Persistent environmental toxicants PCP, TCHQ, and HCB drive PANoptosis and RNA granule remodeling in human lung...

Pentachlorophenol (PCP), its metabolite tetrachlorohydroquinone (TCHQ), and the co-occurring pollutant hexachlorobenzene (HCB) remain a toxicological concern due to their environmental persistence and bioaccumulation. Both PCP and TCHQ exhibit well-documented toxicities and have likely contributed to substantial occupational and environmental exposures worldwide, owing to their efficient absorption through multiple routes. While HCB, although not a PCP metabolite, similarly poses long-term toxicological risks. These toxicants exhibit distinct toxicological profiles, underscoring their relevance as environmental health hazards. Our previous studies have demonstrated that PCP exposure activates the Hsp70-ROS-autophagy axis in submerged lung alveolar epithelial (A549) monolayers, highlighting its role in initiating early cellular stress responses. Building on our prior investigations, this study evaluates the cellular mechanisms activated by PCP, its metabolite TCHQ, and the co-occurring pollutant HCB at a higher occupationally relevant concentration using submerged monolayer (2D) and 3D air-liquid interface (ALI) models. The computational insights from the STITCH-based network prompted us to validate these links in A549 cells exposed to PCP, TCHQ, and HCB. All tested compounds induced the expression of PANoptosis and RNA granule markers, alongside inflammatory cytokine/chemokine production, implicating integrated cell death pathways and post-transcriptional regulatory mechanisms jointly mediate cellular responses under these conditions. Remarkably, wound healing (in vitro scratch) assays indicated preserved epithelial cell migration capacity despite robust inflammatory and PANoptotic signaling, highlighting a dynamic balance between cellular stress and regenerative resilience. Overall, this study elucidates the role of PANoptosis and RNA granule dynamics as central mediators of toxicant-induced inflammation, providing a mechanistic framework for evaluating the cellular effects of chlorinated environmental pollutants such as PCP and related compounds.