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BMC Neuroscience

, 13:128

Neurobiology of disease


BackgroundAlcohol 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.

ResultsRemarkably, 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.

ConclusionsThese 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.

KeywordsBiomarker Peripheral blood Microarray p53 DNA damage Alcoholism Neuroimaging Electronic supplementary materialThe online version of this article doi:10.1186-1471-2202-13-128 contains supplementary material, which is available to authorized users.

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Autor: Steven D Hicks - Lambert Lewis - Julie Ritchie - Patrick Burke - Ynesse Abdul-Malak - Nyssa Adackapara - Kelly Canfield -

Fuente: https://link.springer.com/

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