Developmental Cigarette Smoke Exposure: Biomarkers of Neurotoxicity

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DESCRIPTION (provided by applicant): Nicotine, a highly addictive psychotropic drug, is rapidly transported to the brain following tobacco smoke inhalation. Approximately 20% of US adults (36 million) are active smokers. Despite extensive national publicity regarding the detrimental effects of tobacco use during pregnancy, 25% of women continue to smoke throughout their pregnancy. As a result, approximately one million infants are exposed prenatally to cigarette smoke each year. Developmental cigarette smoke exposure is associated with decreased in utero growth and perturbations in both cellular and molecular neurodevelopment which are thought to mediate the increased rates of cognitive and behavioral problems that are observed in humans and experimental animal models. In the current application we propose to test the hypotheses that 1) exposure to tobacco smoke results in temporal dysregulation of the serum metabolome which parallels alterations in the hippocampal metabolome and proteome, and 2) such dysregulation persists through the development of neurocognitive deficits. We specifically propose to examine the impact of developmental tobacco smoke exposure on the expression of molecular markers of toxicity in a readily available biofluid (serum) and hippocampal tissue in offspring from a mouse model which simulates maternal cigarette smoking during pregnancy. Metabolome profiling in both Specific Aims 1 and 2 will employ LC-LIT/FT-ICR-MS coupled to spectral preprocessing including background subtraction, normalization, extraction and integration of peak intensities. Spectral features of interest will be identified by accurate mass measurement of parent and daughter ions followed by database searching (metabolites-HMDB, METLIN, and KEGG databases; proteins-NCBInr mammalian forward and reverse databases). If the proposed hypothesis is correct, we will have identified peripheral biomarkers, which are directly indicative of neurodevelopmental abnormalities with corresponding alterations in the hippocampal metabolome and proteome. In addition, we will have identified potential molecular markers of behavioral and neurocognitive abnormalities that persist after withdrawal of the toxic exposure. These biomarkers will provide targets for future investigations into the epigenetic effects of environmental neurotoxins on neuro/cognitive development. PUBLIC HEALTH RELEVANCE: In the United States alone, approximately one million infants are exposed prenatally to cigarette smoke each year! Maternal cigarette smoking has been associated with a variety of adverse fetal, infant, and childhood developmental outcomes - the most striking of which affect neurodevelopment, cognitive function and behavior. Since diagnosis of these outcomes are often complicated and delayed, studies proposed in the current application will utilize a mouse model simulating human maternal cigarette smoking during pregnancy to identify serum biomarkers in offspring that are affected by prenatal cigarette smoke exposure-induced neurotoxicity.