Mouse Genome Informatics
cx1
    Gtf2ird1Tg(Alb1-Myc)166.8Sst/0
Tg(MtTGFA)42Lmb/0

involves: C57BL/6 * CBA * CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• three weeks after zinc administration through drinking water, the first signs of hepatic neoplasia are evident with large hepatocytes with compact nuclei being found around blood vessels
• after six weeks of zinc administration, 80% of mice display these neoplastic lesions
• after ten weeks of zinc administration, foci of dysplastic cells are found throughout the liver nodule
• intravascular spread of tumor cells is also observed ten weeks after zinc administration
• after 16 weeks of zinc administration, over 70% of mice carry single or multifocal nodules of which one quarter consist of well differentiated hepatocellular carcinomas displaying pseudoglandular or trabecular pattern
• the appearance of preneoplastic and neoplastic lesions also occur in mice with a delay of 6 to 8 weeks in mice not receiving zinc treatment


Mouse Genome Informatics
cx2
    Gtf2ird1Tg(Alb1-Myc)166.8Sst/Gtf2ird1+
Tg(MtTGFA)42Lmb/0

involves: C57BL/6 * CBA * CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
• apoptosis of large dysplastic hepatocytes is sometimes observed as part of larger dysplastic morphology changes in the liver of 2 month old mice
• most mice by 2 months of age have extensive dysplastic changes in the liver ranging from moderate cellular pleomorphism and hypertrophy to more advanced poly morphisms with severe cytomegaly and karyomegaly
• hepatocytes often display abnormal nuclear structures (tripolar mitosis, chromosome bridges, aberrant chromosomal migration, intranuclear lipid droplets, and nuclear eosinophilic pseudoinclusions)
• these dysplastic changes started in the perivascular areas of the liver, are most advanced around the central veins and are spreading throughout the hepatic lobe
• metastasis to the lung and spleen is observed only rarely
• dysplastic and neoplastic hepatocytes show the ability to penetrate vascular endothelium and accumulate in the centrilobular veins
• the liver weight/body weight ratio of young mice is significantly higher than controls
• after 4 months of age when large tumor masses are present in the liver, this ratio becomes much larger
• in mice that survive to 12 months of age, liver weight represents nearly 20% of body weight due to invasion of liver tumors into the abdominal cavity
• focal coagulative necrosis of hepatocyte groups with granulocytic reaction is sometimes observed as part of larger dysplastic morphology changes in the liver of 2 month old mice

tumorigenesis
• along with the development of hepatocellular carcinoma, non-malignant tumors also develop with a similar incidence
• malignant neoplastic lesions appear between the 3 and 4 months of age, with 100% of males and 30% of females having carcinomas by 8 months of age
• the average tumor size for male mice is 1.9 x 1.9 cm and for female mice (0.6 x 1.1 cm)
• most malignant lesions display a trabecular histological pattern but solid or pseudoglandular types are also detectable
• these malignant lesions vary from well differentiated to poorly differentiated with the latter associated with intense mitotic activity, proliferation of neocapillaries, and large areas of hemorrhagic necrosis
• in late stage lesions, small ductular-like cells are found in conjunction with inflammatory cells or scattered among tumor cells and are frequently organized into a duct-like pattern
• dysplastic and neoplastic hepatocytes show the ability to penetrate vascular endothelium and accumulate in the centrilobular veins

cellular
• apoptosis of large dysplastic hepatocytes is sometimes observed as part of larger dysplastic morphology changes in the liver of 2 month old mice

Mouse Models of Human Disease
OMIM IDRef(s)
Hepatocellular Carcinoma 114550 J:34434


Mouse Genome Informatics
cx3
    Tg(Alb1-Myc)#Sst/0
Tg(MtTGFA)42Lmb/0

involves: C57BL/6 * CBA * CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
• apoptosis of large dysplastic hepatocytes is sometimes observed as part of larger dysplastic morphology changes in the liver of 2 month old mice
• most mice by 2 months of age have extensive dysplastic changes in the liver ranging from moderate cellular pleomorphism and hypertrophy to more advanced poly morphisms with severe cytomegaly and karyomegaly
• hepatocytes often display abnormal nuclear structures (tripolar mitosis, chromosome bridges, aberrant chromosomal migration, intranuclear lipid droplets, and nuclear eosinophilic pseudoinclusions)
• these dysplastic changes started in the perivascular areas of the liver, are most advanced around the central veins and are spreading throughout the hepatic lobe
• metastasis to the lung and spleen is observed only rarely
• dysplastic and neoplastic hepatocytes show the ability to penetrate vascular endothelium and accumulate in the centrilobular veins
• the liver weight/body weight ratio of young mice is significantly higher than controls
• after 4 months of age when large tumor masses are present in the liver, this ratio becomes much larger
• in mice that survive to 12 months of age, liver weight represents nearly 20% of body weight due to invasion of liver tumors into the abdominal cavity
• focal coagulative necrosis of hepatocyte groups with granulocytic reaction is sometimes observed as part of larger dysplastic morphology changes in the liver of 2 month old mice

tumorigenesis
• along with the development of hepatocellular carcinoma, non-malignant tumors also develop with a similar incidence
• malignant neoplastic lesions appear between the 3 and 4 months of age, with 100% of males and 30% of females having carcinomas by 8 months of age
• the average tumor size for male mice is 1.9 x 1.9 cm and for female mice (0.6 x 1.1 cm)
• most malignant lesions display a trabecular histological pattern but solid or pseudoglandular types are also detectable
• these malignant lesions vary from well differentiated to poorly differentiated with the latter associated with intense mitotic activity, proliferation of neocapillaries, and large areas of hemorrhagic necrosis
• in late stage lesions, small ductular-like cells are found in conjunction with inflammatory cells or scattered among tumor cells and are frequently organized into a duct-like pattern
• dysplastic and neoplastic hepatocytes show the ability to penetrate vascular endothelium and accumulate in the centrilobular veins

cellular
• apoptosis of large dysplastic hepatocytes is sometimes observed as part of larger dysplastic morphology changes in the liver of 2 month old mice


Mouse Genome Informatics
cx4
    Nphp3pcy/Nphp3pcy
Tg(MtTGFA)42Lmb/0

involves: CD-1 * DBA/2Fg * KK
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
• at 8.5 weeks, kidney size is increased compared to in wild-type mice and Nphp3pcy homozygotes
• cysts are first observed in mice supplemented with zinc at 4 to 6.5 weeks and progresses
• at 8.5 weeks, cyst size is larger than in wild-type mice and Nphp3pcy homozygotes


Mouse Genome Informatics
tg5
    Tg(MtTGFA)42Lmb/Tg(MtTGFA)42Lmb
involves: CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• at 6 weeks of age, zinc treated females exhibit a delay in epithelium penetration into the mesenchymal fat pad compared to wild-type mice (J:28452)
• at 7 weeks of age, active epithelial cells are located in the subtending duct as well as the end bud region compared to wild-type mice in which active cells are only located in the end bud region (J:28452)
• however, by week 12 mammary development is normal (J:28452)
• the pancreas shows progressive hyperplasia of the stroma, tubular structures, and florid ductular metaplasia
• exposure to zinc increases severity of lesions
• older mice exhibit severe perilobular and intralobular fibrosis
• pancreatic fibrosis is less severe in zinc restricted mice

liver/biliary system
• mice exhibit progressive liver lesions that begin after 2 months of age with karyomegaly and cytomegaly of hepatocytes
• at 7 to 8 months of age, mice exhibit foci's heterogeneity of cell size and cellular dysplasia in the liver
• mice exhibit single to multiple foci liver nodules of 0.5 cm in diameter or greater
• liver lesions develop in a progressive fashion, with neoplasia confirmed at autopsy
• after 2 months, mice exhibit foci of hepatocytes that exhibit karyomegaly and cytomegaly
• in severe cases mice exhibit enlarged livers due to the presence of nodular masses

renal/urinary system
• mice supplemented with zinc exhibit increased mesangial compartments due to increased mesangial cell numbers and space compared to similarly treated wild-type mice
• in mice supplemented with zinc
• in mice supplemented with zinc
• mice supplemented with zinc exhibit enlarged glomeruli compared to similarly treated wild-type mice
• in female mice supplemented with zinc compared to similarly treated wild-type mice
• female mice supplemented with zinc exhibit renal cysts of distal tubule origins unlike in similarly treated wild-type mice
• renal cysts in female mice supplemented with zinc are frequently associated with fibrosis
• occasionally cysts are of proximal tubular origins
• some male mice supplemented with zinc exhibit renal cysts
• renal cysts in female mice supplemented with zinc are frequently associated with fibrosis

tumorigenesis
• mice exhibit heptatocellular carcinomas that are none metastatic
• exposure to zinc increases severity of lesions

growth/size
• in mice supplemented with zinc compared to similarly treated wild-type mice

immune system
N
• mice are not diabetic and have no obvious inflammatory reaction (J:28452)

integument
• at 6 weeks of age, zinc treated females exhibit a delay in epithelium penetration into the mesenchymal fat pad compared to wild-type mice (J:28452)
• at 7 weeks of age, active epithelial cells are located in the subtending duct as well as the end bud region compared to wild-type mice in which active cells are only located in the end bud region (J:28452)
• however, by week 12 mammary development is normal (J:28452)


Mouse Genome Informatics
tg6
    Tg(MtTGFA)42Lmb/0
involves: C57BL/6 * CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• mice develop liver tumors at the same frequency as on a CD-1 background


Mouse Genome Informatics
tg7
    Tg(MtTGFA)42Lmb/0
involves: CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• noradrenaline levels in the hypothalamus are elevated in female mice compared to wild-type mice
• serotonine levels in the cortex and brain are elevated in female mice compared to wild-type mice
• the ratio of 5-HIAA and 5-HT (indicating serotonine turn over) is reduced in the male brain stem and the female frontal cortex compared to in wild-type mice


Mouse Genome Informatics
tg8
    Tg(MtTGFA)42Lmb/0
involves: CD-1 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• Background Sensitivity: mice develop fewer liver tumors than on a CD-1 or C57BL/6 and CD-1 background