Progression of hepatic neoplasia in medaka (Oryzias latipes) exposed to diethylnitrosamine

Progression of hepatic neoplasia was assessed in medaka (Olyzias latipes) f ollowing aqueous exposure to diethylnitrosamine (DEN), Larvae (2 weeks old) were exposed to 350 or 500 p.p.m. DEN for 48 h, while adults (3-6 months o ld) were exposed to 50 p.p.m. DEN for 5 weeks, Fish were maintained as long as possible to determine malignant potential of resultant neoplasms, A tot al of 423 medaka with 106 hepatic neoplasms were examined, There were marke d differences in tumor prevalence between exposure groups including: (i) hi gher prevalence of hepatocellular carcinomas in medaka exposed as adults (1 00% of hepatocellular tumors in adult-exposed medaka were malignant, while only 51.5% of larval hepatocellular tumors were malignant); (ii) higher pre valence of biliary tumors in medaka exposed as larvae (46.4% of all tumors in larval-exposed medaka were biliary versus 8.1% in adult-exposed fish); ( iii) higher prevalence bf mixed hepato-biliary carcinomas in adult-exposed medaka (24.3%) compared with those exposed as larvae (3%). In addition, a u nique hepatocellular lesion termed 'nodular proliferation' was only observe d in adult-exposed medaka, The lesion was characterized by small size (50-3 00 mu m), complete loss of normal tubular architecture and variable megaloc ytosis. Nodular proliferation was distinct from preneoplastic foci of cellu lar alteration and may represent microcarcinomas. There was a step wise inc rease in mean diameter with age (days postexposure) from nodular proliferat ion (174 mu m, 17 days) to hepatocellular carcinoma (1856 mu m, 62 days) an d mixed carcinomas (3209 mu m, 93 days) in adult-exposed medaka, Metastasis was observed with 19 neoplasms and tumors with the highest metastatic pote ntial were hepatocellular and mixed carcinomas. The most common form of met astasis was trans-coelomic, followed by direct invasion and distant metasta sis, presumably via the vascular route, Differences in tumor prevalence bet ween exposure groups were believed to be the result of length of DEN exposu re rather than age of fish at the time of exposure. In larval medaka with b rief (48 h) DEN exposure, neoplasms are thought to be the result of dediffe rentiation of hepatic cells, with slow progression of foci of cellular alte ration to benign and then malignant tumors. In contrast, with adult medaka and prolonged (5 week) DEN exposure, neoplasms are believed to result from initiation of committed stem cells and formation of microcarcinomas ('nodul ar proliferation'), before progressing to larger hepatocellular and then mi xed carcinomas.