Neurologic function in children exposed to ambient manganese

描述(由申请人提供)：新出现的证据表明，环境中锰暴露的增加与儿童的认知和行为缺陷有关。然而，到目前为止，对儿童的研究只集中在通过摄取途径接触锰，尽管成人的职业研究已经证实，通过吸入接触锰对认知和运动影响的风险比通过摄入接触更显著。我们将评估空气中锰暴露对生活在受当前或过去铁合金行业影响地区的11-13岁儿童的神经发育影响。我们将对意大利布雷西亚省三个具有良好特征的研究地点的750名儿童进行调查，这三个地点的铁合金工厂活动历史不同：1)Bagnolo Mella，一个有着活跃的铁合金工厂的社区，其空气中的锰含量非常高；2)Valcamonica，一个由于铁合金工厂活动的历史而空气中的锰水平略有上升的地区；以及3)Garda湖，一个有背景空气锰水平但没有铁合金工厂活动史的参照区。该项目将建立在现有的欧盟资助的PHIME(易感人群混合元素暴露对公共健康的影响)研究的基础上，该研究已经检查了来自瓦尔卡莫尼察和加尔达湖的总共300名儿童；我们提议再招募450名儿童来实现我们的目标。我们建议的一个优势是强调环境暴露评估，利用24小时个人空气监测仪测量空气中的锰，家庭存放的粉尘、自来水、土壤中的锰水平和详细的食物频率问卷，再加上全面的认知、行为、运动和感官评估，以及暴露生物标记物的测量(血液、尿液、头发、指甲)和脱落乳牙中的锰，以评估早期生活和终身累积暴露。初步结果表明，瓦尔卡莫尼卡历史暴露地区居民的运动协调、气味识别和智商的变化与空气中的锰水平有关。这项研究将提供独特的机会，通过评估有三种暴露史的儿童来比较不同发育时期的锰的影响：1)自出生以来持续高空气中锰暴露(Bagnolo Mella)，2)出生后头3-5年内暴露于高空气中锰水平，但减少当前暴露(Valcamonica)，以及3)没有空气中锰暴露增加的历史(Garda Lake)。我们还将通过铁代谢途径基因的遗传变异来解决遗传易感性对锰的作用。这将是关于儿童锰神经毒性的第一项研究，这项研究得到了环境锰暴露水平的深刻表征的支持。 公共卫生相关性：拟议的研究将通过详细定义11-13岁儿童的早期生活或持续暴露与认知、行为、运动和感觉缺陷之间的联系，解决我们对环境中锰暴露增加带来的健康风险的认识上的一个重大差距。这项研究还将调查基因多态如何影响接触风险。这些发现肯定会对未来旨在尽量减少与锰接触有关的发病率的研究倡议和公共政策产生强大的影响，特别是在与缺铁、铅接触和其他协变量有关的情况下。鉴于蒙脱石在汽油中的潜在用途，这项研究还将有助于了解空气中锰的潜在风险，这种基于锰的燃料在全球范围内的引入可能会增加这种风险。这一知识将为公共卫生政策和指导方针提供有关世界各地儿童接触适当水平的锰的信息。

DESCRIPTION (provided by applicant): Emerging evidence demonstrates that elevated environmental manganese (Mn) exposure is associated with cognitive and behavioral deficits in children. However, up to now, studies in children have only been focused on exposure via ingestion pathways, although occupational research in adults has established that Mn exposure via inhalation poses a more significant risk for cognitive and motor effects than exposure via ingestion. We will assess the neurodevelopmental effects of airborne Mn exposure in 11-13 year old children living in areas impacted by current or past ferroalloy industries. We will examine 750 children across three well- characterized study sites in the province of Brescia, Italy, that differ in history of ferroalloy plant activity: 1) Bagnolo Mella, a community with an active ferroalloy plant that produces very elevated air Mn levels; 2) Valcamonica, a region with slightly elevated air Mn levels due to a history of ferroalloy plant activity that ended in 2001, and; 3) Garda Lake, a reference region with background air Mn levels and no history of ferroalloy plant activity. The project will build upon the existing EU-funded PHIME (Public Health Impact of Mixed element Exposure in susceptible populations) study that has already examined a total of 300 children from Valcamonica and Garda Lake; we propose to enroll 450 more to achieve our aims. A strength of our proposal is the emphasis on environmental exposure assessment, utilizing measures of airborne Mn with 24 hr personal air monitors, Mn levels in home deposited dust, tap water, soil, and a detailed food frequency questionnaire, coupled with comprehensive cognitive, behavioral, motor, and sensory assessments, along with exposure biomarker measures (blood, urine, hair, nails) and Mn in shed deciduous teeth to assess early life and cumulative lifetime exposures. Preliminary results show changes in motor-coordination, odor identification and IQ among the residents in the historically exposed area of Valcamonica are associated with air Mn levels. This study will offer the unique opportunity to compare effects of Mn at distinct developmental time periods by evaluating children with three exposure histories 1) continuous high airborne Mn exposure since birth (Bagnolo Mella), 2) exposure to high air Mn levels over the first 3 - 5 postnatal years, but reduced current exposure (Valcamonica), and 3) no history of elevated airborne Mn exposure (Garda Lake). We will also address the role of genetic susceptibility to Mn via genetic variation in iron metabolism pathways genes. This will be the first study on Mn neurotoxicity in children supported by a profound characterization of environmental Mn exposure levels. PUBLIC HEALTH RELEVANCE: The proposed studies will address a significant gap in our understanding of the health risks posed by elevated environmental manganese exposure in children by defining in detail the link between early life or continuous exposure and cognitive, behavioral, motor, and sensory deficits in children age 11-13 years. This research will also investigate how genetic polymorphisms influence exposure risk. Such findings will surely be powerful influences on future research initiatives and public policy directed at minimizing the morbidity associated with manganese exposure, especially when associated with iron deficiency, lead exposure and other covariates. Given the potential use of MMT in gasoline, this study will also contribute to understanding the potential risk from airborne manganese that may be increased by the introduction of this manganese-based fuel worldwide. This knowledge will inform public health policies and guidelines on suitable levels of manganese exposure to children worldwide.