The Effects of ROS and DNA Repair on Methylmercury-initiated Neurodevelopmental Deficits
Bibliographic record
Abstract
Methylmercury (MeHg) is an environmental toxin to which we are exposed through the consumption of seafood. Reactive oxygen species (ROS) have been implicated in the mechanism of toxicity, and in vitro studies in our laboratory have implicated DNA oxidation, particularly the DNA repair enzyme oxoguanine glycosylase 1 (OGG1). My studies determined the effects of in utero exposure to MeHg on fetal brain DNA oxidation and postnatal neurodevelopmental deficits, and the role of ROS-mediated oxidative DNA damage using the free radical spin trap, α-phenyl-N-tert-butylnitrone (PBN), and DNA repair-deficient ogg1 knockout mice. While neither MeHg nor PBN altered DNA oxidation in fetal brain, MeHg caused cognitive deficits in passive avoidance and novel object recognition, the latter of which was blocked by PBN pretreatment, suggesting ROS involvement. Preliminary longevity studies following one litter from each treatment group to 16 months suggest that in utero MeHg treatment may shorten lifespan. Endogenous DNA oxidation was increased in the brains of ogg1 knockout fetuses compared to wild-type littermates, although this was not enhanced by MeHg. However, OGG1-deficient animals exhibited cognitive deficits in passive avoidance after MeHg treatment, suggesting a role for DNA damage. Furthermore, ogg1 knockout female mice exhibited a passive avoidance deficit compared to wild-type females regardless of treatment, corroborating a role for oxidative DNA damage in neurodevelopmental deficits. MeHg increased apoptosis in the hippocampal region of fetal brain, and may cause DNA double-strand breaks (DSBs), evidenced by enhanced phosphorylation of histone 2AX (γH2AX). Ogg1 knockout progeny exhibited increased cellular proliferation or migration in the developing hippocampal region, which was blocked by MeHg. My results provide the first evidence that: (1) MeHg may decrease lifespan; (2) PBN protects against some postnatal neurodevelopmental deficits caused by in utero exposure to MeHg; and (3) DNA repair-deficient progeny are more susceptible to postnatal cognitive deficits caused by in utero MeHg exposure, suggesting that ROS-mediated DNA oxidation plays a role in MeHg-initiated neurodevelopmental deficits.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
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".