Ferroptosis-mediated ocular developmental toxicity of biodegradable nanoplastics in zebrafish

Visual function serves as a critical biomarker for assessing ecological risks of environmental contaminants. While epidemiological evidence links synthetic nanoplastics to visual impairment, the ocular developmental toxicity of ‟eco-friendly" biodegradable nanoplastics (BPs) at environmentally relevant concentrations remains uncharacterized. This study systematically investigates the mechanisms underlying BPs-induced ocular toxicity using zebrafish models, integrating developmental toxicology with computational approaches. Polylactic acid (PLA) or polycaprolactone (PCL) nanoparticle exposure during critical developmental stages (33-120 hour post-fertilization (hpf)) disrupted optomotor responses, induced structural ocular defects, and suppressed retinal developmental gene networks. Temporal profiling via qPCR and whole-mount in situ hybridization revealed stage-dependent olig2+ retinal progenitor depletion, correlating with disrupted retinal lamination and photoreceptor dysfunction. Mechanistic analyses demonstrated PLA/PCL competitive binding to Transferrin Receptor 1a (TfR1a), depleting intracellular iron stores and activating Ferroptosis pathways, evidenced by malondialdehyde accumulation and oxidative stress activation. Computational simulations of nanoparticle-protein interactions, validated through Ferroptosis inhibition assays, identified TfR1a-ligand binding affinity as the key driver of iron dysregulation preceding ocular maldevelopment. This work establishes a TfR1a-mediated toxicity pathway for PLA/PCL, wherein competitive binding triggers iron dyshomeostasis and oxidative stress, ultimately leading to Ferroptosis and ocular developmental impairment, thereby uncovering a novel toxic mechanism of such BPs with critical implications for their aquatic ecological risk assessment.

Biodegradable nanoplastics; Computational toxicology; Ferroptosis; Iron dyshomeostasis; Ocular developmental toxicity.