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. 2024 Oct 15:259:119496.
doi: 10.1016/j.envres.2024.119496. Epub 2024 Jun 25.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children

Yijie Li  1 , Brittney O Baumert  1 , Nikos Stratakis  2 , Jesse A Goodrich  1 , Haotian Wu  3 , Shelley H Liu  4 , Hongxu Wang  1 , Emily Beglarian  1 , Scott M Bartell  5 , Sandrah Proctor Eckel  1 , Douglas Walker  6 , Damaskini Valvi  7 , Michele Andrea La Merrill  8 , Thomas H Inge  9 , Todd Jenkins  10 , Justin R Ryder  9 , Stephanie Sisley  11 , Rohit Kohli  12 , Stavra A Xanthakos  13 , Marina Vafeiadi  14 , Aikaterini Margetaki  14 , Theano Roumeliotaki  15 , Max Aung  1 , Rob McConnell  1 , Andrea Baccarelli  16 , David Conti  1 , Lida Chatzi  17
Affiliations

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children

Yijie Li et al. Environ Res. .

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans.

Objective: To investigate associations between PFAS concentrations and miRNA levels in children.

Methods: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs.

Results: Plasma PFAS concentrations were associated with alterations in 475 miRNAs in the Teen-LABs study and 5 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis.

Conclusion: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

Keywords: Carcinogenesis; MicroRNA; Per- and polyfluoroalkyl substances; Persistent organic pollutants; Transcriptomics.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vaia Lida Chatzi reports financial support was provided by The National Institute of Environmental Health Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Correlation plots between PFAS congeners in (a) Teen-LABS and (b) Rhea.
Figure 1.
Figure 1.
Correlation plots between PFAS congeners in (a) Teen-LABS and (b) Rhea.
Figure 2.
Figure 2.
Volcano plots for miRNA associated with PFAS in Teen-LABS. Solid horizonal line represents FDR p = 0.1, and any dots with blue or red colors above the line indicate miRNA with significant associations after multiple comparison. Negative associations are in blue; positive associations are in red; black dots below the solid line represent insignificant miRNA; higher absolute x-value of a dot indicates greater magnitude of change in miRNA levels with PFAS, either increased (x > 0) or decreased (x < 0); higher y-value of a dot indicates smaller FDR p-value of associations.
Figure 3.
Figure 3.
Heatmap for associations between PFAS exposures and miR-148b-3p and miR-29a-3p across cohorts. TL represents associations observed in Teen-LABS participants and Rhea represent associations observed in Rhea participants.
Figure 4.
Figure 4.
Top 10 disease pathways for PFHxS-associated miRNA in the Teen-LABS study. Left histogram shows the number of PFHxS-associated miRNA involved in each pathway identified in IPA; each pathway involves more than 50 PFHxS-related miRNA; right histogram shows the number of intersecting miRNA that overlap in multiple pathways; solid dots connected by lines are pathways that involve miRNA intersections, and number of solid dots on each line suggests number of miRNA intersections; empty dots are pathways that do not involve any miRNA intersections; for example, 12 miRNAs (highest bar on right) are involved in all top 10 pathways; 22 miRNAs are involved in nonobstructive azoospermia (highest bar on left). Note: IPA uses ‘mammary tumor’ to describe breast cancer pathways.
Figure 5.
Figure 5.
Top 10 disease pathways of overlapping PFAS-related miRNA across the Teen-LABS and Rhea study.
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