Potential Contributions of the Tobacco Nicotine-Derived Nitrosamine Ketone to White Matter Molecular Pathology in Fetal Alcohol Spectrum Disorder

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is associated with long-term deficits in cognitive and motor functions. Previous studies linked neurodevelopmental abnormalities to increased oxidative stress and white matter hypotrophy. However, similar effects occur with low-dose nitrosamine exposures, alcohol abuse correlates with cigarette smoking, and tobacco smoke contains tobacco-specific nitrosamines, including NNK. HYPOTHESIS: Tobacco smoke exposure is a co-factor in FASD. DESIGN: Long Evans rat pups were i.p. administered ethanol (2 g/kg) on postnatal days (P) 2, 4, 6 and/or NNK (2 mg/kg) on P3, P5, and P7 to simulate third trimester human exposures. Oligodendroglial myelin-associated, neuroglial, and relevant transcription factor mRNA transcripts were measured using targeted PCR arrays. RESULTS: Ethanol and NNK differentially altered the expression of immature and mature oligodendroglial, neuronal and astrocytic structural and plasticity-associated, and various transcription factor genes. NNK’s effects were broader and more pronounced than ethanol’s, and additive or synergistic effects of dual exposures impacted expression of all four categories of genes investigated. CONCLUSION: Developmental exposures to alcohol and NNK (via tobacco smoke) contribute to sustained abnormalities in brain white matter structure and function via distinct but overlapping alterations in the expression of genes that regulate oligodendrocyte survival, maturation and function, neuroglial structural integrity, and synaptic plasticity. The results support the hypothesis that smoking may contribute to brain abnormalities associated with FASD.