Developmental arsenic exposure produces cognitive impairments

发育期砷暴露会导致认知障碍

• 批准号: 7193124
• 负责人: VINCENT P MARKOWSKI
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF SOUTHERN MAINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2010-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193124
• 关键词: apoptosis; arsenic; basal ganglia; behavior test; brain metabolism; catecholamines; cerebellum; cognition disorders; confocal scanning microscopy; developmental neurobiology; embryo /fetus toxicology; environmental exposure; environmental toxicology; frontal lobe /cortex; gender difference; hippocampus; immunocytochemistry; laboratory mouse; mental health epidemiology; neurotoxicology; neurotransmitter metabolism; prosencephalon; terminal nick end labeling; water pollution; water supply

DESCRIPTION (provided by applicant): Millions of people throughout the world are suffering from chronic arsenic poisoning due to the consumption of contaminated drinking water. Although it is well known that adults experience neurotoxicity when they are acutely exposed to high doses, the developmental neurotoxicity of arsenic is poorly understood. This data gap is alarming because the toxic effects that result from exposure during critical periods of brain development are often permanent and are expressed later in life as behavioral impairments. The proposed research will fill this void by examining a series of reflexive, motor, attention, and learning behaviors following developmental exposure to trivalent arsenic (the most toxic form) in drinking water. These behavioral endpoints will be examined in the C57BL6 inbred mouse strain. Both male and female mice will be examined to identify sex-specific responses. The behavioral tests were carefully selected because each is dependent on the integrity of dopamine or norepinephrine systems in the frontal cortex, hippocampus, basal ganglia, or cerebellum. Previous research has shown that arsenic can increase or decrease catecholamine levels in the brain depending on the dose. It is hypothesized that arsenic exposure during development produces long-term effects on forebrain catecholamine systems. A second objective of the proposed research is to use immunohistochemistry and confocal microscopy to examine the effects of arsenic on the distribution and density of catecholamine neurons in the adult brain. A reduction of the number of neurons in the adult brain may be due to early changes. In vitro studies have shown that arsenic increases neuronal apoptosis. Therefore, it is hypothesized that arsenic exposure during development increases apoptosis in forebrain catecholamine systems. A third objective for this research is to use the TUNEL staining technique to label apoptotic neurons in the neonatal frontal cortex, hippocampus, basal ganglia, or cerebellum. Millions of people worldwide consume arsenic-contaminated drinking water. Some of the affected individuals are pregnant women and the developing fetus is particularly sensitive to arsenic toxicity. The proposed research is designed to determine how inorganic arsenic impairs cognitive function following gestational exposure.

描述（由申请人提供）：全世界数百万人因饮用受污染的饮用水而遭受慢性砷中毒。虽然众所周知，成年人在急性暴露于高剂量时会出现神经毒性，但对砷的发育神经毒性知之甚少。这一数据缺口令人担忧，因为在大脑发育的关键时期暴露于空气中所产生的毒性效应往往是永久性的，并在以后的生活中表现为行为障碍。拟议的研究将通过检查一系列反射，运动，注意力和学习行为来填补这一空白，这些行为是在饮用水中暴露于三价砷（毒性最大的形式）之后发展的。将在C57BL 6近交系小鼠品系中检查这些行为终点。将检查雄性和雌性小鼠，以确定性别特异性反应。这些行为测试都是经过精心挑选的，因为每一项测试都依赖于额叶皮层、海马、基底神经节或小脑中多巴胺或去甲肾上腺素系统的完整性。先前的研究表明，砷可以增加或减少脑中的儿茶酚胺水平，这取决于剂量。据推测，砷暴露在发展过程中产生长期影响前脑儿茶酚胺系统。本研究的第二个目的是利用免疫组化和共聚焦显微镜检查砷对成人脑中儿茶酚胺神经元的分布和密度的影响。成年人大脑中神经元数量的减少可能是由于早期的变化。体外研究表明，砷增加神经细胞凋亡。因此，据推测，砷暴露在发展过程中增加前脑儿茶酚胺系统的细胞凋亡。本研究的第三个目的是使用TUNEL染色技术标记新生儿额叶皮质、海马、基底节或小脑中的凋亡神经元。全世界有数百万人饮用受砷污染的饮用水。一些受影响的个体是孕妇，发育中的胎儿对砷毒性特别敏感。这项拟议的研究旨在确定无机砷如何损害妊娠期暴露后的认知功能。

项目成果

Effects of prenatal exposure to sodium arsenite on motor and food-motivated behaviors from birth to adulthood in C57BL6/J mice.

• DOI: 10.1016/j.ntt.2012.01.001
• 发表时间: 2012-03
• 期刊: NEUROTOXICOLOGY AND TERATOLOGY
• 影响因子: 2.9
• 作者: Markowski, Vincent P.;Reeve, Elizabeth A.;Onos, Kristen;Assadollahzadeh, Mina;McKay, Naomi
• 通讯作者: McKay, Naomi