The long term objective is to provide a means for reducing delayed neuropathy in man and animals exposed to certain organophosphates. As organophosphorus compounds are widely used today in agriculture and industry, risk is relatively high for accidental and occupational exposure. Although antidotes for acute toxicities are available, no specific treatment has been developed for the irreversible neuropathy that occurs weeks to months after exposure to some of these compounds. As recently demonstrated in our laboratory and others, adrenocorticoid hormones appear promising as agents to provide some moderation of the delayed neurotoxic effects of organophosphorus compounds. Using triorthotolyl phosphate (TOTP) to induce delayed neuropathy in chickens, we will examine a wide range of dietary concentrations of a natural corticoid, corticosterone, for effects on indices of this delayed neuropathy, such as clinical signs, histopathology, electrophysiology and neurotoxic esterase activity. We will observe effects of the corticosterone per se on the health of the birds by monitoring the heterophil/lymphocyte ratio, liver function, and feed efficiency. Also, as part of the work proposed, some properties of corticoids that may be relevant in moderation of organophosphate induced delayed neuropathy will be examined. These will include type of corticoid, by using a mineralocorticoid (deoxycorticosterone), a glucocorticoid (triamcinolone), and corticosterone, which has both properties, to modify TOTP-induced delayed neuropathy. The possibility that corticoids may alter metabolism of organophosphates, thereby providing protection, will be examined by comparing delayed neuropathy induced by a protoxicant (TOTP) with that induced by its active metabolite (phenyl saligenin phosphate) in the presence of corticosterone. The possibility that endogenous steroid may be substituting for exogenous steroid, as organophosphates inhibit steroidgenesis, will be examined by attempting to use ACTH rather than corticosterone to protect the birds from TOTP-induced delayed neuropathy. These studies should enhance our understanding of the basic pathogenetic mechanisms in organophosphate-induced delayed neurotoxicity, and, hopefully, lead to rational therapy.
Showing the most recent 10 out of 16 publications
