In cell culture systems, genistein, a soy-derived isoflavone with chemopreventive and estrogenic effects, enhances cAMP-dependent activation of the most common cystic fibrosis-causing mutation, deltaF508-CFTR, by as much as 20-fold. DeltaF508-CFTR is present in the apical membrane at far lower levels than wild-type CFTR. If genistein can enhance cyclic AMP-dependent activity in vivo, the presence of deltaF508-CFTR, at even a few percent of wild-type levels, might permit genistein to be of therapeutic benefit to cystic fibrosis patients with this mutation. Before determining if oral genistein would be of benefit in mice with a deltaF508 mutation in the murine CFTR gene, a maximal dose of oral genistein with minimal side effects needed to be established. Accordingly, C57Bl/6 mice pups were randomly weaned onto soy-free diet, AIN-76, containing between 0 and 1.0 g/kg genistein and allowed to feed ad libitum for 3 weeks. Genistein had no significant effects on growth rates of either male or female mice. Histology of the lung, heart, kidney, liver, and intestine revealed no significant genistein-dependent changes in morphology. When mice on a 1.0 g/kg of genistein diet were sacrificed in the morning, the mean level of serum genistein was 1.4+/-0.2 micro moles/L. Serum genistein increased during the daylight hours reaching a maximum of 7.5+/-0.6 micro moles/L in the early evening. Our results demonstrate that dietary genistein is not inhibitory to growth or caloric intake and up to 1.0 g/kg ad libitum genistein causes no significant organ specific abnormalities.