ECTOPIC EXPRESSION OF METALLOTHIONEIN-III CAUSES PANCREATIC ACINAR CELL NECROSIS IN TRANSGENIC MICE

Mice express four distinct metallothioneins (MTs) that have similar me tal-binding properties. MT-I and MT-II are expressed coordinately in m ost organs, whereas MT-III is expressed predominantly in a subset of n eurons and MT-IV is expressed in certain stratified epithelia. The res tricted expression of MT-III suggests that it may serve a specialized function. To test this hypothesis, transgenic mice were generated that express MT-III in the wider expression domain of MT-L. Similar transg enic lines expressing extra MT-I under the same regulation were genera ted as controls for the effect of over-expression of MT, Transgenic mi ce that express MT-III ectopically frequently die at 2-3 months of age . The pancreata of moribund mice were abnormally small and histologica l examination, at various ages, revealed a progressive degeneration of the acinar cells, At early stages multifocal acinar cell eosinophilia and swollen nuclei were seen and this pathology progressed to multifo cal acinar cell necrosis and fibrosis. The terminal stages were charac terized by a loss of the acinar compartment, leaving the islets embedd ed in a fibrotic remnant, Other organs of these mice were grossly and histologically normal. All organs examined from mice expressing excess MT-I were unremarkable elm though expression of either MT-I or MT-III transgenes resulted in similar accumulations of zinc and copper in th e pancreata. This study indicates that pancreatic acinar cells are unu sually sensitive to chronic expression of MT-III. The mechanism by whi ch MT-III disrupts pancreatic function is unclear, but the results pro vide further evidence that MT isoforms exhibit distinct properties and probably serve distinct biological functions, (C) 1998 Academic Press .