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Title: Maternal fumonisin exposure and risk for neural tube defects: mechanisms in an in vivo mouse model

Author
item GELINEAU-VAN WAES, JANEE - UNEBRASKA MED CEN/OMAHA
item STARR, LOIS - UNEBRASKA MED CEN/OMAHA
item MADDOX, JOYCE - UNEBRASKA MED CEN/OMAHA
item ALEMAN, FRANCISCO - UNEBRASKA MED CEN/OMAHA
item Voss, Kenneth
item WILBERDING, JUSTIN - UNEBRASKA MED CEN/OMAHA
item Riley, Ronald

Submitted to: Birth Defects Research Part A: Clinical and Molecular Teratology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/22/2005
Publication Date: 7/1/2005
Citation: Gelineau-Van Waes, J., Starr, L., Maddox, J.R., Aleman, F., Voss, K.A., Wilberding, J., Riley, R.T. 2005. Maternal fumonisin exposure and risk for neural tube defects: mechanisms in an in vivo mouse model. Birth Defects Part A: Clinical amd Molecular Teratology. 73:487-497.

Interpretive Summary: Fumonisin B1 (FB1) is made by Fusarium verticillioides, a mold which grows on corn. FB1 is found in corn-based foods worldwide. Some evidence suggests that exposure to FB1-contaminated food during early pregnancy increases the risk for often fatal birth defects known as NTDs (neural tube defects), especially in human populations where contaminated corn is a dietary staple. However, an animal model for studying how FB1 might increase the risk of NTDs has been lacking until now. The LM/Bc mouse strain has been used previously to study NTDs. When pregnant LM/Bc mice were injected with FB1 at doses ranging from 5 to 20 mg/kg body weight at a critical time during gestation (a two-day window during which the vitamin folate plays a key role in protecting against NTDs), FB1 caused NTDs at all doses and the number of affected litters and embryos increased as the dose increased. Additional studies were then done to investigate the mechanism by which FB1 caused the NTDs. First, we found that the transport of folate was decreased in FB1-treated mice and that giving folate to the pregnant mice partially protected the embryos from FB1-induced NTDs. When GM1, a type of modified fat that decreases in the tissues of FB1-exposed animals, was given to the pregnant mice, folate uptake was significantly improved and the embryos were almost completely protected from FB1-induced NTDs. These results are important because they establish the first live-animal model for studying FB1-induced NTDs and show that folate transport is likely to be a key target for FB1 in regard to NTD development. The studies also provide a basis for future studies to better understand the molecular mechanisms through which FB1 affects folate and causes NTDs and, ultimately, to determine the extent to which FB1 is an NTD risk factor for humans.

Technical Abstract: Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides which occurs in corn and corn-based foods worldwide. FB1 disrupts de novo sphingolipid biosynthesis by inhibiting the ceramide synthase, thereby causing increases in free sphingoid bases and decreases in glyco- and other complex sphingolipids in tissues. Several lines of evidence suggest that ingestion of FB1-contaminated corn during early pregnancy increases the risk for neural tube defects (NTDs) in human populations where contaminated corn is a dietary staple. Groups of pregnant mice (n=10/dose) of the inbred LM/Bc strain were injected intraperitoneally with 0 (control) or 5-20 mg/kg BW FB1 on gestation days 7.5 and 8.5. As a result, dose-dependent increases in the number of affected litters and embryos were found in all groups given FB1. Four of 10 litters and 5% of the embryos exhibited NTDs at 5 mg/kg BW while 10 of 10 litters and 79% of the embryos exhibited NTDs at the highest dose. Additional experiments established that FB1 (20 mg/kg BW) altered maternal and embryo tissue sphingolipid profiles and reduced both the uptake of 3H-folate and the immunohistochemical expression of the Folbp1 folate receptor. Maternal folate supplementation partially protected the embryos from the effects of FB1, while the glycosphingolipid GM1 significantly restored folate uptake and almost completely protected the embryos against FB1-induced NTDs. Taken together, the results indicate that intraperitoneal injection of FB1 to pregnant LM/Bc mice caused NTDs, that the no effect level (ip injection) lies below 5 mg/kg BW, and that disrupted sphingolipid metabolism and folate transport are mechanistically involved in FB1-induced NTDs. Further, the LM/Bc mouse has been established as an animal model to mechanistically define the reproductive effects of fumonisins in vivo.