Location: Toxicology & Mycotoxin Research2012 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 relates to work conducted to address the parent in-house project objectives 2 (develop biomarkers for fumonisin exposure and effects) and 3 (validate biomarkers in humans). The question we wish to answer is whether or not fumonisin, a toxin found in corn, is in anyway contributing to the high incidence of neural tube defects seen in people who consume large amounts of corn and whose diets are likely to be deficient in folate and B vitamins. A study was conducted in collaboration with Creighton University scientists in female mice to determine the oral dose of fumonisin B1 for induction of maternal toxicity, elevation in urinary fumonisin B1, 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 red blood cells (blood spots) was correlated with subtle evidence of maternal liver toxicity, however, the variability in the levels of sphingoid base 1-phosphates in the blood and tissues was too great to allow for the determination of a threshold for disruption of sphingolipid metabolism that correlated statistically with liver toxicity. Nonetheless, doses of fumonisin B1 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. The urinary fumonisin B1 analysis is in progress. Follow-up studies have been initiated to confirm or not results showing that neural tube defect induction by fumonisin B1 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. Biomarkers for fumonisin exposure (urinary fumonisin B1) and effects (changes in sphingoid base 1-phosphates in blood spots) are being used in Institutional Review Board (IRB) approved studies in humans, in collaboration with Guatemalan scientists through the Centro de Investigaciones en Nutricion y Salud in Guatemala (CIENSA). In the human studies, approximately 1,200 urine and blood spot samples have been collected and analyzed from three locations in rural Guatemala. Maize samples (n=90) from the same locations have been collected and analyzed. The results show that fumonisin B1 in urine is closely correlated with the level of fumonisin in the maize 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. At the request of the Guatemalan Ministry of Health (MOH), a modified human subjects' protocol was submitted and approved by the MOH effective 6/25/2012. Because the results of the first year of the study have demonstrated strong evidence for linking fumonisin exposure to disruption of sphingolipid metabolism in humans, 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 (one high exposure and one low exposure) to be used to validate the findings thus far. This request was approved. A survey of fumonisin contamination in maize across Guatemala is currently in progress, and once completed, the Human Subjects' Protocols will be modified and resubmitted to both the MOH and the Institute of Nutrition of Central America and Panama (an NIH approved IRB) for approval.