F-53B drives placental inflammation via an IL1R1-mediated NLRP3 inflammasome activation: Evidence from epidemiology and a laboratory experiment.

Our prior work suggested that gestational exposure to chlorinated polyfluorinated ether sulfonates (F-53B) induces placental inflammation by activating the NLRP3 inflammasome, but the primary molecular target remains unclear. This study examined whether interleukin-1 receptor type 1 (IL1R1) served as a key target in F-53B-induced placental inflammatory. In this exploratory study of 78 participants from the Shenyang birth cohort, umbilical cord serum F-53B was positively correlated with placental mRNA expression of IL1B (r = 0.25, adjusted-P = 0.029), IL18 (r = 0.23, adjusted-P = 0.045), and NLRP3 (r = 0.27, adjusted-P = 0.016), particularly in preterm birth. Subsequently, in vitro, JEG-3 human placental trophoblast cells exposed to F-53B with or without IL1R1-targeted siRNA or the IL-1 receptor antagonist (IL-1Ra/anakinra), genetic silencing or pharmacological blockade of IL1R1 markedly attenuated high-dose F-53B-induced NLRP3 inflammasome activation, inflammatory cytokine elevation, and cell death. Mechanistically, we identified the IL1R1/NLRP3/IL-1β axis as a key driver of the inflammatory cascade, wherein IL1R1 serves as the critical target of F-53B. Importantly, anakinra mitigates F-53B-induced placental inflammation in JEG-3. These findings identify IL1R1 as a critical mediator of high-dose F-53B-induced placental inflammatory and suggest that this pathway is a valuable target for future validation in more physiologically relevant models.