COMPARATIVE-STUDIES OF CHROMAFFIN CELL-PROLIFERATION IN THE ADRENAL-MEDULLA OF RATS AND MICE

Spontaneous and drug-induced pheochromocytomas are common in rats and rare in mice. The antihypertensive drug reserpine has been shown to bo th induce pheochromocytomas and stimulate chromaffin cell proliferatio n in rats, leading to the hypothesis that reserpine causes pheochromoc ytomas indirectly by providing a proliferative setting in which DNA da mage may occur. The present investigation was undertaken to obtain bas eline information on the relationship across species between chromaffi n cell proliferation and pheochromocytomas. Basal chromaffin cell prol iferation was compared in age-matched young adult mice and rats. In ad dition, mice were studied for adrenal medullary responses to reserpine , and mouse chromaffin cells in vitro were studied for responses to ag ents that are mitogenic for cultured rat chromaffin cells. Concurrentl y maintained F-344 rats and several strains of mice showed no signific ant difference in basal BrdU incorporation over a 1-week period. Mice also showed an adrenal medullary proliferative response to reserpine t hat was comparable to the response previously reported for rats. Howev er, there was a marked disparity between rat and mouse chromaffin cell s in vitro, and cultured mouse chromaffin cells did not respond to any mitogens. The in vivo data indicate that interspecies differences in basal- or reserpine-stimulated chromaffin cell proliferation sufficien t to account for different frequencies of pheochromocytomas are not de tectable at a single time point in young adult animals. However, the p ossibility that such differences might emerge with aging has not been ruled out. These data further suggest either that stimulation of chrom affin cell proliferation might be necessary but not sufficient for dev elopment of pheochromocytomas or that stimulated proliferation in mice might not be sustained. The inability of cultured mouse chromaffin ce lls to respond to mitogens raises the speculation of whether mechanism s that prevent proliferation of normal chromaffin cells in vitro might also help to protect mice from developing pheochromocytomas. (C) 1997 Society or Toxicology.