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Toxicologic Pathology
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An In Vivo Method for Using 5-Bromo-2'-deoxyuridine (BrdU) as a Marker of Chemically-Induced Hepatocellular Proliferation in the Japanese Medaka (Oryzias latipes)

Linda M. Brennan

GEO-CENTERS, INC, Fort Detrick, Maryland 21702-5010

E. Maxine Boncavage-Hennessey

GEO-CENTERS, INC, Fort Collins, Colorado 80523

Marilyn J. Wolfe

Experimental Pathology Laboratories, Herndon, Virginia 20172

Margaret W. Toussaint

GEO-CENTERS, INC, Fort Detrick, Maryland 21702-5010

William E. Dennis

GEO-CENTERS, INC, Fort Detrick, Maryland 21702-5010

Alan B. Rosencrance

US Army Center for Environmental Health Research, Fort Detrick, Maryland 21702-5010

Henry S. Gardner, JR

US Army Center for Environmental Health Research, Fort Detrick, Maryland 21702-5010, hgardner{at}lamar.colostate.edu

Japanese medaka fish ( Oryzias latipes) were used to develop an in vivo method to assess hepatocellular proliferation in a nonmammalian model. Proliferative responses were assessed in medaka at 7, 17, 24, and 94 days after a 48-hour exposure to 10 or 100 mg/L diethylnitrosamine (DEN). Subgroups of medaka were exposed to 50 or 75 mg/L of 5-bromo-2'-deoxyuridine (BrdU) in water for 72 hours, sacrificed, and then processed for immunohistochemical staining. Proliferative indices of BrdU-labeled hepatocytes were quantified and compared using both count and area measurements. There was a significant increase (p < 0.05) in hepatocellular proliferation in the 100 mg/L DEN-treated fish as compared to controls and 10 mg/L DEN-treated fish for the first 3 time points. Hepatocarcinogenicit y was evaluated 26 weeks post-DEN exposure. There was a significant increase (p < 0.0001) in hepatocellular neoplasms in 100 mg/L DEN-treated fish compared to other fish. Effective BrdU-labeling of S-phase hepatocytes in medaka was achieved by adding BrdU to the aquarium water, and an increase in hepatocellular proliferation using this method was detected 7 days after exposure to a carcinogenic concentration of DEN. Additionally, the new method of area measurement indices of proliferation were as precise as count indices (R2≥0.92).

Key Words: 5-bromo-2'-deoxyuridine • Japanese medaka • diethylnitrosamine • carcinogenesis • cell proliferation • labeling index • hepatocarcinogenesis

Toxicologic Pathology, Vol. 29, No. 3, 387-397 (2001)
DOI: 10.1080/019262301316905354
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M. W. Toussaint, A. B. Rosencrance, L. M. Brennan, W. E. Dennis, J. R. Beaman, M. J. Wolfe, F. J. Hoffmann, and H. S. Gardner JR
Chronic Toxicity of Bromodichloromethane to the Japanese Medaka (Oryzias latipes)
Toxicol Pathol, October 1, 2001; 29(6): 662 - 669.
[Abstract] [PDF]