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Activation of pyroptosis and ferroptosis is involved in the hepatotoxicity induced by polystyrene microplastics in
Yingwen Mu1, Jiayin Sun1, Ziyuan Li1
1Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250062, Shandong, People's Republic of China.
Abstract:
Microplastics (MPs) are new environmental pollutants and have received widespread attention in recent years, but the toxicity of the MPs remains to be fully elucidated. To explore the effect of MPs on hepatotoxicity in mice and unravel the mechanism of pyroptosis and ferroptosis in the process of liver injury, we treated mice with 5.0 μm polypropylene microplastics (MPs) at 0.1, 0.5 and 1 mg/mL for 4 weeks. Results revealed that MPs could damage liver structure and function with broken and reduced mitochondrial cristae, as well as increased levels of aspartate minotransferase (AST), alanine aminotransferase (ALT), AST/ALT, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Treatment with MPs resulted in pyroptosis as evidenced by increasing expressions of interleukin IL-1β, IL-18. Additionally, MPs were shown to induce the NOD-like receptor protein 3 (NLRP3) inflammasomes and apoptosis associated speck-like protein (ASC) containing a caspase recruitment domain activation in liver tissue, enabling activation of Caspase-1-dependent signaling pathway induced by inflammatory stimuli resulting from oxidative stress. In addition, the increase of malondialdehyde (MDA) and decrease of glutathione (GSH) and superoxide dismutase (SOD) in the liver indicated that MPs could induce oxidative damage. Moreover, MPs induced lipid peroxidation in the liver of mice could activate the expression of ferroptosis related proteins, including iron metabolism, such as transferrin receptor (TFRC) was active but ferritin heavy chain 1 (FTH1) was inhibited; amino acid metabolism, such as XCT system and glutathione peroxidase 4 (GPX4) were inhibited; lipid metabolism, such as acyl-CoA synthetase long-chain family member 4 (ACSL4) was inhibited. Collectively, these findings evidenced that pyroptosis and ferroptosis occurred in MPs-induced liver injury accompanied by intense oxidative stress and inflammation.
Insights
Microplastics (MPs) cause liver damage in mice by inducing pyroptosis and ferroptosis, leading to oxidative stress and inflammation. This study reveals the mechanisms behind MP-induced hepatotoxicity.
Area of Science:
- Environmental Science
- Toxicology
- Cell Biology
Background:
- Microplastics (MPs) are emerging environmental pollutants with largely unknown toxicity.
- Hepatotoxicity mechanisms, including pyroptosis and ferroptosis, require further elucidation.
Purpose of the Study:
- To investigate the effects of polypropylene microplastics on liver structure and function in mice.
- To explore the underlying mechanisms of pyroptosis and ferroptosis in microplastic-induced liver injury.
Main Methods:
- Mice were treated with 5.0 μm polypropylene microplastics (0.1, 0.5, 1 mg/mL) for 4 weeks.
- Liver function markers (AST, ALT, ALP, LDH), pyroptosis indicators (IL-1β, IL-18, NLRP3, ASC, Caspase-1), oxidative stress markers (MDA, GSH, SOD), and ferroptosis-related proteins were analyzed.
Main Results:
- Microplastic exposure damaged liver structure and function, increasing liver enzyme levels.
- MPs induced pyroptosis via NLRP3 inflammasome activation and Caspase-1 signaling.
- Oxidative stress was evident, with increased MDA and decreased GSH and SOD.
- MPs triggered ferroptosis by altering iron metabolism, amino acid transport, and lipid metabolism proteins.
Conclusions:
- Microplastic exposure causes significant liver injury in mice.
- Pyroptosis and ferroptosis are key mechanisms in microplastic-induced hepatotoxicity.
- Oxidative stress and inflammation are closely associated with these cellular death pathways.
