Glutathione S-transferase-placental form expression and proliferation of hepatocytes in fumonisin B1-treated male and female Sprague-Dawley rats.
Fumonisin B1 (FB1), a mycotoxin produced by a common corn contaminant Fusarium moniliforme and a hepatocarcinogen in rats, has been previously suggested to act as a poor initiator, but a better promoter of gamma-glutamyltranspeptidase (GGT)-positive rat liver preneoplastic lesions. Using glutathione S-transferase-placental form (GSTP) as a more sensitive marker of initiation, we have further evaluated the initiating capacity of various doses of purified FB1 administered (a) intraperitoneally (i.p.) to male Sprague-Dawley (SD) rats for 4 days and (b) orally (PO) to male and female SD rats for 11 days. Compared to their respective controls, significant increases in GSTP-positive hepatocytes were observed in male rats administered FB1 i.p. at 10 mg/kg body weight/day for 4 days, as well as in male and female rats treated with 35 and 75 mg/kg body weight/day FB1 p.o. for 11 days. The percentage section area of liver occupied by GSTP-positive mini-foci comprising of three to 12 cells was increased significantly in male rats given 10 mg/kg FB1 i.p., or in p.o.-treated males and females with 75 mg/kg FB1. Both i.p. and p.o. FB1 treatments resulted in dose-related enhanced hepatocyte proliferation as measured by proliferating cell nuclear antigen (PCNA) labeling with significant increases in the number of PCNA-positive nuclei at the same i.p. and p.o. dose levels where the number of GSTP-positive cells were elevated. In all studies, enhanced PCNA and GSTP expression occurred at FB1 doses which, based on serum biochemical and histopathological data previously reported from our laboratory, were shown to be hepatotoxic. Therefore, our data suggest that in a manner similar to known genotoxic carcinogens, FB1 has the capacity to initiate GSTP-positive hepatocytes with their subsequent development into GSTP mini-foci at exposure levels that induce enhanced hepatocyte proliferation in response to liver toxicity. In SD rats, this occurs as early as within 4 days of i.p. treatment or 11 days of p.o. treatment.
Mehta
R
R
Toxicology Research Division # 2204D2, Bureau of Chemical Safety, Health Canada, Ottawa, Ontario. rekha_mehta@hc-sc.gc.ca
Lok
E
E
Rowsell
P R
PR
Miller
J D
JD
Suzuki
C A
CA
Bondy
G S
GS
D000284:Administration, Oral; D000818:Animals; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D002274:Carcinogens, Environmental / Q000494:pharmacology*; D002455:Cell Division; D005260:Female; D037341:Fumonisins; D005982:Glutathione Transferase / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009183:Mycotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D010920:Placenta / Q000737:chemistry; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D002264:Carboxylic Acids; D002274:Carcinogens, Environmental; D037341:Fumonisins; D009183:Mycotoxins; D018809:Proliferating Cell Nuclear Antigen; C056933:fumonisin B1; D005982:Glutathione Transferase