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Black Phosphorus Quantum Dots (BP-QDs) have potential applications in biomedicine. BP-QDs may enter the body through the respiratory tract during grinding and crushing production and processing, causing respiratory toxicity. Ferroptosis is an oxidative, iron-dependent form of cell death. Here, respiratory toxicity of BP-QDs has been validated in mice and human bronchial epithelial cells. After 24 h of exposure to different doses (4–32 μg/mL) of BP-QDs, intracellular lipid peroxidation and iron overload occurred in Beas-2B cells. After 4 times exposures by noninvasive tracheal instillation at four doses [0, 0.25, 0.5 and 1 (mg/kg/48h)], all animals were sacrificed, organs were removed, processed for pathological examination and molecular analysis. Iron overload, glutathione (GSH) depletion and lipid peroxidation in the lung tissue of mice in the exposure group. Furthermore, based on the ferroptosis-associated protein and mRNA expression, it was hypothesized that BP-QDs induced ferroptosis through increasing intracellular free iron and polyunsaturated fatty acid synthesis. By comparing with previous studies, we speculate that primary cells generally are more sensitive to BP-QDs-induced damage than cancer cells. In summary, findings in the present study confirmed that BP-QDs induce ferroptosis via increasing lipid peroxidation and iron accumulation in vitro and in vivo. [Display omitted] • BP-QDs entered by the respiratory tract could cause lung injury. • BP-QDs induced ferroptosis in vitro and in vivo. • BP-QDs might induce ferroptosis by altering intracellular iron homeostasis. • BP-QDs might promote the synthesis of polyunsaturated fatty acids in cells. [ABSTRACT FROM AUTHOR]

The board application of black phosphorus quantum dots (BP-QDs) increases the risk of inhalation exposure in the manufacturing process. The aim of this study is to explore the toxic effect of BP-QDs on human bronchial epithelial cells (Beas-2B) and lung tissue of Balb/c mice. Methods: The BP-QDs were characterized using transmission electron microscopy (TEM) and a Malvern laser particle size analyzer. Cell Counting Kit-8 (CCK-8) and TEM were used to detect cytotoxicity and organelle injury. Damage to the endoplasmic reticulum (ER) was detected by using the ER-Tracker molecular probe. Rates of apoptosis were detected by AnnexinV/PI staining. Phagocytic acid vesicles were detected using AO staining. Western blotting and immunohistochemistry were used to examine the molecular mechanisms. Results: After treatment with different concentrations of BP-QDs for 24 h, the cell viability decreased, as well as activation of the ER stress and autophagy. Furthermore, the rate of apoptosis was increased. Inhibition of ER stress caused by 4-phenyl butyric acid (4-PBA) was shown to significantly inhibit both apoptosis and autophagy, suggesting that ER stress could be an upstream mediator of both autophagy and apoptosis. BP-QD-induced autophagy can also inhibit the occurrence of apoptosis using molecules related to autophagy including rapamycin (Rapa), 3-methyladenine (3-MA), and bafilomycin A1 (Bafi A1). In general, BP-QDs activate ER stress in Beas-2B cells, which further induces autophagy and apoptosis, and autophagy may be activated as a factor that protects against apoptosis. We also observed strong staining of related proteins of ER stress, autophagy, and apoptosis proteins in mouse lung tissue following intracheal instillation over the course of a week. Conclusion: BP-QD-induced ER stress facilitates autophagy and apoptosis in Beas-2B cells and autophagy may be activated as a protective factor against apoptosis. Under conditions of ER stress induced by BP-QDs, The interplay between autophagy and apoptosis determines cell fate. [Display omitted] • Repeated infusion of BP-QDs for a week resulted in lung injury to mice. • BP-QD-induced ER stress facilitates autophagy and apoptosis in Beas-2B cells. • 4-PBA can partly resist autophagy and apoptosis induced by BP-QDs. • Defective autophagy or dysfunction of autophagic flux promotes cell apoptosis. • Autophagy may be activated as a protective factor against apoptosis. [ABSTRACT FROM AUTHOR]