Journal Article Ppublish 2 citations
PubMed: 40401629 DOI: 10.1242/dmm.052150
Effects of alcohol on the transcriptome, methylome and metabolome of in vitro gastrulating human embryonic cells.
Dis Model Mech 18(6)
Authors: E Wallén, K Rämö, J Vehviläinen, J Sokka, M Lehtonen, T Otonkoski, R Trokovic, P Auvinen, O Kärkkäinen, N Kaminen-Ahola
Affiliations
- Environmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
- Research Programs Unit, Stem Cells and Metabolism and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
- Department of Pediatrics, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, 00290 Helsinki, Finland.
Abstract
Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neurodevelopmental disorders and birth defects. To explore the effects of PAE on gastrulation, we used an in vitro model with subchronic moderate (20 mM) and severe (70 mM) ethanol exposures during the differentiation of human embryonic stem cells into germ layer cells. We analyzed genome-wide gene expression (mRNA sequencing), DNA methylation (EPIC Illumina microarrays) and metabolome (non-targeted LC-MS) of the endodermal, mesodermal and ectodermal cells. The largest number of ethanol-induced alterations were observed in endodermal cells, whereas the most prominent changes were in ectodermal cells. Methionine metabolism and genes of the main signaling pathways involved in gastrulation and body patterning were affected by ethanol in all germ layers. Many of the altered genes, including BMP4, FGF8, SIX3 and LHX2, have previously been associated with PAE and phenotypes of FASD, like defects in heart and corpus callosum development as well as holoprosencephaly. Our findings support the early origin of alcohol-induced developmental disorders and strengthen the role of methionine cycle in the etiology of FASD.
MeSH
Cells, Genes, Fetal Alcohol Spectrum Disorders, Disease Models, Animal, Transcriptome, Phenotype, Gastrulation, Epigenome, Ethanol, Germ Layers