Abstract
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. Tobacco smoke exposure is a co-factor in FASD. 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. 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. 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.
Highlights
Heavy chronic or binge alcohol exposures during development lead to sustained deficits in cognitive and motor functions
The results support the hypothesis that smoking may contribute to brain abnormalities associated with fetal alcohol spectrum disorder (FASD)
The cerebellum, temporal lobe, and white matter are major targets of ethanol’s teratogenic effects, and while there is good evidence that ethanol-induced pathology in the cerebellum and temporal lobe is linked to impaired insulin and insulin-like growth factor type 1 (IGF-1) signaling through Akt-mediated growth, cell survival, metabolic, and neuronal plasticity networks, the nature and pathogenesis of white matter hypotrophy are poorly understood
Summary
Heavy chronic or binge alcohol exposures during development lead to sustained deficits in cognitive and motor functions. Since growth factor, including IGF-1 signaling through phosphatidylinositol-3-kinase (PI3K) and Akt promotes oligodendrocyte survival and function, including myelin synthesis, maintenance, and homeostasis[3,4,5], impairments in insulin/IGF signaling that occur with alcohol exposure could potentially underlie the white matter abnormalities in FASD. Since the white matter hypotrophy may be due to reduced myelin synthesis, maturation and, maintenance or primary loss of axons, evaluating the state of oligodendrocyte function could aid our understanding of its molecular pathogenesis. Fetal alcohol spectrum disorder (FASD) is associated with long-term deficits in cognitive and motor functions. Similar effects occur with lowdose nitrosamine exposures, alcohol abuse correlates with cigarette smoking, and tobacco smoke contains tobacco-specific nitrosamines, including NNK.
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