Dipak K Sarkar1, Omkaram Gangisetty1, Jeffrey R Wozniak2, Judith K Eckerle3, Michael K Georgieff4, Tatiana M Foroud5, Leah Wetherill5, Wladimir Wertelecki6, Christina D Chambers6, Edward Riley7, Natalya Zymak-Zakutnya8, Lyubov Yevtushok9. 1. Rutgers Endocrine Research Program, (DKS, OG), Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey. 2. Department of Psychiatry, (JRW), University of Minnesota Twin Cities, Minneapolis, Minnesota. 3. Department Pediatrics, (JKE), University of Minnesota, Minneapolis, Minnesota. 4. Division of Pediatric Neonatology, (MKG), University of Minnesota, Minneapolis, Minnesota. 5. Department of Medical and Molecular Genetics, (TMF, LW), Indiana University School of Medicine, Indianapolis, Indiana. 6. Department of Pediatrics, (WW, CDC), University of California San Diego, La Jolla, California. 7. Department of Psychology, (ER), Center for Behavioral Teratology, San Diego State University, San Diego, California. 8. Khmelnytsky City Perinatal Center and Omni-Net Center, (NZ-Z), Khmelnytsky, Ukraine. 9. Rivne Diagnostic Center and Omni-Net Center, (LY), Rivne, Ukraine.
Abstract
BACKGROUND: We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (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 3 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. 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.
BACKGROUND: We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (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 3 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 PAEchildren had higher DNA methylation of POMC and PER2. PAEchildren 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. PAEchildren had increased levels of stress hormone cortisol and adrenocorticotropic hormone. 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.
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