A NONBILE DUCT ORIGIN FOR INTESTINAL CRYPT-LIKE DUCTS WITH PERIDUCTULAR FIBROSIS INDUCED IN LIVERS OF F344 RATS BY CHLOROFORM INHALATION

To evaluate the toxic effects of prolonged exposure to chloroform vapo rs, female and male F344 rats were exposed to 0, 2, 10, 30, 90 and 300 p.p.m. chloroform by inhalation for 7 or 5 days/week for up to 13 wee ks, The purpose of this study was to characterize a lesion that occurr ed in the livers of rats in the 300 p.p.m. exposure groups, Atypical g landular structures lined by intestinal-like epithelium and surrounded by dense connective tissue occurred in the livers of rats exposed to strongly hepatotoxic atmospheric concentrations of chloroform, Bile du ct bromodeoxyuridine labeling indices as well as observations of the l ocations of the early lesions at the 3 and 6 week time points indicate that these lesions arose from a population of cells remote from bile ducts, We refer to these lesions as intestinal crypt-like ducts with p eriductular fibrosis to distinguish them from true cholangiofibrosis. Here, intestinal crypt-like ducts with periductular fibrosis were seen only in rats exposed to 300 p.p.m. chloroform, and the multiplicity a nd severity of the lesions were greater in the right liver lobe, The l esion only occurred in association with liver necrosis and dramatic in creases in hepatocyte labeling indices, while labeling indices in bile ducts in the same animals were not significantly different from contr ols, There was a treatment-related increase of transforming growth fac tor-alpha immunoreactivity in hepatocytes, bile duct epithelium, bile canaliculi and oval cells, and an increase in transforming growth fact or-beta immunoreactivity in hepatocytes, bile duct epithelium and inte stinal crypt-like ducts. Thus, intestinal crypt-like ducts with peridu ctular fibrosis appeared to develop from a population of cells unrelat ed to bile ducts, Also, they occurred only in animals exposed to chlor oform concentrations that induced significant hepatocyte necrosis and regenerative cell proliferation and were associated with increased gro wth factor expression or uptake.