Perfluorodecanoic Acid (PFDA) Disrupts Immune Regulation via the Toll-like Receptor Signaling Pathway in Zebrafish

As there are a growing number of per- and polyfluoroalkyl substances (PFAS) alternative substitutes applied globally, it remains paramount to characterize their potential health risks. Perfluorodecanoic acid (PFDA) is the most common alternative PFAS detected in the environment; however, its toxic effects and underlying mechanism of action to aquatic biota remains unclear. In this study, we present <i>in vitro</i> evidence of PFDA-induced immunotoxicity and gain insight into underlying molecular mechanisms. PFDA induced immune dysfunction in zebrafish primarily through immunosuppression, apoptosis, and inflammatory response which further cascaded to suppress innate and adaptive immunities, ultimately weaking the ability of larvae to defend against pathogenic infection. PFDA-induced immunotoxicity was driven by a dysregulation in the toll-like receptor (TLR) signaling pathway, which was validated through a cotreatment of PFDA with either a morpholino knockdown or inhibitor of myeloid differentiation factor 88. Comparative toxicity studies were carried out with a subset of other alternative PFAS (PFBA, PFOA, PFNA) and it was found that PFDA posed a greater immunotoxic response than other commonly identified PFAS in the environment. This work identified a major target of PFDA, disrupting immune function through the TLR signaling pathway, while inducing a greater toxic response among other tested PFAS, which provides novel insights into understanding the potential environmental risks of PFAS substitutes.