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Sex-Dependent Relationships Between PFAS and Placental Transcriptomics Identified by Weighted Gene Co-Expression

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Summary

Prenatal exposure to perfluorononanoic acid (PFNA) alters placental gene expression in a sex-specific manner, potentially impacting neonatal health. This finding highlights PFNA

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Area of Science:

  • Environmental Health
  • Genomics
  • Toxicology

Background:

  • Per- and polyfluoroalkyl substances (PFAS) are environmental toxicants linked to adverse neonatal outcomes.
  • The placenta is a suspected target organ for PFAS, but mechanisms remain unclear.

Purpose of the Study:

  • To identify placental RNA co-expression modules associated with PFAS exposure and birth weight using a systems biology approach.
  • To investigate 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.
  • Weighted gene co-expression network analysis to identify gene modules and their association with PFAS, adjusting for confounders and testing for sex-specific effects.

Main Results:

  • A significant negative association was found between perfluorononanoic acid (PFNA) and one placental gene module (β = -0.012, q = 0.009).
  • This association was sex-specific, with distinct PFAS associations between sexes but similar directional effects.
  • Genes in the PFNA-associated module were enriched for histone modification pathways and Vitamin D Receptor (VDR) targets.

Conclusions:

  • Prenatal PFNA exposure influences placental gene expression differently based on fetal sex, potentially affecting insulin growth factor signaling and histone modification.
  • The identified gene module provides insights into molecular pathways linking PFAS exposure to neonatal health outcomes.
  • Findings support previous research on PFAS and VDR interactions and highlight sex-specific placental responses to environmental toxicants.