Effects of alcohol on the transcriptome, methylome and metabolome of in vitro gastrulating human embryonic cells.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-18 DOI:10.1242/dmm.052150
E Wallén, K Rämö, J Vehviläinen, J Sokka, M Lehtonen, T Otonkoski, R Trokovic, P Auvinen, O Kärkkäinen, N Kaminen-Ahola
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引用次数: 0

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.

酒精对体外原肠胚人胚胎细胞转录组、甲基组和代谢组的影响
产前酒精暴露(PAE)影响胚胎发育,导致可变胎儿酒精谱系障碍(FASD)表型,伴神经发育障碍和出生缺陷。为了探索PAE对原肠胚形成的影响,我们使用了一个体外模型,在人胚胎干细胞向生殖层细胞分化的过程中,亚慢性中度(20 mM)和重度(70 mM)乙醇暴露。我们分析了内胚层、中胚层和外胚层细胞的全基因组基因表达(mRNA测序)、DNA甲基化(EPIC Illumina微阵列)和代谢组(非靶向LC-MS)。乙醇诱导的改变在内胚层细胞中最多,而在外胚层细胞中变化最显著。所有胚层的蛋氨酸代谢和参与原肠形成和机体模式的主要信号通路基因都受到乙醇的影响。许多改变的基因,包括BMP4、FGF8、SIX3和LHX2,以前与PAE和FASD的表型相关,如心脏和胼胝体发育缺陷以及前脑畸形。我们的研究结果支持了酒精诱导的发育障碍的早期起源,并加强了蛋氨酸循环在FASD病因学中的作用。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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