Oxoguanine Glycosylase 1 (OGG1) Protects Cells from DNA Double-Strand Break Damage Following Methylmercury (MeHg) Exposure
Bibliographic record
Abstract
Methylmercury (MeHg) is a potent neurotoxin, teratogen, and probable carcinogen, but the underlying mechanisms of its actions remain unclear. Although MeHg causes several types of DNA damage, the toxicological consequences of this macromolecular damage are unknown. MeHg enhances oxidative stress, which can cause various oxidative DNA lesions that are primarily repaired by oxoguanine glycosylase 1 (OGG1). Herein, we compared the response of wild-type and OGG1 null (Ogg1(-/-)) murine embryonic fibroblasts to environmentally relevant, low micromolar concentrations of MeHg by measuring clonogenic efficiency, cell cycle arrest, DNA double-strand breaks (DSBs), and activation of the DNA damage response pathway.Ogg1(-/-) cells exhibited greater sensitivity to MeHg than wild-type controls, as measured by the clonogenic assay, and showed a greater propensity for MeHg-initiated apoptosis. Both wild-type and Ogg1(-/-) cells underwent cell cycle arrest when exposed to micromolar concentrations of MeHg; however, the extent of DSBs was exacerbated in Ogg1(-/-) cells compared with that in wild-type controls. Pretreatment with the antioxidative enzyme catalase reduced levels of DSBs in both wild-type and Ogg1(-/-) cells but failed to block MeHg-initiated apoptosis at micromolar concentrations. Our findings implicate reactive oxygen species mediated DNA damage in the mechanism of MeHg toxicity; and demonstrate for the first time that impaired DNA repair capacity enhances cellular sensitivity to MeHg. Accordingly, the genotoxic properties of MeHg may contribute to its neurotoxic and teratogenic effects, and an individual's response to oxidative stress and DNA damage may constitute an important determinant of risk.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".