GEO dataset (GDS): GSE1074.
Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome†
Article first published online: 2 JAN 2007
Copyright © 2007 Wiley-Liss, Inc.
Volume 236, Issue 2, pages 613–631, February 2007
How to Cite
Green, M. L., Singh, A. V., Zhang, Y., Nemeth, K. A., Sulik, K. K. and Knudsen, T. B. (2007), Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome. Dev. Dyn., 236: 613–631. doi: 10.1002/dvdy.21048
- Issue published online: 10 JAN 2007
- Article first published online: 2 JAN 2007
- Manuscript Accepted: 6 NOV 2006
- National Institute on Alcohol Abuse and Alcoholism. Grant Numbers: RO1 AA13205, P30 AA11605
- National Institute of Environmental Health Sciences. Grant Number: T32 ES07282
- GEO dataset GSE1074
Fetal Alcohol Spectrum Disorders (FASD) are birth defects that result from maternal alcohol use. We used a non a priori approach to prioritize candidate pathways during alcohol-induced teratogenicity in early mouse embryos. Two C57BL/6 substrains (B6J, B6N) served as the basis for study. Dosing pregnant dams with alcohol (2× 2.9 g/kg ethanol spaced 4 hr on day 8) induced FASD in B6J at a higher incidence than B6N embryos. Counter-exposure to PK11195 (4 mg/kg) significantly protected B6J embryos but slightly promoted FASD in B6N embryos. Microarray transcript profiling was performed on the embryonic headfold 3 hr after the first maternal alcohol injection (GEO data series accession GSE1074). This analysis revealed metabolic and cellular reprogramming that was substrain-specific and/or PK11195-dependent. Mapping ethanol-responsive KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways revealed down-regulation of ribosomal proteins and proteasome, and up-regulation of glycolysis and pentose phosphate pathway in B6N embryos; and significant up-regulation of tight junction, focal adhesion, adherens junction, and regulation of the actin cytoskeleton (and near-significant up-regulation of Wnt signaling and apoptosis) pathways in both substrains. Expression networks constructed computationally from these altered genes identified entry points for EtOH at several hubs (MAPK1, ALDH3A2, CD14, PFKM, TNFRSF1A, RPS6, IGF1, EGFR, PTEN) and for PK11195 at AKT1. Our findings are consistent with the growing view that developmental exposure to alcohol alters common signaling pathways linking receptor activation to cytoskeletal reorganization. The programmatic shift in cell motility and metabolic capacity further implies cell signals and responses that are integrated by the mitochondrial recognition site for PK11195. Developmental Dynamics 236:613–631, 2007. © 2007 Wiley-Liss, Inc.