Event:876

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Event Title

Mutations in Critical Genes, Increase

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
rat Rattus norvegicus Strong NCBI
mouse Mus musculus Strong NCBI
human Homo sapiens Strong NCBI

Level of Biological Organization

Biological Organization
Molecular

How this Key Event works

Respiratory metaplasia requires increases in cell division of local stem cells, which replace olfactory specific cell types with respiratory tissue cell types. The same process occurs during squamous metaplasia. Cell division during respiratory metaplasia occurs under conditions of cellular stress and cytotoxicity, both of which can increase the probability of mutation, as cells exert less effective control over fidelity of the genome[1].

How it is Measured or Detected

Although the presence of tumors implies accumulation of DNA mutations[2], and increased cell division is known to increase mutations[3], direct measurement in vivo is challenging. Traditional methods of assessing the mutagenic potential of acetate ester metabolites[4], for example in vitro systems such as the AMES assay, are appropriate for assessing the direct mutagenic potential[5], but not for the indirect mutagenic potential of cell proliferation induced by respiratory metaplasia. Transgenic models, for example Big Blue [6] are capable of measuring specific types of DNA damage in vivo.

Evidence Supporting Taxonomic Applicability

DNA mutation is an obligate step in carcinogenesis.

References

  1. Cohen and Ellwein (1991). Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51: 6493-6505, Cohen, Purtilo and Ellwein (1991). Ideas in pathology. Pivotal role of increased cell proliferation in human carcinogenesis. Mod Pathol. 4: 371-382, Cohen (1995). Role of cell proliferation in regenerative and neoplastic disease. Toxicol Lett. 82-83: 15-21, Counts and Goodman (1995). Principles underlying dose selection for, and extrapolation from, the carcinogen bioassay: dose influences mechanism. Regul Toxicol Pharmacol. 21: 418-421
  2. Bertram (2000). The molecular biology of cancer. Mol Aspects Med. 21: 167-223, Hanahan and Weinberg (2000). The hallmarks of cancer. Cell. 100: 57-70
  3. Preston-Martin, Pike, Ross, Jones and Henderson (1990). Increased cell division as a cause of human cancer. Cancer Res. 50: 7415-7421, Cohen, Purtilo and Ellwein (1991). Ideas in pathology. Pivotal role of increased cell proliferation in human carcinogenesis. Mod Pathol. 4: 371-382
  4. Albertini (2013). Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. Crit Rev Toxicol. 43: 671-706
  5. Albertini (2013). Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. Crit Rev Toxicol. 43: 671-706
  6. Manjanatha, Shelton, Aidoo, Lyn-Cook and Casciano (1998). Comparison of in vivo mutagenesis in the endogenous Hprt gene and the lacI transgene of Big Blue(R) rats treated with 7, 12-dimethylbenz[a]anthracene. Mutat Res. 401: 165-178