Neurobehavioral Impacts of Early Mn Exposures

描述(由申请人提供)：儿童的流行病学和案例研究报告提供了令人信服的证据，证明与环境和饮食中锰(Mn)暴露增加相关的严重神经行为缺陷。然而，这些研究还没有确定锰暴露与神经行为缺陷之间的因果关系，也没有对认知缺陷的具体性质(即学习、注意力、情绪性等)或潜在的神经化学变化提供详细的了解。目的1利用一种锰神经毒性的啮齿动物模型，确定断奶前或出生后持续的锰暴露是否会在年轻人中产生神经行为缺陷。目的II将探讨断奶前或出生后持续暴露锰导致认知障碍的分子和神经化学机制。目的确定断奶前或出生后持续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的关系。我们将测试最重要的假设：(1)新生儿接触锰会导致认知(即学习、记忆、注意力和/或抑制控制)和情感(唤醒和/或情绪)功能的各个方面的持久功能障碍，以及(2)这些变化与大脑区域(即前额叶皮质、纹状体和海马体)中支持这些功能的多巴胺和谷氨酸能系统的发育变化有关。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同一动物身上测量多巴胺和谷氨酸能系统功能的细胞和神经化学参数，以提供关于锰诱导的辅助这些行为功能的系统变化的信息，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，我们将通过确定锰暴露是否改变多巴胺转运体(DAT)抑制剂哌醋甲酯(利他林)的剂量-反应关系，以及药物是否缓解锰暴露导致的行为缺陷，来直接测试由于锰暴露而引起的多巴胺能系统的改变是否在导致的行为缺陷中起作用。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接触锰水平的神经学后果的最全面评估。这一知识将为公共卫生政策和指导方针提供有关儿童接触适当水平的锰的信息。 与公共健康相关：拟议的研究将通过使用儿童锰暴露的啮齿动物模型，详细定义生命早期或出生后持续的锰暴露与持久的认知缺陷之间的联系，这些缺陷背后的神经化学变化，以及最好地预测暴露和影响的生物标记物，来解决我们对儿童锰暴露带来的健康风险的认识上的重大差距。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接触锰水平的神经学后果的最全面评估。这一知识将为公共卫生政策和指导方针提供有关儿童接触适当水平的锰的信息。

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.