Location: Toxicology & Mycotoxin Research2011 Annual Report
1a. Objectives (from AD-416)
Determine the role of fumonisin exposure in the high incidence of neural tube defects (NTDs) in consumers of maize products.
1b. Approach (from AD-416)
Utilize information developed from Creighton University studies in mouse models to assess and validate the use of sphingolipid and genetic mechanism-based and fumonisin exposure-based biomarkers in women from populations known to consume large amounts of maize potentially contaminated with fumonisin.
3. Progress Report
The progress reported here is for work conducted to address objectives 2 (develop biomarkers for fumonisin exposure and effects) and 3 (validate biomarkers in humans) of the parent in house project. The question we wish to answer is whether or not fumonisin, a toxin found in corn, is in any way contributing to the high incidence of neural tube defects (NTD) seen in people who consume large amounts of corn and whose diets are likely to be deficient in folate and B vitamins. A preliminary study was conducted in collaboration with Creighton University scientists in female mice to determine the oral doses that will be used in a larger mouse study to determine the threshold for fumonisin B1-induction of neural tube defects, maternal toxicity, elevation in urinary fumonisin B1 and elevated sphingoid bases and sphingoid base 1-phosphates in maternal kidney, liver, blood and in the embryos. In this preliminary study we found that in mice dosed at 2.5 to 25 mg fumonisin B1/kg body weight (3 daily doses during the critical time for neural tube closure) there was no significant adverse hepatic pathology. If this finding is confirmed then it is likely that NTDs occur at oral doses which do not cause overt maternal toxicity (by liver pathology) which strengthens concerns for potential risk. In addition, elevation in urinary fumonisin B1 and elevated sphingoid base 1-phosphates in red blood cells (blood spots) could be detected at oral doses that did not induce neural tube defects in mice dosed during the period of neural tube closure. Neural tube defects were-induced at all oral doses greater than 5 mg/kg body weight dosed on gestational days 6.5 to 8.5. The elevation in fumonisin B1 in urine (exposure biomarker) and sphinganine 1-phosphate in blood spots (mechanism biomarker) was dose-dependent and was seen at all dose levels. These biomarkers for fumonisin exposure and effects are being assessed concurrently in humans in collaboration with Guatemalan scientists at the Centro de Investigaciones en Nutricion y Salud in Guatemala (CIENSA). In the human studies approximately 750 urine and blood spot samples have been collected from three locations in rural Guatemala. To date over 450 urine and blood samples have been analyzed. Corn samples (n=27) from the same locations have been collected and analyzed. The preliminary results show that fumonisin B1 in urine is closely correlated with the level of fumonisin in the corn collected from each locality and the urinary fumonisin B1 is significantly correlated with evidence indicating elevated levels of sphingoid base 1-phosphates in blood spots. Progress monitoring was accomplished using conference calls with the Creighton University Principal Investigator and all Co-Investigators on at least three occasions. A site visit to Guatemala to provide training and sampling site selection was accomplished in January 2011 before the first sampling of urine and blood spots. A progress report meeting at USDA-ARS-SAA-RRC was accomplished in July 2011 and included progress reports by all investigators.