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Relationship: 1939
Title
Increase, DNA strand breaks leads to Increase, Chromosomal aberrations
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Oxidative DNA damage leading to chromosomal aberrations and mutations | non-adjacent | High | Low | Brendan Ferreri-Hanberry (send email) | Open for comment. Do not cite | WPHA/WNT Endorsed |
| Deposition of energy leading to lung cancer | non-adjacent | High | Low | Brendan Ferreri-Hanberry (send email) | Open for citation & comment | EAGMST Approved |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
DNA strand breaks (single and double) can arise from endogenous processes (e.g., topoisomerase reaction, excision repair, and VDJ recombination) and exogenous insults (e.g., replications stressors, ionizing radiation, and reactive oxygen species). Single strand breaks (SSBs) are generally repaired rapidly without error. However, multiple SSBs in close proximity to each other and interference of replication by unrepaired SSBs can lead to double strand breaks (DSB). DSB are more difficult to repair and are more toxic than SSB (Kuzminov, 2001). DSBs may lead to chromosomal breakages that may permanently alter the structure of chromosomes (i.e., chromosomal aberrations) and cause loss of DNA segments.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
As described above, statistically significant increases in MN occur, in some cases, at lower concentrations than strand breaks measured with the comet assay (Platel et al., 2001; Watters et al., 2009; Kawaguchi et al., 2010). The two assays measure different endpoints at different time points; the MN test may appear to be more sensitive than the comet assay but it is difficult to directly compare these two assays.
Mughal et al. (2010) study compared different parameters of comet assay (tail moment, length, and % tail DNA) to MN frequency. Depending on the parameter, the observation of increase in strand breaks varied. For example, % tail DNA would show a visible increase in strand breaks at one concentration; however, no change would be observed in the tail moment calculated using the same data. Use of different parameters in presenting comet assay data may add subjectivity to the results that are reported in certain papers.
Rossner Jr. et al. exposed human embryonic lung fibroblasts (HEL12469) to 1, 10, and 25 µM of benzo[a]pyrene (B[a]P) for 24 hours and measured DSB (γH2AX immunodetection by Western blotting) and translocations (by fluorescence in situ hybridization of chromosomes 1, 2, 4, 5, 7, 17) (Rossner Jr. et al., 2014).
- Increases in γH2AX were observed only at 25 µM B[a]P (~2.5 fold increase) after the 24h exposure.
- Translocations were quantified and expressed as the genomic frequency of translocations per 100 cells (FG/100)
- All concentrations of B[a]P induced an elevated frequency of translocations compared to the DMSO control (DMSO: ~0.19/100; 1 µM: ~0.53/100 cells; 10 µM: ~0.33/100; 25 µM: ~0.39/100)
In this study, the increase in translocations was detected at concentrations that did not induce an increase in γH2AX signal. This observation of the discordant relationship between γH2AX and translocations may be due to the differences in assay sensitivity. In addition, immunodetection by Western blotting cannot precisely measure small changes in protein content.
As with the regularly used alkaline comet assay a variety of DNA damage is detected – SSBs, DSBs, alkaline labile sites, as well as sites of DNA repair; thus, a quantitative understanding for specific types of damage is rather difficult. There exists the possibility to quantify the amount of DNA breaks by comparing the induced damage with Gy equivalents (Collins et al., 2008), however, this is not the standard. DSBs can be measured more specific with the neutral version of the Comet assay, however, this version is not that regularly used. As reviewed in Takahashi et al, 2005 the efficiency of DSB detection measured with the PFGE, the neutral Comet assay and the DNA elution assay has a lower detection limit of 100 DSB per cell (Collins et al., 2008). In contrast to this, each Gamma-H2AX focus seems to represent a DNA DSB in vivo (Rogakou et al., 1999).
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
DNA strand breaks and subsequent chromosomal aberrations can occur in any eukaryotic and prokaryotic cell.