Epigenetic Clock Analysis in Children With Fetal Alcohol Spectrum Disorder

Okazaki, Kenji; Otsuka, Ikuo; Shinko, Yutaka; Horai, Tadasu; Hirata, Takashi; Yamaki, Naruhisa; Sora, Ichiro; Hishimoto, Akitoyo

doi:10.1111/acer.14532

Cited by 23 publications

(11 citation statements)

References 68 publications

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“…The study identified one of the epigenetic clocks (GrimAge) was significantly associated with FASD in one buccal and both blood datasets, but no significant associations were reported with the other epigenetic clocks. Meta-analysis of datasets by tissue type also reported a significant association between FASD and the GrimAge epigenetic clock in peripheral blood, but no significant association was reported in buccal cells [ 59 ].…”

Section: Resultsmentioning

confidence: 99%

Association of prenatal alcohol exposure with offspring DNA methylation in mammals: a systematic review of the evidence

et al. 2022

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Background Prenatal alcohol exposure (PAE) is associated with a range of adverse offspring neurodevelopmental outcomes. Several studies suggest that PAE modifies DNA methylation in offspring cells and tissues, providing evidence for a potential mechanistic link to Fetal Alcohol Spectrum Disorder (FASD). We systematically reviewed existing evidence on the extent to which maternal alcohol use during pregnancy is associated with offspring DNA methylation. Methods A systematic literature search was conducted across five online databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Web of Science, EMBASE, Google Scholar and CINAHL Databases were searched for articles relating to PAE in placental mammals. Data were extracted from each study and the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) was used to assess the potential for bias in human studies. Results Forty-three articles were identified for inclusion. Twenty-six animal studies and 16 human studies measured offspring DNA methylation in various tissues using candidate gene analysis, methylome-wide association studies (MWAS), or total nuclear DNA methylation content. PAE dose and timing varied between studies. Risk of bias was deemed high in nearly all human studies. There was insufficient evidence in human and animal studies to support global disruption of DNA methylation from PAE. Inconclusive evidence was found for hypomethylation at IGF2/H19 regions within somatic tissues. MWAS assessing PAE effects on offspring DNA methylation showed inconsistent evidence. There was some consistency in the relatively small number of MWAS conducted in populations with FASD. Meta-analyses could not be conducted due to significant heterogeneity between studies. Conclusion Considering heterogeneity in study design and potential for bias, evidence for an association between PAE and offspring DNA methylation was inconclusive. Some reproducible associations were observed in populations with FASD although the limited number of these studies warrants further research. Trail Registration: This review is registered with PROSPERO (registration number: CRD42020167686).

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Section: Resultsmentioning

confidence: 99%

Association of prenatal alcohol exposure with offspring DNA methylation in mammals: a systematic review of the evidence

et al. 2022

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“…As detection technology and knowledge of DNA methylation states and cofactors improve, there will be improvements in the precision of biomarker detection. Interestingly, while research has established genome-wide DNA methylation profiles as epigenetic clocks for biological aging, there appears to be accelerated epigenetic aging in individuals with FASD (Okazaki et al, 2020 ).…”

Section: Epigenetics: the Interface Between Genome And Environmentmentioning

confidence: 99%

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

Alberry

Laufer

Chater‐Diehl

et al. 2021

Front. Mol. Neurosci.

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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.

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“…A number of epigenetic clocks have been established based on genome-wide DNA methylation (DNAm) profiles [ 8 – 13 ]. Such measures have been revealed an association of epigenetic age acceleration with various conditions including Down syndrome [ 14 ], Werner syndrome [ 15 ], Alzheimer’s disease [ 16 ], schizophrenia [ 17 , 18 ], bipolar disorder [ 19 , 20 ], depressive disorder [ 21 , 22 ], suicide [ 23 ], alcohol related disorders [ 24 , 25 ], and posttraumatic stress disorder [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder

et al. 2022

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Background Autism spectrum disorder (ASD) is characterized by impaired social communication and behavioral problems. An increased risk of premature mortality has been observed in individuals with ASD. Therefore, we hypothesized that biological aging is accelerated in individuals with ASD. Recently, several studies have established genome-wide DNA methylation (DNAm) profiles as ‘epigenetic clocks’ that can estimate biological aging. In addition, ASD has been associated with differential DNAm patterns. Methods We used two independent datasets from blood samples consisting of adult patients with high-functioning ASD and controls: the 1st cohort (38 ASD cases and 31 controls) and the 2nd cohort (6 ASD cases and 10 controls). We explored well-studied epigenetic clocks such as HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge, and DNAm-based telomere length (DNAmTL). In addition, we investigated seven DNAm-based age-related plasma proteins, including plasminogen activator inhibitor-1 (PAI-1), and smoking status, which are the components of GrimAge. Results Compared to controls, individuals with ASD in the 1st cohort, but not in the 2nd cohort, exhibited a trend for increased GrimAge acceleration and a significant increase of PAI-1 levels. A meta-analysis showed significantly increased PAI-1 levels in individuals with ASD compared to controls. Conclusion Our findings suggest there is no epigenetic age acceleration in the blood of individuals with ASD. However, this study provides novel evidence regarding increased plasma PAI-1 levels in individuals with high-functioning ASD. These findings suggest PAI-1 may be a biomarker for high-functioning ASD, however, larger studies based on epigenetic clocks and PAI-1 will be necessary to confirm these findings.

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Epigenetic Clock Analysis in Children With Fetal Alcohol Spectrum Disorder

Cited by 23 publications

References 68 publications

Association of prenatal alcohol exposure with offspring DNA methylation in mammals: a systematic review of the evidence

Association of prenatal alcohol exposure with offspring DNA methylation in mammals: a systematic review of the evidence

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

Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder

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