Decoding PFAS immunotoxicity: a NAMs-based comparison of short vs. long chains
Martina Iulini1, Valentina Galbiati1, Marina Marinovich1
1Laboratory of Toxicology and Risk Assessment, Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan, Italy.
Per- and polyfluoroalkyl substances (PFAS) can harm the immune system. This study found that not just long-chain PFAS, but also short-chain trifluoroacetic acid (TFA), showed immunotoxic effects, highlighting the need for compound-specific risk assessments.
Area of Science:
- Environmental toxicology
- Immunotoxicology
- New Approach Methodologies (NAMs)
Background:
- Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants.
- Long-chain PFAS (PFOS, PFOA) are well-studied for immunotoxicity.
- Limited data exists on the immunotoxic effects of short-chain and ultra-short-chain PFAS alternatives.
Purpose of the Study:
- To evaluate and compare the immunotoxic effects of PFAS with varying chain lengths.
- To assess the immunomodulatory activity of trifluoroacetic acid (TFA) and polytetrafluoroethylene (PTFE).
- To utilize human-relevant in vitro New Approach Methodologies (NAMs) for toxicological assessment.
Main Methods:
- Used two complementary in vitro models: peripheral blood mononuclear cells (PBMCs) and THP-1-derived dendritic cells (DCs).
- Assessed antibody production (IgG, IgM) in PBMCs and dendritic cell maturation markers (CD83, CD86, HLA-DR).
- Tested environmentally and occupationally relevant PFAS concentrations, including long-chain, short-chain, ultra-short-chain, and PTFE.
Main Results:
- Long-chain PFAS (PFOS, PFOA, PFNA) suppressed antibody production and impaired DC maturation.
- Short-chain PFAS exhibited modest to intermediate immunomodulatory activity, with sex-specific trends.
- Trifluoroacetic acid (TFA) showed significant immunotoxicity comparable to PFOS; PTFE had no suppressive effects and showed potential immunostimulation in females.
Conclusions:
- PFAS immunotoxicity is compound-specific, not solely dependent on chain length.
- In vitro NAMs provide valuable mechanistic, human-relevant data for PFAS risk assessment.
- Regulatory frameworks should integrate NAMs for a nuanced understanding of PFAS risks.
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