Measurement of chemically induced cell proliferation in rodent liver and kidney: a comparison of 5-bromo-2′-deoxyuridine and[3H]thymidine administered by injection or osmotic pump

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Abstract
Different labeling methods for quantitating cell proliferation were evaluated in livers and kidneys of control and chemically treated mice and rats. The percentage of cells in S-phase (labeling indices) were compared in tissues of animals given either 5-bromo-2′-deoxyurldlne (BRDU) or [3H]thymidine. These DNA precursor labels were delivered either by a single i.p. injection 2 h prior to killing the animals or via the s.c. implanted osmotic pump for 3 or 6 days. B6C3F1 mice and male F344 rats were exposed to either a peroxisome proliferator and hepatocarcinogen, Wy-14,643 (WY), in the diet at 0.1% for up to 5 days, or a non-genotoxic mouse liver and male rat kidney carcinogen, 1,4-dichlorobenzene (DCB), in corn oil by gavage for up to 5 days in mice (600 mg/kg/day) or up to 3 weeks in rats (300 mg/kg/day, 5 days per week). Labeling indices (LIs) in the liver and kidney were similar in BRDU- and [3H]thymidine-labeled mice and rats. Cell proliferation was increased in the livers of both species of WY- and DCB-treated animals when compared to controls. After 4 days of chemical treatment with continuous administration of a DNA precursor label during the last 3 days of treatment, LIs in controls, DCB- and WY-treated mouse livers were 0.7, 19 and 17% for BRDU and 0.9, 15 and 13% for [3H]thymidine respectively. Furthermore, BRDU and [3H]thymidine labeled the same population of cells as revealed by similar patterns of cell labeling in the livers and kidneys of treated animals. The LI for BRDU- and [3H]thymidinelabeled renal proximal tubular cells was 7.7 and 8.0% respectively, in rats receiving DCB for 4 days and DNA precursor label during the last 3 days of treatment, while the LI for controls was 4.3 and 3.7% respectively. The renal proximal tubular cell LI increased to 11% in BRDU-labeled rats treated with DCB for 3 weeks. LIs in both liver and kidney were greatest in control and treated animals that received the DNA precursor label via osmotic pumps for 6 days, and least in 2 h pulse-labeled animals. However, induction of hepatic LI in treated over control animals was greatest for treated animals labeled for 3 days. These results demonstrate comparable cell labeling of cells in S-phase with either BRDU and [3H]thymidine labeling methods. BRDU presents no radioactive containment problems, and results are obtained more rapidly than [3H] In the present study, BRDU administered in a 3 day osmotic pump was judged to be the method of choice for assessing chemically induced cell proliferation.

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