High-resolution Profiling of Newborn Metabolome to Study the Impact of Tobacco Smoke Exposure During Pregnancy on Adverse Birth Outcomes in The Atlanta African American Maternal-Child Cohort Público

Abstract

Background: Exposure to tobacco smoke during pregnancy is an established risk factor for early birth before full term (≥ 39 weeks), including preterm birth (PTB, <37 weeks) and early term birth (ETB, 37-38 weeks). However, the underlying molecular mechanisms are poorly understood. Here, we aimed to characterize the molecular relationships between prenatal maternal smoke exposure and early birth outcomes via the newborn metabolome.

Method: Participants were enrolled in the Atlanta African American Maternal-Child Cohort between 2016-2020 (N=269). Maternal urine samples were collected during 8-14 weeks gestation for cotinine and trans-3′-hydroxy-cotinine (3HC) measurement. Newborn dried blood spots (DBS) were collected at delivery for high-resolution metabolomics profiling and gestational age (in completed weeks) was ascertained from the medical record. Using an untargeted metabolomic workflow, newborn biological pathways and markers associated with exposure and outcome were estimated with multivariable regression, followed by pathway enrichment and chemical annotation, using the meet-in-the-middle approach.

Results: The geometric mean level of urinary maternal cotinine and 3HC was 7.44 µg/g and 14.89 µg/g, respectively. In total, 648 and 503 metabolomic signals were associated with maternal cotinine and 3HC levels, respectively (p<0.05). Seven pathways were enriched across all metabolome-wide association studies, including tryptophan, leukotriene, and biopterin metabolism (all p<0.05). Six metabolites associated with both tobacco biomarkers and early birth outcomes were confirmed with level-1 evidence, including glutathione and 17hydroxyprogesterone, which are involved in redox reactions and vasoconstriction.

Conclusion: Our findings demonstrate that metabolism is different in newborns delivered early versus full-term due to tobacco exposure during pregnancy. Future research on focusing on targeted investigations is warranted.

Table of Contents

Introduction 1

Design & Methods 2

Study population 2

Measurement of maternal biomarker concentrations 3

Measure of adverse birth outcomes and other factors 4

Untargeted High-Resolution Metabolomics Profiling 4

Statistical analyses 6

Metabolic pathway enrichment analysis and metabolite annotation 7

Meet-in-the-middle analysis 8

Results 8

Pathway enrichment analysis 10

Metabolite annotation and confirmation 10

Sensitivity analysis 11

Discussion 12

Changes in pathways and metabolites in amino acid metabolism 12

Perturbations in pathways enriched in biopterin metabolism 13

Effects in pathways and metabolites enriched in lipid and fatty acid metabolism 14

Study Strength and limitation 15

Conclusion 16

References 17

Tables and Figures 26

About this Master's Thesis

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School	Rollins School of Public Health
Department	Environmental Health
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Obstetrics and Gynecology Health Sciences, Public Health Environmental Health
Palavra-chave	Preterm Birth Tobacco smoke exposure Cotinine High-resolution metabolomics;
Committee Chair / Thesis Advisor	Donghai Liang, Emory University

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