The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues and has become of additional concern with the high level of exposure to children of toddler age and the increase in developmental disorders such as autism and schizophrenia. The formation and interactions between the various cell types in the brain are critically timed events and represent age windows of vulnerability for environmental exposure. One recent issue of concern is the impact of infection or a stimulation or alteration in the immune system during development. One component of this response is the induction of interleukin-6 which has been linked to maternal infection and altered childhood outcomes. This cytokine has both pro- and anti-inflammatory properties but also plays a role as a growth factor. In previous work we demonstrated that tight regulation of this cytokine is critical for maintaining a normal glial response to chemical injury. We now demonstrate that direct exposure of the developing mouse brain to IL-6, in the absence of a full systemic immune response, can alter brain development, produce a long term deficit in myelin, and alter choice behaviors in the adult offspring. We have further examined the role of IL-6 in regulating the process of adult neurogenesis, generation of new neurons in the established brain, in the murine hippocampus. The regulatory role for IL-6 in this process suggests a contribution of the cytokine in the ability of the brain to maintain a critical component required for stabilization of mood, and for short-term hippocampal learning and memory. We have further identified a developmental ontogeny of IL-6 mRNA levels in specific brain regions and a shift in this developmental profile following developmental exposure to known neurotoxicants. We have examined the role of IL-6 as a neuroprotective cytokine in a model of tumor necrosis factor receptor dependent neuronal death in the hippocampus. We have now demonstrated that voluntary exercise is capable of providing a significant level of protection against a known environmental neurotoxicant, the organotin compound, trimethyltin (TMT) and that this protection is associated with an up-regulation of IL-6 within the target region and a subsequent down regulation of TNF. This work demonstrates a critical role for IL-6 in both brain development and in neuroprotective processes and provides a possible link between early developmental exposure to immune mediated events from environmental exposure and long-term alterations in the cognitive functioning of the offspring. In models of acute brain injury allowing for the infiltration of blood borne cells into the brain tissue, brain macrophages and inflammatory cytokines have been implicated to have an adverse effect on adult hippocampal neurogenesis. Using the TMT-induced injury model, we have demonstrated that this adverse effect does not translate to resident brain microglia. In the absence of damage to the blood brain barrier and infiltrating cells, the TNF response within the neurogenic regions serves to promote the generation of new neurons and the associated microglia serve in a supportive role for progenitor cells (1). This protective response was observed in both the adolescent and the mature mouse and suggests that the induction of a resident microglia response is critical for neuroprotection and brain repair/remodeling (1,2,3). Thus, this data raises concerns for the use of therapeutic interventions to downregulate TNF and associated microglia responses in the brain in the absence of an understanding of the nature of the insult. We have developed a model system to examine the progenitor cell population from 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 (3). We are using this model to identify novel signaling factors that can promote adult neurogenesis and improve brain repair and cognitive functioning. To translate these findings, and those of others, to the field of developmental neurotoxicology and gene/environmental interactions, we are developing an approach to assess the developmental profile of a specific set of genes related to critical cellular structures or events during post-natal brain development. Using an approach of a quantitative RNase protection assay array, we will examine the developmental timing of gene expression in discrete brain regions. From this we will generate a profile for a selected number of genetic mouse models associated with neurodevelopmental based disorders such as autism and schizophrenia and for a limited number of known developmental neurotoxicants. From this data base, we hope to generate an approach that will allow for the evaluation of the developmental neurotoxicity of unknown chemicals or genetic alterations and to further advance our understanding of gene/environmental interactions. 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 and con-focal imaging, molecular techniques to examine mRNA level such as qRT-PCR, microarray, RNase protection assays, laser capture microdissection for isolation and enrichment of specific areas, neuroprogenitor cell cultures, adult derived neural stem/progenitor cells, as well as assessment of neurobehavioral functioning.
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