Activation of integrated stress response and disordered iron homeostasis upon combined exposure to cadmium and PCB77

Both cadmium and polychlorinated biphenyls (PCBs) can induce diverse detrimental effects on human health. Though these compounds co-exist in various environmental contexts and in the human body, studies on their joint toxicities are limited. Activation of the integrated stress response (ISR) and iron homeostasis are crucial for erythropoiesis. The impact of cadmium and PCBs on the ISR activation and iron homeostasis of erythroid progenitors is unknown. We investigated the adverse effects and mechanisms of CdCl₂ and PCB77 on HEL cells, a human cell model of erythroid progenitors. We found that at high concentrations of CdCl₂ and PCB77, cytotoxicity and apoptosis of HEL cells were mainly induced by CdCl₂. At low concentrations of CdCl₂ and PCB77, iron homeostasis inside HEL cells was disturbed by both of these two compounds. Both CdCl₂ and PCB77 activated ISR to combat stress, which at high concentration was mainly induced by ROS, leading to apoptosis, and at low concentration was partly induced by disordered iron homeostasis. The patterns of ISR activation and iron homeostasis disorder were different between CdCl₂ and PCB77. Their combined exposure exhibited synergetic effect on activating ISR but antagonistic effect on disturbing iron homeostasis. Our study demonstrates some previously unrecognized harmful characteristics and mechanisms of cadmium and PCB77.