Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study

Gillian England-Mason; Sarah M Merrill; Nicole Gladish; Sarah R Moore; Gerald F Giesbrecht; Nicole Letourneau; Julia L MacIsaac; Amy M MacDonald; David W Kinniburgh; Anne-Louise Ponsonby; Richard Saffery; Jonathan W Martin; Michael S Kobor; Deborah Dewey; APrON Study Team

doi:10.1016/j.envint.2022.107183

Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study

Environ Int. 2022 May:163:107183. doi: 10.1016/j.envint.2022.107183. Epub 2022 Mar 21.

Authors

Affiliations

¹ Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.
² Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
³ Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Department of Psychology, Faculty of Arts, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁴ Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Faculty of Nursing, University of Calgary, Calgary, Alberta, Canada; Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Calgary, Alberta, Canada.
⁵ Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada.
⁶ Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
⁷ Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm, Södermanland, Sweden.
⁹ Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; Program in Child and Brain Development, CIFAR, Toronto, Ontario, Canada.
¹⁰ Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Calgary, Alberta, Canada. Electronic address: dmdewey@ucalgary.ca.

PMID: 35325772
DOI: 10.1016/j.envint.2022.107183

Abstract

Background: Prenatal exposure to phthalates has been associated with adverse health and neurodevelopmental outcomes. DNA methylation (DNAm) alterations may be a mechanism underlying these effects, but prior investigations of prenatal exposure to phthalates and neonatal DNAm profiles are limited to placental tissue and umbilical cord blood.

Objective: Conduct an epigenome-wide association study (EWAS) of the associations between prenatal exposure to phthalates and DNAm in two accessible infant tissues, venous buffy coat blood and buccal epithelial cells (BECs).

Methods: Participants included 152 maternal-infant pairs from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Maternal second trimester urine samples were analyzed for nine phthalate metabolites. Blood (n = 74) or BECs (n = 78) were collected from 3-month-old infants and profiled for DNAm using the Infinium HumanMethylation450 (450K) BeadChip. Robust linear regressions were used to investigate the associations between high (HMWPs) and low molecular weight phthalates (LMWPs) and change in methylation levels at variable Cytosine-phosphate-Guanine (CpG) sites in infant tissues, as well as the sensitivity of associations to potential confounders.

Results: One candidate CpG in gene RNF39 reported by a previous study examining prenatal exposure to phthalates and cord blood DNAm was replicated. The EWAS identified 12 high-confidence CpGs in blood and another 12 in BECs associated with HMWPs and/or LMWPs. Prenatal exposure to bisphenol A (BPA) associated with two of the CpGs associated with HMWPs in BECs.

Discussion: Prenatal exposure to phthalates was associated with DNAm variation at CpGs annotated to genes associated with endocrine hormone activity (i.e., SLCO4A1, TPO), immune pathways and DNA damage (i.e., RASGEF1B, KAZN, HLA-A, MYO18A, DIP2C, C1or109), and neurodevelopment (i.e., AMPH, NOTCH3, DNAJC5). Future studies that characterize the stability of these associations in larger samples, multiple cohorts, across tissues, and investigate the potential associations between these biomarkers and relevant health and neurodevelopmental outcomes are needed.

Keywords: 450K; APrON study; DNA methylation; Epigenetics; Neurodevelopment; Phthalates.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation
Epigenome*
Female
Fetal Blood / chemistry
Humans
Infant
Infant, Newborn
Phthalic Acids
Placenta / metabolism
Pregnancy
Prenatal Exposure Delayed Effects* / genetics

Substances

Phthalic Acids
phthalic acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding