title: Long-term alterations to DNA methylation as a biomarker of prenatal alcohol exposure: From mouse models to human children with fetal alcohol spectrum disorders.
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.
authors.affiliation: Molecular Genetics Unit, Department of Biology, University of Western Ontario, London, Ontario, Canada. Electronic address: blaufer@uwo.ca.
authors.forename: Benjamin I
authors.initials: BI
authors.lastname: Laufer
authors.affiliation: Molecular Genetics Unit, Department of Biology, University of Western Ontario, London, Ontario, Canada. Electronic address: ediehl@uwo.ca.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Chater-Diehl
authors.affiliation: Department of Pediatrics, University of Western Ontario, London, Ontario, Canada. Electronic address: jkapalan@uwo.ca.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kapalanga
authors.affiliation: Molecular Genetics Unit, Department of Biology, University of Western Ontario, London, Ontario, Canada; Department of Pediatrics, University of Western Ontario, London, Ontario, Canada; Program in Neuroscience, University of Western Ontario, London, Ontario, Canada. Electronic address: ssingh@uwo.ca.
authors.forename: Shiva M
authors.initials: SM
authors.lastname: Singh
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects / Q000235:genetics*; D000818:Animals; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects*; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D020869:Gene Expression Profiling; D059647:Gene-Environment Interaction; D005819:Genetic Markers; D005865:Gestational Age; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D013997:Time Factors; D059467:Transcriptome
chemical_list: D005819:Genetic Markers; D000431:Ethanol
keywords: Clustered protocadherins; DNA methylation; Epigenetics; Epigenomics; Fetal alcohol spectrum disorders (FASD); Genomic imprinting; Neurodevelopment; Neuroepigenomics; Personalized medicine; Prenatal alcohol exposure; Translational research