Neurologic function in children exposed to ambient manganese

描述（由申请人提供）：新的证据表明，环境锰（Mn）暴露升高与儿童的认知和行为缺陷有关。然而，到目前为止，在儿童中的研究只集中在通过摄入途径的暴露，虽然在成人中的职业研究已经确定，通过吸入锰暴露对认知和运动影响的风险比通过摄入暴露更大。我们将评估生活在受当前或过去铁合金工业影响的地区的11-13岁儿童暴露于空气中的锰对神经发育的影响。我们将检查意大利布雷西亚省三个特征良好的研究地点的750名儿童，这些地点的铁合金工厂活动历史不同：1）Bagnolo梅拉，一个拥有活跃的铁合金工厂的社区，该工厂产生非常高的空气锰水平; 2）Valcamonica，一个由于2001年结束的铁合金工厂活动历史而导致空气锰水平轻微升高的地区; 3）加尔达湖，一个参考区域，背景空气锰水平，没有铁合金厂活动的历史。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的公共卫生影响）研究的基础上，该研究已经检查了来自Valcamonica和Garda Lake的300名儿童;我们建议再招募450名儿童以实现我们的目标。我们建议的一个优点是强调环境暴露评估，利用24小时个人空气监测器测量空气中的锰，家庭沉积灰尘、自来水、土壤中的锰水平，以及详细的食物频率问卷，加上全面的认知、行为、运动和感官评估，沿着暴露生物标志物测量（血液、尿液、头发、指甲）和脱落乳牙中的锰，以评估生命早期和终生累积暴露量。初步结果表明，在运动协调，气味识别和智商的居民在历史上暴露的Valcamonica与空气锰水平的变化。这项研究将提供一个独特的机会，比较锰在不同的发育时期的影响，通过评估儿童与三个暴露历史1）连续高空气中锰暴露自出生以来（Bagnolo梅拉），2）暴露于高空气中锰水平在出生后的前3 - 5年，但减少目前的暴露（Valcamonica），和3）没有历史的空气中锰暴露（加尔达湖）。我们还将通过铁代谢途径基因的遗传变异来解决锰的遗传易感性的作用。这将是第一项关于儿童锰神经毒性的研究，得到了环境锰暴露水平的深刻表征的支持。

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.