Construction of Adverse Outcome Pathway (AOP) for Triphenyl Phosphate (TPHP)-Induced Autism Spectrum Disorder (ASD) and Risk Identification of Neurodevelopmental Toxicity of Aryl Organophosphorus Flame Retardants (OPFRs) Based on Multidimensional Bioinformatic Data.

Triphenyl phosphate (TPHP) is a widely used plasticizer and organophosphate flame retardant extensively applied in various industrial and consumer products. Due to its pervasive environmental exposure and detection in human samples such as amniotic fluid and breast milk, TPHP has become a pollutant of significant concern in recent years for its potential neurodevelopmental impacts on humans. This study employed a multimethod approach integrating network toxicology, transcriptomics, in silico gene knockout, molecular docking, and molecular dynamic simulations to investigate TPHP's potential toxic role in autism spectrum disorder (ASD). An adverse outcome pathway (AOP) was constructed, revealing that TPHP exposure may induce and exacerbate ASD by downregulating GAD1-the core gene encoding the GABA synthesis rate-limiting enzyme (glutamate decarboxylase)-leading to an excitation-inhibition imbalance in the brain. The batch molecular docking of 85 organophosphate flame retardants (OPFRs) (widely detected in human and biological matrices) with the GAD1 protein identified aryl-OPFRs as disruptors targeting GAD1 to induce neurodevelopmental toxicity. In summary, this research provides mechanistic insights into how TPHP promotes ASD progression and offers a valuable chemical reference for assessing the neurodevelopmental toxicity of OPFRs.