Maternal non-compliance with recommended folic acid supplement use alters global DNA methylation in cord blood of newborns: A cohort study

Eva Morales; María Teresa Prieto-Sánchez; Jaime Mendiola; Ana Cutillas-Tolín; Evdochia Adoamnei; Desirée Valera-Gran; Carmen Martínez-Graciá; Marina Santaella-Pascual; Clara Suárez-Martinez; Jesús Vioque; María Jesús Castaños; Eva Del Castillo; Luis García-Marcos; NELA Study Group

doi:10.1016/j.clnu.2024.04.007

Maternal non-compliance with recommended folic acid supplement use alters global DNA methylation in cord blood of newborns: A cohort study

Clin Nutr. 2024 Apr 16;43(6):1191-1198. doi: 10.1016/j.clnu.2024.04.007. Online ahead of print.

Affiliations

¹ Division of Preventive Medicine and Public Health, Department of Public Health Sciences, Faculty of Medicine, University of Murcia, Murcia, Spain; Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain. Electronic address: evamorales@um.es.
² Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain; Materno-Fetal Medicine Unit, Obstetrics and Gynaecology Service, "Virgen de la Arrixaca" University Clinical Hospital, University of Murcia, Murcia, Spain.
³ Division of Preventive Medicine and Public Health, Department of Public Health Sciences, Faculty of Medicine, University of Murcia, Murcia, Spain; Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain.
⁴ Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain; Department of Nursing, University of Murcia School of Nursing, Murcia, Spain.
⁵ Department of Surgery and Pathology, Miguel Hernandez University, 03550 Alicante, Spain; Grupo de Investigación en Terapia Ocupacional (InTeO), Miguel Hernandez University, 03550 Alicante, Spain; Health and Biomedical Research Institute of Alicante, University Miguel Hernandez (ISABIAL-UMH), Alicante, Spain.
⁶ Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain; Department of Food Science and Technology, Faculty of Veterinary, University of Murcia, Murcia, Spain.
⁷ Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Health and Biomedical Research Institute of Alicante, University Miguel Hernandez (ISABIAL-UMH), Alicante, Spain.
⁸ Obstetrics & Gynecology Service, Virgen de la Arrixaca University Clinical Hospital, University of Murcia, Murcia, Spain.
⁹ Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain; Paediatric Allergy and Pulmonology Units, Virgen de la Arrixaca University Children's Hospital, University of Murcia, Murcia, Spain; ARADyAL Allergy Network, Madrid, Spain.

PMID: 38631086
DOI: 10.1016/j.clnu.2024.04.007

Abstract

Background & aims: Prenatal folate exposure may alter epigenetic marks in the offspring. We aimed to evaluate associations between prenatal exposure to folic acid (FA) in preconception and in utero with cord blood DNA methylation in long interspersed nuclear element 1 (LINE-1) and Alu short interspersed nuclear elements (SINEs) as markers of global DNA methylation levels.

Methods: Data come from 325 mother-child pairs participating in the Nutrition in Early Life and Asthma (NELA) birth cohort (2015-2018). Pregnant women were asked about supplement use, including brand name and dose, one month before pregnancy (preconception) and through the trimesters of pregnancy. Maternal dietary folate intake was assessed using a validated food frequency questionnaire with additional questions for FA supplement use. Folate serum levels were measured in mothers at 24 weeks of gestation and in cord blood of newborns. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 5 LINE-1 and 3 Alu different elements. Associations were estimated using multivariable linear regression models.

Results: A reduction in methylation levels of LINE-1 in newborns was associated with the use of FA supplements below the recommended doses (<400 ug/day) during preconception (-0.50; 95% CI: -0.91, -0.09; P = 0.016), and from preconception up to 12 weeks of gestation (-0.48; 95% CI: -0.88, -0.08; P = 0.018). Maternal use of FA supplements above the tolerable upper intake level of 1000 ug/day from preconception until 12 weeks of gestation was also related to lower methylation in LINE-1 at birth (-0.77; 95% CI: -1.52, -0.02; P = 0.044). Neither FA supplement use after 12 weeks of gestation nor maternal total folate intake (diet plus supplements) were associated with global DNA methylation levels at birth.

Conclusions: Maternal non-compliance with the use of FA supplement recommendations from preconception up to 12 weeks of gestation reduces offspring global DNA methylation levels at birth.

Keywords: Alu; Cord blood; DNA methylation; Folic acid; LINE-1; Supplements.