Archives of Toxicology

, Volume 66, Issue 7, pp 503–507 | Cite as

Cell proliferation induced in the kidneys and livers of rats and mice by short term exposure to the carcinogen p-dichlorobenzene

  • Takashi Umemura
  • Kenji Tokumo
  • Gary M. Williams
Original Investigations


Cell proliferation in the kidneys and livers of rats and mice exposed short-term to p-dichlorobenzene (p-DCB) was evaluated by immunohistochemical measurement of bromodeoxyuridine (BrdU) incorporation into nuclei of DNA-synthesizing cells. p-DCB was given by gavage at two doses up to 600 mg/kg body weight for 4 days. The cumulative fraction of proliferating cells was increased in the proximal tubule epithelial cells of male rats at the high dose, but not at the low dose nor in females at either dose using gamma-glutamyl transferase reaction to identify tubular cells. Also, no increase in cell proliferation was found in mouse kidneys. The fractions of proliferating cells in the livers of rats and mice of both sexes were also increased. The increased cell proliferation in only male rat kidney and in the livers of mice of both sexes correlates with the reported carcinogenic effects of p-DCB in those tissues. However, the finding that p-DCB also induced cell proliferation in the livers of rats of both sexes, which were not a site of p-DCB-induced tumors in bioassays, and in female mice at the low dose, which was not affected by an increase in tumors, reveals a lack of concordance and indicates that acute induction of cell proliferation is not sufficient to lead to carcinogenesis.

Key words

Kidney Liver Cell proliferation Rat Mouse p-Dichlorobenzene 


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  1. Baserga R (ed) (1971) The cell cycle and cancer. The biochemistry of disease, Vol. 1. Marcel Dekker, Inc., New YorkGoogle Scholar
  2. Bomhard E, Luckhaus G, Voight W-H, Loeser E (1988) Induction of light hydrocarbon nephropathy by p-dichlorobenzene. Arch Toxicol 61: 433–439PubMedGoogle Scholar
  3. Charbonneau M, Lock EA, Strasser J, Cox MG, Turner MJ, Bus JS (1987) 2,2,4-Trimethylpentane-induced nephrotoxicity: Metabolic disposition of TMP in male and female Fischer 344 rats. Toxicol Appl Pharmacol 91: 171–181PubMedGoogle Scholar
  4. Charbonneau M, Strasser J Jr, Lock EA, Turner MJ Jr, Swenberg JA (1989) Involvement of reversible binding to alpha-2u-globulin in 1,4-dichlorobenzene-induced nephrotoxicity. Toxicol Appl Pharmacol 99: 122–132PubMedGoogle Scholar
  5. Columbano A, Ledda-Columbano GM, Ennas MG, Curto M, Chelo A, Pani P (1990) Cell proliferation and promotion of rat liver carcinogenesis: different effect of hepatic regeneration and mitogen induced hyperplasia on the development of enzyme-altered foci. Carcinogenesis 11: 771–776PubMedGoogle Scholar
  6. Eldridge SR, Tilbury LF, Goldsworthy TL, Butterworth BE (1990) 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. Carcinogenesis 11: 2245–2251PubMedGoogle Scholar
  7. Harms G, Goor HV, Koudstaar J, Ley LD, Hardonk MJ (1986) Immunohistochemical demonstration of DNA-incorporated 5-bromodeoxyuridine in frozen and plastic embedded sections. Histochemistry, 85: 139–143PubMedGoogle Scholar
  8. Hsu S, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques. A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: 577–580PubMedGoogle Scholar
  9. Lanier TL, Berger EK, Eacho PI (1989) Comparison of 5-bromo-2-deoxyuridine and [3H]thymidine for studies of hepatocellular proliferation in rodents. Carcinogenesis 10: 1341–1343PubMedGoogle Scholar
  10. Lock EA, Charbonneau M, Strasser J, Swenberg JA, Bus JS (1987) 2,2,4-Trimethylpentane-induced nephrotoxicity: The reversible binding of a TMP metabolite to a renal protein fraction containing alpha-2u-globulin. Toxicol Appl Pharmacol 91: 182–192PubMedGoogle Scholar
  11. Loser E, Litchfield MH (1983) Review of recent toxicology studies on p-dichlorobenzene. Food Chem Toxicol 21 [82]: 825–832PubMedGoogle Scholar
  12. Marsman DS, Cattley RC, Conway JE, Popp JA (1988) Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phtalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]-acetic acid (Wy-14643), in rats. Cancer Res 48: 6739–6744PubMedGoogle Scholar
  13. National Toxicology Program Technical Report (1987) Toxicology and Carcinogenesis studies of 1,4-dichlorobenzene (CAS No. 106-46-7) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 319. NIH Publication no. 87-2575Google Scholar
  14. Ohmori T, Hiasa Y, Murata Y, Williams GM (1982) Gamma-glutamyl transpeptidase activity in carcinogen-induced epithelial lesions of rat kidney. Gann 73: 543–548PubMedGoogle Scholar
  15. Rutenburg AM, Kim H, Fischbein JW, Hanker JS, Wasserkrug HL, Seligman AM (1969) Histochemical and ultrastructural demonstration of gamma-glutamyl transpeptidase activity. J Histochem Cytochem 17: 517–526PubMedGoogle Scholar
  16. Schutte B, Reynders MMJ, Bosman FT, Blijham GH (1987) Effect of tissue fixation on anti-bromodeoxyuridine immunohistochemistry. J Histochem Cytochem 35: 1343–1345PubMedGoogle Scholar
  17. Spater HW, Poruchynsky MS, Quintan N, Inoue M, Novikoff AB (1982) Immunocytochemical localization of gamma glutamyltransferase in rat kidney with protein A-horseradish peroxidase. Proc Natl Acad Sci USA 79: 3547–3550PubMedGoogle Scholar
  18. Umemura T, Takada K, Ogawa Y, Kamata E, Saito M, Kurokawa Y (1990) Sex difference in inhalation toxicity of p-dichlorobenzene (p-DCB) in rats. Toxicol Lett 52: 209–214PubMedGoogle Scholar
  19. Ward JM, Hagiwara A, Anderson LM, Lindsey K, Diwan BA (1988) The chronic hepatic or renal toxicity of Di(2-ethylhexyl) phthalate, acetaminophen, sodium barbital, and phenobarbital in male B6C3F1 mice: autoradiographic, immunohistochemical, and biochemical evidence for levels of DNA synthesis not associated with carcinogenesis or tumor promotion. Toxicol Appl Pharmacol 96: 494–506PubMedGoogle Scholar
  20. Williams GM, Watanabe K (1978) Quantitative kinetics of development of N-2-fluorenylacetamide-induced altered (hyperplastic) hepatocellular foci resistant to iron accumulation and of their reversion or persistence following removal of carcinogen. J Natl Cancer Inst 61: 113–121PubMedGoogle Scholar
  21. Williams GM, Weisburger JH (1991) Chemical carcinogen. In: Doull J, Klaassen C, Amdur M (eds) Casarett and Doull's Toxicology. The basic sciences of poisons, 4th Edition. McMillan Publishing Co., New York, pp 127–200Google Scholar
  22. Yelandi AV, Milano M, Subbarao V, Reddy JK, Rao MS (1989) Evaluation of cell proliferation during ciprofibrate-induced hepatocarcinogenesis. Cancer Lett 47: 21–27PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Takashi Umemura
    • 1
  • Kenji Tokumo
    • 2
  • Gary M. Williams
    • 3
  1. 1.Division of ToxicologyNational Institute of Health SciencesTokyoJapan
  2. 2.First Department of Internal MedicineMedical School of Hiroshima UniversityHiroshimaJapan
  3. 3.Division of Pathology and ToxicologyAmerican Health FoundationValhallaUSA

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