Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections

Sarah M Merrill; Nicole Letourneau; Gerald F Giesbrecht; Karlie Edwards; Julia L MacIsaac; Jonathan W Martin; Amy M MacDonald; David W Kinniburgh; Michael S Kobor; Deborah Dewey; Gillian England-Mason; The APrON Study Team

doi:10.3390/epigenomes8010003

Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections

Epigenomes. 2024 Jan 26;8(1):3. doi: 10.3390/epigenomes8010003.

Authors

Sarah M Merrill^{1

2

3}, Nicole Letourneau^{4

5

6

7

8}, Gerald F Giesbrecht^{6

7

9

10}, Karlie Edwards^{2

3}, Julia L MacIsaac^{2

3}, Jonathan W Martin¹¹, Amy M MacDonald¹², David W Kinniburgh^{12

13}, Michael S Kobor^{2

3

14}, Deborah Dewey^{6

7

8

10}, Gillian England-Mason^{6

7}, The APrON Study Team^{15

16}

Affiliations

¹ Department of Psychiatry and Human Behavior, The Warren Alpert Medical School at Brown University, Providence, RI 02903, USA.
² Department of Medical Genetics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³ Centre for Molecular Medicine and Therapeutics, Vancouver, BC V6H 0B3, Canada.
⁴ Faculty of Nursing, University of Calgary, Calgary, AB T2N 1N4, Canada.
⁵ Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
⁶ Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
⁷ Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
⁸ Hotchkiss Brain Institute, Calgary, AB T2N 4N1, Canada.
⁹ Department of Psychology, Faculty of Arts, University of Calgary, Calgary, AB T2N 1N4, Canada.
¹⁰ Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
¹¹ Science for Life Laboratory, Department of Environmental Science, Stockholm University, 106 91 Stockholm, Sweden.
¹² Alberta Centre for Toxicology, University of Calgary, Calgary, AB T2N 1N4, Canada.
¹³ Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
¹⁴ Program in Child and Brain Development, Canadian Institute for Advanced Research, Toronto, ON M5G 1M1, Canada.
¹⁵ University of Calgary, Calgary, AB T2N 1N4, Canada.
¹⁶ University of Alberta, Edmonton, AB T6G 2R3, Canada.

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study's objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal-child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath's pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed.

Keywords: DNA methylation; common cold; epigenetic clock; immunotoxicity; phthalates.

Grants and funding

The APrON cohort was established by an interdisciplinary team grant provided by Alberta Innovates Health Solutions (formally the Alberta Heritage Foundation for Medical Research). The collection and analysis of data presented in this manuscript was enabled through additional funding provided by the Canadian Institutes of Health Research (CIHR) (MOP-123535), Alberta Children’s Hospital Foundation, Palix Foundation, Allergy, Genes and Environment Network (AllerGen NCE Inc., Calgary, AB, USA), and U.S. National Institutes of Health (Exploration/Development Grant 1R21ES021295-01R21). G. England-Mason received salary support through a Fellowship provided by CIHR (HTA-472411) and Postgraduate Fellowship in Health Innovation provided by Alberta Innovates, the Ministry of Economic Development, Trade and Tourism, and the Government of Alberta.