Size-Dependent Disruption of Lipid Metabolism by Polystyrene Micro- and Nanoplastics in Caenorhabditis elegans Revealed Through Multi-Omics and Functional Genetic Validation

Microplastics (MPs) are pervasive contaminants that enter the food chain and cause health issues. However, the size-dependent effects of MPs on lipid metabolism remain inadequately characterized. Using <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), we investigated the size-dependent toxicity of polystyrene (PS)-MPs as model contaminants with sizes of 100 nm and 1 μm, respectively. We evaluated multiple phenotypic endpoints, including lifespan, growth (body length and width), locomotion (head thrashes and body bends), reproduction, and intestinal lipofuscin. The expression of representative lipid metabolism-related transcripts was validated by quantitative PCR. Untargeted metabolomics profiling detected 831 differential metabolites (451down-regulated and 380 up-regulated) across both PS particle exposure groups, with over-representation of lipid metabolic pathways. Integration of multi-omics (transcriptomics and metabolomics) highlighted <i>acdh-1</i>, <i>ech-6</i>, <i>hach-1</i>, and <i>sur-5</i> as core lipid-metabolism genes; RNA interference confirmed that knockdown of these target genes abolished the size-dependent differences in fat accumulation induced by MPs. Notably, it revealed elevated linoleic acid and taurocholic acid, signature metabolites indicative of disrupted lipid turnover by our metabolomic profiling. Collectively, our findings demonstrate that exposure to PS-MPs disrupts lipid homeostasis in <i>C. elegans</i> by perturbing mitochondrial function and key metabolic pathways, which in turn impairs growth, development, feeding, and reproductive capacity. Critically, these disruptive effects exhibit a strong size dependency, with 100 nm PS particles inducing more severe perturbations than the 1 μm particles, and provide novel mechanistic insight into MP-induced metabolic abnormalities, underscoring the importance of considering particle size in assessing the environmental and health risks of MP contamination.