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ARS Home » Southeast Area » Athens, Georgia » U.S. National Poultry Research Center » Toxicology & Mycotoxin Research » Research » Publications at this Location » Publication #314939
Title: In vivo Metabolism of Hydrolyzed Fumonisin B1 and Fumonisin B1

Author
item HARRER, HENNING - Muenster University
item HUMPF, HANS-ULRICH - Muenster University
item Voss, Kenneth

Submitted to: Annual Meeting of the UNJR Panel on Toxic Microorganisms
Publication Type: Abstract Only
Publication Acceptance Date: 1/25/2015
Publication Date: 1/25/2015
Citation: Harrer, H., Humpf, H., Voss, K.A. 2015. In vivo Metabolism of Hydrolyzed Fumonisin B1 and Fumonisin B1. Annual Meeting of the United States Japan Cooperative Program on the Development and Utilizatin of Natural Resources. January 25-30, 2015. New Orleans, Louisiana.

Interpretive Summary:

Technical Abstract: Fumonisin B1 (FB1) is the most prevalent fumonisin mycotoxin found in corn and corn-based foods. It inhibits ceramide synthase, disrupts sphingolipid metabolism and function, is toxic to animals, causes cancer in rodents, and induces neural tube defects in some mouse strains. Its human health effects are uncertain, however, evidence suggests that FB1 is a possible risk factor for cancer and birth defects in populations consuming large amounts of food prepared from contaminated corn. Hydrolyzed FB1 (HFB1) is significantly less toxic to rodents in vivo. It is formed from FB1 during alkaline cooking and found in food products such as masa and tortillas. HFB1 and to a lesser extent FB1 are acylated by ceramide synthase in vitro to ceramide-like compounds known as N-acyl-HFB1 (NAHFB1; also known as N-acyl-AP1) and N-acyl-FB1 (NAFB1), respectively. Studies were therefore done to determine if HFB1 and FB1 are similarly metabolized in vivo using male rats as a model species. In the first trial, the animals were given five daily intraperitoneal (ip) doses of 0 (saline vehicle, n=2) or approximately 0.25, 0.56 or 1.1 mg/kg body weight HFB1 (n=3/group) five consecutive days. In the second study (n=2/group), 0, 0.5, 1.0 or 2.0 mg/kg body weight FB1 or 1.0 mg/kg body weight HFB1 were given ip for five days. One to two hours after the last dose, two rats per group from the first study and all from the second were euthanized. The remaining HFB1-treated animals (first study) were euthanized after a three week “recovery period”. Liver and kidney specimens were collected at necropsy and subsequently processed for HPLC-MS/MS biochemical analyses and microscopic examinations. NAHFB1 was found in liver and kidney. In the first study, metabolites having longer chain fatty acyl moieties predominated with C24 (up to 2.4 nmol/g) NAHFB1 being most prominent followed by C24:1 (0.8 nmol/g), and C22 (0.25 nmol/g) species. No NAHFB1 was detected after the three week recovery period. NAFB1 metabolites were found at concentrations ranging of up to 0.25nmol/g in liver and 0.4nmol/g in kidney during the second trial. NAHFB1 was also found in both tissues at average concentrations of about 0.5 (liver) to 2.7 (kidney) nmol/g. Total FB1 and HFB1 species (parent mycotoxin plus N-acyl metabolites) recovered represented only a small portion of the total dose. Most of the FB1 species found in kidney was unmetabolized mycotoxin: < 0.9% of the dose was recovered as FB1 but <0.1% of the dose was recovered as NAFB1 metabolites. Low but approximately equal amounts of HFB1 and NAHFB1 metabolites (each representing <0.1% of dose) were detected. Greater amounts of HFB1 species (ca. 1.8% of dose) than FB1 species (0.2% to 0.8% of dose) were found in liver but in contrast to kidney about half (40-60%) of both HFB1 and FB1 species were metabolites. N-acyl chain lengths of NAHFB1 and NAFB1 metabolites varied in a tissue-dependent manner. Similar to ceramides, shorter chain lengths (i.e. C16) were more common in kidney whereas longer chains (i.e. C24) were prevalent in liver. This pattern presumably reflected the predominant ceramide synthase isoforms in the two tissues. Microscopic lesions or changes in tissue sphingolipid concentrations were not found in either study in the rats given HFB1 whereas apoptosis, elevated total (sphingoid base plus sphingoid base 1-phosphate) sphinganine and total sphingosine concentrations, and decreased ceramide concentrations were found in both tissues of rats given FB1. In summary, these studies demonstrated for the first time the in vivo metabolism of small amounts of HFB1 and FB1 to ceramide like N-acylated metabolites. The toxicological significance of these novel metabolites is currently unknown.