"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），如异种雌激素（XEs），已被证明通过新的细胞信号传导机制模拟或拮抗生理性雌激素的作用，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（如丝裂原活化蛋白激酶（MAPKs）， G蛋白，Ca2+）而有效而迅速地发挥其作用，导致特定细胞功能端点（细胞增殖，凋亡和分化功能，如肽分泌）的改变。烷基酚（APs）、壬基酚（NP）和结构相关的双酚a （BPA）是已知的在人类血清和尿液中检测到大量的x射线（nM范围）。单个APs激活细胞外调节激酶（ERKs），并在低的环境相关浓度下，具有明显的非单调浓度依赖性，有效地破坏生生性雌激素信号。然而，这些x不是作为单独的化合物存在于环境环境中，而是作为混合物存在。很少有研究考察了雌二醇（E2）诱导的非基因组信号通路和功能反应的组合效应。本研究的总体假设是，在垂体细胞系（GH3/B6/F10）中，双酚a和APs等x离子的混合物可通过膜雌激素受体（mER）亚型对信号的复合不适当调节。为了验证这一假设，提出了以下具体目标：目标一：确定x和生理性雌激素E2在信号通路中的联合作用；目的二：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；目的III：研究复合XE暴露与细胞功能反应破坏之间的信号通路效应之间的相关性。

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.