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Sex-dependent relationships between PFAS and placental transcriptomics identified by weighted gene co-expression
Cynthia Perez1, Kyle Campbell1, Dana Boyd Barr1
1Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA.
Environmental Research
|September 3, 2025
Summary
Per- and polyfluoroalkyl substances (PFAS) exposure is linked to adverse neonatal outcomes. This study identified a specific PFAS, perfluorononanoic acid (PFNA), associated with placental gene expression changes, potentially impacting fetal development.
Area of Science:
- Environmental Health
- Genomics
- Toxicology
Background:
- Per- and polyfluoroalkyl substances (PFAS) are widespread environmental toxicants.
- PFAS exposure is linked to adverse neonatal outcomes, but underlying mechanisms are unclear.
- The placenta is a potential target organ for PFAS toxicity.
Purpose of the Study:
- To identify placental RNA co-expression modules associated with PFAS exposure using a systems biology approach.
- To investigate the relationship between PFAS exposure and birth weight.
- To explore sex-specific effects of PFAS on placental gene expression.
Main Methods:
- RNA-sequencing of 147 placental samples from the GLOWING study.
- Quantification of PFAS concentrations via liquid chromatography-tandem mass spectrometry.
- Construction of a weighted gene co-expression network to identify 20 gene modules and analyze associations with PFAS, adjusting for confounders and testing for sex-specific effects.
Main Results:
- One gene module exhibited a significant negative association with perfluorononanoic acid (PFNA) exposure (q = 0.009).
- This association was sex-specific, indicating differential effects between sexes.
- Genes in the PFNA-associated module were enriched for histone modification pathways and Vitamin D Receptor (VDR) targets.
Conclusions:
- PFAS exposure, specifically PFNA, is associated with distinct placental gene expression patterns.
- These findings suggest that placental gene regulation, potentially involving histone modification and VDR signaling, mediates PFAS effects on neonatal health.
- Further research is needed to elucidate the precise mechanisms linking PFNA, placental function, and birth outcomes.

