The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues. While current exposure levels to environmental agents does not represent an acute injury, disruption to the nervous system may be associated with either a structural alteration in the formation of the neural network and/or in nervous system functioning. It is the goal of this project to develop and validate test methods that will allow us to assess various types of chemical-induced perturbations of the brain during development. 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 chemical induced perturbations during development of the nevous as indicated by alterations in the spatio-temporal expression of mRNA for various developmentally regulated proteins associated with distinct processes of development, distribution of compounds to the nervous system, and the neurobehavioral outcome of such exposure. The specific projects under study include 1) distribution of mercury to the brain of young animals following the intramuscular injection of various mercuricals. 2) alterations in the neurobehavioral functioning following early exposure to the pro-inflammatory cytokine IL-6 as a model of maternal infection and premature delivery. 3) Alterations in neuronal processes in the brain following exposure to compounds that perturb homeostatic maintenance of thyroid hormone during gestational and postnatal development. With regard to delivery of mercury to the brain following an intramuscular injection of either methyl mercury, ethyl mercury, thimerosal, as compared to an oral administration of methyl mercury demonstrated a distribution pattern distinct between the two routes of exposure suggesting a sequestration of the metal within the muscle resulting a minimal level within the brain. Neuroinflammation in the young mouse brain as generated by a direct delivery of hyper-IL6 to the cortical layer resulted in subtle alterations in neurobehavioral functioning characterized by a hyper-reactivity to environmental stimuli and a relatively inflexibility in learning and performance that continued in the adult animal. Alterations in thyroid hormone levels during gestation and lactation induced by either hexachlorobenzene or PCBs produced distinct patterns of disruption in cerebellar neurons as demonstrated by Golgi staining of neuronal processes. For PCBs this pattern of disruption was transient and may be linked to the period of active development. Early developmental exposure to inorganic lead is known to alter brain development. Based upon our previous studies examining specific neuronal and glia markers following low level lead exposure we initiated a study to examine in a more broad manner the developmental ontogeny of multiple nervous system specific genes using DNA array techniques. One specific finding of these studies was the shift in the developmental pattern for a specific chlorid plexus gene suggesting an early maturation of the chlorid plexus as a protective mechanism against a heavy metal exposure however, the consequences to such an early maturation is yet to be studied. For these studies we have used 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, as well as assessment of neurobehavioral functioning.
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