|Howard, Paul - NCTR/FDA, JEFFERSON, AR|
|Warbritton, Alan - PATH ASSOC INTL/NCTR, AR|
|Lorentzen, Ronald - CFSAN/FDA, WASHINGTON, DC|
|Thurman, J Dale - PATH ASSOC INTL/NCTR, AR|
|Kovach, Robert - PATH ASSOC INTL/NCTR, AR|
|Bucci, Thomas - PATH ASSOC INTL/NCTR, AR|
Submitted to: Environmental Health Perspectives
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 16, 2000
Publication Date: May 1, 2001
Interpretive Summary: Fumonisin B1 and other fumonisins are toxins made by Fusarium molds. They occur in corn and corn-based foods and some evidence suggests that fumonisins cause esophageal cancer in some humans. Fumonisin B1 caused cancer in rats and mice, but the sequence of events leading to cancer formation (mode of action) is not understood. Fumonisins cause a type of cell death known as apoptosis. We hypothesized that apoptosis and regeneration (increased cell division to replace apoptotic cells in tissues) are an important part of fumonisin's mode of action. Rats were fed diets containing fumonisin B1, and apoptosis and cell division in liver and kidney were evaluated. Both occurred more readily in the liver of female rats compared to males, whereas apoptosis and regeneration were more pronounced in the kidneys of males. Both results are consistent with the degree of liver and kidney injury caused by fumonisins in females and males, respectively. Furthermore, kidney apoptosis and regeneration were correlated with the number of kidney tumors found in male rats fed fumonisin B1 for up to 2 years. Altogether, the findings indicate that apoptosis and regeneration do play an important role in cancer induction by fumonisins. Determining the mode of action is important for comparing the effects of fumonisins among species and, ultimately, for determining if fumonisins pose a cancer risk to humans.
Technical Abstract: Fumonisin B1 (FB1) is a mycotoxin made by Fusarium moniliforme, a fungus found in corn worldwide. Fumonisins are suspected human carcinogens. In rats fed diets with >50 ppm FB1, FB1 was carcinogenic to liver (BD IX males) or kidney (F344 males). FB1, >50 ppm in the diet, was also hepatocarcinogenic to female B6C3F1 mice. Several groups have shown that FB1 is not genotoxic. Carcinogenicity of FB1 therefore likely involves a (was yet undefined) nongenotoxic mode of action. FB1 causes apoptosis in vitro and in in vivo. We fed diets having <484 ppm FB1 to F344 rats for 28 days. Apoptosis and mitosis in liver and kidney were evaluated using histochemical techniques. Females were more sensitive to induction of hepatocellular apoptosis and mitosis then males, a result consistent with observations that female rats are more sensitive to FB1-induced hepatotoxicity. Conversely, renal tubule apoptosis and regeneration were more pronounced in males. Induction of renal tubule apoptosis and hyperplasia were correlated with the incidences of renal tubule carcincomas found in male F344 rats fed FB1 for two years. Based on these findings, it is hypothesized that continuous compensatory regeneration of tubule epithelial cells, in response to ongoing cell loss caused by FB1-induced apoptosis, is a key element in the nongenotoxic mode of action of FB1.