Monomethylated trivalent arsenic species disrupt steroid receptor interactions with their DNA response elements at non-cytotoxic cellular concentrations.
Monomethylated trivalent arsenic species disrupt steroid receptor interactions with their DNA response elements at non-cytotoxic cellular concentrations.
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DOI：
10.1002/jat.2898
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发表时间：
2014-05
影响因子：
3.3
通讯作者：
Bodwell, Jack E.
中科院分区：
文献类型：
--
作者：
Gosse, Julie A.;Taylor, Vivien F.;Jackson, Brian P.;Hamilton, Joshua W.;Bodwell, Jack E.
关键词：
砷（As）被认为是人类健康的首要环境化学品，因为它与癌症，糖尿病，心血管疾病以及生殖和发育问题等不良健康影响有关。在一些细胞培养和动物模型中，As作为内分泌干扰物，这可能是其许多健康影响的基础。以前的工作表明，类固醇受体（SR）驱动的基因表达被破坏与无机砷（亚砷酸盐，iAs+3）处理的细胞。在这些研究中，低浓度iAs+3（0.1-0.7 μM）刺激了细胞毒性诱导型转录，而稍高但仍无细胞毒性的水平（1-3 μM）则抑制了转录。本次调查的重点是这些抑制作用的机制，并评估的作用，甲基化的三价作为代谢产物SR功能。最近的证据表明，与iAs相比，甲基化形式可能具有不同的生化效应。在这里，荧光偏振（FP）的实验，利用纯化的，糖皮质激素结合的人糖皮质激素（GR）和孕酮受体（PR）已经证明，无论是无机的（iAs+3），也不二甲基化（DMA+3）的三价As影响受体与糖皮质激素DNA反应元件（GRES）的相互作用。然而，单甲基化形式（单甲基亚砷酸盐，MMA+3和单甲基胂酸二谷氨酸盐，MADG）强烈抑制GR-GRE和PR-GRE结合。此外，iAs+3处理的H4 IIE大鼠肝癌细胞的物种形成研究表明，在导致抑制GRE诱导基因转录的处理条件下，MADG的细胞内浓度足以抑制体内GR-GRE和PR-GRE相互作用。这些结果表明，砷的抑制性内分泌干扰作用可能部分是由甲基化代谢物的SR的能力，结合DNA反应元件，是至关重要的砷驱动的基因转录的中断。
Arsenic (As) is considered a top environmental chemical of human health because it has been linked to adverse health effects including cancer, diabetes, cardiovascular disease, and reproductive and developmental problems. In several cell culture and animal models, As acts as an endocrine disruptor, which may underlie many of its health effects. Previous work showed that steroid receptor (SR)-driven gene expression is disrupted in cells treated with inorganic As (arsenite, iAs+3). In those studies, low iAs+3 concentrations (0.1–0.7 μM) stimulated hormone-inducible transcription, whereas somewhat higher but still non-cytotoxic levels (1–3 μM) inhibited transcription. This investigation focuses on the mechanisms underlying these inhibitory effects and evaluates the role of methylated trivalent As metabolites on SR function. Recent evidence suggests that, compared with iAs, methylated forms may have distinct biochemical effects. Here, fluorescence polarization (FP) experiments utilizing purified, hormone-bound human glucocorticoid (GR) and progesterone receptor (PR) have demonstrated that neither inorganic (iAs+3) nor dimethylated (DMA+3) species of trivalent As affect receptor interactions with glucocorticoid DNA response elements (GREs). However, monomethylated forms (monomethylarsenite, MMA+3 and monomethylarsonic diglutathione, MADG) strongly inhibit GR-GRE and PR-GRE binding. Additionally, speciation studies of iAs+3-treated H4IIE rat hepatoma cells show that, under treatment conditions that cause inhibition of hormone-inducible gene transcription, the intracellular concentration of MADG is sufficient to inhibit GR-GRE and PR-GRE interactions in vivo. These results indicate that arsenic’s inhibitory endocrine disruption effects are probably caused in part by methylated metabolites’ disruption of SR ability to bind DNA response elements that are crucial to hormone-driven gene transcription.
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