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Title: DEMONSTRATION OF IN-SITU APOPTOSIS IN MOUSE LIVER AND KIDNEY AFTER SHORT-TERM REPEATED EXPOSURE TO FUMONISIN B1

Author
item SHARMA, RAGHUBIR - VET. MED./UGA, ATHENS, GA
item DUGYALA, RAVIPRAKASH - VET. MED./UGA, ATHENS, GA
item Voss, Kenneth

Submitted to: Journal of Comparative Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/11/1997
Publication Date: N/A
Citation: N/A

Interpretive Summary: Fumonisins are toxins produced by molds called Fusarium moniliforme that grow on corn. Fumonisins cause fatal diseases in horses and swine, and are suspected causes of human esophageal cancer. Scientists at RRC established that fumonisins induce toxicity by altering a specific metabolism of lipid called sphingolipids. However, other events leading up pto disease development are not well characterized. One RRC scientist in collaboration with UGA scientists injected mice with different levels of fumonisin for five days. It was established that a certain type of specific programmed cell death, referred to as apoptosis, was increased in the liver and kidneys of treated mice. Apoptosis, which is the process by which abnormal cells are removed from organs, is regulated by sphingolipid and is believed to play a role in cancer development. These findings contribute fundamental information to the mechanism of fumonisin toxicity which is important for evaluating the role of the fumonisins in health risk to humans and agriculturally important animals.

Technical Abstract: Fumonisin B1, a mycotoxin produced by Fusarium moniliforme, is associated with moldy corn. It is a potent inhibitor of ceramide synthetase, the key enzyme in sphingolipid biosynthesis, leading to accumulation of sphinganine and sphingosine. Ceramide and other sphingolipid pathways have been implicated in signal-induced apoptosis in cells. It was previously reported that fumonisin B1 induced apoptosis in cultured human keratinocyte and CV-1 cells, but not in COS-7 cells. Apoptosis was proposed as a mechanism for toxicity in mammalian target organs, however, direct evidence of such process has been lacking. In the current study, male BALB/c mice were injected subcutaneously with 0, 0.25, 0.75, 2.25, and 6.25mg/kg fumonisin B1 daily for 5 days and their liver and kidneys were sampled 1 day after the last injection. A decrease in kidney weights was observed after fumonisin treatment. A blind-random microscopic evaluation of stained sections revealed dose-dependent fumonisin B1-associated hepatic and renal lesions in all groups. Terminal UTP nick-end apoptotic cells at all treatment levels. It is apparent that fumonisin B1 toxicity involves apoptotic process at relatively low doses after a brief exposure. Parenteral administration of fumonisin B1 was more toxic than that previously reported after oral feeding. The exact mechanism of how an apoptotic signal is initiated is under investigation.