ORIGINAL RESEARCH article
Front. Toxicol.
Sec. Environmental Toxicology
This article is part of the Research TopicNew methods and approaches in toxicology of emerging environmental contaminantsView all 7 articles
Decoding PFAS immunotoxicity: a NAMs-based comparison of short vs long chains
Provisionally accepted
- Universita degli Studi di Milano, Milan, Italy
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Per-and polyfluoroalkyl substances (PFAS) are a class of persistent environmental pollutants that are known to have potential immunotoxic effects. The majority of toxicological investigations focused on long-chain PFAS, such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Short-chain alternatives, including ultra-short-chain compounds such as trifluoroacetic acid (TFA), are being used increasingly, with limited toxicological data. This study aimed to evaluate and compare the immunotoxic effects of PFAS with varying chain lengths, including representatives of long-, short-and ultra-short chains and fluoropolymer chains representatives (polymer polytetrafluoroethylene - PTFE), using human-relevant new approach methodologies (NAMs). Immunotoxicity was assessed using two complementary in vitro models: peripheral blood mononuclear cells (PBMCs) from healthy donors to evaluate antibody (IgG and IgM) production, and THP-1-derived dendritic cells (DCs) to evaluate the effect on the expression of maturation markers (CD83, CD86 and HLA-DR). A range of environmentally and occupationally relevant PFAS concentrations were tested. PFOS, PFOA and perfluorononanoic acid (PFNA) were found to suppress antibody production and impair DCs maturation in a concentration-dependent manner, which is consistent with previous in vivo and epidemiological data. Perfluorohexanesulfonic acid (PFHxS), perfluorobutanesulfonate acid (PFBS), perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA) showed modest to intermediate immunomodulatory activity, although subtle immunosuppressive trends were observed in female donors. Interestingly, the ultra-short-chain TFA reduced antibody production at levels comparable to those of PFOS, indicating that chain length alone is not a reliable predictor of immunotoxic potential. PTFE had no suppressive effects, on the contrary an increased antibody release in female donors was observed, which indicates possible sex-dependent immunostimulation. Our findings support a nuanced, compound-specific approach to risk assessment, rather than a simple long-vs short-chain distinction. In vitro methods provided mechanistic and human-relevant insights and support their integration into the regulatory framework.
Keywords: New approach methodologies (NAMs), PFAS, Hazard identification, Human PBMCs, Dendritic Cells, in vitro
Received: 13 Jul 2025; Accepted: 06 Nov 2025.
Copyright: © 2025 Iulini, Galbiati, Marinovich and Corsini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Martina Iulini, martina.iulini@unimi.it
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.