A nonparasitic lamprey in Japan, Lethenteron reissneri, stops feeding prior to the commencement of metamorphosis. Resumption of feeding cannot take place due to major alterations in the digestive system, including loss of the gall bladder (GB) and biliary tree in the liver. This degeneration of bile ducts is considered to depend on programmed cell death or apoptosis, but molecular evidence of apoptosis remains lacking. Using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunohistochemistry with an antibody against active caspase-3, we showed that epithelial cells of the cystic duct (CD) and GB became TUNELpositive by the early metamorphosing stage. Immunohistochemical staining of active caspase-3, a key mediator in the apoptotic cascade, showed that the apoptotic signal was initiated in the region around the CD in the late larval phase. In later stages, active caspase-3-positive epithelial cells were also observed in the large intrahepatic bile duct (IHBD) and peripheral small IHBDs. At the early metamorphosing stage, bile canaliculi between hepatocytes were dilated and displayed features resembling canaliculi in cholestasis. Onset of apoptosis around the CD, which is the pathway for the storage of bile juice, and progression of apoptosis towards the large IHBD, which is the pathway for the secretion of bile juice, may lead to temporary intrahepatic cholestasis. The present study represents the first precise spatial and temporal analysis of apoptosis in epithelial cells of the biliary tract system during metamorphosis of any lamprey species. Anat Rec, 293:1155Rec, 293: -1166

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Congenital biliary dilatation is frequently complicated by biliary tract cancer, and anomalous junction of the pancreaticobiliary ductal system, a major factor constituting the pathology of this disease, is considered to be important as a back ground for carcinogenesis in the biliary tract. To clarify the mechanism of car cinogenesis in the biliary tract under the circumstance of anomalous junction, we evaluated the mutagenicity of the contents of the biliary tract in patients with congenital biliary dilatation and analyzed the nuclear atypia of the biliary epithelium by fluorocytometry. A mutagenicity test using Bacillus subtilis showed positive results in 6 of 12 patients. Since mutagenicity correlates well with car cinogenicity, these results suggest the necessity of separation surgery between the bile and pancreatic ducts in patients with anomalous junction regardless of the presence or absence of biliary dilatation. On the other hand, DNA histograms of the nuclei of gallbladder epithelial cells produced by fluorocytometry in 4 patients revealed a high incidence of polyploid DNA in 2 patients with marked hypertrophic changes. These patients were also positive for mutagenicity of the contents of the biliary tract, suggesting that mutagens are involved in the atypia at the cellular and nuclear levels.