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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA027466-03
Application #
8120395
Study Section
Special Emphasis Panel (ZDA1-JXR-D (06))
Program Officer
Satterlee, John S
Project Start
2009-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$177,656
Indirect Cost
Name
University of Louisville
Department
Dentistry
Type
Schools of Dentistry
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Neal, Rachel E; Jagadapillai, Rekha; Chen, Jing et al. (2016) Developmental cigarette smoke exposure II: Hippocampus proteome and metabolome profiles in adult offspring. Reprod Toxicol 65:436-447
Neal, Rachel E; Jagadapillai, Rekha; Chen, Jing et al. (2016) Developmental cigarette smoke exposure II: Kidney proteome profile alterations in 6 month old adult offspring. Reprod Toxicol 65:425-435
Neal, Rachel E; Chen, Jing; Webb, Cindy et al. (2016) Developmental cigarette smoke exposure II: Hepatic proteome profiles in 6 month old adult offspring. Reprod Toxicol 65:414-424
Neal, Rachel E; Chen, Jing; Jagadapillai, Rekha et al. (2014) Developmental cigarette smoke exposure: hippocampus proteome and metabolome profiles in low birth weight pups. Toxicology 317:40-9
Mukhopadhyay, Partha; Rezzoug, Francine; Kaikaus, Jahanzeb et al. (2013) Alcohol modulates expression of DNA methyltranferases and methyl CpG-/CpG domain-binding proteins in murine embryonic fibroblasts. Reprod Toxicol 37:40-8
Canales, Lorena; Chen, Jing; Kelty, Elizabeth et al. (2012) Developmental cigarette smoke exposure: liver proteome profile alterations in low birth weight pups. Toxicology 300:1-11
Mukhopadhyay, Partha; Brock, Guy; Webb, Cynthia et al. (2012) Strain-specific modifier genes governing craniofacial phenotypes. Birth Defects Res A Clin Mol Teratol 94:162-75
Jagadapillai, Rekha; Chen, Jing; Canales, Lorena et al. (2012) Developmental cigarette smoke exposure: kidney proteome profile alterations in low birth weight pups. Toxicology 299:80-9
Lutz, Paula M; Kelty, Elizabeth A; Brown, Tina D et al. (2012) Environmental cigarette smoke exposure modulates IgE levels of Pb-exposed children. Toxicology 291:43-50
Mukhopadhyay, Partha; Horn, Kristin H; Greene, Robert M et al. (2010) Prenatal exposure to environmental tobacco smoke alters gene expression in the developing murine hippocampus. Reprod Toxicol 29:164-75

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