Sex- and Tissue-Specific Effects of Binge-Level Prenatal Alcohol Consumption on DNA Methylation at Birth

Abstract

Background: Binge-level prenatal alcohol exposure (PAE) causes developmental abnormalities, which may be mediated in part by epigenetic mechanisms. Despite this, few studies have characterised the association of binge PAE with DNA methylation in offspring. Methods: We investigated the association between binge PAE and genome-wide DNA methylation profiles in a sex-specific manner in neonatal buccal and placental samples. Results: We identified no differentially methylated CpGs or differentially methylated regions (DMRs) at false discovery rate <0.05. However, using a sum-of-ranks approach, we identified a DMR in each tissue of female offspring. The DMR identified in buccal samples is located near regions with previously-reported associations to fetal alcohol spectrum disorder (FASD) and binge PAE. Conclusion: Our findings warrant further replication and highlight a potential epigenetic link between binge PAE and FASD.

Lay abstract

Women who binge-drink alcohol in pregnancy are more likely to have children with health and behavioural problems. It is possible that this happens through changes to the ‘epigenetic’ switches that control our genes. Yet few have tried to prove this. To test this idea, we designed a study called ‘Asking QUestions about Alcohol in pregnancy’. We carefully measured levels of drinking across all trimesters in volunteers who were pregnant. Then we measured one type of ‘gene switch’ in cells from the placenta and from the cheeks of their babies. We did not find strong evidence that maternal binge drinking changed ‘epigenetic’ gene switches in babies. However, when we looked at female offspring only, we did find some evidence. The genes that we found had been seen by others in similar studies. Our findings have no immediate medical application but provide evidence for conducting larger studies.

Keywords::

• binge
• buccal
• DNA methylation
• epigenetics
• placenta
• prenatal alcohol exposure
• newborn

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/imt-2021-0285

Author contributions

J Halliday, JM Craig and E Muggli conceived and designed the study. E Muggli, J Halliday, S Lewis and EJ Elliott were involved in the design, recruitment, and sample collection of AQUA cohort. S Lewis provided AQUA covariates for analysis. YJ Loke analyzed the data with input from J Ryan, E Muggli, JM Craig and J Halliday. YJ Loke and JM Craig wrote the manuscript with input from J Ryan, E Muggli, J Halliday, R Saffrey, EJ Elliott and S Lewis. All authors read and approved the final manuscript.

Acknowledgments

The authors are extremely grateful to all the women and their children who are taking part in this study and thank the researchers who were involved in sample collection. A special mention to J Maksimovic for her expertise and advice on analyzing genome-wide DNA methylation data.

Financial & competing interests disclosure

This work was supported by the Australian National Health and Medical Research Council Grant no. 1011070; Senior Research Fellowship no. 1021252 (J Halliday) and no. 1045161 (R Saffrey), and Practitioner Fellowship no. 1021480 (EJ Elliott); the Medical Research Futures Fund Next Generation Fellowship no. 1135959 (EJ Elliott); and the Victorian State Government’s Operational Infrastructure Support Program. The study has also received funding from the McCusker Charitable Trust to assist with the biospecimen collection at birth, Jack Brockhoff Foundation no. 3525 for genome-wide DNA methylation data generation of placenta samples, and Foundation for Children no. 2015-111 for genome-wide DNA methylation data generation of buccal samples. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The AQUA project was approved by the Eastern Health Research and Ethics Committee (E54/1011) and the Human Research Ethics Committees of Mercy Health (R11/14), Monash Health (11071B), the Royal Women’s Hospital (11/20) and the Royal Children’s Hospital (31055A). In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the Australian National Health and Medical Research Council Grant no. 1011070; Senior Research Fellowship no. 1021252 (J Halliday) and no. 1045161 (R Saffrey), and Practitioner Fellowship no. 1021480 (EJ Elliott); the Medical Research Futures Fund Next Generation Fellowship no. 1135959 (EJ Elliott); and the Victorian State Government’s Operational Infrastructure Support Program. The study has also received funding from the McCusker Charitable Trust to assist with the biospecimen collection at birth, Jack Brockhoff Foundation no. 3525 for genome-wide DNA methylation data generation of placenta samples, and Foundation for Children no. 2015-111 for genome-wide DNA methylation data generation of buccal samples. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.