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Nicotine and Its downstream metabolites in maternal and cord sera: biomarkers of prenatal smoking exposure associated with offspring DNA methylation

Nicotine and Its downstream metabolites in maternal and cord sera: biomarkers of prenatal smoking exposure associated with offspring DNA methylation
Nicotine and Its downstream metabolites in maternal and cord sera: biomarkers of prenatal smoking exposure associated with offspring DNA methylation
Nicotine is a major constituent of cigarette smoke. Its primary metabolite in maternal and cord sera, cotinine, is considered a biomarker of prenatal smoking. Nicotine and cotinine half-lives are decreased in pregnancy due to their increased rate of metabolism and conversion to downstream metabolites such as norcotinine and 3-hydroxycotinine. Hence, downstream metabolites of nicotine may provide informative biomarkers of prenatal smoking. In this study of three generations (F0-mothers, F1-offspring who became mothers, and F2-offspring), we present a biochemical assessment of prenatal smoking exposure based on maternal and cord sera levels of nicotine, cotinine, norcotinine, and 3-hydroxycotinine. As potential markers of early effects of prenatal smoking, associations with differential DNA methylation (DNAm) in the F1- and F2-offspring were assessed. All metabolites in maternal and cord sera were associated with self-reported prenatal smoking, except for nicotine. We compared maternal self-report of smoking in pregnancy to biochemical evidence of prenatal smoking exposure. Self-report of F0-mothers of F1 in 1989–1990 had more accuracy identifying prenatal smoking related to maternal metabolites in maternal serum (sensitivity = 94.6%, specificity = 86.9%) compared to self-reports of F1-mothers of F2 (2010–2016) associated with cord serum markers (sensitivity = 66.7%, specificity = 78.8%). Nicotine levels in sera showed no significant association with any DNAm site previously linked to maternal smoking. Its downstream metabolites, however, were associated with DNAm sites located on the MYO1G, AHRR, and GFI1 genes. In conclusion, cotinine, norcotinine, and 3-hydroxycotinine in maternal and cord sera provide informative biomarkers and should be considered when assessing prenatal smoking. The observed association of offspring DNAm with metabolites, except for nicotine, may imply that the toxic effects of prenatal nicotine exposure are exerted by downstream metabolites, rather than nicotine. If differential DNA methylation on the MYO1G, AHRR, and GFI1 genes transmit adverse effects of prenatal nicotine exposure to the child, there is a need to investigate whether preventing changes in DNA methylation by reducing the metabolic rate of nicotine and conversion to harmful metabolites may protect exposed children.
1660-4601
E9552
Kheirkhah Rahimabad, Parnian
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Anthony, Thilani M.
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Jones, A. Daniel
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Eslamimehr, Shakiba
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Mukherjee, Nandini
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Ewart, Susan
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Holloway, John W.
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Commodore, Sarah
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Karmaus, Wilfried
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Arshad, Syed
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Kheirkhah Rahimabad, Parnian
fa337379-ff1a-4c4e-849d-b849c634a41e
Anthony, Thilani M.
43000f81-4eee-4d16-9865-cb0af2f646c9
Jones, A. Daniel
373d5a88-2568-4684-99a9-ed1076179d1b
Eslamimehr, Shakiba
11fb403f-2c15-4499-bf16-97eb849bc13d
Mukherjee, Nandini
f64f02d6-2fd0-40db-88ee-5f85b59b8e0b
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Commodore, Sarah
bca3511d-2e55-4f29-b636-c86ef2305337
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853
Arshad, Syed
917e246d-2e60-472f-8d30-94b01ef28958

Kheirkhah Rahimabad, Parnian, Anthony, Thilani M., Jones, A. Daniel, Eslamimehr, Shakiba, Mukherjee, Nandini, Ewart, Susan, Holloway, John W., Commodore, Sarah, Karmaus, Wilfried and Arshad, Syed (2020) Nicotine and Its downstream metabolites in maternal and cord sera: biomarkers of prenatal smoking exposure associated with offspring DNA methylation. International Journal of Environmental Research and Public Health, 17 (24), E9552. (doi:10.3390/ijerph17249552).

Record type: Article

Abstract

Nicotine is a major constituent of cigarette smoke. Its primary metabolite in maternal and cord sera, cotinine, is considered a biomarker of prenatal smoking. Nicotine and cotinine half-lives are decreased in pregnancy due to their increased rate of metabolism and conversion to downstream metabolites such as norcotinine and 3-hydroxycotinine. Hence, downstream metabolites of nicotine may provide informative biomarkers of prenatal smoking. In this study of three generations (F0-mothers, F1-offspring who became mothers, and F2-offspring), we present a biochemical assessment of prenatal smoking exposure based on maternal and cord sera levels of nicotine, cotinine, norcotinine, and 3-hydroxycotinine. As potential markers of early effects of prenatal smoking, associations with differential DNA methylation (DNAm) in the F1- and F2-offspring were assessed. All metabolites in maternal and cord sera were associated with self-reported prenatal smoking, except for nicotine. We compared maternal self-report of smoking in pregnancy to biochemical evidence of prenatal smoking exposure. Self-report of F0-mothers of F1 in 1989–1990 had more accuracy identifying prenatal smoking related to maternal metabolites in maternal serum (sensitivity = 94.6%, specificity = 86.9%) compared to self-reports of F1-mothers of F2 (2010–2016) associated with cord serum markers (sensitivity = 66.7%, specificity = 78.8%). Nicotine levels in sera showed no significant association with any DNAm site previously linked to maternal smoking. Its downstream metabolites, however, were associated with DNAm sites located on the MYO1G, AHRR, and GFI1 genes. In conclusion, cotinine, norcotinine, and 3-hydroxycotinine in maternal and cord sera provide informative biomarkers and should be considered when assessing prenatal smoking. The observed association of offspring DNAm with metabolites, except for nicotine, may imply that the toxic effects of prenatal nicotine exposure are exerted by downstream metabolites, rather than nicotine. If differential DNA methylation on the MYO1G, AHRR, and GFI1 genes transmit adverse effects of prenatal nicotine exposure to the child, there is a need to investigate whether preventing changes in DNA methylation by reducing the metabolic rate of nicotine and conversion to harmful metabolites may protect exposed children.

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Accepted/In Press date: 15 December 2020
Published date: 20 December 2020

Identifiers

Local EPrints ID: 446014
URI: http://eprints.soton.ac.uk/id/eprint/446014
ISSN: 1660-4601
PURE UUID: 0986a56a-0dcc-4a98-bd6d-73ecb96ce550
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 19 Jan 2021 17:30
Last modified: 26 Nov 2021 02:40

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Contributors

Author: Parnian Kheirkhah Rahimabad
Author: Thilani M. Anthony
Author: A. Daniel Jones
Author: Shakiba Eslamimehr
Author: Nandini Mukherjee
Author: Susan Ewart
Author: Sarah Commodore
Author: Wilfried Karmaus
Author: Syed Arshad

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