Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B1 in the F344/N/Nctr BR rat.
Fumonisin B1(FB1) is a fungal metabolite of Fusarium verticillioides (= F. moniliforme), a fungus that grows on many crops worldwide. Previous studies demonstrated that male BD IX rats consuming diets containing 50 ppm fumonisin B1 developed hepatocellular carcinomas. In our recent studies, diets containing FB1 at 50 ppm or higher concentrations induced renal tubule carcinomas in male F344/N/Nctr BR rats and hepatocellular carcinomas in female B6C3F1/Nctr BR mice. The carcinogenicity of FB1 in rats and mice is not due to DNA damage, as several laboratories have demonstrated that FB1 is not a genotoxin. FB1 induces apoptosis in cells in vitro. Including FB1 in the diets of rats results in increased hepatocellular and renal tubule epithelial cell apoptosis. In studies with F344/N/Nctr BR rats consuming diets containing up to 484 ppm FB1 for 28 days, female rats demonstrated more sensitivity than male rats in the induction of hepatocellular apoptosis and mitosis. Conversely, induction of renal tubule apoptosis and regeneration were more pronounced in male than in female rats. Induction of renal tubule apoptosis and hyperplasia correlated with the incidence of renal tubule carcinomas that developed in the 2-year feeding study with FB1 in the F344/N/Nctr BR rats. The data are consistent with the hypothesis that the induction of renal tubule carcinomas in male rats could be partly due to the continuous compensatory regeneration of renal tubule epithelial cells in response to the induction of apoptosis by fumonisin B1.
Howard
P C
PC
National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA. phoward@nctr.fda.gov
Warbritton
A
A
Voss
K A
KA
Lorentzen
R J
RJ
Thurman
J D
JD
Kovach
R M
RM
Bucci
T J
TJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D002264:Carboxylic Acids / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002470:Cell Survival; D004848:Epithelium / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D037341:Fumonisins; D022781:Hepatocytes / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000503:physiopathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008938:Mitosis / Q000187:drug effects; D009183:Mycotoxins / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012038:Regeneration / Q000187:drug effects*
D002264:Carboxylic Acids; D002274:Carcinogens, Environmental; D037341:Fumonisins; D009183:Mycotoxins; C056933:fumonisin B1