沉默而导致黄体酮抵抗。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会在子宫内膜碎片中产生雌激素主导的环境，从而促进它们在腹膜表面上的建立。我们还提出，在位子宫内膜和异位病变中 PGR 和 Hand2 表达的下调，响应于长期暴露于这些化学物质，可能通过激活 FGFR 至 ERK1/2 介导的 MAPK 信号通路，进一步促进孕酮抵抗并加速疾病进展。我们设计了两个目标，探索 BPA 或 DEHP 作用在调节孕激素抵抗和子宫内膜异位症发病机制中的影响和潜在分子机制。具体的 Aim-1 将研究年轻雌性长期接触低水平 BPA 或 DEHP 时子宫内膜的变化如何促进小鼠异位病变的建立和发展。具体的 Aim-2 将确定 BPA 和 DEHP 通过调节在位子宫内膜和异位病变中的 PGR 和 HAND2 表达（很可能是通过 DNA 甲基化）来增强孕酮抵抗的分子机制。这些实验的成功完成将帮助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，并填补关于这些化学物质对子宫内膜异位症病因学贡献的巨大知识空白。