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

描述（由申请人提供）：内分泌干扰化学物质（EDCs），例如异雌激素（XE），已被证明可以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，从而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对信号传导途径的联合作用;目标II：鉴定XE混合物启动非基因组信号传导途径的膜结合雌激素受体（mER）亚型;目标III：检查联合XE暴露对细胞功能反应破坏的信号传导途径作用之间的相关性。

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.