Potential Co-Factor Role of Tobacco Specific Nitrosamine Exposures in the Pathogenesis of Fetal Alcohol Spectrum Disorder.

Valerie Zabala,Suzanne M De La Monte,Ming Tong,Edward Re,Tomas Andreani,Teresa Ramirez,Elizabeth Silbermann,Fusun Gundogan

doi:10.17140/goroj-2-125

Abstract

BackgroundCerebellar developmental abnormalities in Fetal Alcohol Spectrum Disorder (FASD) are linked to impairments in insulin signaling. However, co-morbid alcohol and tobacco abuses during pregnancy are common. Since smoking leads to tobacco specific Nitrosamine (NNK) exposures which have been shown to cause brain insulin resistance, we hypothesized that neurodevelopmental abnormalities in FASD could be mediated by ethanol and/or NNK.MethodsLong Evans rat pups were intraperitoneal (IP) 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. The Cerebellar function, histology, insulin and Insulin-like Growth Factor (IGF) signaling, and neuroglial protein expression were assessed.ResultsEthanol, NNK and ethanol+NNK groups had significant impairments in motor function (rotarod tests), abnormalities in cerebellar structure (Purkinje cell loss, simplification and irregularity of folia, and altered white matter), signaling through the insulin and IGF-1 receptors, IRS-1, Akt and GSK-3β, and reduced expression of several important neuroglial proteins. Despite similar functional effects, the mechanisms and severity of NNK and ethanol+NNK induced alterations in cerebellar protein expression differed from those of ethanol.ConclusionsEthanol and NNK exert independent but overlapping adverse effects on cerebellar development, function, insulin signaling through cell survival, plasticity, metabolic pathways, and neuroglial protein expression. The results support the hypothesis that tobacco smoke exposure can serve as a co-factor mediating long-term effects on brain structure and function in FASD.

Highlights

We found that low-dose exposures to N-nitrosodiethylamine, a nitrosamine found in processed and preserved foods, cause sustained deficits in neurobehavioral function with impairments in brain insulin/Insulin-like Growth Factor (IGF) signaling, increased oxidative stress, and reduced expression of neuroglial genes.[31]
Alcohol disrupts neuronal insulin and IGF signaling networks needed for neuronal growth, survival, metabolism, migration, plasticity and neurotransmitter function.[1,2]
These adverse effects of ethanol are mediated at all levels of the cascade, from ligand-receptor binding and activation of receptor tyrosine kinases, through downstream Akt and Glycogen Synthase Kinase-3β (GSK-3β) pathways.[3,6,7]

Summary

Introduction

Since smoking leads to tobacco specific Nitrosamine (NNK) exposures which have been shown to cause brain insulin resistance, we hypothesized that neurodevelopmental abnormalities in FASD could be mediated by ethanol and/or NNK. Results: Ethanol, NNK and ethanol+NNK groups had significant impairments in motor function (rotarod tests), abnormalities in cerebellar structure (Purkinje cell loss, simplification and irregularity of folia, and altered white matter), signaling through the insulin and IGF-1 receptors, IRS-1, Akt and GSK-3β, and reduced expression of several important neuroglial proteins. Conclusions: Ethanol and NNK exert independent but overlapping adverse effects on cerebellar development, function, insulin signaling through cell survival, plasticity, metabolic pathways, and neuroglial protein expression.

Methods

Results

Conclusion