Exposure to environmental toxicants is almost always to complex mixtures. In order to determine the risks and the mechanisms by which these agents alter human health it is necessary to understand the interactions between the toxicants. We propose to determine the effects of perinatal exposure to PCBs, dibenzofurans and dioxins and the interactions of these agents on neurochemical development of the rat. All of these toxicants are present in high concentrations in soil and wildlife at Massena, NY and are present in breast milk from exposed Akwesasne women. Perinatal exposure of the rat to ortho-substituted PCB congeners or to non-ortho-substituted dioxin-like congeners yield differential effects on brain dopamine function. We hypothesize that the biochemical mechanisms by which these agents alter the developing nervous system differ and that simultaneous exposure to these halogenated aromatic hydrocarbons will modify the neurological responses seen following exposure to the individual agents. We will expose pregnant rats to: (1) individual PCB congeners and mixtures of congeners found in Akwesasne breast milk; (2) 2,3,7,8-dibenzofuran and dioxin; (3) mixtures of ortho-substituted and non-ortho-substituted PCB congeners and dioxins and dibenzofurans and determine the effects of these manipulations on brain dopamine concentrations. We will measure brain catecholamines by HPLC with electrochemical detection, brain PCBs and dibenzofurans and dioxins by gas- chromatography and high-resolution mass spectrometry, and brain and liver AHH activity by UV spectrometry. Using in-vivo microdialysis procedures we will determine the biochemical mechanisms by which these agents affect the synthesis, catabolism, release and uptake of dopamine, the neurotransmitter shown to be most affected by exposure to halogenated aromatic hydrocarbons. Data from these experiments will determine the neurotoxicity of the halogenated aromatic hydrocarbons found at the Akwesasne Superfund site, the interactions that occur following simultaneous exposure to these agents, the biochemical mechanisms responsible for the alterations in brain dopamine content and the relationship between neurochemical change and AHH induction. This information will allow a more realistic estimate of risk of exposure to complex environmental mixtures of halogenated aromatic hydrocarbons and provide insights to the biochemical mechanisms responsible for the neurological dysfunctions observed in PCB-exposed infants by Jacobson and Rogan and that we suggest may occur at the Massena Superfund site.
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