Abstract
Ethanol-induced neuro-developmental abnormalities are associated with impaired insulin and IGF signaling, and increased oxidative stress in CNS neurons. We examined the roles of ethanol and its principal toxic metabolite, acetaldehyde, as mediators of impaired insulin/IGF signaling and oxidative injury in immature cerebellar neurons. Cultures were exposed to 3.5 mM acetaldehyde or 50 mM ethanol ± 4-methylpyrazole (4-MP), an inhibitor of ethanol metabolism, and viability, mitochondrial function, oxidative stress, DNA damage, and insulin responsiveness were measured 48 hours later. Acetaldehyde or ethanol increased neuronal death and levels of 8-OHdG and 4-HNE, and reduced mitochondrial function. Ethanol inhibited insulin responsiveness, whereas acetaldehyde did not. 4-MP abated ethanol-induced oxidative stress and mitochondrial dysfunction, but failed to restore insulin responsiveness. Furthermore, alcohol and aldehyde metabolizing enzyme genes were inhibited by prenatal ethanol exposure; this effect was mediated by acetaldehyde and not ethanol + 4MP. These findings suggest that brain insulin resistance in prenatal alcohol exposure is caused by direct effects of ethanol, whereas oxidative stress induced neuronal injury is likely mediated by ethanol and its toxic metabolites. Moreover, the adverse effects of prenatal ethanol exposure on brain development may be exacerbated by down-regulation of genes needed for metabolism and detoxification of alcohol in the brain.
Highlights
Prenatal alcohol exposure causes fetal alcohol spectrum disorder (FASD), which is associated with multiple and varied developmental abnormalities in the brain and results in sustained deficits in cognitive and motor functions [1,2,3,4,5,6]
To determine if these effects could be mediated by acetaldehyde, 96-well acetaldehyde (3.5 mM) or vehicle treated (48 h) microcultures were stimulated with 10 nM insulin for up to 60 minutes, after which they were fixed in situ and examined for immunoreactivity to pERK, total ERK, pAkt, or total Akt by cellular enzyme-linked immunosorbent assays (ELISAs)
In FASD, the main focus has been on the role of ethanolmediated neurotoxicity and the functional abnormalities leading to impairments in neurodevelopment
Summary
Prenatal alcohol exposure causes fetal alcohol spectrum disorder (FASD), which is associated with multiple and varied developmental abnormalities in the brain and results in sustained deficits in cognitive and motor functions [1,2,3,4,5,6]. Ethanol exerts its neurotoxic and teratogenic effects [7, 8] by promoting oxidative stress and impairing insulin and insulin-like growth factor (IGF) signaling in the developing brain [9, 10]. Whether these effects are mediated by direct toxic effects of ethanol or its principal metabolite, acetaldehyde, has not yet been determined. Ethanolinduced MtDNA damage and impaired Mt function increase cellular sensitivity to toxins and promote Mt permeability transition resulting in necrosis or apoptosis [12, 23, 29, 30] These adverse effects of ethanol are likely mediated by increased oxygen free radical production, lipid peroxidation, and inhibition of Mt glutathione. Increased levels of ROS can impair neuronal viability by inhibiting electron transport chain function and ATP formation [14, 48, 49]
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