Polystyrene nanoplastic exposure exacerbates epileptic vulnerability in SCN1A mutation models

Micro- and nanoplastics are pervasive contaminants detected in human tissues that cross the blood-brain barrier to induce neuroinflammation, apoptosis, and neurotoxicity. Here, we examined whether polystyrene nanoplastic (PS-NP) exposure alters seizure susceptibility in SCN1A^+/- cerebral organoids and Scn1a^+/- mice, modeling the severe genetic epilepsy Dravet syndrome. At equal mass concentrations, 50 nm PS-NPs penetrated organoids more deeply and upregulated inflammatory and neurotoxic gene expression more robustly than 100 nm particles, inducing apoptotic activation and significant DNA fragmentation. Exposure disrupted steroid homeostasis-causing genotype-dependent cortisol elevations-and perturbed neurotransmitter systems in SCN1A-deficient models via reduced GABA and glutamate, accompanied by decreased GAD2 and increased VGLUT2 expression. In vivo, exposed Scn1a^+/- mice exhibited hyperactivity and reached Racine stages 3-5 more rapidly under thermal induction, demonstrating a reduced seizure threshold. Pharmacological inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversed this hyperactivity but failed to restore the seizure threshold. Together, these findings indicate that PS-NP exposure exacerbates seizure vulnerability in genetically susceptible backgrounds, accompanied by marked neurochemical, endocrine, and apoptotic disruptions. These results support a 'second-hit' model wherein environmental nanoplastics act as external triggers in genetic epilepsy, underscoring the vital need to incorporate gene-environment interactions into neurotoxicological risk assessments.