Lipid metabolic dysregulation: A novel developmental toxicity pathway of aged nanoplastics via inhibition of lipophagy in zebrafish

The widespread occurrence of micro/nanoplastics (MNPs) in ecosystems poses significant environmental challenges. Although environmentally aged MNPs predominate, their developmental toxicity remains poorly understood. We demonstrate that both pristine and aged polystyrene nanoplastics (PSNPs) induce abnormal lipid accumulation and impair early development in zebrafish larvae. Lipidomics revealed aged PSNPs significantly increased triglycerides via disrupted glycerophospholipid metabolism. Mechanistically, aged PSNPs did not alter LC3-II/LC3-I ratios but upregulated RAB7 and p62 while downregulating lysosomal biogenesis regulator TFEB. They also reduced ATG5, essential for autophagosome formation via LC3 lipidation. These molecular alterations, together with lysosomal inhibition assays, functionally support lysosomal dysfunction as a key constraint on lipophagy. This impairment inhibits lipid utilization, promotes accumulation, and disrupts development. Critically, aged PSNPs caused stronger disruption than pristine particles despite both interfering with lipophagy. Our study provides mechanistic insights into the developmental toxicity of UV-aged PSNPs in zebrafish, highlighting the importance of considering aging-related changes in nanoplastic risk evaluation. SYNOPSIS: Aged nanoplastics exacerbate developmental toxicity in zebrafish by suppressing lipophagy to drive lipid accumulation, underscoring ecological risks in aquatic systems.