Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: February 26, 2010
Publication Date: March 7, 2010
Citation: Gelineau-Van Waes, J., Maddox, J., Voss, K.A., Riley, R.T. 2010. Lipid mediators link cells progression with placental and neural tube defects after maternal fumonisin exposure. Toxicologist. 114(S1):182. Technical Abstract: Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of maize. Increased risk for neural tube defects (NTDs) is observed in populations that rely on maize as a dietary staple. FB1 inhibits ceramide synthase, resulting in altered pools of biologically active sphingolipids. FB1 (20mg/kg/day ip, E7.5-8.5) was administered to pregnant LM/Bc and SWV mice. On E9.5, maternal blood, embryonic and placental tissue was collected for LC-ESI-MS analysis of sphingolipid metabolites. Embryos/placentas were processed for histology, and TEM/SEM observation of neuroepithelial ultrastructure. Neural tissue from E9.5 control and FB1-exposed embryos was collected for Affymetrix microarray analysis. Maternal FB1 resulted in placental abnormalities and NTDs in the LM/Bc strain. Elevated levels of sphinganine (Sa), 1-deoxy-Sa, and Sa-1-phosphate (Sa1P) were measured in maternal blood and placental tissue. 1-deoxy-Sa is known to cause cell cycle arrest and Sa1P functions as a ligand for G protein-coupled S1P receptors (known modulators of lymphocyte chemotaxis). FB1 resulted in altered migration of uterine NK cells and increased differentiation of giant trophoblast cells. The neuroepithelium of exencephalic embryos was deficient in primary cilia, and microarray analysis revealed differential expression of genes involved in cell cycle progression, ciliogenesis, and Wnt signaling. FB1 alters the pools of bioactive lipids in maternal blood, placenta, and developing embryo. Lipid mediators play important roles in chemotaxis and cell cycle progression. Primary cilia are involved in neural tube closure, and assembly/disassembly of the primary cilium is coordinately regulated with cell cycle. Giant trophoblast cells differentiate by exiting the cell cycle at G2/M. Elevated levels of Sa1P and 1-deoxy-Sa may therefore impact signaling pathways involved in uNK cell migration, cell cycle progression, giant trophoblast cell differentiation, ciliogenesis, and neural tube closure.