Persistent Changes in Stress-Regulatory Genes in Pregnant Women or Children Exposed Prenatally to Alcohol

Abstract

Background: We have recently shown that binge or heavy levels of alcohol drinking increases DNA methylation and reduces gene expression of POMC and PER2 in adult human subjects (Gangisetty et al., 2019). One hypothesis would be that methylation of these two genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of PAE. Results of the present study provided some support for this hypothesis. Methods: We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from three separate cohorts of patients i) pregnant women who consumed moderate to high levels of alcohol or low/unexposed controls, ii) children with PAE and non-alcohol exposed controls, and iii) children with PAE treated with or without choline. Results: We found pregnant women who consumed moderate to high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone (ACTH). Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. Conclusions: These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.