Manganese Exposure Windows and Neurologic Function in Adolescence

 描述（由申请人提供）：本研究的主要目的是表征环境锰（Mn）暴露对青少年神经发育的影响。虽然长期以来被认为是一个关键的神经发育期在儿科/心理学，很少有人知道的影响有毒化学品暴露在青春期的神经表型。锰是一种值得在青春期研究的神经毒物，因为：i）锰是一种必需的微量金属，但在高暴露量下也具有神经毒性; ii）儿茶酚胺能系统是Mn的众所周知的靶点，并且青春期神经发育涉及多巴胺能系统的实质性变化，iii）Mn暴露比先前认识到的更普遍，但其在改变脑发育中的作用并不众所周知，以及iv）关于Mn在青春期的影响存在显著的知识差距。初步研究结果显示，青春期前/早期锰暴露水平升高与注意力、神经运动、认知和嗅觉功能缺陷有关 小儿我们将在240名青少年的队列中建立这些发现，以确定：1）Mn暴露时间对青少年执行功能、行为和自我调节的作用，通过应用新的暴露生物标志物和统计方法来识别和定义易感性的关键发育窗口，和2）受Mn影响的功能和解剖神经表型，关注有助于执行功能的脑区域，行为，以及青春期的自我调节（例如，PFC，腹侧纹状体，杏仁核）使用功能和解剖MRI。我们建立的PHIME（锰暴露的公共卫生影响）队列为实现这些重要目标提供了独特的机会。PHIME旨在调查长期锰暴露时间;它包括生活在北方意大利三个特征明显的社区的受试者（现在是青少年），这些社区在环境锰暴露的时间和强度方面与当前或历史铁锰合金工厂运营不同。此外，最近的创新，在暴露科学现在允许我们回顾性重建锰暴露在胎儿期/儿童早期使用一种新的牙齿生物标志物的暴露这些研究将是第一个纵向评估环境锰对青少年神经发育和行为的作用，并客观地确定关键的暴露窗口，可以告知未来的公共卫生干预措施的时机。

 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.