Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: fumonisin B(1) as an example.
The rates of cell proliferation and cell loss in conjunction with the differentiation status of a tissue are among the many factors contributing to carcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F(1) mice, the mycotoxin fumonisin B(1) caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BD-IX rats, fumonisin B(1) caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B(1) exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following fumonisin B(1) administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by fumonisin B(1). Fumonisin B(1) is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA-synthesis assay. Fumonisin B(1) may be the first example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration.
Dragan
Y P
YP
Ohio State University, James Cancer Center, 1148 James CHRI, 300 W. 10th Avenue, Columbus, Ohio 43210-1240, USA.
Bidlack
W R
WR
Cohen
S M
SM
Goldsworthy
T L
TL
Hard
G C
GC
Howard
P C
PC
Riley
R T
RT
Voss
K A
KA
D000349:Africa / Q000453:epidemiology; D000818:Animals; D017209:Apoptosis; D002264:Carboxylic Acids / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity*; D002681:China / Q000453:epidemiology; D004247:DNA / Q000378:metabolism*; D003657:Decision Making; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000150:complications* / Q000453:epidemiology; D005260:Female; D037341:Fumonisins; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009183:Mycotoxins / Q000145:classification / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012307:Risk Factors; D013107:Sphingolipids / Q000378:metabolism*
D002264:Carboxylic Acids; D037341:Fumonisins; D009183:Mycotoxins; D013107:Sphingolipids; C056933:fumonisin B1; D004247:DNA