Ceramide: a novel inducer for neural tube defects.

ABSTRACT

BACKGROUND: Circulating plasma ceramides, a class of bioactive sphingolipids, are elevated in metabolic disorders, including obesity. Infants of women with these disorders are at 2- to 3-fold greater risk for developing a neural tube defect (NTD). This study aimed to test the effects of embryonic exposure to C2-ceramides (C2) during neural tube closure. Preliminary data shows an increase in NTDs in chick embryos after C2 exposure, and addresses potential mechanisms. RESULTS: Cell and embryo models were used to examine redox shifts after ceramide exposure. While undifferentiated P19 cells were resistant to ceramide exposure, neuronally differentiated P19 cells exhibited an oxidizing shift. Consistent with these observations, GSH E h curves revealed a shift to a more oxidized state in C2 treated embryos without increasing apoptosis or changing Pax3 expression, however cell proliferation was lower. Neural tube defects were observed in 45% of chick embryos exposed to C2, compared to 12% in control embryos. CONCLUSIONS: C2 exposure during critical developmental stages increased the frequency of NTDs in the avian model. Increased ROS generation in cell culture, along with the more oxidative GSH E h profiles of C2 exposed cells and embryos, support a model wherein ceramide affects neural tube closure via altered tissue redox environments.