Manipulation of Lead Using Carboxylic Acid Ionophores

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DESCRIPTION (provided by applicant): The use of antibiotics in agricultural is often criticized because resistant strains of bacteria arise from the practice. There may be additional grounds for concern in the case of antibiotic ionophores, which are added to the feed of nearly all species that are employed by this industry. More specifically, these compounds are long know to be ionophores for physiological cations such as Na+, K+, and Ca2+, however, we have found that they are actually much more active and highly selective as ionophores for Pb2+. Since the compounds are known to carryover into the human diet, the prospect arises that the use of ionophores as feed additives impacts upon the pathophysiology of lead as a toxin in humans, as well as in the animals. The studies proposed here are designed to will test those possibilities from several perspectives. We will use rats as an animal model to determine it Pb2+ transporting ionophores increase or decrease lead absorption via the gut, when they are administered at levels that are typical of agricultural practices. We will also determine if Pb2+ transporting ionophores redistribute an existing lead burden between bone and soft tissues and between individual soft tissues, including heart, brain, kidney, liver, and testis. We will furthermore determine if Pb2+ transporting ionophores improve access of previously accumulated lead to circulating chelators, and thereby shorten the otherwise lengthy duration of chelation therapy for lead intoxication. We will administer the ionophores to rats in feed and drinking water, respectively. Lead levels in organs, blood, urine and feces will be determined by electrothermal atomic absorption spectroscopy. Ionophore levels will be determined by HPLC using post-column derivatization with vanillin or fluorescent reagents. These animal studies will be complimented by a physical-chemical investigation of ionophore mediated Pb2+ transport in phospholipid vesicles and by an analogous investigation of Pb2+ transport in cultured cells. The physical-chemical studies emphasize spectroscopic and solution chemical methods. Taken in total, the proposed studies will reveal if the use of ionophores in agriculture might pose an unrecognized threat to the public health. They may furthermore identify improved methods for the treatment of lead intoxication.