Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Environ Health Perspect. 2009 Nov;117(11):1702-6. doi: 10.1289/ehp.0900800. Epub 2009 Jun 16.
Ethylene glycol monomethyl ether (EGME) exposure is associated with impaired reproductive function. The primary metabolite of EGME is methoxyacetic acid (MAA), a short-chain fatty acid that inhibits histone deacetylase activity and alters gene expression.
Because estrogen signaling is necessary for normal reproductive function and modulates gene expression, the estrogen-signaling pathway is a likely target for MAA; however, little is known about the effects of MAA in this regard.
We evaluated the mechanistic effects of MAA on estrogen receptor (ER) expression and estrogen signaling using in vitro and in vivo model systems.
MAA potentiates 17beta-estradiol (E(2)) stimulation of an estrogen-responsive reporter plasmid in HeLa cells transiently transfected with either a human ERalpha or ERbeta expression vector containing a cytomegalovirus (CMV) promoter. This result is attributed to increased exogenous ER expression due to MAA-mediated activation of the CMV promoter. In contrast to its effects on exogenous ER, MAA decreases endogenous ERalpha expression and attenuates E(2)-stimulated endogenous gene expression in both MCF-7 cells and the mouse uterus.
These results illustrate the importance of careful experimental design and analysis when assessing the potential endocrine-disrupting properties of a compound to ensure biological responses are in concordance with in vitro analyses. Given the established role of the ER in normal reproductive function, the effects of MAA on the endogenous ER reported here are consistent with the reproductive abnormalities observed after EGME exposure and suggest that these toxicities may be due, at least in part, to attenuation of endogenous ER-mediated signaling.
乙二醇单甲醚（EGME）暴露与生殖功能受损有关。EGME 的主要代谢物是甲氧基乙酸（MAA），一种短链脂肪酸，可抑制组蛋白去乙酰化酶活性并改变基因表达。
因为雌激素信号对于正常生殖功能是必需的，并调节基因表达，所以雌激素信号通路可能是 MAA 的一个靶标；然而，关于这方面，人们对 MAA 的影响知之甚少。
我们使用体外和体内模型系统评估了 MAA 对雌激素受体（ER）表达和雌激素信号的机制影响。
MAA 增强了 HeLa 细胞中瞬时转染人 ERalpha 或 ERbeta 表达载体（含 CMV 启动子）的雌激素反应报告质粒对 17β-雌二醇（E2）的刺激作用。这一结果归因于 MAA 介导的 CMV 启动子激活导致外源性 ER 表达增加。与对外源性 ER 的作用相反，MAA 降低了 MCF-7 细胞和小鼠子宫中内源性 ERalpha 的表达，并减弱了 E2 刺激的内源性基因表达。
这些结果说明了在评估化合物潜在的内分泌干扰特性时，仔细设计和分析实验的重要性，以确保生物反应与体外分析一致。鉴于 ER 在正常生殖功能中的既定作用，这里报道的 MAA 对内源性 ER 的作用与 EGME 暴露后观察到的生殖异常一致，并表明这些毒性至少部分归因于内源性 ER 介导的信号转导的减弱。
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