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Event: 876

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Mutations in Critical Genes

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
eukaryotic cell

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
mutation	deoxyribonucleic acid	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
pH Induced Nasal Tumors	KeyEvent	Cataia Ives (send email)	Open for citation & comment	Under Review
Ionizing Radiation-Induced AML	KeyEvent	Allie Always (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI
human	Homo sapiens	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

DNA mutation is an obligate step in carcinogenesis.

References

List of the literature that was cited for this KE description. More help

↑ 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
↑ 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
↑ 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
↑ Albertini (2013). Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. Crit Rev Toxicol. 43: 671-706
↑ Albertini (2013). Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. Crit Rev Toxicol. 43: 671-706
↑ 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