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

Waes, Janée Gelineau-van; Starr, Lois J.; Maddox, Joyce R.; Aleman, Francisco; Voss, Kenneth A.; Wilberding, Justin; Riley, Ronald T.

doi:10.1002/bdra.20148

Cited by 169 publications

(129 citation statements)

References 64 publications

(71 reference statements)

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…The critical role of sphingolipids for morphogenesis has been suggested by previous studies showing that incubation of embryos with FB1 results in deficient neural tube closure (14,15). The embryonic lethality of knock-out mice for sphingosine kinases or glycosyltransferases clearly shows that the expression of particular ceramide derivatives is vital for embryo development (35,36).…”

Section: Discussionmentioning

confidence: 90%

“…FB1 inhibits (dihydro)ceramide synthases, a group of enzymes catalyzing the penultimate step in ceramide biosynthesis. Their inhibition has been linked to neural tube defects in humans and animals caused by the disruption of sphingolipid biosynthesis, indicating the significance of ceramide or its derivatives for developmental processes prior to or during neurulation (14,15).Ceramide depletion elevated apoptosis and prevented primitive ectoderm morphogenesis in cultured EBs. Our results suggest that this was because of down-regulation of PKC/-mediated phosphorylation of glycogen synthase kinase-3␤…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Ceramide Regulates Atypical PKCζ/λ-mediated Cell Polarity in Primitive Ectoderm Cells

Krishnamurthy

Wang

Silva

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

In mammals, the primitive ectoderm is an epithelium of polarized cells that differentiates into all embryonic tissues. Our study shows that in primitive ectoderm cells, the sphingolipid ceramide was elevated and co-distributed with the small GTPase Cdc42 and cortical F-actin at the apicolateral cell membrane. Pharmacological or RNA interference-mediated inhibition of ceramide biosynthesis enhanced apoptosis and impaired primitive ectoderm formation in embryoid bodies differentiated from mouse embryonic stem cells. Primitive ectoderm formation was restored by incubation with ceramide or a ceramide analog. Ceramide depletion prevented plasma membrane translocation of PKC/, its interaction with Cdc42, and phosphorylation of GSK-3␤, a substrate of PKC/. Recombinant PKC formed a complex with the polarity protein Par6 and Cdc42 when bound to ceramide containing lipid vesicles. Our data suggest a novel mechanism by which a ceramide-induced, apicolateral polarity complex with PKC/ regulates primitive ectoderm cell polarity and morphogenesis.Our studies have shown that the membrane sphingolipid ceramide regulates apoptosis during embryonic stem (ES) 3 cell differentiation (1-5). This regulation is initiated by direct physical interaction of ceramide with atypical PKC or (5). Homozygous knock-out of PKC in mice results in lethality at embryonic day 9 because of severe defects of post-gastrulation morphology (6). This suggests that atypical PKCs are critical for aspects of early embryonic development, although the degree of functional overlap as well as specific effects and regulation of the two isoforms are not known yet. Our results obtained with ES cells suggest that ceramide-dependent regulation of atypical PKCs contributes to the function of PKC/ during embryonic development.In the pregastrulation embryo, inner cell mass-derived cells give rise to two adjacent epithelia of polarized cells, the primitive endoderm and the underlying primitive ectoderm. The formation of the primitive ectoderm is followed by the removal of cells that are not in contact with the primitive endoderm derived basal lamina. These cells die by apoptosis giving rise to the proamniotic cavity, a process termed cavitation (7). This developmental process is recapitulated in embryoid bodies (EBs) generated from in vitro differentiating ES cells. ES cellderived EBs have been used to determine key regulatory factors of primitive germ layer formation and cavitation, and are a bona fide, in vitro model for early embryo morphogenesis (8 -10). A key experiment to determine the significance of ceramide for cavitation and primitive ectoderm morphogenesis is depleting EBs of ceramide by disruption of ceramide biosynthesis. Ceramide biosynthesis is initiated and regulated by serine palmitoyltransferase (SPT), an enzyme consisting of the two subunits SPT-1 and SPT-2. Homozygous knock-out of SPT-1 or SPT-2 results in embryonic lethality at a stage of development well before E15 indicating the absolute requirement of ceramide biosynthesis for embryo development (...

show abstract

Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Ceramide Regulates Atypical PKCζ/λ-mediated Cell Polarity in Primitive Ectoderm Cells

Krishnamurthy

Wang

Silva

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…After the setting of the JECFA TDI, it was found that fumonisin causes neural tube birth defects (NTDs) in mouse somites (Sadler et al 2002) and a rodent model in vivo (Gelineau-van Waes et al 2005). 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).…”

Section: Introductionmentioning

confidence: 99%

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

Miller

2008

Food Additives & Contaminants: Part A

195

130

View full text Add to dashboard Cite

This paper reviews the challenges relating to chronic contamination of small grains and maize with deoxynivalenol and related compounds, fumonisin and the use of ensiled cereals in cool dairy areas. Uncertainties in the tolerable daily intakes for deoxynivalenol and fumonisin are discussed as they have the potential to affect current regulatory limits. In addition, climate change is resulting in more extreme rainfall and drought events which favour formation of deoxynivalenol and fumonisin, respectively. The development and refinement of models for predicting mycotoxin accumulation from weather data will become an essential tool for managing these events. Such models are also important for providing timely food aid to developing countries, which experience increased occurrence of acute toxicities, especially in children. Chronic contamination of silage in some areas with some Penicillium toxins deserves more attention in terms of their economic effects and possible implications for the purity of milk.

show abstract

“…FB 1 has also been implicated in the aetiology of neural tube defect (NTD) in parts of Texas, Mexico, Guatemala, and South Africa. Studies on mouse embryos in culture and on pregnant mice have provided evidence that FB 1 has the potential to produce embryotoxicity and NTD (9,10). In a case-control study conducted on Mexican American women in Texas, maternal exposure to FB 1 (assessed as level of FB 1 in tortillas consumed by mothers and level of biomarker of FB 1 exposure in maternal serum) was associated with increased incidence of NTD in children (11).…”

mentioning

confidence: 99%

Fumonisin B1: A Neurotoxic Mycotoxin / Fumonizin B1: Neurotoksični Mikotoksin

Domijan

2012

Archives of Industrial Hygiene and Toxicology

View full text Add to dashboard Cite

Fumonisin B 1 (FB 1 ) is a mycotoxin produced by Fusarium spp. moulds that contaminate crop, predominantly maize, all around the world. More than 15 types of fumonisins have been indentifi ed so far, but FB 1 is the most abundant and toxicologically the most signifi cant one. FB 1 has a wide range of toxic effects, depending on animal species. In horses FB 1 causes equine leukoencephalomalacia (ELEM), in pigs pulmonary oedema and in experimental rodents nephrotoxicity and hepatotoxicity. In humans exposure to FB 1 is linked with higher incidence of primary liver cancer and oesophageal cancer, which are frequent in certain regions of the world (such as Transkei region in South Africa) where maize is staple food. The occurrence of neural tube defect in children in some countries of Central America (such as Mexico and Honduras) is connected with the consumption of FB 1 -contaminated maize-based food. However, possible involvement of FB 1 in the development of human diseases is not clear. Nevertheless, the International Agency for Research on Cancer (IARC) has classifi ed FB 1 as a possible carcinogen to humans (group 2B). FB 1 is a causative agent of ELEM, a brain disorder in equines, indicating that brain is a target organ of FB 1 toxicity. Several studies on experimental animals or on cell cultures of neural origin have established that FB 1 has a neurodegenerative potential, although the mechanism of its neurotoxicity is still vague. The aim of this article is to give an overview of available literature on FB 1 neurotoxicity and involved mechanisms, and to offer a new perspective for future studies.

show abstract

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

Abstract: Maternal FB1 exposure altered sphingolipid metabolism and folate concentrations in LM/Bc mice, resulting in a dose-dependent increase in NTDs that could be prevented when adequate folate levels were maintained.

Cited by 169 publications

References 64 publications

Ceramide Regulates Atypical PKCζ/λ-mediated Cell Polarity in Primitive Ectoderm Cells

Ceramide Regulates Atypical PKCζ/λ-mediated Cell Polarity in Primitive Ectoderm Cells

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

Fumonisin B1: A Neurotoxic Mycotoxin / Fumonizin B1: Neurotoksični Mikotoksin

Contact Info

Product

Resources

About