Developmental arsenic exposure produces cognitive impairments

描述(申请人提供)：全世界有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，但人们对砷的发育神经毒性知之甚少。这一数据差距令人担忧，因为在大脑发育的关键时期暴露于环境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。这项拟议的研究将通过检测在发育过程中暴露于饮用水中的三价砷(最有毒的形式)后的一系列反射、运动、注意力和学习行为来填补这一空白。这些行为终点将在C57BL6近交系小鼠身上进行检测。雄性和雌性小鼠都将接受检查，以确定特定性别的反应。行为测试是经过精心挑选的，因为每个测试都依赖于额叶皮质、海马体、基底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，砷可以增加或降低大脑中的儿茶酚胺水平，具体取决于剂量。据推测，发育期间的砷暴露会对前脑儿茶酚胺系统产生长期影响。这项拟议研究的第二个目标是使用免疫组织化学和共聚焦显微镜来研究砷对成人大脑中儿茶酚胺神经元分布和密度的影响。成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，砷会增加神经细胞的凋亡。因此，推测发育过程中的砷暴露增加了前脑儿茶酚胺系统的凋亡。这项研究的第三个目标是使用TUNEL染色技术标记新生儿额叶皮质、海马体、基底节或小脑中的凋亡神经元。全世界有数百万人饮用被砷污染的饮用水。一些受影响的人是孕妇，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在孕期暴露后如何损害认知功能。

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.