Abstract
Fetal alcohol syndrome (FAS) is a devastating developmental disorder resulting from alcohol exposure during fetal development. It is a considerable public health problem worldwide and is characterized by central nervous system abnormalities, dysmorphic facial features, and growth retardation. Imprinted genes are known to play an important role in growth and development and therefore four imprinting control regions (ICRs), H19 ICR, IG-DMR, KvDMR1 and PEG3 DMR were examined. It is proposed that DNA methylation changes may contribute to developmental abnormalities seen in FAS and which persist into adulthood. The participants included FAS children and controls from the Western and Northern Cape Provinces. DNA samples extracted from blood and buccal cells were bisulfite modified, the ICRs were amplified by PCR and pyrosequencing was used to derive a quantitative estimate of methylation at selected CpG dinucleotides: H19 ICR (six CpG sites; 50 controls and 73 cases); KvDMR1 (7, 55, and 86); IG-DMR (10, 56, and 84); and PEG3 DMR (7, 50, and 79). The most profound effects of alcohol exposure are on neuronal development. In this study we report on epigenetic effects observed in blood which may not directly reflect tissue-specific alterations in the developing brain. After adjusting for age and sex (known confounders for DNA methylation), there was a significant difference at KvDMR1 and PEG3 DMR, but not the H19 ICR, with only a small effect (0.84% lower in cases; p = 0.035) at IG-DMR. The two maternally imprinted loci, KvDMR1 and PEG3 DMR, showed lower average locus-wide methylation in the FAS cases (1.49%; p < 0.001 and 7.09%; p < 0.001, respectively). The largest effect was at the PEG3 DMR though the functional impact is uncertain. This study supports the role of epigenetic modulation as a mechanism for the teratogenic effects of alcohol by altering the methylation profiles of imprinted loci in a locus-specific manner.
Highlights
Alcohol is a potent teratogen with devastating effects on the developing fetus
To address tissue specificity of DNA methylation at an imprinted locus, we showed that there was no significant difference in percentage methylation at the H19 imprinting control regions (ICRs) locus CpG sites between buccal and blood samples from 50 random participants from another study
In addition Woodfine et al (2011) examined the methylation patterns of 17 germline differentially methylated regions (DMRs) amongst several somatic tissues and reported that the average methylation did not vary amongst the tissues
Summary
The most profound effects of prenatal alcohol exposure are on neuronal development, resulting in adverse cognitive and behavioral outcomes with lifelong implications, distinct dysmorphic features (shortened palpebral fissures, smooth philtrum, and thin vermilion border to the upper lip), and preand postnatal growth retardation (Stratton et al, 1996; Riley and McGee, 2005; Floyd et al, 2006). It is an international problem that shows no racial boundaries (Clarren and Smith, 1978; Masotti et al, 2006) and the consequences of prenatal alcohol exposure represent a major public health problem worldwide (May and Gossage, 2001; Sokol et al, 2003; Riley et al, 2011). The prevalence of FAS in South Africa is one of the highest reported in the world, at 40.5–46.4 per 1000 children of school going age in the Western Cape Province (May et al, 2000), www.frontiersin.org
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