|Voss, Kenneth - Ken|
Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/10/2006
Publication Date: 6/1/2006
Citation: Riley, R.T., Voss, K.A. 2006. Differential sensitivity of rat kidney and liver to fumonisin toxicity: organ specific differences in toxin accumulation and sphingoid base metabolism. Toxicological Sciences. 92(1):335-345. Interpretive Summary: Fumonisins are toxic chemicals produced by a fungus that is commonly found on maize. The Joint Expert Committee on Food Additives has recommended a tolerable daily intake in foods based on fumonisin toxicity to rat kidney. The fumonisins are known to block an enzyme that makes a unique group of fats known as sphingolipids. In liver and kidney of fumonisin fed rats there is in a marked increase in a sphingolipid known as sphinganine. This study was conducted to investigate the differential time- and dose-dependent changes in sphinganine and a breakdown product of sphinganine known as sphinganine 1-phosphates. The effects on levels of these two fats were compared to the actual levels of fumonisins in the organs and the actual damage done to the organs. There was a time- and dose-dependent increase in sphinganine in both liver and kidney that was closely correlated with the tissue concentration of fumonisin and the extent and severity of tissue damage. However, the sphinganine alone greatly under estimated the degree of disruption of fat metabolism since accumulated sphinganine was quickly metabolized to sphinganine 1-phosphate in kidney but not liver. The concentration of fumonisin in liver and kidney that first elicited an increase in sphinganine was similar in both liver and kidney, however, over time, the kidney accumulated significantly more fumonisin (10X) and total sphinganine and sphinganine 1-phosphate compared to liver. Thus, the relative sensitivity of male rat kidney and liver is most likely a consequence of differences in the mechanisms responsible for both fumonisin uptake/clearance and sphinganine metabolism. This finding is important because the rat kidney is the critical target organ used in the fumonisin risk analysis and upon which the recommended fumonisin tolerable daily intakes are based. Until now, the reason that rat kidney is more sensitive than liver to fumonisin toxicity was not known.
Technical Abstract: Fumonisins (FB) are mycotoxins in maize and are inhibitors of ceramide synthase (CS); the most likely proximate cause of FB toxicity. In liver and kidney, the primary target organs in FB fed rats, inhibition of CS results in a marked increase in the ceramide precursor sphinganine (Sa). This study was conducted to investigate the differential time- and dose-dependent changes in Sa, sphingosine (So), Sa-1-phosphate (Sa-1-P) and So-1-phosphate (So-1-P) in kidney, liver, serum and heart of male Sprague-Dawley rats (3-4 weeks old) fed diets containing 1.1, 13.5 and 88.6 ÿg/g of total FB for 10 days. The tissues were microscopically examined for the presence and severity of lesions consistent with FB exposure. There was a time- and dose-dependent increase in Sa in both liver and kidney that was closely correlated with the tissue concentration of FB1 and histopathologic findings. However, the Sa alone greatly under estimated the degree of disruption of sphingolipid metabolism since accumulated Sa and So were quickly metabolized to Sa-1-P and So-1-P as evidenced by large increases in these metabolites in kidney but not liver. The concentration of FB1 in liver and kidney that first elicited an increase in Sa was similar in both tissues, however, over time, the kidney accumulated significantly more FB1 (10X) and total Sa (Sa plus Sa-1-P) compared to liver. Thus, the relative sensitivity of male Sprague-Dawley rat kidney and liver is most likely a consequence of differences in the mechanisms responsible for both FB1 uptake/clearance and Sa metabolism.