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Maternal urinary phthalate metabolites are associated with lipidomic signatures among pregnant women in Puerto Rico

Abstract

Background

Phthalates have been reported to alter circulating lipid concentrations in animals, and investigation of these associations in humans will provide greater understanding of potential mechanisms for health outcomes.

Objective

To explore associations between phthalate metabolite biomarkers and lipidomic profiles among pregnant women (n = 99) in the Puerto Rico PROTECT cohort.

Methods

We measured 19 urinary phthalate metabolites during 24–28 weeks of pregnancy. Lipidomic profiles were identified from plasma samples by liquid chromatography-mass spectrometry-based shotgun lipidomics. Relationships between phthalate metabolites and lipid profiles were estimated using compound-by-compound comparisons in multiple linear regression and dimension reduction techniques. We derived sums for each lipid class and sub-class (saturated, mono-unsaturated, polyunsaturated) which were then regressed on phthalate metabolites. Associations were adjusted for false discovery.

Results

After controlling for multiple comparisons, 33 phthalate-lipid associations were identified (False discovery rate adjusted p value < 0.05), and diacylglycerol 40:7 and plasmenyl-phosphatidylcholine 35:1 were the most strongly associated with multiple phthalate metabolites. Metabolites of di-2-ethylhexyl phthalate, bis(2-ethylhexyl) phthalate, dibutyl phthalates, and diisobutyl phthalate were associated with increased ceramides, lysophosphatidylcholines, lysophosphatidylethanolamines, and triacylglycerols, particularly those containing saturated and mono-unsaturated fatty acid chains.

Significance

Characterization of associations between lipidomic markers and phthalate metabolites during pregnancy will yield mechanistic insight for maternal and child health outcomes.

Impact

  • This study leverages emerging technology to evaluate lipidome-wide signatures of phthalate exposure during pregnancy.

  • The greatest lipid signatures of phthalate exposure were observed for diacylglycerol 40:7 and plasmenyl-phosphatidylcholine 35:1.

  • Polymerized glycerides are important for energy production and regulated through hormone signaling, while plasmenyl-phosphatidylcholines have been implicated in membrane dynamics and important for cell-to-cell signaling.

  • Characterization of these mechanisms are relevant for informing the etiology of maternal and children’s health outcomes.

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Fig. 1: Manhattan plot showing individual lipids associated with urinary phthalate metabolite concentrations.
Fig. 2: Percent change in lipid subgroup sum z-score associated with urinary phthalate metabolite concentrations.
Fig. 3: Correlation matrix between specific gravity corrected concentrations of phthalate metabolites and all lipid classes (N = 99).
Fig. 4: Percent change in lipid class sum z-score associated with urinary phthalate metabolite concentrations.

Data availability

Data utilized for this analysis can be obtained by reasonable request by contacting the corresponding author (JDM, meekerj@umich.edu)

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Acknowledgements

We thank the nurses and research staff who participated in cohort recruitment and follow up, as well as the Federally Qualified Health Centers (FQHC) and clinics in Puerto Rico who facilitated participant recruitment, including Morovis Community Health Center (FQHC), Prymed: Ciales Community Health Center (FQHC), Camuy Health Services, Inc. (FQHC), and the Delta OBGyn (Prenatal Clinic). This study was supported by the Superfund Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (grants P42ES017198 and). Additional support was provided from NIEHS grant numbers P50ES026049, R01ES032203, and P30ES017885 and the Environmental influences on Child Health Outcomes (ECHO) program grant number UH3OD023251. Support for Max Aung was provided in part by NIH award P30ES030284.

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Authors

Contributions

PA: Statistical analysis; Investigation; Methodology; Writing, review and editing. MTA: Writing, review and editing. DJW: Conceptualization; Funding acquisition. BM: Conceptualization; Supervision; Funding acquisition. ZR: Data curation; Project administration. CMV: Data curation; Project administration. AA: Conceptualization; Funding acquisition. JFC: Conceptualization; Funding acquisition. JDM: Conceptualization; Funding acquisition; Supervision.

Corresponding author

Correspondence to John D. Meeker.

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Ashrap, P., Aung, M.T., Watkins, D.J. et al. Maternal urinary phthalate metabolites are associated with lipidomic signatures among pregnant women in Puerto Rico. J Expo Sci Environ Epidemiol 32, 384–391 (2022). https://doi.org/10.1038/s41370-022-00410-3

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  • DOI: https://doi.org/10.1038/s41370-022-00410-3

Keywords

  • Biomarkers
  • Exposure
  • Phthalates
  • Lipidomics
  • Puerto Rico

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