Ethanol-induced cerebellar transcriptomic changes in a postnatal model of fetal alcohol spectrum disorders: Focus on disease onset

Abstract

Fetal alcohol spectrum disorders (FASD) are a group of neurodevelopmental disorders caused by ethanol exposure in utero, which can result in neurocognitive and behavioral impairments, growth defects, and craniofacial anomalies. FASD affects up to 1-5% of school-aged children in the United States, and there is currently no cure. The underlying mechanisms involved in ethanol teratogenesis remain elusive and need greater understanding to develop and implement effective therapies. Using a third trimester human equivalent postnatal mouse model of FASD, we evaluate the transcriptomic changes induced by ethanol exposure in the cerebellum on P5 and P6, after only 1 or 2 days of ethanol exposure, with the goal of shedding light on the transcriptomic changes induced early during the onset and development of FASD. We have highlighted key pathways and cellular functions altered by ethanol exposure, which include pathways related to immune function and cytokine signaling as well as the cell cycle. Additionally, we found that ethanol exposure resulted in an increase in transcripts associated with a neurodegenerative microglia phenotype, and acute- and pan-injury reactive astrocyte phenotypes. Mixed effects on oligodendrocyte lineage cell associated transcripts and cell cycle associated transcripts were observed. These studies help to elucidate the underlying mechanisms that may be involved with the onset of FASD and provide further insights that may aid in identifying novel targets for interventions and therapeutics.

Recent Breakthroughs in Understanding the Cerebellum's Role in Fetal Alcohol Spectrum Disorder: A Systematic Review

“…These effects were relatively short-lived, lasting at least 6 days after the end of ethanol exposure on P4-9 and returning to baseline by adolescence (Cealie et al, 2023; C. J. M. Kane et al, 2021). It is exciting to see that investigators have been using state-of-the-art techniques to characterize the neuroinflammatory effects of ethanol in the cerebellum, including RNA sequencing (Holloway et al, 2023) and two-photon microscopy in vivo imaging (Cealie et al, 2023).…”

“…The final number of papers that were decided to be included for the final data extraction was 98 (Fig 1). The search was re-run on September, 2023 for articles published between 2022-2023 and 6 additional papers were determined to fit the inclusion criteria (Boateng et al, 2023;Carugati, Goodlett, Cudd, & Washburn, 2022;Cealie et al, 2023;Fraize et al, 2023;Holloway et al, 2023;Todd, Clapp, Dains, Karacay, & Bonthius, 2022).…”

Editorial: Physiology and pathology of neuroglia

“…Fetal Alcohol Syndrome (FAS) is a public health problem with a prevalence of 2–5% in the USA. FAS disturbs the structure and function of the brain, but the underlying mechanisms remain elusive (Holloway et al, 2023 ). Zheng et al , observed loss of the tubulin-binding cofactor B resulting in disorganized microtubules and shortening of astrocytic processes in a model of chronic alcohol exposure.…”