French National Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Dept Toxicology and Biomonitoring, 1 rue Morvan, F-54519 Vandoeuvre les Nancy, France.
French National Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS), Dept Toxicology and Biomonitoring, 1 rue Morvan, F-54519 Vandoeuvre les Nancy, France.
Toxicol Lett. 2023 Nov 1;389:11-18. doi: 10.1016/j.toxlet.2023.10.006. Epub 2023 Oct 9.
To date, long-term rodent carcinogenesis assays are the only assays recognized by regulators to assess non-genotoxic carcinogens, but their reliability has been questioned. In vitro cell transformation assays (CTAs) could represent an interesting alternative to animal models as it has the advantage of detecting both genotoxic and non-genotoxic transforming chemicals. Among them, Bhas 42 CTA uses a cell line that has been transfected with the oncogenic sequence v-Ha-ras. This sequence confers an "initiated" status to these cells and makes them particularly sensitive to non-genotoxic agents. In a previous work, transcriptomic analysis revealed that the treatment of Bhas 42 cells with transforming silica (nano)particles and 12-O-tetradecanoylphorbol-13-acetate (TPA) commonly modified the expression of 12 genes involved in cell proliferation and adhesion. In the present study, we assess whether this signature would be the same for four other soluble transforming agents, i.e. mezerein, methylarsonic acid, cholic acid and quercetin. The treatment of Bhas 42 cells for 48 h with mezerein modified the expression of the 12 genes of the signature according to the same profile as that of the TPA. However, methylarsonic acid and cholic acid gave an incomplete signature with changes in the expression of only 7 and 5 genes, respectively. Finally, quercetin treatment induced no change in the expression of all genes but exhibited higher cytotoxicty. These results suggest that among the transforming agents tested, some may share similar mechanisms of action leading to cell transformation while others may activate different additional pathways involved in such cellular process. More transforming and non-transforming agents and gene markers should be tested in order to try to identify a relevant gene signature to predict the transforming potential of non-genotoxic agents.
迄今为止，长期啮齿动物致癌性测定法是监管机构唯一认可的用于评估非遗传毒性致癌物质的测定法，但它们的可靠性受到了质疑。体外细胞转化测定法（CTA）可能是动物模型的一个有趣替代方法，因为它具有检测遗传毒性和非遗传毒性转化化学物质的优势。其中，Bhas 42 CTA 使用已转染致癌序列 v-Ha-ras 的细胞系。该序列赋予这些细胞“起始”状态，使它们对非遗传毒性物质特别敏感。在之前的一项工作中，转录组分析表明，用转化二氧化硅（纳米）颗粒和 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）处理 Bhas 42 细胞通常会改变 12 个参与细胞增殖和黏附的基因的表达。在本研究中，我们评估了该特征是否适用于另外四种可溶性转化剂，即密执毒素、甲基砷酸、胆酸和槲皮素。用密执毒素处理 Bhas 42 细胞 48 小时，根据与 TPA 相同的模式改变了特征的 12 个基因的表达。然而，甲基砷酸和胆酸的特征仅改变了 7 个和 5 个基因的表达，分别为不完整的特征。最后，槲皮素处理没有改变所有基因的表达，但表现出更高的细胞毒性。这些结果表明，在所测试的转化剂中，一些可能具有相似的作用机制，导致细胞转化，而另一些可能激活不同的额外途径，参与这种细胞过程。为了尝试鉴定与非遗传毒性物质的转化潜力相关的基因特征，应该测试更多的转化和非转化剂和基因标记。
