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Induction of oxidative stress and DNA damage in rat brain by a folate/methyl-deficient diet.
Brain Res. 2008 Oct 27; 1237:44-51.BR

Abstract

The age-associated decline in cellular antioxidant defenses and resultant accumulation of DNA damage in central nervous system has been mechanistically implicated in the etiology and pathogenesis of neurodegenerative diseases. Neurons possess a high metabolic activity and are especially vulnerable to the long-term effects of continuous exposure to endogenous reactive oxygen species. It is well recognized that adequate availability of essential nutrients involved in cellular one-carbon metabolism is essential for normal brain development and function. Additionally, the synthesis of the primary low-molecular cellular antioxidant glutathione is inter-dependently linked to one-carbon metabolic pathway. Thus, any aberrant disruptions in one-carbon metabolism can result in potentially deleterious effects including cell death as a result of an imbalance in the cellular redox state. Hence, in the present study, we examined the long-term effects of a folate/methyl-deficient (FMD) diet on cellular antioxidant defenses and DNA damage in the rat brain. Feeding male Fisher 344 rats a FMD diet resulted in perturbations in the levels of one-carbon metabolites along with induction of oxidative stress and oxidative DNA damage in the brain. This was evidenced by a decrease in the reduced oxidized/glutathione ratio, imbalance of cellular antioxidant defense system; specifically, altered activity and expression of antioxidant enzymes Mn-containing superoxide dismutase (Mn-SOD), catalase, and glutathione peroxidase (GPX), increased accumulation of oxidative DNA lesions, 8-hydroxydeoxyguanosine (8-OH-dG) and DNA single-strand breaks, even in the presence of increased expression of critical DNA repair genes apurinic/apyrimidinic endonuclease 1 (Apex1) and DNA polymerase beta (Polbeta), and apoptosis in the brains of folate/methyl-deficient rats. These results indicate that chronic methyl group deficiency leads to an imbalance in cellular antioxidant defense systems, increased oxidative stress, and apoptosis. Any of these events may compromise normal central nervous system function and contribute to the development of various neurological, behavioral, and neurocognitive dysfunctions.

Authors+Show Affiliations

Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. tetyana.bagnyukova@fda.hhs.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18694737

Citation

Bagnyukova, Tetyana V., et al. "Induction of Oxidative Stress and DNA Damage in Rat Brain By a Folate/methyl-deficient Diet." Brain Research, vol. 1237, 2008, pp. 44-51.
Bagnyukova TV, Powell CL, Pavliv O, et al. Induction of oxidative stress and DNA damage in rat brain by a folate/methyl-deficient diet. Brain Res. 2008;1237:44-51.
Bagnyukova, T. V., Powell, C. L., Pavliv, O., Tryndyak, V. P., & Pogribny, I. P. (2008). Induction of oxidative stress and DNA damage in rat brain by a folate/methyl-deficient diet. Brain Research, 1237, 44-51. https://doi.org/10.1016/j.brainres.2008.07.073
Bagnyukova TV, et al. Induction of Oxidative Stress and DNA Damage in Rat Brain By a Folate/methyl-deficient Diet. Brain Res. 2008 Oct 27;1237:44-51. PubMed PMID: 18694737.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of oxidative stress and DNA damage in rat brain by a folate/methyl-deficient diet. AU - Bagnyukova,Tetyana V, AU - Powell,Christine L, AU - Pavliv,Oleksandra, AU - Tryndyak,Volodymyr P, AU - Pogribny,Igor P, Y1 - 2008/07/29/ PY - 2008/06/23/received PY - 2008/07/16/revised PY - 2008/07/17/accepted PY - 2008/8/13/pubmed PY - 2009/4/10/medline PY - 2008/8/13/entrez SP - 44 EP - 51 JF - Brain research JO - Brain Res VL - 1237 N2 - The age-associated decline in cellular antioxidant defenses and resultant accumulation of DNA damage in central nervous system has been mechanistically implicated in the etiology and pathogenesis of neurodegenerative diseases. Neurons possess a high metabolic activity and are especially vulnerable to the long-term effects of continuous exposure to endogenous reactive oxygen species. It is well recognized that adequate availability of essential nutrients involved in cellular one-carbon metabolism is essential for normal brain development and function. Additionally, the synthesis of the primary low-molecular cellular antioxidant glutathione is inter-dependently linked to one-carbon metabolic pathway. Thus, any aberrant disruptions in one-carbon metabolism can result in potentially deleterious effects including cell death as a result of an imbalance in the cellular redox state. Hence, in the present study, we examined the long-term effects of a folate/methyl-deficient (FMD) diet on cellular antioxidant defenses and DNA damage in the rat brain. Feeding male Fisher 344 rats a FMD diet resulted in perturbations in the levels of one-carbon metabolites along with induction of oxidative stress and oxidative DNA damage in the brain. This was evidenced by a decrease in the reduced oxidized/glutathione ratio, imbalance of cellular antioxidant defense system; specifically, altered activity and expression of antioxidant enzymes Mn-containing superoxide dismutase (Mn-SOD), catalase, and glutathione peroxidase (GPX), increased accumulation of oxidative DNA lesions, 8-hydroxydeoxyguanosine (8-OH-dG) and DNA single-strand breaks, even in the presence of increased expression of critical DNA repair genes apurinic/apyrimidinic endonuclease 1 (Apex1) and DNA polymerase beta (Polbeta), and apoptosis in the brains of folate/methyl-deficient rats. These results indicate that chronic methyl group deficiency leads to an imbalance in cellular antioxidant defense systems, increased oxidative stress, and apoptosis. Any of these events may compromise normal central nervous system function and contribute to the development of various neurological, behavioral, and neurocognitive dysfunctions. SN - 0006-8993 UR - https://www.unboundmedicine.com/medline/citation/18694737/Induction_of_oxidative_stress_and_DNA_damage_in_rat_brain_by_a_folate/methyl_deficient_diet_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(08)01815-5 DB - PRIME DP - Unbound Medicine ER -