Black Michael B, Dodd Darol E, McMullen Patrick D, Pendse Salil, MacGregor Judith A, Gollapudi B Bhaskar, Andersen Melvin E
The Hamner Institutes for Health Sciences, Six Davis Drive, PO Box 12137, Research Triangle Park, NC 27709, USA.
Toxicology Consulting Services, 26881 Wedgewood Dr., Bonita Springs, FL 34134, USA.
Regul Toxicol Pharmacol. 2015 Oct;73(1):339-47. doi: 10.1016/j.yrtph.2015.07.017. Epub 2015 Jul 23.
Many compounds test positive for lung tumors in two-year NTP carcinogenicity bioassays in B6C3F1 mice. V2O5 was identified as a lung carcinogen in this assay, leading to its IARC (International Agency for Research on Cancer) classification as group 2b or a "possible" human carcinogen. To assess potential tumorigenic mode of action of V2O5, we compared gene expression and gene ontology enrichment in lung tissue of female B6C3F1 mice exposed for 13 weeks to a V2O5 particulate aerosol at a tumorigenic level (2.0 mg/m(3)). Relative to 12 other compounds also tested for carcinogenicity in 2-year bioassays in mice, there were 1026 differentially expressed genes with V2O5, of which 483 were unique to V2O5. Ontology analysis of the 1026 V2O5 differentially expressed genes showed enrichment for hyaluronan and sphingolipid metabolism, adenylate cyclase functions, c-AMP signaling and PKA activation/signaling. Enrichment of lipids/lipoprotein metabolism and inflammatory pathways were consistent with previously reported clinical findings. Enrichment of c-AMP and PKA signaling pathways may arise due to inhibition of phosphatases, a known biological action of vanadate. We saw no enrichment for DNA-damage, oxidative stress, cell cycle, or apoptosis pathway signaling in mouse lungs exposed to V2O5 which is in contrast with past studies evaluating in vivo gene expression in target tissues of other carcinogens (arsenic, formaldehyde, naphthalene and chloroprene).
在B6C3F1小鼠进行的为期两年的国家毒理学计划致癌性生物测定中，许多化合物对肺部肿瘤检测呈阳性。在该测定中，五氧化二钒被鉴定为一种肺致癌物，这使其被国际癌症研究机构（IARC）归类为2B组或“可能的”人类致癌物。为了评估五氧化二钒潜在的致癌作用模式，我们比较了暴露于致癌水平（2.0毫克/立方米）的五氧化二钒颗粒气溶胶13周的雌性B6C3F1小鼠肺组织中的基因表达和基因本体富集情况。相对于在小鼠两年生物测定中也测试了致癌性的其他12种化合物，五氧化二钒有1026个差异表达基因，其中483个是五氧化二钒独有的。对这1026个五氧化二钒差异表达基因的本体分析显示，透明质酸和鞘脂代谢、腺苷酸环化酶功能、c-AMP信号传导和PKA激活/信号传导有富集。脂质/脂蛋白代谢和炎症途径的富集与先前报道的临床发现一致。c-AMP和PKA信号通路的富集可能是由于磷酸酶的抑制，这是钒酸盐已知的生物学作用。在暴露于五氧化二钒的小鼠肺中，我们没有看到DNA损伤、氧化应激、细胞周期或凋亡途径信号传导的富集，这与过去评估其他致癌物（砷、甲醛、萘和氯丁二烯）靶组织体内基因表达的研究形成对比。
