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Author Notes:

Donghai Liang, Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory, University, 1518 Clifton Rd NE, Atlanta, GA 30322, USA, Tel: 404-712-9583. Email: donghai.liang@emory.edu

Youran Tan: Formal Analysis, Investigation, Writing-Original Draft, Visualization. Dana Boyd Barr: Methodology, Validation, Resources, Data Curation, Writing-Review&Editing, Funding acquisition. P. Barry Ryan: Methodology, Resources, Data Curation, Writing-Review&Editing, Funding acquisition. Veronika Fedirko: Methodology, Resources, Writing-Review&Editing. Jeremy A. Sarnat: Methodology, Resources, Writing-Review&Editing. Audrey J. Gaskins: Methodology, Resources, Writing-Review&Editing. Che-Jung Chang: Data Curation, Writing-Review&Editing. Ziyin Tang: Data Curation, Writing-Review&Editing. Carmen J. Marsit: Resources, Writing-Review&Editing, Funding acquisition. . Elizabeth J. Corwin: Resources, Data Curation, Writing-Review&Editing, Funding acquisition. Dean P. Jones: Methodology, Resources, Writing-Review&Editing, Funding acquisition. Anne L. Dunlop: Investigation, Resources, Data Curation, Writing-Review&Editing, Project administration, Funding acquisition. Donghai Liang: Conceptualization, Methodology, Investigation, Writing-Original Draft, Writing-Review&Editing, Supervision, Funding acquisition. Declaration of interests

Additionally, we are grateful for our colleagues -Nathan Mutic, Cierra Johnson, Erin Williams, Priya D’Souza, Estefani Ignacio Gallegos, Nikolay Patrushev, Kristi Maxwell Logue, Castalia Thorne, Shirleta Reid, Cassandra Hall, and the clinical health care providers and staff at the prenatal recruiting sites for helping with data and sample collection and logistics and sample chemical analyses in the laboratory. We also thank the participants themselves for their additions to this project.


Research Funding:

This work was supported by the National Institute of Health (NIH) research grants [R01NR014800, R01MD009064, R24ES029490, R01MD009746, R21ES032117], NIH Center Grants [P50ES02607, P30ES019776, UH3OD023318, U2CES026560], and Environmental Protection Agency (USEPA) center grant [83615301].

V. Fedirko is supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Rising Stars Award (Grant ID RR200056).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Environmental Sciences
  • Environmental Sciences & Ecology
  • Tobacco smoke exposure
  • High-resolution metabolomics
  • Cotinine
  • Preterm birth
  • Shorter gestational age
  • RISK

High-resolution metabolomics of exposure to tobacco smoke during pregnancy and adverse birth outcomes in the Atlanta African American maternal-child cohort

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Journal Title:



Volume 292, Number Pt A


, Pages 118361-118361

Type of Work:

Article | Post-print: After Peer Review


Exposure to tobacco smoke during pregnancy has been associated with a series of adverse reproductive outcomes; however, the underlying molecular mechanisms are not well-established. We conducted an untargeted metabolome-wide association study to identify the metabolic perturbations and molecular mechanisms underlying the association between cotinine, a widely used biomarker of tobacco exposure, and adverse birth outcomes. We collected early and late pregnancy urine samples for cotinine measurement and serum samples for high-resolution metabolomics (HRM) profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014–2016). Maternal metabolome perturbations mediating prenatal tobacco smoke exposure and adverse birth outcomes were assessed by an untargeted HRM workflow using generalized linear models, followed by pathway enrichment analysis and chemical annotation, with a meet-in-the-middle approach. The median maternal urinary cotinine concentrations were 5.93 μg/g creatinine and 3.69 μg/g creatinine in early and late pregnancy, respectively. In total, 16,481 and 13,043 metabolic features were identified in serum samples at each visit from positive and negative electrospray ionization modes, respectively. Twelve metabolic pathways were found to be associated with both cotinine concentrations and adverse birth outcomes during early and late pregnancy, including tryptophan, histidine, urea cycle, arginine, and proline metabolism. We confirmed 47 metabolites associated with cotinine levels, preterm birth, and shorter gestational age, including glutamate, serine, choline, and taurine, which are closely involved in endogenous inflammation, vascular reactivity, and lipid peroxidation processes. The metabolic perturbations associated with cotinine levels were related to inflammation, oxidative stress, placental vascularization, and insulin action, which could contribute to shorter gestations. The findings will support the further understanding of potential internal responses in association with tobacco smoke exposures, especially among African American women who are disproportionately exposed to high tobacco smoke and experience higher rates of adverse birth outcomes.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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