Prepuberty exposure to polystyrene nanoplastics induces cardiac inflammation through calcium overload-mediated...

Polystyrene nanoparticles (PS-NPs) pose a significant threat to human health. In the present study, we aimed to investigate the toxicological effects of low-dose of PS-NPs on cardiac development and function following prepubertal exposure. Postpartum dams and their offspring were exposed to PS-NPs at concentrations of 0, 50 mg/L, and 100 mg/L via their daily drinking water, commencing from gestational day 1 and continuing until postnatal day (PND) 35. The results demonstrated that PS-NPs induced cardiac developmental toxicity in offspring. Proteomic analysis indicated that PS-NP exposure led to differentially expressed proteins, which were mainly enriched in JAK/STAT3 signaling pathway, inflammatory response pathway and antioxidant response signaling pathway. We subsequently found that exposure to PS-NPs in HL-1 cells increased the levels of reactive oxygen species (ROS), IL-6, IL-17, and TNF-α, as well as upregulated the expression of pJAK1 and pSTAT3. Treatment of HL-1 cells with N-Acetylcysteine (NAC) normalized the activity of the JAK1/STAT3 pathway and the levels of inflammatory cytokines. Furthermore, either inhibition of JAK1 with upadacitinib or knockdown of STAT3 in PS-NP-exposed HL-1 cells led to proinflammatory cytokine levels comparable to those in control cells. Given the well-established link between oxidative stress and mitochondrial calcium dysregulation, we demonstrated that PS-NP exposure impaired mitochondrial function by promoting calcium influx, which is mediated by the increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). This process facilitated calcium transfer through the IP3R3-GRP75-VDAC1 complex. Notably, pharmacological inhibition of calcium flux attenuated PS-NP-induced mitochondrial dysfunction, oxidative stress, and inflammatory responses in HL-1 cardiomyocytes. Collectively, our findings indicate that prepubertal PS-NP exposure triggers cardiac inflammation, which is likely mediated by MAM-dependent mitochondrial calcium overload and subsequent activation of the ROS/JAK1/STAT3 signaling axis.