Microplastics (MP) are ubiquitous in the environment, and are toxic to various living organisms. Proper application of biodegradable plastics may alleviate the hazards of conventional non-biodegradable plastics. In the current study, multi-omics analyses were performed to compare the biodegradable polyhydroxyalkanoates (PHA) and non-biodegradable polypropylene (PP) MP for their toxicity on mouse liver and lung. Airborne PHA MP induced nasal microbiome dysbiosis, pulmonary microbiome alteration, pulmonary and serum metabolome disruption, and hepatic transcriptome disturbances, resulting in mild pulmonary toxicity. By contrast, airborne PP MP caused greater alterations in nasal and pulmonary microbiome, pulmonary and serum metabolome, and hepatic transcriptome, resulting in pulmonary and hepatic toxicity. Both foodborne PHA and PP MP caused intestinal microbiome dysbiosis, while foodborne PHA MP caused slighter intestinal and serum metabolome disruption, hepatic transcriptome disturbances and hepatotoxicity (e.g., lower serum aspartate aminotransferase and alanine aminotransferase) compared to foodborne PP MP. Some potential differential biomarkers were determined between PP and PHA MP exposures, i.e., nasal Allobaculum and pulmonary Alloprevotella for airborne PHA
nasal Lactobacillus and pulmonary Acinetobacter for airborne PP
intestinal Faecalibacterium for foodborne PHA
and intestinal unclassified_Erysipelatoclostridiaceae for foodborne PP. The results show that PHA MP can induce less pulmonary and hepatic toxicity compared to PP MP, suggesting PHA is a potential substitution for PP. The findings can benefit the hazard assessment of airborne and foodborne PHA and PP MP.