α-Naphthylisothiocyanate Induces Intrahepatic Bile Duct with Greater Proliferation in Female Rats than in Males

Abstract

The present study was conducted with the original purpose of investigating the possibility that α-naphthylisothiocyanate (ANIT) might induce intrahepatic cholangiocellular neoplasms in rats after appropriate carcinogenesis-initiating treatments, based on its known effect of causing intrahepatic bile duct proliferation. Fischer 344 rats (6 weeks old) were given 3 weekly intraperitoneal administrations of vehicle (female and male), N-nitrosobis(2-oxopropyl)amine (BOP) (20 mg/kg body weight, female and male) or N-nitrosodimethylamine (DMN) (10 mg/kg body weight, male only), and fed a basal diet with or without 200 ppm of ANIT from the commencement for up to 24 weeks. Animals were sequentially sacrificed at the ends of weeks 8, 16 and 24 to examine morphological changes in the liver. ANIT caused proliferation of intrahepatic bile duct epithelial cells with no atypia when administered alone or in combination with BOP (female and male) or DMN (male only), while neither BOP nor DMN caused bile duct proliferation per se or altered the magnitude of the effect of ANIT. The degree of bile duct proliferation caused by ANIT was greater in females than in males. No hepatocellular or liver (pre)neoplastic changes were observed. These results indicate that although ANIT does not induce any neoplastic changes in the liver even after initiation with BOP (female and male) or DMN (male), it causes non-neoplastic intrahepatic bile duct proliferation with a clear sex difference.