PFAS:VDR interactions and immunotoxicity through disruption of monocyte differentiation

Accumulating evidence indicates that per- and polyfluoroalkyl substances (PFAS) have the capacity to modulate vitamin D receptor (VDR) signaling however, the underlying mechanisms governing these interactions remain poorly understood. In the present study, we investigated direct interactions between PFAS and VDR signaling, as well as a novel, putative mechanism by which PFAS may induce immunotoxicity through disruption of VDR molecular functionalities. VDR is widely expressed across both the innate and adaptive branches of the immune system, where it plays critical roles in regulating immune cell activation, differentiation, and function. While PFAS exposure has been consistently associated with immune dysregulation and reduced vaccine responsiveness in both human and animal studies, the molecular basis of PFAS-induced immunotoxicity is only partially defined. To address these knowledge gaps, we examined a panel of PFAS compounds previously identified through computational modeling to possess measurable binding affinities for the VDR. We employed a suite of complementary, orthogonal bioassays to characterize the functional interactions between PFAS and the vitamin D receptor. These included a transient transactivation assay to assess global receptor agonist and antagonist activity, a Mammalian two-Hybrid (M2H) assay to evaluate PFAS effects on VDR interactions with its obligate heterodimerization partner (RXR), coactivator (SRC-1), and corepressor (NCoR1), and a THP-1 cell differentiation/transcription assay to probe the transcriptional consequences of PFAS exposure on vitamin D-facilitated monocyte cell differentiation. Collectively, our findings reveal that select PFAS engage in complex molecular interactions with the VDR and act as potent antagonists, effectively inhibiting vitamin D-mediated receptor function and downstream THP-1 cell signaling.