Manganese (Mn) plays an essential role in normal growth and development; however, overexposure to Mn can result in neurotoxicity. This dual role of Mn as essential mineral and neurotoxicant appears as a biphasic dose-response curve for neurodevelopmental health outcomes in children. Children may be particularly susceptible to the neurotoxic effects of ambient Mn exposure, as their brains are undergoing a dynamic process of growth, differentiation, pathway direction, and apoptosis, all of which can be influenced by environmental factors. Recent developments in magnetic resonance imaging (MRI) and spectroscopy (MRS) can provide novel, quantitative information about the effects of Mn on brain anatomy and physiology; yet these imaging methods have never been applied to an adolescent population exposed to chronic ambient Mn. Given the role of Mn as both nutrient and neurotoxicant, we anticipate that biomarkers of Mn exposure will exhibit a biphasic dose- response association with adolescent neurobehavior, neuromotor function, brain anatomy and physiology, and hypothesize that both low (1st quartile) and high (4th quartile) levels of exposure will be significantly associated with deficits in these domains. This overarching hypothesis will be addressed through two specific aims. Specific Aim 1: Evaluate neurodevelopment with historic and current biomarkers of Mn in a cohort of rural adolescents in order to evaluate the impact of Mn from essential to excess on executive function, attention and reaction time, cognition, achievement, behavior, and neuromotor status. Specific Aim 2: Conduct a sub-study of adolescents based on previously determined Mn biomarkers using quantitative MRI/S in order to evaluate the effects of Mn exposure from essential to excess on neuroanatomy, metabolism, organization, function and connectivity. Neuroimaging outcomes (volume, metabolite concentrations, metrics for diffusion tensor, functional activation, and network connectivity) will be compared with historic and current biomarkers of Mn. This well-characterized longitudinal cohort study of adolescents will advance our understanding of the impact of Mn on neurodevelopment, and brain anatomy and physiology using innovative MRI methodologies. These patterns may be useful in defining the lines of essential benefit and neurotoxicological harm from Mn. The findings from this study will have regional, national and global implications for advancement of neuroscience and will be used to inform policy related to Mn in gasoline and ambient air standards. This proposal leverages the only cohort available in the United States that can directly address these aims.

Although health disparities among rural children are widely documented, rural Appalachian American children bear an undue burden of psychological, socioeconomic, and environmental factors known to attribute to these health disparities. Parents of children in Appalachian communities report a greater prevalence of behavioral problems in their children of as compared to national parental reports. Moreover, Appalachian communities are exposed to environmental toxicants known to cause deficits in neurodevelopment. The relationship among psychosocial and environmental influences on children's neurodevelopment remains unclear. Thus, we hypothesize that exposure to airborne neurotoxicants are associated with neurobehavioral deficits including measures of cognition, attention, memory, neuromotor function in an underserved Appalachian American pediatric population and this association is modified by socioeconomic conditions, rearing environment, and other factors. In order to test the hypothesis, the following specific aims will be accomplished: Specific Aim 1: Assess the overall context in which childhood environmental exposure occurs, including socioeconomic, familial, nutrition, and other factors, in order to examine the dynamic process of environmental health in rural underserved communities. Specific Aim 2: Determine if children exposed to airborne neurotoxicants are at increased risk for deficits in neurodevelopment using a battery of well-validated assessments. Our project is a novel, community-based participatory research project that will for the first time evaluate multiple risk factors believed to influence Appalachian child health using sensitive biological and behavioral markers. Ultimately, this project will lead to the identification of the key multiple risk exposures for targeted public health interventions for rural, underserved Appalachian Americans. Given the unique susceptibility of children to neurotoxicant exposure in combination with psychosocial factors, we anticipate the results of this study to have a major impact on the community, national policy, and regulatory changes and broad implications for addressing health disparities in Appalachian Americans.

Manganese (Mn) is an essential element, yet is neurotoxic in excess. Despite the fact that infants and young children may be at greater risk for Mn neurotoxicity than adults, very few studies have evaluated the effect of chronic Mn exposure on child development. Marietta, Ohio, a rural Appalachian community, has been home to the only metal refinery in the US and Canada for over 50 years. In response, the community formed Neighbors for Clean Air (NCA). The University of Cincinnati (UC) has been asked by NCA to assist them in understanding their exposure and related health effects, if any. For this project, Marietta Community Actively Researching Exposure Study (CARES), the community has defined the research agenda, determining the research questions, objectives, specific aims and identifying resources available within the community to conduct the research. Members of the community will be engaged in all facets of the research project, including environmental sampling, neurobehavioral assessment, project coordination, and collection of biological specimens. The primary objectives of this application are to examine biological indicators of Mn exposure in children and understand the effects of chronic manganese exposure in children. UC will provide training, oversight and expertise in environmental health research, to address the following hypothesis: Exposure to Mn during early childhood is significantly associated with neurodevelopmental deficits in high exposed children ages 7-8 years compared to an age matched low/unexposed group. In order to test the hypothesis, the following community-driven specific aims will be accomplished. Specific Aim 1: Assess environmental Mn exposure within a high Mn exposure community, Marietta, OH and a low Mn exposure community, Cambridge, Ohio. Specific Aim 2: Evaluate comparisons of the neurobehavioral effects in children exposed to Mn in a high Mn exposure community, Marietta, OH and a low Mn exposure community, Cambridge, Ohio. Specific Aim 3: Evaluate comparisons of the neuromotor effects in children exposed to Mn exposure community, Marietta, OH and a low Mn exposure community, Cambridge, Ohio. Given the unique susceptibility of children to toxicant exposure and the opportunity to study Mn exposure in a chronically exposed community, we anticipate this project to significantly impact local and national public health policy related to Mn exposure.

Marietta-Parkersburg Metropolitan Area is a rural Appalachian community. The area has been home to the only manganese (Mn) refinery in the US and Canada for over 50 years. The residents are very concerned about the quality of their air and related health effects. Caroline Beidler, a local resident, has created and directs, Neighbors for Clean Air (NCA). Beidler has sought the assistance of Dr. Erin Haynes at the University of Cincinnati to help her and her community understand the health effects of chronic exposure to air Mn. Together we have conducted a community-wide survey to evaluate the community's level of concern about environmental air pollution in their region caused by industrial emissions and to learn about their perceptions of air quality and its impact on their health. Their sources of information related to local industrial emissions, their level of trust for these information sources, and how they rate the level of knowledge from each information source was also evaluated. We found that the community relies upon local media for air quality information, yet these reporters are not trained in science or environmental journalism. The community also uses websites to search for information on industrial emissions and health effects; however, reliable sites are difficult to find, navigate, and interpret. Thus, Beidler and Haynes have created a "University of Cincinnati-Marietta- Parkersburg Metropolitan Area Reciprocal Research Relationship" Project. The goal of this project is to create reciprocal research partnerships to determine the health effects associated with the Marietta-Parkersburg Metropolitan Area community's exposure to Mn while engaging the community in the research process to ultimately inform regional and national policy for Mn emissions. Our main objective is to implement and evaluate a multifaceted Community Based Participatory Research (CBPR) program that bridges the gap between an affected community and the research scientists. The following specific aims for the project are: Specific Aim 1: Create reciprocal training and research opportunities for the Marietta-Parkersburg Metropolitan Area community and University of Cincinnati scientific researchers; Specific Aim 2: Create a reciprocal educational relationship among Marietta-Parkersburg Metropolitan Area journalists (radio, newspaper and TV reporters), University of Cincinnati research scientists and environmental journalists to establish a well-defined network between journalists and research scientists; and Specific Aim 3: Evaluate the success of the overall community-research partnership through qualitative research methods. Given the community's intense interest in understanding their air quality and resulting health effects, the developing partnership between UC and the Marietta-Parkersburg Metropolitan area, and the opportunity for community involvement in innovative research studies, we anticipate that the results of this proposal will provide a model community-research partnership with reproducible deliverables for national and international community-based participatory research studies.