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

ABSTRACT: BACKGROUND:Cerebellar 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. METHODS:Long 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. 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-3?, 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. 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. 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.

SUBMITTER: Zabala V

PROVIDER: S-EPMC5570438 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Zabala Valerie V Silbermann Elizabeth E Re Edward E Andreani Tomas T Tong Ming M Ramirez Teresa T Gundogan Fusun F de la Monte Suzanne M SM

Gynecology and obstetrics research : open journal 20160315 5

<h4>Background</h4>Cerebellar 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.<h4>Methods</h4>Long Evans rat pups were intraperi ...[more]

PMID: 28845454

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Project description:Background: Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2-5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Methods: Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5-18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). Results: We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. Conclusion: These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD.

Dataset Information

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

Publications

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

Similar Datasets

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