PCB 153, a non-dioxin-like tumor promoter, selects for β-catenin (Catnb)-mutated mouse liver tumors

Julia Strathmann, Michael Schwarz, Job C. Tharappel, Howard P. Glauert, Brett T. Spear, Larry W. Robertson, Klaus E. Appel, Albrecht Buchmann

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants which act as liver tumor promoters in rodents and can be classified as either dioxin-like or non-dioxin (phenobarbital [PB])-like inducers of cytochrome P-450. Since we have previously shown that tumor promotion by PB leads to clonal outgrowth of β-catenin (Catnb)- mutated but not Ha-ras-mutated mouse liver tumors, we were interested to know whether the non-dioxin-like tumor promoter 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB 153) shows the same selective pressure during tumor promotion. Male B6129SF2/J mice were given a single injection of N-nitrosodiethylamine (90 mg/kg body weight) at 9 weeks of age, followed by 39 weeks of treatment with PCB 153 (20 biweekly ip injections of 300 μmol/kg body weight) or corn oil as a control. Animals were killed 15 weeks after the last PCB 153 injection and liver tumors were identified by immunohistochemical staining of glutamine synthetase (GS) and analyzed for Catnb, Ha-ras, and B-raf mutations. Quantitative analyses revealed that GS-positive tumors were much larger and more frequent in livers from PCB 153-treated mice than in control animals, whereas GS-negative tumors were similar in both groups. Almost 90% (34/38) of all tumors from PCB 153-treated animals contained Catnb mutations, which compares to ∼ 45% (17/37) of tumors in the control group. Ha-ras- and B-raf-mutated liver tumors were rare and not significantly different between treatment groups. These results clearly indicate that PCB 153 strongly selects for Catnb-mutated, GS-positive liver tumors, which is similar to the known action of PB, a prototypical tumor promoter in rodent liver.

Original languageEnglish
Pages (from-to)34-40
Number of pages7
JournalToxicological Sciences
Volume93
Issue number1
DOIs
StatePublished - Sep 15 2006

Bibliographical note

Funding Information:
We acknowledge the excellent technical assistance of Elke Zabinsky. This work was financially supported by the Federal Institute for Risk Assessment, Berlin, Germany, the National Institutes of Health (ES 07380, ES 013661), the Department of Defense (DAMD 17-02-1-0241), and the Kentucky Agricultural Experiment Station. The financial support of the Alexander von Humboldt Foundation is also gratefully acknowledged.

Keywords

  • Catnb mutations
  • Mouse liver
  • Polychlorinated biphenyls
  • Tumor promotion
  • β-catenin

ASJC Scopus subject areas

  • Toxicology

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