Early‐Life Polyethylene Microplastic Exposure Exacerbates ADHD‐Like Behaviors in Mice via PI3K/AKT1/Nrf2 Signaling: Evidence From the Pilot Cohort and Multi‐Omics Analyses

Microplastic pollution may influence neurodevelopment, yet its relationship with attention-deficit/hyperactivity disorder (ADHD) remains unclear. We integrated a pediatric cohort, multi-omics analyses, network toxicology, and animal experiments to investigate polyethylene (PE) microplastic exposure in ADHD vulnerability. Among 90 children, PE was the predominant polymer detected in blood and was more abundant in children with ADHD. Higher PE burden was associated with greater symptom severity, increased IL-6, and reduced antioxidant capacity. Multi-omics and network analyses converged on PI3K/AKT1/Nrf2 signaling. In a perinatal nicotine mouse model, developmental PE co-exposure exacerbated ADHD-like behaviors, dopaminergic dysfunction, and oxidative injury. Melatonin partially alleviated these abnormalities by restoring PI3K/AKT1/GSK3β and Nrf2 signaling, whereas AAV-mediated PI3K knockdown weakened its protective effects. Collectively, the human findings identify circulating PE burden as an environmental correlate of ADHD-related neurodevelopmental vulnerability, while the animal experiments provide evidence that developmental PE co-exposure can aggravate ADHD-like abnormalities in a susceptible background.