"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）：内分泌干扰化学品（EDCs），如异种雌激素（XE），已被证明可通过新型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。我们实验室先前在垂体细胞中的研究表明，这些类固醇模拟化合物通过激活非基因组信号传导途径[例如促分裂原活化蛋白激酶（MAPK），G蛋白，Ca 2 +]有效且快速地发挥其作用，导致特定细胞功能终点（细胞增殖，增殖和分化功能，如肽分泌）的改变。烷基酚（APs;壬基酚（NP）和结构上相关的双酚-A（BPA））是已知的在人血清和尿中检测到大量（nM范围）的XE。单个AP激活细胞外调节激酶（ERK），并且在低的环境相关浓度下以显著的非单调浓度依赖性有效地破坏生理雌激素信号传导。然而，这些Xe并不是以单独的化合物存在于环境中，而是以混合物存在。很少有研究探讨的组合效应，以改变非基因组信号通路和功能性反应诱导的雌二醇（E2）。这项研究的总体假设是，混合物的XEs，如BPA和AP可以引起复合不适当的调节信号通过膜雌激素受体（mER）亚型在垂体细胞系（GH 3/B6/F10）。为了验证这一假设，提出了以下具体目标：目标I：确定XE与生理雌激素E2对信号通路的综合影响;目标II：确定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; AIM III：检查联合XE暴露对细胞功能反应破坏的信号通路效应之间的相关性。