The long-term goal of Research Project III is to identify molecular and cellular mechanisms that underlie idiosyncratic responses within autistic children to chemicals to which they are exposed in in utero and during periods of early postnatal brain development. The pressing worldwide concern about the role of vaccine antigens, the mercurial preservative thimerosal, and environmental exposure to mixtures of methylmercury and PCBs, justify detailed analysis of the underlying mechanisms of these factors in autism. We will first focus on three hypotheses relating to synergistic actions of mercurials and PCBs agents, known to be immunotoxic and neurotoxic. The hypotheses to be tested are: Hypothesis I addresses how peripheral blood mononuclear cells (PBMCs) from autistic children exhibit significant differences in their sensitivity and/or pattern of cell activation and cytokine secretion when challenged in vitro with vaccine antigens. How Non-coplanar PCBs of environmental relevance, thimerosal and other environmental agents identified by the Center's units exacerbate these differences will be studied. Hypothesis II determines how organic mercurials (thimerosal and MeHg) and non-coplanar PCBs (PCBs 118, 138, 153, 170, and 180 singly or in combination) act synergistically to influence glia/neural cell signaling pathways leading to altered patterns of dendritic spine growth, dendritic branching and synaptogenesis. Products of antigen- stimulated and control PBMCs (isolated from autistic and non-autistic children) characterized and quantified in Hypothesis I will be used to address their differential effects on neuronal cell growth. Hypothesis III utilizes mice exposed to PCBs and organic mercurials in vivo (PROJECT II) to assess functional and biochemical changes associated with social behavioral deficits. We will identify differences in patterns of evoked potentials and excitability in hippocampus/amygdala slice preparations from mice that have been perinatally or neonatally exposed to PCBs, organic mercurials, singly or in combination in Project II. We will elucidate the underlying biochemical mechanisms of these effects.
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