Arsenic as an endocrine disruptor:: Effects of arsenic on estrogen receptor-mediated gene expression in vivo and in cell culture
Arsenic as an endocrine disruptor:: Effects of arsenic on estrogen receptor-mediated gene expression in vivo and in cell culture
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DOI：
10.1093/toxsci/kfm013
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发表时间：
2007-07-01
影响因子：
3.8
通讯作者：
Hamilton, Joshua W.
中科院分区：
文献类型：
--
作者：
Davey, Jennifer C.;Bodwell, Jack E.;Hamilton, Joshua W.
饮用水中的砷污染被认为是一种严重的全球环境健康威胁，与皮肤癌、肺癌、膀胱癌和其他癌症等疾病风险增加有关；2型糖尿病；血管和心血管疾病；生殖和发育影响；以及对神经和认知的影响。低至10-50 ppb可能会增加健康风险，而在实验动物和细胞培养系统中观察到的生物效应则低得多。我们之前报道过，As是一种有效的内分泌干扰物，当浓度低至0.01 μ M（类似于0.7 ppb）时，它可以通过密切相关的糖皮质激素、矿物皮质激素、黄体酮和雄激素类固醇受体（SRs）改变基因调控。极低剂量增强激素介导的基因转录，而稍高但仍无细胞毒性的剂量则具有抑制作用。我们在此报告，As也破坏更多的远端相关雌激素受体（ER）在体内和细胞培养。在体内无细胞毒性剂量（1 ~ 50 μ mol/kg亚砷酸盐）下，鸡胚肝内17 β -雌二醇（E2）诱导的卵黄原素II基因的er依赖基因转录被强烈抑制。在细胞培养中，在人乳腺癌MCF-7细胞中，无细胞毒性水平（0.25-3 μ M，类似于20-225 ppb）的As显著抑制e2介导的er调节的报告基因和天然er调节的GREB1基因的基因激活。虽然砷对内质网依赖性基因调控的影响与砷对其他SRs的影响大致相似，但存在特定差异，特别是在最低剂量下缺乏显着增强，这可能为可能的机制提供见解。
Arsenic (As) contamination of drinking water is considered a serious worldwide environmental health threat that is associated with increased disease risks including skin, lung, bladder, and other cancers; type 2 diabetes; vascular and cardiovascular diseases; reproductive and developmental effects; and neurological and cognitive effects. Increased health risks may occur at as low as 10-50 ppb, while biological effects have been observed in experimental animal and cell culture systems at much lower levels. We previously reported that As is a potent endocrine disruptor, altering gene regulation by the closely related glucocorticoid, mineralocorticoid, progesterone, and androgen steroid receptors (SRs) at concentrations as low as 0.01 mu M (similar to 0.7 ppb). Very low doses enhanced hormone-mediated gene transcription, whereas slightly higher but still noncytotoxic doses were suppressive. We report here that As also disrupts the more distally related estrogen receptor (ER) both in vivo and in cell culture. At noncytotoxic doses (1-50 mu mol/kg arsenite) As strongly suppressed ER-dependent gene transcription of the 17 beta-estradiol (E2)-inducible vitellogenin II gene in chick embryo liver in vivo. In cell culture, noncytotoxic levels (0.25-3 mu M, similar to 20-225 ppb) of As significantly inhibited E2-mediated gene activation of an ER-regulated reporter gene and the native ER-regulated GREB1 gene in human breast cancer MCF-7 cells. While the effects of As on ER-dependent gene regulation were generally similar to As effects on the other SRs, there were specific differences, particularly the lack of significant enhancement at the lowest doses, that may provide insights into possible mechanisms.