ABSTRACT
Rodent models of Fetal Alcohol Spectrum Disorders (FASD) have revealed that prenatal alcohol exposure (PAE) results in differential DNA cytosine methylation in the developing brain. The resulting genome-wide methylation changes are enriched in genes with neurodevelopmental functions. The profile of differential methylation is dynamic and present in some form for life. The methylation changes are transmitted across subsequent mitotic divisions, where they are maintained and further modified over time. More recent follow up has identified a profile of the differential methylation in the buccal swabs of young children born with FASD. While distinct from the profile observed in brain tissue from rodent models, there are similarities. These include changes in genes belonging to a number of neurodevelopmental and behavioral pathways. Specifically, there is increased methylation at the clustered protocadherin genes and deregulation of genomically imprinted genes, even though no single gene is affected in all patients studied to date. These novel results suggest further development of a methylation based strategy could enable early and accurate diagnostics and therapeutics, which have remained a challenge in FASD research. There are two aspects of this challenge that must be addressed in the immediate future: First, the long-term differential methylomics observed in rodent models must be functionally confirmed. Second, the similarities in differential methylation must be further established in humans at a methylomic level and overcome a number of technical limitations. While a cure for FASD is challenging, there is an opportunity for the development of early diagnostics and attenuations towards a higher quality of life.
Subject(s)
Alcohol Drinking/genetics , DNA Methylation/drug effects , Epigenesis, Genetic/drug effects , Ethanol/adverse effects , Fetal Alcohol Spectrum Disorders/genetics , Maternal Exposure/adverse effects , Prenatal Exposure Delayed Effects , Alcohol Drinking/adverse effects , Animals , Disease Models, Animal , Female , Fetal Alcohol Spectrum Disorders/diagnosis , Fetal Alcohol Spectrum Disorders/therapy , Gene Expression Profiling , Gene-Environment Interaction , Genetic Markers , Gestational Age , Humans , Mice , Pregnancy , Risk Factors , Time Factors , TranscriptomeABSTRACT
AIM: Prenatal alcohol exposure (PAE) can cause fetal alcohol spectrum disorders (FASD). Previously, we assessed PAE in brain tissue from mouse models, however whether these changes are present in humans remains unknown. MATERIALS & METHODS: In this report, we show some identical changes in DNA methylation in the buccal swabs of six children with FASD using the 450K array. RESULTS: The changes occur in genes related to protocadherins, glutamatergic synapses, and hippo signaling. The results were found to be similar in another heterogeneous replication group of six FASD children. CONCLUSION: The replicated results suggest that children born with FASD have unique DNA methylation defects that can be influenced by sex and medication exposure. Ultimately, with future clinical development, assessment of DNA methylation from buccal swabs can provide a novel strategy for the diagnosis of FASD.
