Epigenetic Impacts of Early Life Stress in Fetal Alcohol Spectrum Disorders Shape the Neurodevelopmental Continuum

Abstract

Neurodevelopment in humans is a long, elaborate, and highly coordinated process involving three trimesters of prenatal development followed by decades of postnatal development and maturation. Throughout this period, the brain is highly sensitive and responsive to the external environment, which may provide a range of inputs leading to positive or negative outcomes. Fetal alcohol spectrum disorders (FASD) result from prenatal alcohol exposure (PAE). Although the molecular mechanisms of FASD are not fully characterized, they involve alterations to the regulation of gene expression via epigenetic marks. As in the prenatal stages, the postnatal period of neurodevelopment is also sensitive to environmental inputs. Often this sensitivity is reflected in children facing adverse conditions, such as maternal separation. This exposure to early life stress (ELS) is implicated in the manifestation of various behavioral abnormalities. Most FASD research has focused exclusively on the effect of prenatal ethanol exposure in isolation. Here, we review the research into the effect of prenatal ethanol exposure and ELS, with a focus on the continuum of epigenomic and transcriptomic alterations. Interestingly, a select few experiments have assessed the cumulative effect of prenatal alcohol and postnatal maternal separation stress. Regulatory regions of different sets of genes are affected by both treatments independently, and a unique set of genes are affected by the combination of treatments. Notably, epigenetic and gene expression changes converge at the clustered protocadherin locus and oxidative stress pathway. Functional studies using epigenetic editing may elucidate individual contributions of regulatory regions for hub genes and further profiling efforts may lead to the development of non-invasive methods to identify children at risk. Taken together, the results favor the potential to improve neurodevelopmental outcomes by epigenetic management of children born with FASD using favorable postnatal conditions with or without therapeutic interventions.

Adverse childhood experiences and neurodevelopmental disorders among youth with and without prenatal substance exposure: A longitudinal matched register-based cohort study

“…ACEs causing severe stress and prolonged institutional rearing have detrimental consequences on the biological stress systems and the development of brain areas responsible for cognitive control, self-regulation and memory ( De Bellis & Zisk, 2014 ; Miguel et al, 2019 ; Noble et al, 2012 ; Tottenham et al, 2010 ; van IJzendoorn et al, 2020 ). The results are in line with the view of Alberry et al (2021) that a stressful postnatal environment may worsen the outcomes of PAE. In addition, Fisher et al (2011) have shown that early adversities have an equal effect to PSE in the onset and growth of behaviour dysregulation during adolescence.…”

“…However, based on brain research ( Miguel et al, 2019 ; Tottenham et al, 2010 ), it is possible to assume that ACEs may also increase neurodevelopmental disorders, manifesting especially in cognitive control, self-regulation and memory functions. According to a review by Alberry et al (2021) , a stressful environment in early life may worsen the neurodevelopmental outcomes of prenatal alcohol exposure through epigenetic changes.…”

“…The relationship between PAE, ACEs and neurodevelopmental disorders has not been well studied (Alberry et al, 2021;Koponen et al, 2009;Kambeitz et al, 2019;Price et al, 2017). The few existing studies suggest that ACEs may increase the likelihood of neurodevelopmental problems appearing in attention, memory, intelligence, language development and behaviour (Koponen, 2006;Koponen et al, 2009Koponen et al, , 2013Coggins et al, 2007;Henry et al, 2007;Hyter, 2012;Kambeitz et al, 2019).…”

Epigenetics and Neuroinflammation Associated With Neurodevelopmental Disorders: A Microglial Perspective

“…DNMT3A haploinsufficiency in mice causes behavioral abnormalities and epigenomic dysregulation that overlap with Rett syndrome and ASD ( Christian et al, 2020 ). Notably, the expression of Mecp2 , Uhrf1 , Tet2 , Dnmt1 , and Dnmt3a is also dysregulated in various rodent FAS models ( Chen et al, 2013 ; Kim et al, 2013 ; Nagre et al, 2015 ; Varadinova and Boyadjieva, 2015 ; Veazey et al, 2017 ; Boschen et al, 2018 ; Alberry et al, 2021 ; Lussier et al, 2021 ). Epigenetic dysregulation caused by exposure to environmental chemicals during development may cause neuroinflammation and NDDs through polarization of microglia into pro-inflammatory phenotypes.…”

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

“…This foundational centrality of epigenotoxicity to the understanding of cannabinoid toxicity is highly reminiscent of the central understanding which the fundamentally epigenomic nature of fetal alcohol syndrome has been shown to display [ 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 ]. Indeed, fetal alcohol syndrome has been shown to be primarily mediated epigenomically via cannabinoid type 1 receptors (CB1Rs) [ 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 , 331 ].…”