CJB Risk Analysis, 5915 Beech Bluff Lane, Durham, NC, 27705, USA.
Toxys B.V., Robert Boyleweg 4, 2333 CG, Leiden, The Netherlands.
Mutat Res Genet Toxicol Environ Mutagen. 2021 May;865:503333. doi: 10.1016/j.mrgentox.2021.503333. Epub 2021 Feb 15.
Antimony (Sb) and its compounds are negative in gene mutation assays in bacteria and cultured mammalian cells but positive in some assays for clastogenicity and/or DNA damage. In order to better understand the modes of action for antimony genotoxicity, we assessed reporter gene activation by antimony and antimony compounds in the new expanded ToxTracker assay. ToxTracker evaluates the activation of biomarkers for different cellular defense mechanisms using a series of green fluorescent protein reporters inserted into mouse embryonic stem cell lines. The assay responds to: 1) DNA damage and inhibition of DNA replication; 2) oxidative stress; 3) unfolded protein response (protein damage); and 4) p53-dependent cellular stress. Sb metal powder, six trivalent (Sb(III)) compounds, and five pentavalent antimony (Sb(V)) compounds were assessed. Sb powder and all six Sb(III) compounds activated oxidative stress ToxTracker reporters at non-toxic doses. Of the five Sb(V) compounds, antimony pentachloride and potassium hexahydroantimonate induced a robust oxidative stress response while sodium antimonate induced only a weak oxidative stress response. At higher concentrations (up to either 75 % toxicity or the highest dissolved concentration tested), Sb powder and all Sb(III) compounds except for antimony trichloride induced the unfolded protein response. Of the five Sb(V) compounds tested, only potassium hexahydroantimonate induced weak activation of the unfolded protein response and was also the only pentavalent compound to yield modest (30 %) cytotoxicity. None of the compounds tested activated the DNA damage/inhibition of DNA replication reporters, nor did they activate the p53-dependent response. All Sb(III) compounds, Sb powder, and three of the five Sb(V) compounds activated the oxidative stress reporters, but there was no activation of reporters associated with DNA damage and repair or p53-dependent cellular stress. The consistent activation of reporters for oxidative stress suggests this mode of action may underlie genotoxicity responses for antimony and its compounds.
锑（Sb）及其化合物在细菌和培养的哺乳动物细胞中的基因突变检测中呈阴性，但在一些致裂测试和/或 DNA 损伤检测中呈阳性。为了更好地了解锑遗传毒性的作用模式，我们在新扩展的 ToxTracker 检测中评估了锑和锑化合物对报告基因的激活作用。ToxTracker 使用插入到小鼠胚胎干细胞系中的一系列绿色荧光蛋白报告基因，评估不同细胞防御机制的生物标志物的激活。该检测法对以下内容作出响应：1）DNA 损伤和 DNA 复制抑制；2）氧化应激；3）未折叠蛋白反应（蛋白损伤）；和 4）p53 依赖性细胞应激。评估了 Sb 金属粉末、六种三价（Sb(III)）化合物和五种五价锑（Sb(V)）化合物。Sb 粉末和所有六种 Sb(III)化合物在非毒性剂量下激活了氧化应激 ToxTracker 报告基因。在五种 Sb(V)化合物中，五氯化锑和六氢合锑酸钠诱导了强烈的氧化应激反应，而五氧化二锑仅诱导了微弱的氧化应激反应。在较高浓度（高达毒性的 75%或测试的最高溶解浓度）下，Sb 粉末和除三氯化锑以外的所有 Sb(III)化合物诱导了未折叠蛋白反应。在测试的五种 Sb(V)化合物中，只有六氢合锑酸钠微弱地诱导了未折叠蛋白反应的激活，也是唯一导致适度（30%）细胞毒性的五价化合物。测试的化合物均未激活 DNA 损伤/抑制 DNA 复制报告基因，也未激活 p53 依赖性反应。所有 Sb(III)化合物、Sb 粉末和五种 Sb(V)化合物中的三种激活了氧化应激报告基因，但没有激活与 DNA 损伤和修复或 p53 依赖性细胞应激相关的报告基因。氧化应激报告基因的一致激活表明，这种作用模式可能是锑及其化合物遗传毒性反应的基础。
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