Early-Life Exposure to Organophosphorus Pesticide Mixtures and Impaired Neonatal Neurodevelopment: A Cohort Study Integrating Comprehensive Multi-Omics and Machine Learning.

Early-life exposure to low-dose organophosphorus pesticide (OPP) mixtures and their impact on neonatal neurodevelopment remain insufficiently characterized. In this study, plasma samples from 281 newborns were analyzed for 21 OPPs, and neurodevelopment was assessed using the Neonatal Behavioral Neurological Assessment (NBNA). Mixture models consistently identified fenamiphos and fenitrothion as major contributors to lower NBNA scores. To explore potential underlying mechanisms, network toxicology and infant fecal 16S rRNA sequencing were employed. Higher OPP exposure risk scores were associated with altered gut microbiota, including increased abundance of opportunistic genera such as Acinetobacter and Ralstonia, and decreased levels of beneficial taxa including Lactiplantibacillus. Predicted functional profiling revealed enrichment of microbial pathways related to secretion systems and tryptophan metabolism, which correlated with poorer neurodevelopment. Furthermore, a random forest model integrating microbial functional features showed modestly improved prediction of motor outcomes at age 5, assessed via the Ages and Stages Questionnaires (ASQ), compared with models based on conventional clinical indicators alone. These findings suggest that early-life exposure to OPP mixtures is linked to impaired neonatal neurodevelopment, potentially linked to gut microbiota dysregulation and predicted functional alterations. Importantly, microbial functional signatures may have potential as early-life predictive markers for later motor deficits, highlighting the critical interplay between environmental exposures and the gut-brain axis in shaping neurodevelopmental outcomes. These findings highlight the importance of reducing early-life pesticide exposure and support further research into microbiota-related pathways that may inform strategies to mitigate long-term neurodevelopmental risks.