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（Mn）暴露升高与儿童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入途径暴露，尽管成人的职业研究已经确定，通过吸入接触锰比通过摄入接触对认知和运动影响的风险更大。我们将评估生活在目前或过去受铁合金工业影响地区的11-13岁儿童空气中锰暴露对神经发育的影响。我们将对意大利布雷西亚省三个特征鲜明的研究地点的750名儿童进行研究，这些地点的铁合金工厂活动历史不同：1)Bagnolo Mella，一个拥有活跃铁合金工厂的社区，空气中锰含量非常高；2) Valcamonica，由于铁合金植物活动的历史（2001年结束），空气Mn水平略有升高；3) Garda Lake是一个具有背景空气Mn水平且没有铁合金植物活动历史的参考区域。该项目将以现有的欧盟资助的phme（易受影响人群接触混合元素对公共健康的影响）研究为基础，该研究已经检查了瓦尔卡莫尼卡和加尔达湖总共300名儿童；我们打算再招收450人来实现我们的目标。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Mn，家庭沉积灰尘，自来水，土壤中的Mn水平，以及详细的食物频率问卷，结合全面的认知，行为，运动和感官评估，以及暴露生物标志物测量（血液，尿液，头发，指甲）和脱落的乳牙中的Mn来评估早期生活和累积一生暴露。初步结果表明，历史暴露区居民的运动协调、气味识别和智商的变化与空气锰水平有关。本研究将提供独特的机会，通过评估具有三种暴露史的儿童来比较不同发育时期Mn的影响：1)自出生以来持续高空气Mn暴露（Bagnolo Mella）， 2)在出生后的前3 - 5年内暴露于高空气Mn水平，但目前暴露减少（Valcamonica）， 3)没有空气Mn暴露升高的历史（Garda Lake）。我们还将通过铁代谢途径基因的遗传变异来解决对锰的遗传易感性的作用。这将是第一个对环境锰暴露水平进行深入表征的儿童锰神经毒性研究。

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.