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Relationship: 2728

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, DNA damage and mutation leads to Increase chromosomal aberrations

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
DNA damage and mutations leading to Metastatic Breast Cancer non-adjacent High High Usha Adiga (send email) Under development: Not open for comment. Do not cite Under Development

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mice Mus sp. High NCBI
human Homo sapiens High NCBI
human and other cells in culture human and other cells in culture Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Not Specified

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Not Specified

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Increased DNA damage leads to increased chromosomal aberrations

The presented relationship outlines a direct correlation between two genetic events. The upstream event, "Increased DNA damage," signifies an augmentation in the occurrence of genetic lesions and alterations within the DNA molecule. This damage can result from various sources, such as exposure to radiation, chemicals, or errors during DNA replication.

The downstream event in this relationship is "increased chromosomal aberrations," which signifies a rise in the number or frequency of structural abnormalities in chromosomes. Chromosomal aberrations can encompass various changes, including deletions, insertions, translocations, or inversions of genetic material within chromosomes.

This relationship underscores the close connection between genetic lesions and chromosomal abnormalities. Increased DNA damage can directly contribute to an elevated occurrence of chromosomal aberrations, as the integrity of DNA is essential for maintaining the proper structure of chromosomes. Understanding this relationship is crucial in the context of genomic stability and its implications for various biological outcomes, including genetic disorders and cancer development.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Animal studies,Cell lines and human studies were searched.

With careful adherence to OECD guidelines, a meticulous evidence collection strategy was executed to validate the Key Event Relationship (KER) "Increased DNA damage and mutation leads to Increased chromosomal aberrations." Commencing with the induction of DNA damage and mutation, a range of established genotoxicity assays was employed to directly quantify the occurrence and extent of genetic lesions. Assays such as the Ames test and in vitro micronucleus assay provided direct evidence of DNA damage and mutagenesis, solidifying the initial event.

Mechanistic insights were further deepened through molecular investigations that explored the link between DNA damage, mutation, and chromosomal aberrations. Techniques like karyotyping and comparative genomic hybridization allowed for the direct visualization and quantification of chromosomal abnormalities, supporting the proposed relationship.

Validation of the KER was enhanced by employing various experimental models, including different cell types, exposure scenarios, and mutagenic agents. These diverse contexts contributed to the robustness and generalizability of the relationship's findings.

Real-world relevance was established by drawing parallels between laboratory-induced DNA damage and mutation and scenarios in which environmental exposures or genetic predispositions lead to increased genetic lesions and subsequent chromosomal aberrations. By skillfully integrating experimental data, mechanistic insights, and relevant contextual studies in accordance with OECD principles, a comprehensive evidence base for the KER "Increased DNA damage and mutation leads to Increased chromosomal aberrations" was effectively constructed.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

DNA double-strand breaks (DSB) are the crucial lesions underlying the formation of CA [M.A Bender et al.,1974; G.Obe et al., 2002]. Chromosomes are uninemic; each chromatid contains one continuous DNA molecule. Consequently, an unrepaired DSB, appears at mitosis as a terminal deletion (or an incomplete exchange), leading to loss of genetic material and eventually cell death or loss of heterozygosity in diploid cells. On the other hand, misrepaired DSB generate intra- or inter-chromosomal exchanges which may or may not be lethal, depending on the exact form they take. Concluding a controversy that lasted a number of  years ([K.H Chandwick et al.,1981] and references therein), there is now a general agreement that the dose–response curve for the induction of DSB is linear over several orders of magnitude [K Rothkamm et al., 2003]

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

DNA damage and unrepaired or insuffificiently repaired DNA double-strand breaks as well as telomere shortening contribute to the formation of structural chromosomal

aberrations (CAs). Non-specifific CAs have been used in the monitoring of individuals

exposed to potential carcinogenic chemicals and radiation. The frequency of CAs in

peripheral blood lymphocytes (PBLs) has been associated with cancer risk and the

association has also been found in incident cancer patients. CAs include chromosome

type aberrations (CSAs) and chromatid-type aberrations (CTAs) and their sum CAtot.

Structural CAs may be specifific, such as translocations and inversions, or non-specifific, such as chromatid breaks, fragmented or missing parts of chromosomes, and fusions

resulting in dicentric and ring chromosomes (Bignold, 2009).

The former are often recurrent and they are currently analyzed by molecular cytogenetic methods while the latter are scored by classical cytogenetic techniques, which are able to recognize chromosome-type aberrations (CSAs) and chromatid-type aberrations (CTAs) according to morphological changes (Hagmar et al., 2004). CTAs are formed due to insufficiently repaired double-strand breaks (DS00Bs) during the late S or G2 phase of the 

cell cycle (Natarajan and Palitti, 2008; Bignold, 2009; Durante et al., 2013), whereas CSAs are the result of direct DNA damage due to radiation, chemical mutagens, or shortening of telomeres during the G0/G1 phase (Albertini et al., 20; Jones et al., 2012). Non-specifific CAs have been used in the monitoring of populations occupationally exposed to potential carcinogenic chemicals and radiation and an increased frequency of CAs in peripheral blood lymphocytes (PBLs) has been associated with cancer risk and the association has also been found in incident cancer patients (Rossner et al., 2005; Vodicka et al., 2010; Vodenkova et al., 2015).

Unrepaired or insuffiffifficiently repaired DSBs, as well as telomerase dysfunction, represent the mechanistic bases for the formation of structural CAs (Natarajan and Palitti, 2008;

Bignold, 2009; Durante et al., 2013; Vodicka et al., 2018; Srinivas et al., 2020). However, even other types of DNA repair pathways may contribute to CA formation as these are

found in inherited syndromes manifesting DNA repair gene mutations (Rahman, 2014).

 

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

In contrast, no significant differences were found in CAs frequencies between individuals working in different laboratories of a Cancer Research Institute, including an anatomical pathology laboratory (Pala M et al.,2008)

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Multiaberrant cells frequency was significantly higher (4-fold) in formaldehyde-exposed workers than in control individuals, whereas aberrant cells frequency was significantly increased by 1.7-fold in the exposed group(Solange et al., 2015).

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

It is generally accepted that exchanges formed in the G1-phase originate from the interaction of two spatially distinct radiogenic damaged sites (DSB) [Heck et al., 2008], which runs counter to the once-popular concept encompassed by so-called “one-hit models” for the formation of translocations, dicentrics and other exchanges [Pala M et al.,2008].

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not known.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Not specific,

References

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

Albertini, R. J., Anderson, D., Douglas, G. R., Hagmar, L., Hemminki, K., Merlo, F., ... & Aitio, A. (2000). IPCS guidelines for the monitoring of genotoxic effects of carcinogens in humans. Mutation Research/Reviews in Mutation Research463(2), 111-172.

Bignold, L. P. (2009). Mechanisms of clastogen-induced chromosomal aberrations: A critical review and description of a model based on failures of tethering of DNA strand ends to strand-breaking enzymes. Mutation Research/Reviews in Mutation Research681(2-3), 271-298.

Costa, S., Carvalho, S., Costa, C., Coelho, P., Silva, S., Santos, L. S., ... & Teixeira, J. P. (2015). Increased levels of chromosomal aberrations and DNA damage in a group of workers exposed to formaldehyde. Mutagenesis30(4), 463-473.

Durante, M., Bedford, J. S., Chen, D. J., Conrad, S., Cornforth, M. N., Natarajan, A. T., ... & Obe, G. (2013). From DNA damage to chromosome aberrations: joining the break. Mutation Research/Genetic Toxicology and Environmental Mutagenesis756(1-2), 5-13.

  1. Obe, P. Pfeiffer, J.R.K. Savage, C. Johannes, W. Goedecke, P. Jeppsen, A.T. Natarajan,W.Martinez-Lopez, G.A. Folle,M.E. (2002) Drets,Chromosomal aberrations: formation, identifification, and distribution, Mutat. Res. 504.3–16.

Hagmar, L., Strömberg, U., Tinnerberg, H., & Mikoczy, Z. (2004). Epidemiological evaluation of cytogenetic biomarkers as potential surrogate end-points for cancer. IARC scientific publications, (157), 207-215.

 He, J. L., Jin, L. F., & Jin, H. Y. (1998). Detection of cytogenetic effects in peripheral lymphocytes of students exposed to formaldehyde with cytokinesis-blocked micronucleus assay. Biomedical and environmental sciences: BES11(1), 87-92.

Heck, H. D. A., & Casanova, M. (2004). The implausibility of leukemia induction by formaldehyde: a critical review of the biological evidence on distant-site toxicity. Regulatory Toxicology and Pharmacology40(2), 92-106.

Jakab, M. G., Klupp, T., Besenyei, K., Biró, A., Major, J., & Tompa, A. (2010). Formaldehyde-induced chromosomal aberrations and apoptosis in peripheral blood lymphocytes of personnel working in pathology departments. Mutation Research/Genetic Toxicology and Environmental Mutagenesis698(1-2), 11-17. 

Jones, C. H., Pepper, C., & Baird, D. M. (2012). Telomere dysfunction and its role in haematological cancer. British journal of haematology156(5), 573-587.

 K.H. Chadwick, H.P. Leenhouts, The Molecular Theory of Radiation Biology, Springer-Verlag, Berlin, (1981).

Kitaeva, L. V., Mikheeva, E. A., Shelomova, L. F., & PIa, S. (1996). Genotoxic effect of formaldehyde in somatic human cells in vivo. Genetika32(9), 1287-1290.

K. Rothkamm, M. Löbrich, (2003).Evidence for a lack of DNAdouble-strand break repair  in human cells exposed to very low X-ray doses, Proc. Natl. Acad. Sci. U. S. A. 100. 5057–5062.

Liu, Q., Cao, J., Li, K. Q., Miao, X. H., Li, G., Fan, F. Y., & Zhao, Y. C. (2009). Chromosomal aberrations and DNA damage in human populations exposed to the processing of electronics waste. Environmental science and pollution research16(3), 329-338.

 

  1. A. Bender, H.G. Griggs, J.S. Bedford,(1974). Mechanisms of chromosomal aberration production. III: chemicals and ionizing radiation, Mutat. Res. 23.197–212.

 

Marchetti, F., Bishop, J., Gingerich, J., & Wyrobek, A. J. (2015). Meiotic interstrand DNA damage escapes paternal repair and causes chromosomal aberrations in the zygote by maternal misrepair. Scientific reports5(1), 1-7.

Natarajan, A. T., & Palitti, F. (2008). DNA repair and chromosomal alterations. Mutation Research/Genetic Toxicology and Environmental Mutagenesis657(1), 3-7.

Pala, M., Ugolini, D., Ceppi, M., Rizzo, F., Maiorana, L., Bolognesi, C., ... & Vecchio, D. (2008). Occupational exposure to formaldehyde and biological monitoring of Research Institute workers. Cancer detection and prevention32(2), 121-126.

Plotnikov, E., Silnikov, V., Gapeyev, A., & Plotnikov, V. (2016). Investigation of DNA-damage and chromosomal aberrations in blood cells under the influence of new silver-based antiviral complex. Advanced Pharmaceutical Bulletin6(1), 71.

Rahman, N. (2014). Realizing the promise of cancer predisposition genes. Nature505(7483), 302-308.

Rossner, P., Boffetta, P., Ceppi, M., Bonassi, S., Smerhovsky, Z., Landa, K., ... & Šrám, R. J. (2005). Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer. Environmental health perspectives113(5), 517-520.

Solange Costa, Sandra Carvalho, Carla Costa, Patrícia Coelho, Susana Silva, Luís S. Santos, Jorge F. Gaspar, Beatriz Porto, Blanca Laffon, João P. Teixeira, Increased levels of chromosomal aberrations and DNA damage in a group of workers exposed to formaldehyde, Mutagenesis, Volume 30, Issue 4, July 2015, Pages 463–473,

Srinivas, N., Rachakonda, S., & Kumar, R. (2020). Telomeres and telomere length: a general overview. Cancers12(3), 558.

Tsuda, H., Shimlzu, C. S., Taketomi, M. K., Hasegawa, M. M., Hamada, A., Kawata, K. M., & Inui, N. (1993). Acrylamide; induction of DNA damage, chromosomal aberrations and cell transformation without gene mutations. Mutagenesis8(1), 23-29.

 

Vodicka, P., Musak, L., Vodickova, L., Vodenkova, S., Catalano, C., Kroupa, M., ... & Hemminki, K. (2018). Genetic variation of acquired structural chromosomal aberrations. Mutation Research/Genetic Toxicology and Environmental Mutagenesis836, 13-21.

 

Vodicka, P., Polivkova, Z., Sytarova, S., Demova, H., Kucerova, M., Vodickova, L., ... & Hemminki, K. (2010). Chromosomal damage in peripheral blood lymphocytes of newly diagnosed cancer patients and healthy controls. Carcinogenesis31(7), 1238-1241.

 

Vodenkova, S., Polivkova, Z., Musak, L., Smerhovsky, Z., Zoubkova, H., Sytarova, S., ... & Vodicka, P. (2015). Structural chromosomal aberrations as potential risk markers in incident cancer patients. Mutagenesis30(4), 557-563.