title: Differential Sphingolipid and Phospholipid Profiles in Alcohol and Nicotine-Derived Nitrosamine Ketone-Associated White Matter Degeneration.
abstract: BACKGROUND
  Alcohol-mediated neurodegeneration is associated with white matter (WM) atrophy due to targeting of myelin and oligodendrocytes. However, variability in disease severity suggests cofactors contribute to WM degeneration. We examined the potential cofactor role of the tobacco-specific nitrosamine, nicotine-derived nitrosamine ketone (NNK), because smoking causes WM atrophy and most heavy drinkers consume tobacco products.
  
  
  METHODS
  This 8-week study of Long Evans rats had 4 treatment groups: control; NNK-2 mg/kg, 3×/wk in weeks 3 to 8; ethanol (EtOH) (chronic-26% caloric + binge-2 g/kg, 3×/wk in weeks 7 to 8); and EtOH + NNK. Exposure effects on WM lipid biochemical profiles and in situ distributions were examined using matrix-assisted laser desorption/ionization imaging mass spectrometry and tandem mass spectrometry.
  
  
  RESULTS
  NNK mainly caused WM fiber degeneration and fiber loss, EtOH caused demyelination, and dual exposures had additive effects. EtOH and EtOH + NNK decreased WM (including corpus callosum) and/or gray matter (hypothalamus, cortex, medial temporal) levels of several phosphatidylserine, phosphatidylinositol, and sphingolipid (sulfatide [ST]) species, while NNK increased or had minimal effect on these lipids. EtOH + NNK had broader and larger inhibitory effects on phospholipids and ST than EtOH or NNK alone. Principal component analysis clustered control with NNK, and EtOH with EtOH + NNK groups, highlighting the independent EtOH- rather than NNK-driven responses.
  
  
  CONCLUSIONS
  Chronic EtOH exposures decreased several phospholipid and sphingolipid species in brain, while concomitant NNK exposures exacerbated these effects. These findings support our hypothesis that tobacco smoking is a pathogenic cofactor in alcohol-mediated WM degeneration.
authors.affiliation: Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.|Rhode Island Hospital and the Alpert Medical School of Brown University (EBY, MT, SMdlM), Providence, Rhode Island.
authors.forename: Emine B
authors.initials: EB
authors.lastname: Yalcin
authors.affiliation: Brown University, Providence, Rhode Island.
authors.forename: Kavin
authors.initials: K
authors.lastname: Nunez
authors.affiliation: Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.|Rhode Island Hospital and the Alpert Medical School of Brown University (EBY, MT, SMdlM), Providence, Rhode Island.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Liver Research Center, Division of Gastroenterology, Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.|Rhode Island Hospital and the Alpert Medical School of Brown University (EBY, MT, SMdlM), Providence, Rhode Island.|Departments of Neurology, Neurosurgery and Pathology (SMdlM), Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000818:Animals; D000431:Ethanol / Q000633:toxicity*; D007659:Ketones / Q000633:toxicity*; D009538:Nicotine / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D013107:Sphingolipids / Q000378:metabolism*; D066127:White Matter / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D007659:Ketones; D009602:Nitrosamines; D010743:Phospholipids; D013107:Sphingolipids; D000431:Ethanol; D009538:Nicotine
keywords: Alcohol; Imaging Mass Spectrometry; MALDI; Nicotine-Derived Nitrosamine Ketone; Smoking; Tobacco-Specific Nitrosamine; White Matter Degeneration