Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome

Abstract

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.

Advancing the understanding of the embryo transcriptome co-regulation using meta-, functional, and gene network analysis tools

“…Our findings also corroborate reports that some toxic agents that can cause birth defects have the same or similar effects on the transcriptome (Nemeth et al 2005. The meta-study approaches also support reports of additional condition-dependent effects of teratogenic agents with gene expression patterns highly dependent on the treatment levels compared, including toxic factor, dose, sampling time, and strain (Green et al 2007). …”

“…Maunoury et al (1992) described the association between the regulation of villin gene activity during mouse embryogenesis and the tissue-specific expression observed in adults. Villin is responsible for establishing and maintaining the apical/basal membrane polarity and Green et al (2007) reported differential expression of cytoskeleton genes in the presence of alcohol and the present meta-analysis confirmed this finding. Lee et al (1997) reported dependency of tropomyosin transcripts on alcohol.…”

“…The findings from the meta-analyses approaches corroborate reports that numerous toxic agents that can cause birth defects share some of the same effects on the transcriptome, while others are unique to the dose, exposure timing, embryogenetic line, and other factors (Finnell et al 2002, Green et al 2007, Suzuki et al 2007. Our findings also corroborate reports that some toxic agents that can cause birth defects have the same or similar effects on the transcriptome (Nemeth et al 2005.…”

“…Soleman et al (2003) described the activation of the mitochondrial apoptotic pathway in mouse embryos by the teratogenic agents and Singh et al (2005) noted the critical role of mitochondria in embryo development. Green et al (2007) reported significant representation of genes associated with protein degradation and translocation, glycolysis, chaperone proteins, and proteasome subunits on the embryos treated with ethanol. The significant presence of genes associated with carbohydrate metabolism in study GSE 1074 was expected because these processes are activated by the presence of alcohol.…”

“…The GEO series are GSE 1068, GSE 1069, GSE 1070, GSE 1072, GSE 1074, GSE 1075, GSE 1076, GSE 1077, and GSE 1079 used the same two-dye cDNA platform and fluorescence intensities were available for 2382 sequence-verified human gene elements that effectively hybridize to mouse, human, and rat target mRNA. Detailed description of the treatment doses and timing, sampling time, mouse strains, platform, RNA isolation, labeling, and hybridization is available in the GEO database and are also provided by Nemeth et al (2005), Singh et al (2005) and Green et al (2007). These microarray experiments were conducted to assess the expression profile of mouse embryos exposed to teratogenic agents that can potentially interfere with normal embryo development and cause birth defects.…”