Sucralose and PMMA Microplastics Synergistically Induce Obesity with Altered Locomotion and Metabolism in <i>Caenorhabditis elegans</i>

Emerging anthropogenic pollutants such as artificial sweeteners and microplastics (MPs) widely co-occur in natural environments, yet their combined toxicity, particularly obesogenic effects, is completely unknown. This study investigated the effects of sucralose (SUC) and UV-aged poly(methyl methacrylate) (PMMA) MPs using an <i>in vivo</i> model of <i>Caenorhabditis elegans</i>. Exposure to SUC and/or MPs (1-100 μg/L) induced significant obesity phenotypes, including increased body width and volume alongside elevated lipid accumulation and lipid droplet levels in a concentration-dependent manner. Critically, coexposure produced stronger obesogenic effects than predicted additive values from single exposures, demonstrating a synergistic interaction. Behavioral analyses revealed that coexposure concurrently increased pharyngeal pumping rates but decreased crawling locomotion, with obesogenic parameters positively correlating with feeding activity and negatively with locomotor capacity. Molecular analysis confirmed the corresponding dysregulation of genes governing feeding behavior (<i>mgl-1</i>), energy sensing (<i>aak-2</i>), and lipid metabolism (<i>daf-16</i>, <i>sbp-1</i>), supporting the hyperphagia-hypolocomotion phenotype. Metabolomics analysis demonstrated exposure-specific disruption of nicotinate/nicotinamide metabolism and glutamate-mediated biosynthesis pathways, which collectively accelerated lipid accumulation. These results suggest that MPs can act not merely as obesogens but also synergistically amplify SUC's obesogenic toxicity associated with altered locomotion and metabolism. Our findings highlight the necessity to incorporate cocontaminant interaction assessments into microplastic risk frameworks for addressing underestimated environmental health threats.