Dataset Information

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

ABSTRACT:

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).

SUBMITTER: Bestry M

PROVIDER: S-EPMC8785586 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Prenatal alcohol exposure (PAE) can alter the development of neurobiological systems, leading to lasting neuroendocrine, neuroimmune, and neurobehavioral deficits. Although the etiology of this reprogramming remains unknown, emerging evidence suggests DNA methylation as a potential mediator and biomarker for the effects of PAE due to its responsiveness to environmental cues and relative stability over time. Here, we utilized a rat model of PAE to examine the DNA methylation profiles of rat hypothalami and leukocytes at four time points during early development to assess the genome-wide impact of PAE on the epigenome and identify potential biomarkers of PAE. Our model of PAE resulted in blood alcohol levels of ~80-150 mg/dl throughout the equivalent of the first two trimesters of human pregnancy. Hypothalami were analyzed on postnatal days (P) 1, 8, 15, 22 and leukocytes at P22 to compare central and peripheral markers. Genome-wide DNA methylation analysis was performed by methylated DNA immunoprecipitation followed by next-generation sequencing. Results: PAE resulted in lasting changes to DNA methylation profiles across all four ages, with 118 differentially methylated regions (DMRs) displaying persistent alterations across the developmental period at a false-discovery rate (FDR) < 0.05. In addition, 299 DMRs showed the same direction of change in the hypothalamus and leukocytes of P22 pups at an FDR < 0.05, with some genes overlapping with the developmental profile findings. The majority of these DMRs were located in intergenic regions, which contained several computationally-predicted transcription factor binding sites. Differentially methylated genes were generally involved in immune function, epigenetic remodeling, metabolism, and hormonal signaling, as determined by gene ontology analyses. Conclusions: Persistent DNA methylation changes in the hypothalamus may be associated with the long-term physiological and neurobehavioral alterations in observed in PAE. Furthermore, correlations between epigenetic alterations in peripheral tissues and those in the brain will provide a foundation for the development of biomarkers of fetal alcohol spectrum disorder (FASD). Finally, findings from studies of PAE provide important insight into the etiology of neurodevelopmental and mental health disorders, as they share numerous phenotypes and comorbidities.

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