Manganese (Mn) is an emerging neurotoxicant. Two critical issues in the neurotoxicology of Mn include the 1) extrapolation of animal results to humans, and 2) limitations in defining/assessing critical exposure windows in epidemiologic studies. Because randomized trials cannot be conducted for neurotoxic agents, research translation in neurotoxicology involves epidemiologic observational studies that rely on parallel research in animals to determine mechanisms of action. However, such studies seldom measure the same functional domtheains or address exposures at the same life stages, at least not in a coordinated fashion. Although there are several caveats when extrapolating results from animals to humans, one caveat, the use of different neurophenotypes, can now be overcome, given the development of computerized tests of animal/human behavior, such as the virtual radial arm maze and temporal response differentiation test (a fixed interval response). The investigators will employ these tests and others in children in parallel to conducting animal toxicology studies that also address Mn exposure in specific life stages. Their team has also developed a method to reconstruct past Mn exposure using deciduous teeth that expands upon prior work by measuring Mn in specific growth rings corresponding to discrete life stages. In effect, the investigators can now reconstruct past exposure to Mn at multiple developmental windows, a technique that may even be superior to prospective blood Mn levels. In this supplement, the investigators will leverage an ongoing cohort study in Mexico City to assess Mn exposure and child neurodevelopment, while tightly coupling our findings to animal toxicology studies measuring the same neurophenotypes. This ViCTER application is a new transdisciplinary collaboration among investigators with expertise in animal toxicology (Smith) and manganese epidemiology/exposure assessment (Lucchini/Arora), bringing them together to form a unique virtual consortium to study Mn toxicity in children.
In this ViCTER proposal the investigators outline a plan to integrate animal toxicology research with human epidemiologic research on the same neurotoxicant-manganese (Mn). They propose to measure the same functional domains in animals and humans and to use dental Mn measures to reduce exposure misclassification in humans. Their results will be critical for informing clinical and public policy decision making and could be a model for future studies that combine animal and human research to assess chemical neurotoxicity.
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