Hepatic Transcriptome Comparative In Silico Analysis Reveals Similar Pathways and Targets Altered by Legacy and
Dakota R Robarts1,2, Jiayin Dai3, Christopher Lau4
1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Toxics
|December 22, 2023
Summary
Newer per- and poly-fluoroalkyl substances (PFAS) alternatives share molecular targets with legacy PFAS, impacting liver gene expression similarly. This toxicogenomic analysis reveals overlapping effects, crucial for understanding environmental health risks of these persistent chemicals.
Area of Science:
- Environmental Toxicology
- Molecular Toxicology
- Genomics
Background:
- Per- and poly-fluoroalkyl substances (PFAS) are persistent environmental contaminants linked to adverse health effects, including hepatotoxicity.
- Legacy PFAS (e.g., PFOS, PFOA) are being replaced by alternatives, whose toxicological profiles are less understood.
- Understanding the molecular targets of diverse PFAS is crucial for assessing their potential health and environmental risks.
Purpose of the Study:
- To conduct a comparative toxicogenomic analysis of legacy and alternative PFAS in mouse liver.
- To identify shared and distinct molecular targets, particularly PPARα activation, among various PFAS.
- To evaluate the potential hazards of emerging PFAS alternatives by comparing their transcriptomic profiles to known PFAS.
Main Methods:
- Gene expression profiling in mouse livers following exposure to legacy PFAS, alternative PFAS, and known PPARα activators.
- Comparative analysis using hierarchical clustering and pathway analysis to identify overlapping molecular targets.
- Development and application of predictive biomarkers to assess specific pathway activations (e.g., CAR, NRF2, SREBP, STAT5b).
Main Results:
- Most alternative PFAS significantly modulated molecular targets overlapping with legacy PFAS.
- Only three of the 11 tested PFAS (Nafion BP2, 6:2 FTSA, 6:2 FTCA) did not substantially activate PPARα.
- Predictive biomarkers indicated broad activation of CAR, suppression of STAT5b, and activation of NRF2 and SREBP by most tested PFAS, irrespective of chemical structure.
Conclusions:
- Legacy and alternative PFAS share common molecular targets and induce similar transcriptomic changes in the liver.
- The findings highlight the need for thorough toxicological assessment of PFAS alternatives due to conserved mechanisms of action.
- This study provides valuable insights into the toxicological diversity and similarities within the broad class of PFAS.
