ARACHIDONATE PRODUCTS IN DIOXIN AND PCB TOXICITY

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We propose to examine abnormalities in arachidonic acid metabolism that may be caused by dioxin and other polyhalogenated aromatic hydrocarbons (PAH) and the role of arachidonic acid metabolites in PAH toxicity. We will examine the effects of PAH on the synthesis of prostaglandins, leukotrienes and other lipoxygenase products from endogenous arachidonic acid and from exogenous (14C) labelled arachidonic acid in potential target organs of PAH toxicity. Prostaglandins will be assayed by RIA and TLC and lipoxygenase products by bioassay, TLC and HPLC. PAH effects on cytochrome P-450 mediated as well as on classical (non-P-450 mediated) pathways of arachidonic acid metabolism will be examined using selective incubation conditions and assay procedures. We will determine whether changes in arachidonic acid metabolism by PAH are associated with activation of the Ah receptor by comparing the effects of PAH which are P-448 type inducers and noninudcers on arachidonic acid metabolism and by comparing the does-response relationships for PAH effects on arachidonic acid metabolism and on P-488 mediated mixed function oxidase induction in liver and in potential target organs of PAH toxicity. We will examine whether arachidonic acid products may participate in eliciting the toxic manifestations of PAH by examining the effect of cyclooxygenase and lipoxygenase inhibitors and of mixed function oxidase inhibitors and inducers (if we find that they alter arachidonic acid metabolism) on PAH cardiotoxicity as evidenced by a decreased contractile response to norepinephrine, and generalized toxicity as evidenced by increased mortality, increased incidence of edema and thymic involution. we will also investigate whether the cardiotoxic response can be elicited in vitro by those arachidonic acid metabolites whose production is increased by PAH exposure in ovo and attenuated in vitro by inhibitors of arachidonic acid metabolism.