"Mixtures of Xenoestrogens Alter Estradiol-induced Non-Genomic Signaling"

“异种雌激素混合物改变雌二醇诱导的非基因组信号传导”

• 批准号: 8257385
• 负责人: Rene Vinas
• 金额: $ 2.8万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257385
• 关键词: Address; Affect; Apoptosis; Binding; Biochemistry; Biological Assay; Cell Line; Cell Proliferation; Cells; Cessation of life; Chemicals; Cyclic GMP-Dependent Protein Kinases; Dependence; Development; Diet; Dose; Endocrine Disruptors; Endocrinology; Environment; Equilibrium; Estradiol; Estrogen Receptors; Estrogens; Exposure to; Fellowship; Food; GTP-Binding Proteins; Health; Human; Individual; Industrial Waste; JNK-activating protein kinase; Knowledge; MAPK14 gene; Mediating; Membrane; Methods; Mitogen-Activated Protein Kinases; Mucous Membrane; Pattern; Peptides; Phenols; Phosphotransferases; Physiological; Phytoestrogens; Pit and Fissure Sealants; Pituitary Gland; Plastics; Prolactin; Public Health; Publishing; RBM5 gene; Rattus; Regulation; Risk; Risk Assessment; Serum; Signal Pathway; Signal Transduction; Skin; Steroids; Testing; Time; Toxicology; Urine; Water; base; bisphenol A; combinatorial; exposed human population; extracellular; high throughput screening; inhibitor/antagonist; insight; interdisciplinary approach; interest; non-genomic; nonylphenol; novel; reproductive; response; xenoestrogen

DESCRIPTION (provided by applicant): Endocrine disrupting chemicals (EDCs), such as xenoestrogens (XEs), have been shown to mimic or antagonize the effects of physiological estrogens via novel cellular signaling mechanisms, increasing the likelihood of reproductive and developmental abnormalities. Previous studies from our lab in pituitary cells demonstrated that these steroid-mimicking compounds potently and rapidly exert their effects via activation of non-genomic signaling pathways [e.g. mitogen-activated protein kinases (MAPKs), G proteins, Ca2+] leading to alterations of specific cellular functional endpoints (cell proliferation, apoptoss and differentiated functions such as secretion of peptides). Alkylphenols (APs; nonylphenol (NP) and the structurally related bisphenol-A (BPA)) are known XEs that have been detected in significant amounts in human serum and urine (nM range). Individual APs activate extracellular-regulated kinases (ERKs) as well as potently disrupt physiologic estrogen signaling at low, environmentally relevant concentrations with pronounced non-monotonic concentration- dependence. These XEs, however, do not exist in an environmental setting as individual compounds, but rather as mixtures. Few studies have examined the combinatorial effects to alter non-genomic signaling pathways and functional responses induced by estradiol (E2). The overall hypothesis underlying this study is that mixtures of XEs such as BPA and APs can cause compounded inappropriate regulation of signaling via membrane estrogen receptor (mER) subtypes in a pituitary cell line (GH3/B6/F10). To test this hypothesis the following Specific Aims are proposed: Aim I: Determine the combined effect of XEs with the physiologic estrogen E2, on signaling pathways; Aim II: Identify the membrane-bound estrogen receptor (mER) subtype by which XE mixtures initiate non-genomic signaling pathways; AIM III: Examine correlations between the signaling pathway effects of combined XE exposure to disruption of cellular functional responses.

描述（由申请人提供）：内分泌干扰化学物质（EDC），例如异雌激素（XE），已被证明可以通过新颖的细胞信号传导机制模拟或拮抗生理雌激素的作用，增加生殖和发育异常的可能性。我们实验室之前对垂体细胞的研究表明，这些类固醇模拟化合物通过激活非基因组信号通路有效且快速地发挥其作用[例如，丝裂原激活蛋白激酶 (MAPK)、G 蛋白、Ca2+] 导致特定细胞功能终点的改变（细胞增殖、凋亡和分化功能，例如肽的分泌）。烷基酚（AP、壬基酚 (NP) 和结构相关的双酚 A (BPA)）是已知的 XE，已在人血清和尿液中检测到大量（nM 范围）。单个 AP 会激活细胞外调节激酶 (ERK)，并在环境相关的低浓度下有效破坏生理雌激素信号传导，具有明显的非单调浓度依赖性。然而，这些 XE 在环境环境中并不以单独的化合物存在，而是以混合物的形式存在。很少有研究探讨改变雌二醇 (E2) 诱导的非基因组信号通路和功能反应的组合效应。这项研究的总体假设是，BPA 和 AP 等 XE 的混合物可通过垂体细胞系 (GH3/B6/F10) 中的膜雌激素受体 (mER) 亚型导致信号传导的复合不当调节。为了检验这一假设，提出了以下具体目标： 目标 I：确定 XE 与生理雌激素 E2 对信号通路的综合作用；目标 II：鉴定 XE 混合物启动非基因组信号通路的膜结合雌激素受体 (mER) 亚型；目标 III：检查联合 XE 暴露与细胞功能反应破坏的信号通路效应之间的相关性。