Cu(OH)₂ nanopesticide induced adolescent social behavior deficits via long noncoding RNA-mediated synaptic network...

Despite the extensive agricultural utilization owing to distinctive physicochemical properties and robust broad-spectrum antimicrobial activity, Cu(OH)₂ nanopesticide (NP) has raised escalating neurotoxic concerns due to its environmental persistence and bioaccumulation potential. Adolescence constitutes a pivotal window of postnatal neurodevelopment, characterized by maturation and refinement of synaptic architecture and neural circuitry, which critically determines cognitive ontogeny. In the present investigation, adolescent C57BL/6 mice were subjected to subchronic oral administration via gavage of Cu(OH)₂ NP or vehicle control over a 30-day exposure period. This exposure regimen was demonstrated to elicit neurodevelopmental perturbations, manifesting as pronounced impairments in social interaction and novelty-seeking behavior, phenotypes resembling depression and autism spectrum disorders, concurrent with dysregulated synaptic molecular signatures and compromised neurotransmission equilibrium. These observed aberrations were pathologically linked to aberrant copper homeostasis and induction of cuproptosis pathways in mitochondrion, identified as principal drivers of neurodevelopmental impairment. The Cu(OH)₂ NP-mediated epigenetic reprogramming of the transcription factor (TF) Kdm1a, executed through the long noncoding RNAs (lncRNAs) Shank1-204 and Acsl1-206, delineated the core molecular pathogenesis underpinning this NP-evoked neurodevelopmental deficits. Collectively, these discoveries substantially advanced the current insights into the developmental neurotoxicity attributable to engineered NPs, providing an essential scientific foundation for establishing rigorous neurotoxicological risk assessment paradigms.