STUDIES ON THE INDUCTION OF NEURAL TUBE DEFECTS IN THE LM/BC AND CD1 MOUSE STRAINS FOLLOWING ORAL OR INTRAPERITONEAL FUMONISIN EXPOSURE

Authors: Voss, Kenneth; Riley, Ronald; BURNS, TANTIANA - TOX., UGA, ATHENS, GA; GELINEAU-VAN WAES, JANEE - U.NEB.MED.CEN., OMAHA, NE

Submitted to: United States-Japan Cooperative Program in Natural Resources
Publication Type: Abstract Only
Publication Acceptance Date: 10/21/2005
Publication Date: 11/16/2005
Citation: Voss, K.A., Riley, R.T., Burns, T.D., Gelineau-Van Waes, J.B. 2005. Studies on the induction of neural tube defects in the lm/bc and cd1 mouse strains following oral or intraperitoneal fumonisin exposure. Proceedings of the 40th Joint Panel Meeting of the United States-Japan Cooperative Program on Natural Resources. Matusushima, Japan. p. 58

Interpretive Summary: Abstract - no summary.

Technical Abstract: The human health effects of Fusarium verticillioides and fumonisins are uncertain. There is evidence however suggesting that fumonisins disrupt folate utilization and increase the risk of neural tube defects (NTDs = birth defects cause by failure of the neural tube to close properly) in populations that depend heavily on fumonisin-contaminated corn as a food source. Fumonisin B1 (FB1) was not teratogenic when given orally (gavage) to pregnant CD1 mice on gestation days (GD) 7-15 whereas intraperitoneal (ip) injection of > 5 mg/kg BW FB1 on GD7 and GD8, the critical time for neural tube closure, to pregnant LM/Bc mice caused NTDs. Experiments were therefore done to compare the incidence of NTDs in litters of LM/Bc and CD1 dams given FB1 by two different dosing protocols: (a) dietary exposure to fumonisins (provided by adding F. verticillioides culture material to the diet) beginning 5 weeks before mating and (b) ip administration of FB1 on GD7 and GD8. The results of the feeding studies were inconclusive. Diets containing 50 ppm FB1 did not cause NTDs in either strain. At the maternally hepatotoxic dose of 150 ppm FB1, one of five LM/Bc litters was NTD positive (1/10 fetuses affected) whereas fetal death rates were higher but no NTDs were found in the CD1 strain (n=9 litters). Increased sphinganine to sphingosine ratios were found in the livers of LM/Bc, but not CD1, fetuses indicating that in utero exposure to fumonisins was greater in the LM/Bc strain. However, in a second feeding trial using LM/Bc mice only, NTDs were not found in the fetuses of dams fed diets containing 150 or 300 ppm FB1. A dose-related increase in NTDs (exencephaly) was found in the litters of CD1 dams (n=8-10/dose level) given FB1 by ip injection on GD7 and GD8: 0, 11, 0, and 40 percent of the litters were NTD positive at doses of 0, 15, 30 and 45 mg/kg BW FB1, respectively. This result was corroborated in a second experiment. NTDs were found in 0, 8.3, 16.6, 36.4, 54.5 percent of the litters of CD1 dams (n=8-12/dose level) given 0, 10, 23, 45 or 100 mg FB/kg BWt FB1 ip on GD7 and GD8. In affected litters of dams given < 45 ppm FB1, 33 percent or less of the CD1 fetuses had NTDs. The number of affected fetuses per NTD-positive litter tended to be higher when CD1 dams were given 100 mg/kg BWt FB1: 15 to 100 percent exhibited NTD (average mean for the group = 42 percent). In contrast, 100 percent of the litters and > 50 percent of the fetuses from LM/Bc dams given > 15 mg/kg FB1 by this ip dosing schedule were NTD positive. These results indicate that (a) both mouse strain and dosing regimen affect NTD induction; (b) induction of NTDs by ip FB1 exposure during the critical time for neural tube closure is not unique to the LM/Bc mouse strain; (c) LM/Bc mice are more sensitive to NTD induction than CD1 mice; and (d) unequivocal induction of NTDs by dietary exposure to fumonisins remains to be shown. Comparative studies using fumonisin-exposed LM/Bc and CD1 mice will be useful for elucidating the physiological and biochemical events involved in NTD formation in vivo.