Fumonisins Disrupt Sphingolipid Metabolism, Folate Transport, and Neural Tube Development in Embryo Culture and In Vivo: A Potential Risk Factor for Human Neural Tube Defects among Populations Consuming Fumonisin-Contaminated Maize

Abstract

Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metabolism (sphinganine and other sphingoid bases and derivatives) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor alpha). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant association between NTD and consumption of tortillas during the first trimester. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.

Mycotoxins in small grains and maize: Old problems, new challenges

“…These studies arose from a transient increase in NTDs from 10 to 27 per 10,000 live births in Mexican-Americans in Cameron County Texas (Hendricks 1999; Marasas et al 2004). A followup study found that increased NTD risk was associated with fumonisins exposure (Missmer et al 2006) and, for a number of reasons, animal models had failed to predict this possibility (IPCS 2000).…”

“…The mechanism relates to material exposure to fumonisin prior to the formation of the placenta. Fumonisin affects folate transport, which results in lowered folate in the embryo (Sadler et al 2002;Marasas et al 2004). A study of tortilla production in Cameron County revealed that some preparation methods in local facilities left intact fumonisin in the final product (De La Campa et al 2004) and NTDs are very high in fumonisin endemic areas (Marasas et al 2004).…”

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

“…Very high concentrations (100 μM) of regular LCBs are also toxic to cultured neurons (7,8). In addition, intoxication with fumonisin B1, a fungal ceramide synthase inhibitor causing elevation of LCBs and reduction of ceramides, leads to neural tube and neurological defects in humans and cattle (9). However, whether accumulation of regular LCBs in vivo or LCB treatment at physiologically relevant concentrations in vitro causes neuron death or damage has not been thoroughly investigated.…”

Relação entre níveis de fumonisina B1 e ácido fólico em farinha de milho e a concentração de ácido fólico no soro humano

“…Nessa região, a incidência de DTN dobrou no mesmo período em que houve um surto epizoótico associado à contaminação de milho por fumonisinas (Missmer et al, 2006). Incidências relativamente elevadas de DTN também foram observadas em regiões da África do Sul (35-61/10 mil habitantes), norte da China (57-73/10 mil habitantes) e Guatemala (até 106/10 mil habitantes), onde a população possui elevada exposição à toxina, pela utilização do milho como base alimentar (Marasas et al, 2004).…”

“…A FB 1 causa interrupção no metabolismo de esfingolipídios, o que interfere na absorção celular de diversos nutrientes, principalmente de folatos (Stevens; Tang, 1997). Essa deficiência intracelular da vitamina, ocasionada pela depleção de esfingolipídeos induzida pela FB 1 , tem sido considerada como um possível mecanismo para a indução de DTN pelas fumonisinas (Marasas et al, 2004).…”