Lead Exposure and Early Brain Development

 描述(由申请人提供)：儿童时期接触铅与许多不利的身心健康后果有关，包括认知能力下降和行为问题增加。这些神经认知和神经行为结果被广泛假设为神经发育异常的结果。然而，尽管对早期大脑发育的调查报告表明，铅暴露会导致神经元生长减少和脑白质成熟(髓鞘减少)受损，但这些研究仅在动物身上进行。目前尚不清楚这些关键的神经发育过程是否以及如何在人类儿童身上发生类似的改变，以及在何种程度的暴露下异常变得显著。因此，关于铅对发育中的人脑的神经毒性作用，以及潜在的变化如何最终导致认知缺陷，我们的知识存在显著差距。这项研究旨在通过对12至24个月大的儿童进行初步纵向研究，检查血铅水平(BLL)与髓鞘形成和轴突(结合树突和轴突)密度的磁共振成像(MRI)测量之间的关系，以解决这些差距。作为第一步，我们将招募36名10至14个月大、血铅水平在0至10μg/dL之间的健康幼儿，他们将接受核磁共振检查和全面的认知和行为评估。术后12个月复查BLL、MRI和神经心理学评估。从这组数据中，我们将调查BLL、脑结构和认知能力在每个年龄点之间的联系，以及这些指标中每一个指标的纵向变化之间的关系。这项研究将提供第一个也是最早的证据，证明不同程度的铅暴露儿童的大脑结构发生了变化，并建立了它们与认知和行为功能同时测量的关系。我们假设，血铅水平的增加将与髓鞘和轴突含量的减少显著相关，这些结构异常将在血铅水平和认知能力之间的关系中发挥中介作用。这项初步调查将为这一紧迫的公共卫生问题提供至关重要的新见解，这一问题会带来巨大的社会和经济代价。预计结果将对当前的筛查和预防政策产生深远的影响。

 DESCRIPTION (provided by applicant): Childhood lead exposure is associated with many adverse physical and mental health outcomes, including reduced cognitive ability and increased behavioral problems. These neurocognitive and neurobehavioral outcomes are broadly hypothesized to result from abnormalities in neurodevelopment. However, while investigations of early brain development report reduced neuronal growth and impaired white matter maturation (hypomyelination) in response to lead exposure, these studies have exclusively been performed in animals. It is unclear if, and how, these key neurodevelopmental processes are similarly altered in human children; and at what level of exposure abnormalities become significant. Thus, there are significant gaps in our knowledge regarding the neurotoxic actions of lead on the developing human brain, and how potential alterations ultimately give rise to cognitive deficits. This research aims to address these gaps by examining the relationships between blood lead level (BLL) and magnetic resonance imaging (MRI) measures of myelination and neurite (combined dendrites and axons) density in a preliminary longitudinal study following children from 12 to 24 months of age. As a first step, we will recruit 36 healthy toddlers between 10 and 14 months of age with blood lead levels between 0 and 10μg/dL, who will receive MRI and a comprehensive cognitive and behavioral assessment. BLL, MRI and neuropsychological assessments will be repeated at 12 month follow-up. From this complement of data, we will investigate the relationships linking BLL, brain structure, and cognitive ability t each age-point; as well as the relationships between the longitudinal changes in each of these measures. This study will provide the first and earliest evidence of brain structure alteration in children with varying degrees of lead exposure, and establish their relationship to concurrent measures of cognitive and behavioral functioning. We hypothesize that increased levels of blood lead will be significantly associated with reduced myelin and neurite content, and that these structural abnormalities will mediate the relationship between blood lead levels and cognitive ability. This preliminary investigation will provide crucial new insight into a pressing public health issue that carries significant social and economic cost. Results are anticipated to have far reaching consequences in regard to current screening and prevention policies.