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Epidemiologic studies have demonstrated high rates of smoking among alcoholics, and neuroimaging studies have detected white matter atrophy and degeneration in both smokers and individuals with alcohol-related brain disease (ARBD). These findings suggest that tobacco smoke exposure may be a co-factor in ARBD. The present study examines the differential and additive effects of tobacco-specific nitrosamine (NNK) and ethanol exposures on the structural and functional integrity of white matter in an experimental model.Adolescent Long Evans rats were fed liquid diets containing 0 or 26% ethanol for 8 weeks. In weeks 3–8, rats were treated with nicotine-derived nitrosamine ketone (NNK) (2 mg/kg, 3×/week) or saline by i.p. injection. In weeks 7–8, the ethanol group was binge-administered ethanol (2 g/kg; 3×/week).Ethanol, NNK and ethanol + NNK caused striking degenerative abnormalities in white matter myelin and axons, with accompanying reductions in myelin-associated glycoprotein expression. Quantitative RT-PCR targeted array and heatmap analyses demonstrated that ethanol modestly increased, whereas ethanol + NNK sharply increased expression of immature and mature oligodendroglial genes, and that NNK increased immature but inhibited mature oligodendroglial genes. In addition, NNK modulated expression of neuroglial genes in favor of growth cone collapse and synaptic disconnection. Ethanol- and NNK-associated increases in FOXO1, FOXO4 and NKX2-2 transcription factor gene expression could reflect compensatory responses to brain insulin resistance in this model.Alcohol and tobacco exposures promote ARBD by impairing myelin synthesis, maturation and integrity via distinct but overlapping mechanisms. Public health measures to reduce ARBD should target both alcohol and tobacco abuses.