Neurobehavioral Impacts of Early Mn Exposures

描述（由申请人提供）：儿童流行病学和病例研究报告提供了令人信服的证据，证明与环境和饮食锰（Mn）暴露升高相关的显著神经行为缺陷。然而，这些研究没有建立锰暴露和神经行为缺陷之间的因果关系，也没有提供对认知缺陷的具体性质的详细理解（即，学习、注意力、情感等），或潜在的神经化学变化。目的1将确定是否断奶前或连续产后锰暴露产生神经行为缺陷的年轻成年人，使用啮齿动物模型锰神经毒性。目的二探讨断奶前或出生后连续锰暴露引起认知功能障碍的分子和神经化学机制。目的III将确定断奶前或连续出生后锰暴露与暴露生物标志物的关系，以及这些暴露生物标志物与神经行为和神经化学改变相关的程度。我们将测试总体假设，即（1）新生儿锰暴露导致认知（即，学习、记忆、注意力和/或抑制控制）和情感（唤醒和/或情绪）功能，和（2）这些变化与促进这些功能的脑区域中多巴胺能和多巴胺能系统的发育改变有关（即，前额皮质、纹状体和海马体）。我们将通过微透析/生物传感器、受体结合和免疫组织化学在接受认知测试的相同动物中测量多巴胺能和多巴胺能系统功能的细胞和神经化学参数，以提供关于锰诱导的系统变化的信息，这些系统有助于这些行为功能，并确定这些神经变化中的一个或多个是否与行为缺陷相关。此外，我们将通过确定Mn暴露是否改变哌甲酯（利他林）（多巴胺转运蛋白（DAT）抑制剂）的剂量-反应关系，以及药物是否减轻Mn暴露引起的行为缺陷，直接测试Mn暴露引起的多巴胺能系统的改变是否在所得行为缺陷中起作用。这些研究将是迄今为止对婴儿和儿童在其环境中可能遇到的早期生活暴露于锰水平的神经后果的最全面的评估。这些知识将为公共卫生政策和指导方针提供信息，以确定儿童接触锰的适当水平。 公共卫生相关性：拟议的研究将解决一个显着的差距，在我们的理解所造成的健康风险升高锰暴露在儿童详细定义之间的联系，早期生活或连续产后锰暴露和持久的认知缺陷，神经化学改变这些缺陷的基础上，和生物标志物，最好的预测暴露和影响，使用啮齿动物模型的儿童锰暴露。这些研究将是迄今为止对婴儿和儿童在其环境中可能遇到的早期生活暴露于锰水平的神经后果的最全面的评估。这些知识将为公共卫生政策和指导方针提供信息，以确定儿童接触锰的适当水平。

DESCRIPTION (provided by applicant): Epidemiological and case study reports in children have provided compelling evidence for significant neurobehavioral deficits associated with elevated environmental and dietary manganese (Mn) exposure. However, these studies have not established a causal relationship between Mn exposure and neurobehavioral deficits, nor have they provided a detailed understanding of the specific nature of the cognitive deficits (i.e., learning, attention, emotionality, etc.), or underlying neurochemical alterations. Aim 1 will determine whether pre-weaning or continuous postnatal Mn exposure produces neurobehavioral deficits in young adults, using a rodent model of Mn neurotoxicity. Aim II will explore the molecular and neurochemical mechanisms underlying the cognitive deficits induced by pre-weaning or continuous postnatal Mn exposure. Aim III will determine the relationship of pre-weaning or continuous postnatal Mn exposures with biological markers of exposure, and the extent that these exposure biomarkers are associated with neurobehavioral and neurochemical alterations. We will test the overarching hypotheses that (1) neonatal Mn exposure causes lasting dysfunction in various aspects of cognitive (i.e., learning, memory, attention and/or inhibitory control) and affective (arousal and/or emotion) functioning, and (2) that these changes are linked to developmental alterations in dopaminergic and glutamatergic systems in brain regions which subserve these functions (i.e., the prefrontal cortex, striatum, and hippocampus). We will measure cellular and neurochemical parameters of dopaminergic and glutamatergic system function by microdialysis/biosensor, receptor binding, and immunohistochemistry in the same animals that underwent cognitive testing, in order to provide information about Mn-induced changes in systems that subserve these behavioral functions, and to determine whether one or more of these neural changes correlate with behavioral deficits. Further, we will directly test whether alteration of the dopaminergic system due to Mn exposure plays a role in the resulting behavioral deficits by determining whether Mn exposure alters the dose- response relationship of methylphenidate (Ritalin), a dopamine transporter (DAT) inhibitor, and whether the drug alleviates behavioral deficits due to Mn exposure. These studies will be the most comprehensive assessments to date on the neurological consequences of early life exposure to levels of manganese that infants and children are likely to encounter in their environment. This knowledge will inform public health policies and guidelines on suitable levels of Mn exposure to children. PUBLIC HEALTH RELEVANCE: The proposed studies will address a significant gap in our understanding of the health risks posed by elevated manganese exposure in children by defining in detail the link between early life or continuous postnatal manganese exposure and lasting cognitive deficits, the neurochemical alterations underlying those deficits, and biomarkers that best predict exposure and effects, using a rodent model of childhood Mn exposure. These studies will be the most comprehensive assessments to date on the neurological consequences of early life exposure to levels of manganese that infants and children are likely to encounter in their environment. This knowledge will inform public health policies and guidelines on suitable levels of Mn exposure to children.