The movement of fluoride (F) across epithelia is an integral component of F absorption, urinary excretion and secretion. A detailed understanding of the mechanism of F transport across epithelia has important implications for the therapeutic uses of F and the minimizing of toxic effects. The pH dependence of F transfer across some epithelia (e.g. stomach, urinary F excretion) has led to the proposal that the predominant permeable species is the undissociated acid HF, rather than fluoride ion F-, implying transport as a weak electrolyte. Intestinal F absorption has not been investigated systematically, but should serve as a representative epithelial tissue for the detailed study of epithelia F transport. Despite the high pH of the small intestine, F absorption occurs readily from this site. Our preliminary studies indicate that F transport across intestinal epithelium is not influenced by pH, at least over a physiological range. As an extension of these studies we propose a systematic study of gastrointestinal F absorption, to determine the role of the small intestine in F absorption, and the mechanism of F transfer across intestinal epithelium. As a preliminary approach to understanding F transport at the cellular level, isolate epithelial cells (MDCK cells) grown in monolayer culture will also be used to investigate mechanisms by which F transport is regulated. This proposal consists of three parts: In the first, a series of in vivo studies will be conducted in rats, to measure F absorption from different sites. Both intact animal experiments and perfusion of different segments of the gastrointestinal tract will be undertaken. In the second part, isolated intestinal segments will be used in vitro to determine whether F transport occurs primarily by diffusion as a weak electrolyte (as undissociated acid HF), or as ionic transport coupled to transport of other ions? Finally, as an initial approach to studying epithelial F transport at the cellular level MDCK cells will be used in cell culture studies. These cells, of canine kidney origin, can be grown as a monolayer on filters, and show a typical epithelial polarity with apical and basolateral areas of the cell separated by tight junctions. Effects of pH, inhibition of sodium and chloride transport, and abolition of potential difference across the cell layer will allow a discrimination between transport as a weak electrolyte vs ionic transport.
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