Ming Tong1, Rosa Yu2, Elizabeth Silbermann3, Valerie Zabala4, Chetram Deochand5, Suzanne M de la Monte6. 1. Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA. 2. Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA. 3. Warren Alpert Medical School of Brown University, Providence, RI, USA. 4. Molecular Pharmacology and Physiology Graduate Program, Brown University, Providence, RI, USA. 5. Biotechnology Graduate Program, Brown University, Providence, RI, USA. 6. Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA suzanne_delamonte_md@brown.edu.
Abstract
AIM: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.
AIM: 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. METHODS: 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). RESULTS: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. CONCLUSION: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.
Authors: Arthur L Brody; Mark A Mandelkern; Murray E Jarvik; Grace S Lee; Erlyn C Smith; Joe C Huang; Robert G Bota; George Bartzokis; Edythe D London Journal: Biol Psychiatry Date: 2004-01-01 Impact factor: 13.382
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Authors: Rosa Yu; Chetram Deochand; Alexander Krotow; Raiane Leão; Ming Tong; Amit R Agarwal; Enrique Cadenas; Suzanne M de la Monte Journal: J Alzheimers Dis Date: 2016 Impact factor: 4.472
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Authors: Yun Feng; Yanru Wang; Hongliang Liu; Zhensheng Liu; Coleman Mills; Younghun Han; Rayjean J Hung; Yonathan Brhane; John McLaughlin; Paul Brennan; Heike Bickeboeller; Albert Rosenberger; Richard S Houlston; Neil E Caporaso; Maria Teresa Landi; Irene Brueske; Angela Risch; Yuanqing Ye; Xifeng Wu; David C Christiani; Christopher I Amos; Qingyi Wei Journal: Sci Rep Date: 2017-04-11 Impact factor: 4.379