Unraveling the Molecular Links between Fine Particulate Matter Exposure and Early Birth Risks in African American Mothers: A Metabolomics Study in the Atlanta African American Maternal-Child Cohort

Abstract

In the United States, African Americans (AA) are disproportionately exposed to elevated levels of ambient fine particulate matter (PM_2.5) while suffering from the highest rates of early births. To elucidate the largely unknown underlying mechanism, we analyzed serum metabolomics from 330 participants in the Atlanta AA Maternal-Child Cohort and performed high-throughput mediation analysis to identify intermediate metabolites and pathways linking PM_2.5 to early births. Energy-metabolism-related metabolites (carnitine and adenosine triphosphate), along with lysoPE(20:3) and acetylcysteine, were both associated with PM_2.5 exposure and elevated early birth risks. Perturbations in protein digestion and absorption and aromatic amino acid (phenylalanine, tyrosine, and tryptophan) metabolism may potentially mediate the associations between PM_2.5 and early births. We identified significant indirect effects of cortexolone (Proportion mediated: -11.8%) and lysoPE(20:3) (9.4%) in mediating the relationship between PM_2.5 and early births. Our findings might aid in early birth prevention among AA communities by providing novel insights into the underlying biological mechanism.

Keywords: amino acid metabolism; early term birth; energy metabolism; environmental justice; fine particulate matter; high-dimensional mediation analysis; high-resolution metabolomics; minority health; preterm birth.

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Graphical overview of the present study. (A) Mediation framework with metabolomics as mediators; (B) temporal precedence of the exposure, mediator, and outcome; (C) parallel analysis strategy to evaluate the potential mediating metabolic features. ^aThe date of first prenatal care visit varied by participating mothers from 6 to 17 gestational weeks. ^b Metapone was an R package to conduct pathway enrichment analysis for untargeted metabolomics data. ^cConducted by the R package HIMA. Mz, mass-to-charge ratio; rt, retention time; MWAS, metabolome-wide association study. Figure was created by the authors using Microsoft PowerPoint.

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Confirmed metabolites associated with periconceptional exposures to ambient fine particulate matter (PM_2.5) among pregnant participants in the Atlanta African American Maternal-Child Cohort, 2014–2018. The effect estimate is associated with one-unit (μg/m³) increase in PM_2.5 exposures. We log-transformed the relative intensity of metabolites, so the effect estimate was denoted as percent change [%, (e ^β–1) × 100]. The exogenous metabolites were marked in black, derivatives of amino acids in blue, nucleotides in red, and lipids in green. Metabolites shown met the significance threshold of FDR_B–H < 0.2, based on Benjamini-Hochberg adjusted p-values.

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Overlapping biological pathways detected by the meet-in-the-middle approach coupled with the pathway enrichment analysis. Each significant biological pathways were enriched by at least two significant metabolic features associated with either PM_2.5 exposure or early birth. The number of enriched significant metabolic features (a) and the number of total metabolites in the corresponding pathway (b) were labeled as “a/b” on each bar.

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Significant metabolic features (adjusted p-value <0.2 via Benjamini-Hochberg procedure) mediating PM_2.5 exposure and early birth detected by high-dimensional mediation analysis. For ease of reading, the links from exposure to the mediator and from the mediator to outcomes have been color-coded based on PM_2.5 exposure periods or early birth outcomes. The size is proportional to the number of mediated indirect associations.

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Potential molecular mechanisms partially illustrated as metabolic networks for the association between PM_2.5 exposure and early birth among pregnant participants in the Atlanta African American Maternal-Child Cohort, 2014–2018. We colored metabolites associated with PM_2.5 in blue, metabolites associated with PTB or ETB in red, and metabolites mediating the association in green. Dashed arrows denote the multiple reactions required. Figure was created by the authors using Microsoft PowerPoint.