Abstract
Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). FASD is one of the leading preventable forms of neurodevelopmental disorders. In the light of prevention and early intervention, knowledge on how ethanol exposure induces fetal damage is urgently needed. Besides direct ethanol and acetaldehyde toxicity, alcohol increases oxidative stress, and subsequent general effects (e.g., epigenetic imprinting, gene expression, and metabolite levels). The current review provides an overview of the existing knowledge about specific downstream pathways for FASD that affects e.g., the SHH pathway, cholesterol homeostasis, neurotransmitter signaling, and effects on the cytoskeleton. Available human data vary greatly, while animal studies with controlled ethanol exposition are only to a certain limit transferable to humans. The main deficits in knowledge about FASD are the lack of pathophysiological understanding and dose–response relationships, together with the lack of reliable biomarkers for either FASD detection or estimation of susceptibility. In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention.
Highlights
These authors contributed : Friederike Ehrhart and Sylvia Roozen.A substantial scientific knowledge about the harmful effects of alcohol consumption during pregnancy on the developing fetus exists
Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term used to describe the range of birth defects caused by prenatal exposure to alcohol (which is ethyl alcohol (EtOH))
Depending on the nature and severity of the damage, the following diagnoses under the FASD umbrella term can be given: fetal alcohol syndrome (FAS), partial fetal alcohol syndrome, alcohol-related neurodevelopmental deficiencies (ARND), alcohol-related birth defects (ARBD), or neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE) [1, 7,8,9,10,11]
Summary
These authors contributed : Friederike Ehrhart and Sylvia Roozen. A substantial scientific knowledge about the harmful effects of alcohol consumption during pregnancy on the developing fetus exists. There are several omics data driven approaches to investigate the downstream effects of EtOH-induced damage, which lead to the distinct phenotype of FASD These investigations can be done by (1) analysis of omics data to reveal the differently expressed genes, differentially affected molecular pathways, or biological processes (e.g., by performing pathway analysis or gene ontology analysis). Certain variants of SHH and GLI2 were found in animal models susceptible to EtOH-induced skeletal damage, indicating that the degree of damage is dependent on the genetic background as well [44] Another approach performed by Lombard et al is based on the integrational approach of combining literature and prior knowledge databases to identify potential affected genes and found TGF-β, MAPK, and Hedgehog signaling pathways to be potential candidates for disease causing pathways [45]. Some modifications can be inherited through cell division, whereas the exact mechanism for how histone modifications are copied after DNA strand split is unclear
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