Location: Toxicology and Mycotoxin Research
2012 Annual Report
2. Determine the dietary “no observed effect” and “lowest observed effect levels” for neural tube defect induction and determine the dose-response thresholds for elevation in sphingolipid biomarkers in blood spots and fumonisins in urine using animal models.
3. Determine the relationship between fumonisin consumption, urinary fumonisin (exposure biomarker) and changes in sphingolipids in blood spots (effect biomarker) in human populations consuming corn.
4. Determine the specific mechanism(s) by which fumonisins are readily taken up by corn plant roots and yet have limited translocation into above ground vegetative tissues.
5. Determine the effectiveness of alkaline cooking for reducing the toxic potential of fumonisin-contaminated whole kernel corn.
2. Conduct dose-response studies in susceptible mouse strains to determine the thresholds for changes in biomarkers of exposure and effect and induction of neural tube defects.
3. Conduct epidemiological studies to identify humans consuming large amounts of corn-based foods in communities where FB is infrequently detected and frequently detected and sample and analyze urine (FBs) and blood spots (sphingolipids).
4. Conduct dose response studies to determine FB1 affects on plant transpiration and levels of sphingoid bases and their 1-phosphates in roots and aerial tissues in FB1-sensitive and -insensitive genotypes of corn.
5. Utilize FB-contaminated whole kernel corn to determine the processing conditions that maximize FB1 reduction using chemical analysis and in vivo animal bioassays.
Objective 2: A study was conducted in collaboration with Creighton University to determine the oral dose of FB1 for induction of maternal toxicity, elevation in urinary FB1, and elevated sphingoid bases and sphingoid base 1-phosphates in maternal kidney, liver, and blood. This study showed that elevation in sphingoid base 1-phosphates in blood spots was correlated with subtle evidence of liver toxicity. Doses of FB1 of less than 10 mg/kg body weight per day for 4 days, induced little or no evidence suggestive of disrupted sphingolipid metabolism or liver toxicity. Follow-up studies were initiated to confirm or not results showing that neural tube defect induction by FB1 was significantly reduced in mice fed folate deficient diets. Follow-up confirmation is needed due to the unexpected and, based on earlier understandings of interactions between folate and fumonisins, counterintuitive findings of an earlier study.
Objective 3: Biomarkers for FB exposure are being used in Institutional Review Board (IRB) approved studies in humans in collaboration with Guatemalan scientists. Approximately 1,200 urine and blood spot samples and 90 maize samples have been collected and analyzed from three locations in rural Guatemala. The results show that FB1 in urine is closely correlated with the level of FB in the maize collected from each locality and the urinary FB1 is significantly correlated with evidence indicating elevated levels of sphingoid base 1-phosphates in blood spots. At the request of the Guatemalan Ministry of Health (MOH) a modified human subjects' protocol was submitted and approved. A request was made to the NIH National Institute of Child Health & Human Development to modify the study design so as to identify two new sampling locations to be used to validate the findings thus far. This request was approved. Objective 4: Studies were conducted to determine if water uptake and transpiration in corn plants are modulated during the plant-Fusarium interaction. Transpiration may be negatively impacted by accumulation of sphingoid base 1-phosphates. We developed a growth chamber assay to address transpiration responses in plants treated with either FB alone or with F. verticillioides. Treatment with abscisic acid (ABA) plus FB1 resulted in reduced accumulation of FB1 in seedling roots compared to seedlings treated only with FB1. FB1 alone and infection with F. verticillioides both had a moderate effect on transpiration.
Objective 5: An in vivo bioassay was conducted and showed that nixtamalization (alkaline cooking followed by three fresh water rinses) of whole kernel corn, as practiced in households and industry, significantly reduces the amount of measurable FB1 and, consequently, the toxicity of FB in the corn.
Voss, K.A., Riley, R.T., Jackson, L.S., Jabloski, J.E., Bianchini, A., Bullerman, L.B., Hanna, M.A., Ryu, D. 2011. Extrusion cooking with glucose supplementation of fumonsin-contaminated corn grits protects against nephrotoxicity and disrupted sphingolipid metabolism in rats. Molecular Nutrition and Food Research. 55:S312-S320. DOI: 10.1002/mnfr.201100067.
Callihan, P., Zitomer, N., Stoeling, M., Kennedy, P., Lynch, K.R., Riley, R.T., Hooks, S.B. 2012. Distinct generation, pharmacology, and distribution of sphingosine 1-phosphate and dihydro-sphingosine 1-phosphate in human neural progenitor cells. Neuropharmacology. 62:988-996.
Jackson, L.W., Jablonski, J.E., Bullerman, L.B., Bianchini, A., Hanna, M.A., Voss, K.A., Hollub, A.D., Ryu, D. 2011. Reduction of fumonisin B1 in corn grits by twin-screw extrusion. Journal of Food Science. 76(6):150-155.
Riley, R.T., Torres, O., Showker, A.J., Zitomer, N.C., Matute, J., Voss, K.A., Gelineau-van Waes, J., Maddox, J.R., Gregory, S.G., Ashley-Koch, A.E. 2012. The kinetics of urinary fumonisin B1 excretion in humans consuming maize-based diets. Molecular Nutrition and Food Research. 56:1445-1455.