Transcriptomic changes due to early, chronic alcohol exposure during cortical development implicate regionalization, cell-type specification, synaptogenesis and WNT signaling as primary determinants of fetal alcohol Spectrum Disorders

Abstract

Ethanol (EtOH) exposure in early development can lead to profound consequences on neural progenitor cells (NPC) and the neurons that they generate. The clusters of neurological and anatomical hallmarks associated with prenatal EtOH exposure are collectively referred to as fetal alcohol spectrum (FAS). Because EtOH affects multiple developmental processes depending on dosage, frequency and timing of exposure, FAS symptoms exists on a spectrum from relatively benign to severely debilitating intellectual disability, including difficulties with learning, memory and executive function. While animal models successfully recapitulate multiple aspects of FAS including characteristically altered craniofacial morphogenesis and behavioral deficits, much less is understood regarding how EtOH exposure affects human NPCs and neuronal development. In this study, we utilize an in vitro human pluripotent stem cell-based (hPSC) model of early neurogenesis to probe the differences in the development of NPCs and post-mitotic neurons using bulk RNA sequencing. Our findings include specific alterations in the areas of WNT signaling, cortical regionalization and synapse formation.

Investigating the influence of perinatal nicotine and alcohol exposure on the genetic profiles of dopaminergic neurons in the VTA using miRNA–mRNA analysis

“…Pathways in cancer, Wnt signaling pathway, long-term potentiation, Huntington's disease, and Parkinson's disease were among the many significantly enriched KEGG pathways following the nicotine-alcohol perinatal exposure group compared to the alcohol perinatal exposure group. Prenatal alcohol exposure has been shown in previous studies to disrupt Wnt signaling pathway and has been a determinant of FASD 106,107 . In the central nervous system, Wnt signaling is known to modulate neuronal proliferation, migration, adhesion, differentiation, and axon outgrowth [108][109][110][111][112] .…”

Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases

“…In translational work, chronic alcohol is also associated with changes in the transcriptomic profile of the oxidative stress pathway ( Bogenpohl et al, 2019 ). Prenatal alcohol has even more severe effects on the transcription of multiple targets within pathways that mediate neuronal migration and synaptic function ( Fischer et al, 2019 ).…”