Antimony induces mitochondria-dependent and ER stress-triggered apoptosis via the oxidative stress-activated JNK signaling pathway in pancreatic islet β-cells

Antimony (Sb), a silvery-white metal, is a heavy metal of particular prevalence that has the ability to result in adverse effects in humans through environmental exposure resulting from natural processes and human activities. Epidemiological studies have suggested that Sb has an association with the potential for diabetes mellitus (DM) development. However, the mechanisms by which Sb exerts toxicological effects on pancreatic islet β-cells are still not clear. In this investigation, Sb exposure significantly inhibited rat pancreatic islet β-cell-derived RIN-m5F cell viability and insulin secretion, while inducing mitochondria-dependent apoptotic signals, inclusive of increased apoptotic cell populations, caspase-3 activity, the expression of PARP and caspase-3/-7/-9, and mitochondrial dysfunction. RIN-m5F cells exposure to Sb also led to the triggering of endoplasmic reticulum (ER) stress via the induction of a number of vital molecules, including CHOP, XBP-1s, and caspase-12. In Sb-exposed RIN-m5F cells, 4-PBA pretreatment (an inhibitor of ER stress) significantly suppressed protein expression related to ER stress and events of an apoptotic nature. Furthermore, exposure to Sb resulted in the significant activation of AMPKα, ERK1/2, and JNK signaling, as well as reactive oxygen species (ROS) generation. Pretreatment with SP600125 (an inhibitor of JNK) and antioxidant NAC, but not PD98059 (an inhibitor of ERK) or compound C (an inhibitor of AMPK), effectively abrogated the cytotoxicity, ER stress responses, mitochondrial dysfunction, apoptotic events, insulin secretion inhibition, and JNK activation in Sb-exposed rat pancreatic islet β-cells. However, SP600125 did not prevent ROS generation, which was inhibited by the antioxidant NAC. Collectively, the results demonstrate exposure to Sb to exert β-cell cytotoxicity through oxidative stress-activated JNK signaling downstream-regulated mitochondria-dependent and ER stress-triggered cell apoptotic pathways, eventually resulting in the death of rat pancreatic islet β-cells.