Chlorpyrifos-induced autism and depression-like behaviors are ameliorated by trehalose: Integrating network pharmacology and toxicology analyses and animal experiments

The risk of autism spectrum disorder (ASD) is elevated by exposure to the organophosphate pesticide chlorpyrifos (CPF) during pregnancy and lactation. As a neurodevelopmental disorder, ASD often co-occurs with depression, exacerbating the social isolation experienced by affected individuals. Trehalose (Tre), a naturally occurring non-reducing sugar, has neuroprotective properties. Nevertheless, the mechanisms by which it exerts protective effects against CPF-induced ASD and depression-like behaviors remain unclear. The objective of study was to investigate the mechanisms underlying Tre combating CPF-induced ASD and depression through network pharmacology and toxicology analyses. In animal studies, Tre was administered to offspring mice exposed to CPF during pregnancy and lactation. Behavioral assessments revealed that Tre alleviated CPF-induced repetitive and stereotypic behaviors, social deficits, and depression-like behaviors in offspring mice. Findings from network pharmacology and toxicology analyses and animal experiments supported the notion that mammalian target of rapamycin-related autophagy and TLR4-related necroptosis signaling may contribute to the protective effects of Tre against CPF-induced hippocampal damage. This research offers valuable information regarding the potential protective effects of Tre against neurodevelopmental disorders linked to environmental chemicals.