The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues. The formation and interactions between the various cell types in the brain are critically timed events. Such windows of vulnerability is assummed to be a major component in the differential susceptibility of the developing organism to environmental insult. This project examines genetically modified mice for alterations in brain development as well as chemical induced perturbations during development of the nervous system as indicated by various alterations in the morphology and molecular profile in the developing brain and assoicated neurobehavioral outcome in adolescent and aging animals. The laboratory has extensive experience in developmental toxicology and developmental neurotoxicology and is currently establishing expertise in the study of aging related processes. This allows us to be able to integrate the questions of genetic or exposure related factors on development on shifting the susceptibility of the aged animal. We have previously demonstrated long-term and latent effects of early exposure to environmental heavy metals. Working with the Toxicology Operations Branch of the National Toxicology Program, we have implemented a testing protocol to examine the neurodevelopmental toxicities of environmental chemicals that can be employed in an applied manner to evaluate compounds of concern for developmental neurotoxicity. In addition to changes occurring during development, this project will continue to develop approachs to evaluate latent effects or effects on the aged brain as the result of early developmental exposure to environmental chemicals. One of these approaches focuses on the capability for brain repair. The adult brain maintains specific regions of neurogenic capability, i.e., there is a proliferative capacity for neural stem or progenitor cells. This response can be induced with injury and the capacity shifts with aging. We have developed a model system to examine the progenitor cell population from one of these brain sites, the subgranular zone of the hippocampus and to determine if toxicant or drug exposure will alter these cells directly or alter the in vivo environment such that the ability of these progenitor cells to differentiate to mature functioning neurons is altered. We have expanded this model system to the examination of progenitor cells isolated from the aged mouse brain to examine age related changes as a function of genetic background, early environmental exposure, and gene-environment interactions. In addition, we are using this model to identify novel signaling factors that can promote adult neurogenesis and improve brain repair and cognitive functioning. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry, molecular techniques to examine mRNA levels, laser capture microdissection for isolation and enrichment of specific areas, as well as assessment of neurobehavioral functioning.
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