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Relationship: 2728
Title
Increased, DNA damage and mutation leads to Increase chromosomal aberrations
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite | Under Development |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
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | Not Specified |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | Not Specified |
Key Event Relationship Description
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
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
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
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).
Empirical Evidence
A study by Solange et al evaluated the effects of exposure to formaldehyde (FA) in human peripheral blood lymphocytes, a group of laboratory workers exposed occupationally to FA and control subjects were tested for chromosomal aberrations (CAs) and DNA damage (comet assay)( Solange et al 2015). The level of exposure to FA in the workplace air was evaluated. The association between genotoxicity biomarkers and polymorphic genes of xenobiotic - metabolising and DNA repair enzymes were also assessed.
All cytogenetic parameters evaluated—total-CA, CSAs, CTAs, gaps and aneuploidies—were significantly elevated in anatomy pathology professionals exposed to FA (mean 0.38 ppm) compared with control subjects. FA-exposed individuals showed an increase of 91% in total-CAs frequency compared with controls. Mean frequencies of both CAs types, CSAs and CTAs were also significantly higher in exposed workers . Although there is a paucity of studies assessing CAs in FA occupationally exposed subjects, our findings are in agreement with most of the published literature. (He.J.L et al. 1998)found higher frequencies of CAs in PBLs of 13 anatomy students exposed to FA (mean level 2.37 ppm) during a 12-week anatomy class. Similarly, in a recent study involving FA-exposed personnel working in pathology departments (n = 21; mean level 0.72 ppm), total-CA and CTAs were significantly elevated
compared with controls (Jakab et al., 2010). A significant increase in CAs frequencies was also observed in industrial workers (kitaeva et al.,1996).
Multiaberrant cells frequency was significantly higher (4-fold) in FA-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).
Uncertainties and Inconsistencies
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
Quantitative Understanding of the Linkage
Method/ measurement reference |
Reliability |
Strength of evidence |
Assay fit for purpose |
Repeatability/ reproducibility |
Direct measure |
|
Mice |
Chromosomal abberation assay, Genotoxicity assessment assay, (Evgenii Plotnikov., et al 2016) CT8 Assay (Francesco Marchett., et al 2015) |
+ |
Strong |
Yes |
Yes |
Yes |
Human |
Micronuclease (CBMN) Assay, Comet assay, (Qiang Liu., et al 2009.) CAs analysis, Comet assay, PCR-RFLP (S. Costa et al., 2015)
|
+ |
Strong |
Yes |
Yes |
Yes |
Human Cell lines |
Polyploid assay, Sister chromatid exchange test, V79/HPRT mutation assay, Cell transformation assay, Tumorigenicity test, ,spore rec assay (Hirohisa Tsuda et al., 1993) |
+ |
Strong |
Yes |
Yes |
Yes |
Response-response Relationship
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
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
Not known.
Domain of Applicability
Not specific,
References
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