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Accumulation of oxidatively generated DNA damage in the brain: a mechanism of neurotoxicity
- Source :
- Free radical biologymedicine. 42(3)
- Publication Year :
- 2006
-
Abstract
- Unrepaired or erroneously repaired DNA lesions drive genomic instability and contribute to cellular and organ decline. Since delayed neuropathologies are common in survivors of smoke inhalation injuries, we asked whether the integrity of brain DNA might be compromised by acute exposure to combustion smoke. Although many studies demonstrate that the brain is equipped to repair oxidatively damaged DNA, to date, the capacity for accurate DNA repair under conditions of disrupted oxygenation and oxidative stress has not been defined. We show that DNA adducts detectable by their ability to block PCR amplification form in the rat hippocampus after acute exposure to smoke. To identify the different types of adducts and to dissect their temporal formation and repair profiles in vivo in the brain, we used DNA-modifying enzymes to convert specific adducts into strand breaks prior to PCR amplification. Using this strategy, we detected formation of oxidative DNA adducts early on after smoke inhalation, while mismatched bases emerged at the later recovery times, potentially due to an erroneous DNA repair process. Erroneous repair can be mutagenic and because the initial smoke-induced oxidative damage to DNA is extensive, compromised fidelity of DNA repair may underlie neurotoxicity and contribute to delayed death of hippocampal neurons.
- Subjects :
- Genome instability
DNA repair
DNA damage
Smoke inhalation
Biology
medicine.disease_cause
Biochemistry
Hippocampus
Article
Rats, Sprague-Dawley
chemistry.chemical_compound
DNA Adducts
Physiology (medical)
medicine
Animals
Neurons
Cell Death
Neurotoxicity
Base excision repair
Smoke Inhalation Injury
medicine.disease
Cell biology
Rats
Oxidative Stress
chemistry
Nerve Degeneration
Lipid Peroxidation
Oxidation-Reduction
DNA
Oxidative stress
DNA Damage
Subjects
Details
- ISSN :
- 08915849
- Volume :
- 42
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Free radical biologymedicine
- Accession number :
- edsair.doi.dedup.....de1f9c77bef2caf62b156abe7806d863