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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online February 16, 2006 as doi:10.1096/fj.05-5091fje. |
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* Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, University of Montana, Missoula, Montana, USA;
Neurotoxicology and Epigenomics Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA; and
Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
1Correspondence: N.Z.: University of Rhode Island, 227 Fogarty Hall, Kingston, RI 02881, USA. E-mail: nzawia{at}uri.edu; D.K.L.: Indiana University School of Medicine, 791 N. Union Dr., Indianapolis, Indiana 46202, USA. E-mail: dlahiri{at}iupi.edu
SPECIFIC AIMS
The clinical manifestations of Alzheimer’s disease (AD) appear in old age; however, the initial events that trigger this disease may begin very early in life. Similar to cancer, a progressive accumulation of damage occurs in AD patients during a long asymptomatic period (perhaps decades) before the disease is clinically detectable. The progressive and latent nature of neurodegeneration suggests that the triggering event occurs much earlier in life. Our recent work on rodents showed that neonatal exposure to lead (Pb) results in an over expression of the ß amyloid (Aß) precursor protein (APP) gene and a commensurate elevation in the levels of APP and its proteolytic product, the Aß peptide, in old age. Aß is cytotoxic and known to generate reactive oxygen species and promote neurodegeneration in the aging brain. To corroborate whether early exposure to Pb impacts the onset of oxidative damage late in life, we measured the levels of 8-hydroxyl-2'-deoxyguanosine (oxo8dG) and the associated activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase (Ogg1) in the brain cerebral tissue of aging rats exposed to Pb during postnatal brain development and/or during old age. A further aim was to find a relationship between structure of gene regulatory regions and response to Pb exposure in the early developmental period.
PRINCIPAL FINDINGS
1. Levels of oxo8dG and Ogg1 activity are inversely related
There was an overall inverse relationship between the pattern of oxo8dG levels and Ogg1 activity across the lifespan of mature animals presented in this study, with the exception of early development (Fig. 1
A, B). While oxo8dG levels accumulated in aging rats exposed to Pb during development, Ogg1 activity was not affected. The inverse relationship between oxo8dG levels and Ogg1 activity was uncoupled by early exposure to Pb.
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2. Alteration in oxo8dG levels is a latent effect of developmental Pb exposure
In addition, to test whether the increase in oxo8dG levels was a latent effect of developmental Pb exposure, oxo8dG levels were also determined in DNA isolated from the brain cerebral tissue of animals exposed to Pb from 18–20 months of age (Pb-L group). No significant oxo8dG accumulation was found in the Pb-L group as compared with control animals (Fig. 1C
) although Pb concentrations in the blood (60 µg/dl) and cortex (0.32 µg/g wet of weight of tissue) of these animals were significantly elevated. The brain cerebral tissue of aging rats exposed to Pb during development accumulates a greater amount of oxo8dG as compared with unexposed animals. However, this increased accumulation of DNA damage is not reproduced in animals exposed to Pb during adulthood, providing evidence of a window of susceptibility during development that renders this population of neurons compromised later in life.
3. Gene response to developmental Pb exposure corresponds to lower CpG density in the promoter region
When mean cumulative CpG content of respective 2 kb 5'-flanking regions was compared between genes that have been shown to respond ("responding") and those that did not respond ("nonresponding") to developmental lead exposure; "nonresponding" genes tended to have greater cumulative CpG than did "responding" genes (Fig. 2
). This difference was not significant (P<0.05) by t test at –400, –800, –1600, and –2000 bp upstream of the transcription start site (TSS). It was significant at –100 bp. This suggests that the mechanism for the effects of developmental Pb exposure may depend on hypomethylation. A more refined association among response to developmental Pb exposure, CpG methylation, and the presence or absence of binding sites for specific stimulatory protein (SP) family, zinc finger, and methylation—selective transcription factors may likewise exist. Alternatively, this may be a form of "flock defense," wherein greater density of potential targets would reduce the likelihood of a specific critically-positioned CpG dinucleotide being subjected to a single random methylation event. Genes with lower 5'-flanking CpG density would, thus, be more susceptible to a single methylation event that would significantly alter binding capacity to potentially important nuclear factors.
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4. Endogenous antioxidant levels did not change due to developmental Pb exposure
Additional analysis of key antioxidants was also evaluated in an attempt to further characterize the factors participating in the oxidative status of the brain cerebral tissues of developmentally Pb-exposed rats. Postnatal Pb exposure does not appear to significantly alter the levels of reduced glutathione (GSH) in the cerebral cortex of these rats at any of the age groups evaluated. Levels of GSH remain relatively constant through the ages evaluated with the exception of the postnatal day (PND) 60 samples which demonstrate approximately 30% of the total GSH found in the cerebral cortex of other age groups. Activities of both Cu/Zn superoxide dismutase (SOD1) and Mn SOD (SOD2) were also unchanged from controls in Pb-exposed rat cerebral cortical samples.
CONCLUSIONS AND SIGNIFICANCE
In the present investigation, we have measured the lifetime levels of cerebral oxo8dG and the activity of the DNA repair enzyme Ogg1 in the cerebral cortex of control and developmental Pb-exposed (PND 1–20) rats. We found that after developmental exposure to Pb, the levels of oxo8dG was transiently increased (early in life-postnatal day 5), and notably again elevated at 20 months long after exposure to Pb had ceased. Interestingly, Ogg1 levels in these animals remained unaltered. An age-dependent loss in the inverse correlation between Ogg1 activity and Oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age (18–20 months of age). Neither early nor late Pb exposure resulted in significant alteration of GSH or SOD1 or SOD2 levels.
It has been proposed that an accumulation of oxo8dG in Alzheimer’s brain might be a result of a decrease in the activity of Ogg1, suggesting an involvement of the relationship between oxo8dG and Ogg1 activity as a mechanism within the pathogenesis of this neurodegenerative disease. This study suggests that oxidative stress exhibited in aging rats due to developmental Pb exposure may be explained by a loss of the vital relationship between oxo8dG accumulation and Ogg1 activity as well as latent build-up in Aß levels. Specifically, up-regulation of "responding" genes by developmental Pb exposure results in greater expression of genes such as SP1 and APP. Higher levels of APP result in greater Aß concentrations, which facilitates Aß aggregation. Aß alone or in aggregates is neurotoxic and leads to oxidative damage. In susceptible species, these higher levels of Aß my lead to greater formation of amyloid plaque and resultant disease (Fig. 3
). These disturbances originate early in life and may influence the potential onset of neurodegenerative diseases and behavioral alterations associated with aging, suggesting that oxidative damage and neurodegeneration in the aging brain could be impacted by developmental disturbances.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-5091fje;
This article has been cited by other articles:
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  G. Kronenberg, C. Harms, R. W. Sobol, F. Cardozo-Pelaez, H. Linhart, B. Winter, M. Balkaya, K. Gertz, S. B. Gay, D. Cox, et al. Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase J. Neurosci., July 9, 2008; 28(28): 7219 - 7230. [Abstract] [Full Text] [PDF]
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J. Wu, Md. R. Basha, B. Brock, D. P. Cox, F. Cardozo-Pelaez, C. A. McPherson, J. Harry, D. C. Rice, B. Maloney, D. Chen, et al. Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD J. Neurosci., January 2, 2008; 28(1): 3 - 9. [Abstract] [Full Text] [PDF]
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