Abstract Per- and polyfluoroalkyl substances (PFASs) are man-made organofluoride chemicals widely present in the environment, with exposure associated to various adverse health effects, including immunotoxicity. Recently, we showed that PFASs can directly impair antibody production, leading to decreased immunoglobulin (Ig) M and IgG release in human peripheral blood mononuclear cells (PBMCs) obtained from both male and female healthy donors. However, the underlying molecular mechanisms remain largely unknown. In this study, we aimed to address this gap by performing RNA sequencing to identify pathways and genes potentially involved in the observed immunotoxic effects. PBMCs were exposed to selected PFASs for 24 h, and to assess effects on antibody secretion, a subset was subsequently stimulated with CpG oligodeoxynucleotide ODN2006 and rhIL-2 for an additional six days. Transcriptomic analysis indicated activation of the glucocorticoid receptor (GR) and associated signaling pathways, supported by the upregulation of several GR-target genes and the prediction of glucocorticoids or the GR agonist dexamethasone as upstream regulators in Ingenuity Pathway Analysis. Moreover, the inhibitory effects of PFASs on antibody secretion were shown to be reversable by the GR antagonist Mifepristone, supporting the involvement of the GR in PFAS-mediated suppression of antibody secretion. Overall, this research advances our understanding of PFAS-induced immunotoxicity and identifies potential biomarkers for evaluating PFAS exposure and its associated health effects. Graphical abstract
Iulini et al. (Thu,) studied this question.