Reproductive and sphingolipid metabolic effects of fumonisin B1 and its alkaline hydrolysis product in LM/Bc mice: hydrolyzed fumonisin B1 did not cause neural tube defects

Authors: Voss, Kenneth; Riley, Ronald; Snook, Maurice; GELINEAU-VAN WAES, JANEE - University Of Nebraska

Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/2/2009
Publication Date: 12/1/2009
Citation: Voss, K.A., Riley, R.T., Snook, M.E., Gelineau-Van Waes, J.B. 2009. Reproductive and sphingolipid metabolic effects of fumonisin B1 and its alkaline hydrolysis product in LM/Bc mice: hydrolyzed fumonisin B1 did not cause neural tube defects. Toxicological Science 112:459-467.

Interpretive Summary: Fumonisins are fungal toxins that contaminate corn and foods prepared from corn using an alkaline cooking method known as nixtamalization. Nixtamalized products such as tortillas contain a mixture of fumonisins and hydrolyzed fumonisins that form because of the alkaline conditions of nixtamalization. Fumonisins are toxic to animals and toxicity results from disruption of sphingolipid (lipids having signaling and metabolic functions) metabolism. Fumonisins have also been implicated as possible risk factors for serious birth defects in humans known as neural tube defects. The most common fumonisin, fumonisin B1 (FB1), disrupts sphingolipid metabolism and causes neural tube defects when given to a sensitive tester strain of mice at a critical time during pregnancy. However, the ability of its hydrolyzed form (HFB1) to cause neural tube defects in this sensitive mouse model was unknown. We therefore compared the ability of HFB1 and FB1 to disrupt sphingolipid metabolism and cause neural tube defects. When given to the pregnant females at a dose of 20 mg/kg body weight, HFB1 had a slight effect on maternal sphingolipid metabolism and did not cause maternal liver damage or neural tube defects. In contrast, a lower dose (10 mg/kg body weight) of FB1 dramatically altered sphingolipids and caused liver damage. Neural tube defects were found in all litters and involved approximately two-thirds of the fetuses. The results indicate that, compared to FB1, HFB1 is not a significant risk factor for neural tube defects and that future studies to determine if fumonisins are risk factors for neural tube defects should focus on FB1.

Technical Abstract: Fumonisins are mycotoxins produced by Fusarium verticillioides. They are toxic to animals and exert their effects through mechanisms involving disruption of sphingolipid metabolism. Fumonisins and their hydrolyzed analogues are found in alkaline-cooked, maize-based foods such as tortillas and the consumption of tortillas has been implicated as a risk factor for neural tube defects (NTD). The teratogenic potential of fumonisin B1 (FB1) and hydrolyzed FB1 (HFB1) was compared using the LM/Bc mouse, a sensitive model for NTD induction by FB1. The dams were dosed (ip) with 2.5, 5.0, 10 or 20 mg/kg (< 49 µmol/kg) body weight HFB1 on E7-8. Negative and positive control groups were given vehicle or 10 mg/kg (14 µmol/kg) body weight FB1, respectively. The high dose of HFB1 disrupted sphingolipid metabolism slightly but did not, however, cause maternal liver lesions or NTD (n=8-10 litters/group). In contrast, 10 mg/kg body weight FB1 markedly disrupted maternal sphingolipid metabolism, caused hepatic apoptosis in the dams, increased fetal death rates and decreased fetal weights. Furthermore, NTD were found in all FB1-exposed litters (n=10) and 66 + 24 percent of the fetuses were affected. The findings indicate that HFB1 does not cause NTD in the sensitive LM/Bc mouse model at doses up to 7-fold higher (µmol/kg body weight basis) than the previously reported lowest observed adverse effect level for FB1.