Investigation of biological effects from ambient temperature exposure on preterm birth in the Atlanta African American Maternal-Child Cohort using untargeted high-resolution metabolomics Restricted; Files Only

Bhanushali, Priyanka (Spring 2023)

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Exposure to heat exposure in the era of climate change induced global warming has been associated with numerous adverse health outcomes especially birth outcomes. However, the underlying biological mechanisms leading to the adverse outcome are still unknown. In this study, we conduct metabolome- wide association studies to observe the overlapping metabolic pathways between ambient temperature exposure and preterm birth outcome in Atlanta African American cohort of 330 participants throughout their pregnancy to evaluate the maternal metabolome profile during early and late stage of pregnancy. This was assessed by utilizing untargeted HRM followed by pathway enrichment analysis, chemical annotation, and meet-in-the-middle approach to check the overlap between the pathways. A total of 13,616 and 11,600 metabolic features were identified in HILIC and C18 columns respectively. It was observed that 11 and 6 metabolic pathways were significantly associated with at least 2 temperature exposure window and preterm birth during early and late pregnancy respectively. Lysine metabolism, Methionine and cysteine metabolism, Vitamin B6 (pyridoxine) were the three pathways overlapping between Exposure during both stages of pregnancy and preterm birth. A total of 6 metabolites were associated with ambient temperature exposure were significant for at least 3 exposure windows. A total of 6 metabolites overlapped between preterm birth and ≥ 2 exposure windows including methionine and choline. The metabolites seen to have a significant association were linked with amino acid metabolism, lipid metabolism, Tryptophan metabolism, inflammatory pathways, and xenobiotics biosynthesis which can lead to adverse birth outcomes. The findings from this study will potentially be a groundwork for the future research to understand the underlying biological mechanisms of preterm birth and assess the role of ambient temperature exposure.

Table of Contents

Introduction. 1

Methods. 3

Study Population. 3

Questionnaire data. 4

Exposure Assessment 4

High-Resolution Metabolomics. 4

Statistical Analysis. 5

Pathway Enrichment Analysis. 7

Metabolite Confirmation and Annotation. 7

Meet-in-the-middle (MITM) Framework. 8

Results. 8


Pathway Enrichment Analysis. 9

Metabolite Confirmation and Annotation. 10

Discussion. 11

Maternal Metabolomic Signatures in Early/Mid Pregnancy. 11

Maternal Metabolomic Signatures in Mid/Late Pregnancy. 12

Maternal Metabolomic Signatures Across Pregnancy. 12

Confirmed and Annotated Metabolites. 13

Strengths and Limitations. 14

Conclusion. 14

References. 15

Tables and Figures. 18

Table 1. Characteristics of participants by maternal metabolome analytic sample in the Atlanta African American Maternal-Child Cohort, (2014-2018). 18

Table 2. Average daily maximum ambient temperature at Atlanta Hartsfield Jackson Airport, 2014-2018 19

Table 3. Metabolic features in the maternal metabolome by temperature exposure window, Atlanta African American Maternal-Child Cohort, 2014-2018. 19

Table 4. Confirmed metabolites significantly associated with ≥3 temperature exposure windows. 20

Table 5. Metabolites associated with 2 temperature exposure windows. 21

Table 6. Metabolites associated with Preterm Birth Outcome. 26

Fig 1a. Heatmap of intermediate biological pathways in the maternal metabolome at early/mid pregnancy. 28

Fig 1b. Heatmap of intermediate biological pathways in the maternal metabolome at mid/late pregnancy. 28

Fig.2. Overlapping pathways in the maternal serum metabolome between periconceptional ambient temperature exposure and preterm birth throughout pregnancy. 29

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