Developmental Cigarette Smoke Exposure: Biomarkers of Neurotoxicity

描述（由申请人提供）：尼古丁是一种高度成瘾的精神药物，在吸入烟草烟雾后迅速转运至大脑。大约20%的美国成年人（3600万）是活跃吸烟者。尽管全国广泛宣传怀孕期间吸烟的有害影响，但仍有25%的妇女在整个怀孕期间继续吸烟。因此，每年约有100万婴儿在产前暴露于香烟烟雾。发育中的香烟烟雾暴露与子宫内生长减少以及细胞和分子神经发育的扰动有关，这被认为介导了在人类和实验动物模型中观察到的认知和行为问题的增加率。在本申请中，我们提出测试以下假设：1）暴露于烟草烟雾导致血清代谢组的暂时失调，这与海马代谢组和蛋白质组的改变平行，以及2）这种失调在神经认知缺陷的发展中持续存在。我们特别建议研究发育烟草烟雾暴露对小鼠模型（模拟妊娠期间母亲吸烟）后代中现成的生物流体（血清）和海马组织中毒性分子标志物表达的影响。特定目的1和2中的代谢物组分析将采用LC-LIT/FT-ICR-MS结合光谱预处理，包括背景扣除、归一化、提取和峰强度积分。将通过母离子和子离子的准确质量测量，然后进行数据库检索（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），鉴别感兴趣的光谱特征。如果提出的假设是正确的，我们将确定外周生物标志物，这是直接指示神经发育异常与海马代谢组和蛋白质组的相应改变。此外，我们将确定潜在的行为和神经认知异常的分子标记物，这些标记物在停止毒性暴露后仍然存在。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目标。 公共卫生相关性：仅在美国，每年就有大约100万婴儿在产前暴露于香烟烟雾中！母亲吸烟与各种不利的胎儿，婴儿和儿童发育结果有关-其中最引人注目的是影响神经发育，认知功能和行为。由于这些结果的诊断通常是复杂和延迟的，因此本申请中提出的研究将利用模拟妊娠期间人类母体吸烟的小鼠模型来鉴定后代中受产前吸烟诱导的神经毒性影响的血清生物标志物。

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.