Manganese Exposure Windows and Neurologic Function in Adolescence

 描述(由申请人提供)：这项研究的主要目标是描述环境中锰(Mn)暴露对青少年神经发育的影响。尽管长期以来，有毒化学物质暴露对青春期神经表型的影响，在儿科/心理学中一直被认为是神经发育的关键时期，但人们对此知之甚少。在青春期，锰是一种引人注目的神经毒物，因为：i)锰是一种必需的微量金属，但在高暴露时也是神经毒性的；ii)儿茶酚胺能系统是锰的众所周知的靶点，青春期神经发育涉及多巴胺能系统的实质性变化，iii)锰暴露比以前认识的更普遍，但它在改变大脑发育中的作用还不是很清楚，以及iv)关于锰在青春期的影响存在重大的知识空白。我们最初资助期间的初步结果表明，青春期前/早期暴露于锰的增加与注意力、神经运动、认知和嗅觉功能的缺陷有关。 在孩子们身上。我们将以这些发现为基础，在240名青少年队列的基础上，确定：1)通过应用新型暴露生物标记物和统计方法来确定和定义关键的发育易感窗口，来确定锰暴露时机对青少年执行功能、行为和自我调节的作用；2)使用功能和解剖学MRI，重点关注青春期辅助执行功能、行为和自我调节的大脑区域(例如，PFC、腹侧纹状体、杏仁核)，研究受锰影响的功能和解剖神经表型。我们建立的PHIME(锰暴露对公共健康的影响)队列为实现这些重要目标提供了一个独特的机会。PHIME的目的是调查长期接触锰的时间；它包括居住在意大利北部三个特征良好的社区的受试者(现在是青少年)，这些社区的环境锰暴露的时间和强度与当前或历史上的锰铁合金厂运营不同。此外，暴露科学的最新创新现在使我们能够使用一种新的暴露牙齿生物标志物来追溯重建胎儿生命/儿童早期的锰暴露。这些研究将是第一批纵向评估环境中的锰对青少年神经发育和行为的作用，并客观地确定关键暴露窗口的研究之一，这些暴露窗口可以为未来的公共卫生干预提供信息。

 DESCRIPTION (provided by applicant): The primary objectives of this study are to characterize the effects of environmental manganese (Mn) exposure on adolescent neurodevelopment. Although long known to be a critical neurodevelopmental period in pediatrics/psychology, little is known about the impact of toxic chemical exposures on neurophenotypes in adolescence. Mn is a compelling neurotoxicant to study in adolescence because: i) Mn is an essential trace metal, but it is also neurotoxic at elevated exposures; ii) th catecholaminergic system is a well-known target of Mn, and adolescence neurodevelopment involves substantial changes to the dopaminergic system, iii) Mn exposure is more ubiquitous than previously recognized, but its role in altering brain development is not well known, and iv) there are significant knowledge gaps regarding the impacts of Mn in adolescence. Preliminary results from our initial grant period show that elevated Mn exposure during pre/early adolescence is associated with deficits in attention, neuromotor, cognitive, and olfactory function in children. We will build upon these findings in a cohort of 240 adolescents to determine: 1) the role of Mn exposure timing on adolescent executive function, behavior, and self-regulation by applying novel exposure biomarkers and statistical methods to identify and define critical developmental windows of susceptibility, and 2) functional and anatomical neurophenotypes that are impacted by Mn, focusing on brain areas that subserve executive function, behavior, and self-regulation in adolescence (e.g., PFC, ventral striatum, amygdala) using functional and anatomical MRI. Our established PHIME (Public Health Impact of Manganese Exposure) cohort presents a unique opportunity to achieve these important goals. PHIME was designed to investigate long-term Mn exposure timing; it onsists of subjects (now adolescents) living in three well-characterized communities in Northern Italy that differ in the timing and intensity of environmental Mn exposure from current or historic ferromanganese alloy plant operations. Moreover, recent innovations in exposure science now allow us to retrospectively reconstruct Mn exposure across fetal life/early childhood using a novel tooth biomarker of exposure These studies will be among the first to longitudinally assess the role of environmental Mn on adolescent neurodevelopment and behavior and to objectively determine critical exposure windows that can inform the timing of future public health interventions.