PCB 153, a non-dioxin-like tumor promoter, selects for beta-catenin (Catnb)-mutated mouse liver tumors.
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 beta-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 mumol/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 approximately 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.
Strathmann
Julia
J
Department of Toxicology, University of Tuebingen, 72074 Tuebingen, Germany.
Schwarz
Michael
M
Tharappel
Job C
JC
Glauert
Howard P
HP
Spear
Brett T
BT
Robertson
Larry W
LW
Appel
Klaus E
KE
Buchmann
Albrecht
A
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D017931:DNA Primers; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D009154:Mutation; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051176:beta Catenin / Q000235:genetics*
D002273:Carcinogens; D017931:DNA Primers; D051176:beta Catenin; D011078:Polychlorinated Biphenyls; C014024:2,4,5,2',4',5'-hexachlorobiphenyl