|Voss, Kenneth - Ken|
|Merrill, Jr., A|
Submitted to: Environmental Health Perspectives
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2000
Publication Date: 5/1/2001
Citation: Interpretive Summary: Fumonisin is a chemical produced by a mold that grows on corn throughout the world. This chemical is now known to cause cancer in the liver and kidney of laboratory rodents (rats and mice). But fumonisins do not act directly on the genetic material (DNA) of the animals. Thus they are considered to be non-genotoxic carcinogens. The question then is "how do fumonisins cause cancer in animals"? There is growing evidence that the fumonisins cause cancer by changing the way that a very unusual group of fats are made inside cells. The group of fats that are changed are called "sphingolipids". They are named after the mysterious sphinx of Greek and Egyptian mythology. They were so named because their function in cells was unknown and they were very difficult to work with. Recently, however, it has become clear that these mysterious fats play a ver important role in regulating now cells behave and especially how and when cells are selected to live or die. Because cancer is a disease where cells that should die do not die, chemicals like the fumonisins that change the way sphingolipids are made and broken down, could cause cells that should die to not die and cells that should not die to die. If the cells that survive have defects in their DNA, then the defective DNA will persist. Persistence of defective DNA could increase the risk of cancer.
Technical Abstract: Altered sphingolipid metabolism is associated with fumonisin-induced animal diseases including increased oncosis, and carcinogenesis in rodent liver and kidney. The biochemical consequences of fumonisin-disruption of sphingolipid metabolism most likely to alter cell regulation are: increased free sphingoid bases and their 1-phosphates, alterations in complex sphingolipids, and decreased ceramide biosynthesis. Because free sphingoid bases and ceramide can induce cell death, the fumonisin inhibition of ceramide synthase can inhibit cell death induced by ceramide, but can promote free sphingoid base-induced cell death. Theoretically, at any time the balance between the intracellular concentration of effectors that protect cells from apoptosis (decreased ceramide, increased sphingosine 1-phosphate) and those that induce apoptosis (increased ceramide, free sphingoid bases, altered fatty acids) will determine the cellular response. The balance between the rates of apoptosis and proliferation are important in tumorigenesis. Cells sensitive to the proliferative effect of decreased ceramide and increased sphingosine 1-phosphate may be selected to survive and proliferate when free sphingoid base concentration is not growth inhibitory. Conversely, if the increase in free sphingoid bases exceeds a cell's ability to convert sphingoid bases to ceramides or sphingoid base 1-phosphates, then free sphingoid bases will accumulate. In this case cells that are sensitive to sphingoid base induced growth arrest will die and insensitive cells will survive. If the cells selected to die are normal phenotypes and the cells selected to survive are abnormal, then cancer risk will increase.