title: Differential Contributions of Alcohol and Nicotine-Derived Nitrosamine Ketone (NNK) to White Matter Pathology in the Adolescent Rat Brain.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Yu
authors.affiliation: Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Silbermann
authors.affiliation: Molecular Pharmacology and Physiology Graduate Program, Brown University, Providence, RI, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Zabala
authors.affiliation: Biotechnology Graduate Program, Brown University, Providence, RI, USA.
authors.forename: Chetram
authors.initials: C
authors.lastname: Deochand
authors.affiliation: 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.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000818:Animals; D004357:Drug Synergism; D000431:Ethanol / Q000009:adverse effects*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D020439:Growth Cones / Q000187:drug effects; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000096:biosynthesis; D008297:Male; D018992:Myelin-Associated Glycoprotein / Q000096:biosynthesis; D009410:Nerve Degeneration / Q000139:chemically induced*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009538:Nicotine / Q000031:analogs & derivatives*; D009602:Nitrosamines / Q000009:adverse effects*; D009836:Oligodendroglia / Q000378:metabolism; D051381:Rats; D013569:Synapses / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis; D066127:White Matter / Q000187:drug effects* / Q000473:pathology*; D029961:Zebrafish Proteins; D000071161:Forkhead Box Protein O1
chemical_list: D000431:Ethanol; D051858:Forkhead Transcription Factors; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins; D009538:Nicotine; D009602:Nitrosamines; D014157:Transcription Factors; D029961:Zebrafish Proteins; C524737:FOXO4 protein, rat; C000715628:Nkx2-2 protein, rat; C000715630:nkx2.2b protein, zebrafish; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone