Association of prenatal acetaminophen use and acetaminophen metabolites with DNA methylation of newborns: analysis of two consecutive generations of the Isle of Wight birth cohort

Author:

Eslamimehr Shakiba1ORCID,Jones A Daniel2,Anthony Thilani M2,Arshad S Hasan345,Holloway John W56ORCID,Ewart Susan7,Luo Rui1,Mukherjee Nandini1,Kheirkhah Rahimabad Parnian1,Chen Su8,Karmaus Wilfried1ORCID

Affiliation:

1. Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis , Robison Hall 3825 DeSoto Avenue Memphis, TN 38152, USA

2. Department of Biochemistry & Molecular Biology, Michigan State University , 603 Wilson Rd Rm 212, East Lansing, MI 48823, USA

3. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton , Hartley Library B12, University Rd, Highfield, Southampton SO17 1BJ, UK

4. The David Hide Asthma and Allergy Research Centre , Hartley Library B12, University Rd, Highfield, Southampton, Isle of Wight SO17 1BJ, UK

5. NIHR Southampton Biomedical Research Centre, University Hospital Southampton , Hartley Library B12, University Rd, Highfield, Southampton SO17 1BJ, UK

6. Human Development and Health, Faculty of Medicine, University of Southampton , Hartley Library B12, University Rd, Highfield, Southampton SO17 1BJ, UK

7. Department of Large Animal Clinical Sciences, Michigan State University , 736 Wilson Road, D202 East Lansing, MI 48824, USA

8. Department of Biostatistics, College of Public Health, University of Nebraska Medical Center , Omaha, NE, USA

Abstract

Abstract Acetaminophen is used by nearly two-thirds of pregnant women. Although considered safe, studies have demonstrated associations between prenatal acetaminophen use and adverse health outcomes in offspring. Since DNA methylation (DNAm) at birth may act as an early indicator of later health, assessments on whether DNAm of newborns is associated with gestational acetaminophen use or its metabolites are needed. Using data from three consecutive generations of the Isle of Wight cohort (F0-grandmothers, F1-mothers, and F2-offspring) we investigated associations between acetaminophen metabolites in F0 serum at delivery with epigenome-wide DNAm in F1 (Guthrie cards) and between acetaminophen use of F1 and F2-cord-serum levels with F2 cord blood DNAm. In epigenome-wide screening, we eliminated non-informative DNAm sites followed by linear regression of informative sites. Based on repeated pregnancies, indication bias analyses tested whether acetaminophen indicated maternal diseases or has a risk in its own right. Considering that individuals with similar intake process acetaminophen differently, metabolites were clustered to distinguish metabolic exposures. Finally, metabolite clusters from F1-maternal and F2-cord sera were tested for their associations with newborn DNAm (F1 and F2). Twenty-one differential DNAm sites in cord blood were associated with reported maternal acetaminophen intake in the F2 generation. For 11 of these cytosine-phosphate-guanine (CpG) sites, an indication bias was excluded and five were replicated in F2 with metabolite clusters. In addition, metabolite clusters showed associations with 25 CpGs in the F0-F1 discovery analysis, of which five CpGs were replicated in the F2-generation. Our results suggest that prenatal acetaminophen use, measured as metabolites, may influence DNAm in newborns.

Funder

National Institute of Allergy and Infectious Diseases

Publisher

Oxford University Press (OUP)

Subject

Health, Toxicology and Mutagenesis,Genetics (clinical),Genetics,Molecular Biology

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