Implication of ferroptosis in hepatic toxicity upon single or combined exposure to polystyrene microplastics and cadmium

Microplastics (MPs) are a newly emerging type of pollutants. To date, MPs have been found in the atmosphere, soil, water, and even in human samples, posing a non-negligible threat to humans. Furthermore, multiple heavy metals have been found to co-exist with MPs or be absorbed by MPs. This leads to a widespread concern about their combined toxicity, which is currently elusive. Herein, we investigated the single or combined toxic effects of polystyrene MPs (PS-MPs) and cadmium chloride (CdCl2) on the liver and hepatocytes. After co-incubation, cadmium (Cd) can be absorbed by PS-MPs, resulting in physiochemical alterations of PS-MPs. In vivo and in vitro experiments revealed that PS-MPs solely or together with CdCl2 induced ferroptosis in hepatocytes, a newly defined programmed cell death characterized by lipid oxidation and iron accumulation. PS-MPs exerted more ferroptotic effect on hepatocytes than CdCl2, and combined exposure to PS-MPs and CdCl2 enhanced their ferroptotic effect, mainly by stimulating reactive oxygen species (ROS) production and inhibiting antioxidant activity. Upon single or combined exposure to PS-MPs and CdCl2, the induction of ferroptosis in hepatocytes can be inhibited by N-acetyl-cysteine (NAC, an ROS scavenger), deferoxamine (DFO, an iron chelator), and particularly ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). Fer-1 efficiently rescued the cell viability of hepatocytes upon exposure to PS-MPs and CdCl2 through enhancing the antioxidant system via upregulating GPX4 and SLC7A11. These findings would contribute to an in-depth understanding of the single and combined toxicity of microplastics and cadmium.

Automated summary

Microplastics (MPs) are a newly emerging type of pollutants that have been found in various environments, including the atmosphere, soil, water, and even human samples. The co-existence of multiple heavy metals with MPs raises concerns about their combined toxicity. This study investigated the toxic effects of polystyrene MPs (PS-MPs) and cadmium chloride (CdCl2) on the liver and hepatocytes. The findings revealed that PS-MPs alone or combined with CdCl2 induced a form of programmed cell death called ferroptosis in hepatocytes, which was characterized by lipid oxidation and iron accumulation. The ferroptotic effect was enhanced by ROS production and inhibited antioxidant activity, but could be rescued by specific inhibitors.