Developmental Cigarette Smoke Exposure: Biomarkers of Neurotoxicity

发育期香烟烟雾暴露：神经毒性的生物标志物

• 批准号: 8120395
• 负责人: Rachel Elizabeth Neal
• 金额: $ 17.77万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120395
• 关键词: Acrolein; Adult; Affect; Age-Months; Animal Model; Area; Behavior; Behavioral; Biological Markers; Brain; Breathing; Butadiene; C57BL/6 Mouse; Cadmium; Carbon Dioxide; Chemicals; Childhood; Chloroform; Cigarette; Cognitive; Cognitive deficits; Coupled; Data; Databases; Daughter; Defect; Development; Devices; Diagnosis; Disease; Employee Strikes; Epigenetic Process; Experimental Animal Model; Exposure to; Fourier transform ion cyclotron resonance; Future; Gene Expression Profile; Growth; Hippocampus (Brain); Human; Impairment; Infant; Intoxication; Investigation; Ions; Laboratories; Lead; Lipids; Maps; Measurement; Measures; Mediating; Methanol; Molecular; Molecular Profiling; Morphogenesis; Nature; Neurocognitive; Neurocognitive Deficit; Neurotoxins; Nicotine; Nitric Oxide; Outcome; Parents; Pattern; Peripheral; Pharmaceutical Preparations; Pregnancy; Problem behavior; Proteins; Proteome; Proteomics; Psychotropic Drugs; Resolution; Rodent Model; Serum; Simulate; Smoke; Smoker; Smoking; Structure; Testing; Time; Tissues; Tobacco; Tobacco Industry; Tobacco smoke; Tobacco use; Toxic effect; Toxicant exposure; United States; Withdrawal; Woman; Work; brain behavior; cigarette smoking; cigarette smoking; cognitive function; fetal; fetal tobacco exposure; in utero; interest; maternal cigarette smoking; molecular marker; mouse model; neurochemistry; neurodevelopment; neurotoxicity; offspring; postnatal; prenatal exposure; public health relevance; socioeconomics

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.

描述（由申请人提供）：尼古丁是一种高度成瘾性的精神药物，在吸入烟草烟雾后迅速输送到大脑。大约20%的美国成年人（3600万）是活跃吸烟者。尽管全国对怀孕期间使用烟草的有害影响进行了广泛宣传，但仍有25%的妇女在整个怀孕期间继续吸烟。因此，每年约有100万婴儿在出生前暴露在香烟烟雾中。在人类和实验动物模型中观察到，发育中的香烟烟雾暴露与子宫内生长减少和细胞和分子神经发育紊乱有关，这被认为是导致认知和行为问题发生率增加的原因。在当前的应用中，我们建议测试以下假设：1)暴露于烟草烟雾导致血清代谢组的时间失调，这与海马代谢组和蛋白质组的改变相似；2)这种失调通过神经认知缺陷的发展持续存在。我们特别建议通过模拟母亲在怀孕期间吸烟的小鼠模型来研究发育过程中烟草烟雾暴露对后代生物体液（血清）和海马组织中毒性分子标记表达的影响。在Specific Aims 1和2中，代谢组分析将采用LC-LIT/FT-ICR-MS结合光谱预处理，包括背景减除、归一化、提取和峰强度整合。通过对亲本离子和子离子进行精确的质量测量，然后进行数据库搜索（代谢物- hmdb、METLIN和KEGG数据库；蛋白质- ncbinr哺乳动物正向和反向数据库），确定感兴趣的光谱特征。如果提出的假设是正确的，我们将确定外周生物标志物，这些标志物直接指示海马代谢组和蛋白质组的相应改变的神经发育异常。此外，我们将确定潜在的行为和神经认知异常的分子标记，这些异常在停止接触有毒物质后仍然存在。这些生物标志物将为未来研究环境神经毒素对神经/认知发育的表观遗传影响提供靶点。