title: Evaluation of cell proliferation, apoptosis, and DNA-repair genes as potential biomarkers for ethanol-induced CNS alterations.
abstract: BACKGROUND
  Alcohol use disorders (AUDs) lead to alterations in central nervous system (CNS) architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs) produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure.
  
  
  RESULTS
  Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs) of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP) assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1) was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5) showed a highly significant correlation with AUD-induced decreases in the volume of the left parietal supramarginal gyrus and neuropsychological measures.
  
  
  CONCLUSIONS
  These results demonstrate that alcohol-induced changes in genes related to proliferation, apoptosis, and DNA-repair are observable in the peripheral blood and may serve as a useful biomarker for CNS structural damage and functional performance deficits in human AUD subjects.
authors.affiliation: Department of Neuroscience, Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Hicks
authors.forename: Lambert
authors.initials: L
authors.lastname: Lewis
authors.forename: Julie
authors.initials: J
authors.lastname: Ritchie
authors.forename: Patrick
authors.initials: P
authors.lastname: Burke
authors.forename: Ynesse
authors.initials: Y
authors.lastname: Abdul-Malak
authors.forename: Nyssa
authors.initials: N
authors.lastname: Adackapara
authors.forename: Kelly
authors.initials: K
authors.lastname: Canfield
authors.forename: Erik
authors.initials: E
authors.lastname: Shwarts
authors.forename: Karen
authors.initials: K
authors.lastname: Gentile
authors.forename: Zsuzsa Szombathyne
authors.initials: ZS
authors.lastname: Meszaros
authors.forename: Frank A
authors.initials: FA
authors.lastname: Middleton
mesh_terms: D000328:Adult; D019973:Alcohol-Related Disorders / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D009483:Neuropsychological Tests; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D025341:Principal Component Analysis; D051381:Rats; D064249:Securin; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; C489423:MCM5 protein, human; D009363:Neoplasm Proteins; D064249:Securin; D016159:Tumor Suppressor Protein p53; C578002:pituitary tumor-transforming protein 1, human; D000431:Ethanol; C071447:ERCC1 protein, human; D004720:Endonucleases