|Sharma, R - UGA/VET MED/PHYSIOL/PHARM|
Submitted to: International IUPAC Symposium on Mycotoxins and Phycotoxins
Publication Type: Review Article
Publication Acceptance Date: August 24, 2000
Publication Date: June 1, 2001
Interpretive Summary: Review Article - No interpretive summary.
Technical Abstract: Fumonisins are suspected human carcinogens and produce species- specific toxic responses. Fumonisins, structurally related to sphingoid bases, cause accumulation of sphinganine and sphingosine in tissues. The cell-selective responses to fumonisins include necrosis and apoptosis, and even inhibition of apoptosis. The expression of proinflammatory cytokines in relationship to ceramide synthase inhibition in fumonisin B1 (FB1)-induced toxicity was investigated after five daily subcutaneous injections in male mice. Hepatopathy characterized by apoptotic hepatocytes was noticed in several strains, renal toxicity was variably present. Peritoneal macrophages derived from FB1-treated mice produced increased amount of tumor necrosis factor (TNF). Macrophages treated with FB1 in vitro also produced TNF. The acute hemopoietic effects of FB1 were abrogated by pretreatment with anti-TNF. There was an increased expression of TNF in liver, less so in kidney, but not in spleen, suggesting the source of TNF was not systemic macrophages. Hepatotoxicity by FB1 was reduced in TNF receptor knockout mice. Paradoxically, the mice carrying the human TNF-transgene had reduced hepatotoxicity to FB1; related to induction of NFKB. In all cases the toxic response to FB1 was correlated with ceramide synthase inhibition. Results strongly suggest that TNF is involved in FB-induced apoptotic response, and that the TNF pathway is ceramide synthase dependent.