Location: Toxicology & Mycotoxin Research2013 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 seen in people who consume large amounts of corn and whose diets are likely to be deficient in folate and B vitamins. Studies in female mice in collaboration with Creighton University scientists determined 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. The final part of this study was completed this year and showed that the fumonisin B1 was quickly cleared from the urine (< 48 hours post dosing) but the sphingoid base 1-phosphates in the blood remained elevated for at least 72 hours post dosing. Studies in mouse neural progenitor cells and embryonic fibroblast cells showed that fumonisin B1 -treatment resulted in increased nuclear sphingoid base-1-phosphates and altered the acetylation of nuclear histones indicating that epigenomic modifications after fumonisin exposure could result in remodeling of the chromatin and altered expression of genes critical for proper neural tube closure in our mouse model. In another in vitro mouse model it was shown that the bicistronic CerS1-Gdf1 gene appears to be a novel regulator of the balance between nuclear and cytosolic sphingoid base 1-phosphates that regulate cell signaling pathways involved in neural tube closure. Thus genetic variation in the Gdf1 gene could confer enhanced susceptibility to fumonisin B1-induced neural tube defects. Follow-up studies have been completed to confirm results showing that neural tube defect induction by fumonisin B1 was significantly reduced in mice fed folate deficient diets. Future studies will hopefully reveal how folate deficient diets could protect against fumonisin-induced neural tube defects in this mouse model and whether it is relevant to humans. 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 Nutrición y Salud in Guatemala (CIENSA). At the end of FY2012 we requested 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 was completed and the Human Subjects Protocols were modified and resubmitted and approved by the Ministry of Health and the Institute of Nutrition of Central America and Panama (an NIH approved Institutional review Board) for approval. A total of 640 corn samples from all 22 departamentos (equivalent to counties in the U.S.A.) were analyzed for both fumonisin and aflatoxins. Very high levels of aflatoxins and fumonisin were detected in corn from the Departamento of Petén. High levels of fumonisin, but not aflatoxins, were also detected in the Departamentos of Chiquimula and Santa Rosa and very low levels of fumonisin and aflatoxin were detected in the highland Departamento of Sacatepéquez. Human blood (n=390) and urine (n=390), as well as corn (n=30) for human consumption, were collected and analyzed from Sacatepequez (low fumonisin exposure), Chiquimula (high fumonisin exposure), and Santa Rosa (high fumonisin exposure). Analysis of the urinary fumonisin exposure biomarker confirmed low exposure in Sacatepequez and high exposure in Chiquimula and Santa Rosa. The sphingolipid biomarkers in blood are currently being analyzed. Progress monitoring was accomplished through a site visit at the Centro de Investigaciones en Nutrición y Salud (CIENSA) in Guatemala City in March 2013. In addition, conference calls with the Creighton University Principal Investigator and all Co-Investigators were conducted on at least three occasions. A progress report meeting in Guatemala was accomplished in March 2013 and included progress reports by all investigators.