Vol. 285, Issue 1, 317-324, April 1998

Tumor Necrosis Factor- as a Contributor in Fumonisin B₁ Toxicity¹

Raviprakash R. Dugyala² , Raghubir P. Sharma, Masashi Tsunoda and Ronald T. Riley

Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia (R.R.D., R.P.S., M.T.), and Toxicology and Mycotoxin Research Unit, Agricultural Research Service, United States Department of Agriculture (R.T.R.), Athens, Georgia

Fumonisin B₁ is a toxic product of Fusarium moniliforme, which inhibits ceramide synthase, leading to accumulation of free sphingoid bases. Despite its known biochemical action, the mechanism of toxicity is not fully understood. Male BALB/c mice were injected subcutaneously with 0 to 6.75 mg/kg/day of fumonisin B₁ for 5 days. One day after the last treatment, spleens were collected, and peritoneal macrophages were obtained from separate groups after an intraperitoneal injection of thioglycolate broth. Peripheral leukocyte counts were increased and kidney weights were decreased by fumonisin B₁ treatment. Presence of apoptotic cells in the liver and kidney of treated mice was confirmed by enzymatic immunoassay. Macrophages cultured with lipopolysaccharide indicated an increased secretion of tumor necrosis factor- (TNF-) but not of interleukin-1. No effect was seen on interferon- production when splenocytes were incubated with concanavalin A. Elevation of leukocyte and reticulocyte counts was abrogated by pretreatment with anti-TNF- antibody before a single dose of fumonisin B₁ (25 mg/kg), supporting the hypothesis that the fumonisin B₁ toxicity involves TNF-. Cultures of J774A.1 cells, when treated with fumonisin B₁, produced TNF- in vitro. Results indicate that fumonisin B₁ toxicity may involve secretion of TNF- by TNF--producing cells without altering interleukin-1 or interferon-. The influence on TNF--production may be a contributing factor to fumonisin B₁-induced apoptosis and other observed toxic effects in animals.