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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

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
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
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.
DNA methylation, Isle of Wight, acetaminophen metabolites, cohort studies, epigenetic, pharmacoepidemiology
dvac002
Eslamimehr, Shakiba
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Jones, A Daniel
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Anthony, Thilani M
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Arshad, S Hasan
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Holloway, John W
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Ewart, Susan
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Luo, Rui
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Mukherjee, Nandini
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Kheirkhah Rahimabad, Parnian
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Chen, Su
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Karmaus, Wilfried
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Eslamimehr, Shakiba
11fb403f-2c15-4499-bf16-97eb849bc13d
Jones, A Daniel
373d5a88-2568-4684-99a9-ed1076179d1b
Anthony, Thilani M
43000f81-4eee-4d16-9865-cb0af2f646c9
Arshad, S Hasan
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Holloway, John W
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Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Luo, Rui
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Mukherjee, Nandini
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Kheirkhah Rahimabad, Parnian
fa337379-ff1a-4c4e-849d-b849c634a41e
Chen, Su
f15e6a35-9b68-482c-b207-2eababe6b337
Karmaus, Wilfried
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Eslamimehr, Shakiba, Jones, A Daniel, Anthony, Thilani M, Arshad, S Hasan, Holloway, John W, Ewart, Susan, Luo, Rui, Mukherjee, Nandini, Kheirkhah Rahimabad, Parnian, Chen, Su and Karmaus, Wilfried (2022) 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. Environmental Epigenetics, 8 (1), dvac002, [dvac002]. (doi:10.1093/eep/dvac002).

Record type: Article

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.

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Accepted/In Press date: 27 January 2022
e-pub ahead of print date: 2 February 2022
Published date: 19 March 2022
Additional Information: Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases [R01AI091905] and the National Heart, Lung, and Blood Institute [R01HL132321] to W.K and [R01HL082925] to S.H.A. A.D.J. acknowledges support from Michigan AgBioResearch through the USDA National Institute of Food and Agriculture, Hatch project number MICL02474. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA. Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases [R01AI091905] and the National Heart, Lung, and Blood Institute [R01HL132321] to W.K and [R01HL082925] to S.H.A. A.D.J. acknowledges support from Michigan AgBioResearch through the USDA National Institute of Food and Agriculture, Hatch project number MICL02474. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA. Publisher Copyright: © 2022 Published by Oxford University Press 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Keywords: DNA methylation, Isle of Wight, acetaminophen metabolites, cohort studies, epigenetic, pharmacoepidemiology

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Local EPrints ID: 456682
URI: http://eprints.soton.ac.uk/id/eprint/456682
PURE UUID: 14036167-9156-400c-8eb5-0d2a6ee40ec3
ORCID for John W Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 06 May 2022 16:45
Last modified: 04 Aug 2022 01:36

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Contributors

Author: Shakiba Eslamimehr
Author: A Daniel Jones
Author: Thilani M Anthony
Author: S Hasan Arshad
Author: John W Holloway ORCID iD
Author: Susan Ewart
Author: Rui Luo
Author: Nandini Mukherjee
Author: Parnian Kheirkhah Rahimabad
Author: Su Chen
Author: Wilfried Karmaus

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