Organophosphate flame retardants exposure and neuroaxonal injury in adults: A systematic study integrating human data and network toxicology.

Organophosphate flame retardants (OPFRs) have been increasingly implicated in developmental neurotoxicity. However, evidence linking OPFRs exposure to neurotoxic effects in adult populations remains limited. The present study aimed to investigate this association and the underlying mechanisms by leveraging cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), combined with network toxicology and molecular docking approaches. The results showed that among the metabolites of OPFRs assessed in adult participants, the urinary concentrations of dibutyl phosphate (DBP), diphenyl phosphate (DPP), and bis(1,3-dichloro-2-propyl) phosphate (BDCPP) demonstrated an increasing trend, whereas those of bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCPP) exhibited a decreasing trend over the period spanning 2011-2018. Additionally, urinary DBP, a metabolite of tributyl phosphate (TBP), was found to be positively associated with serum neurofilament light chain (sNfL), a specific biomarker for neuroaxonal injury, during the 2013-2014 cycle. Moreover, the mixed exposure models revealed an overall positive relationship between OPFRs and sNfL. Furthermore, network toxicology analysis identified 17 core targets shared by TBP and neurotoxicity. Among these, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), peroxisome proliferator-activated receptor gamma (PPARG), sterol regulatory element-binding transcription factor 1 (SREBF1), and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) were screened as the top central hubs, which are involved in insulin resistance, AMPK signaling, amino acid biosynthesis, PPAR signaling, and metabolic pathways. Molecular docking validated the high-affinity binding of TBP to the key targets GAPDH and PPARG. GeneMANIA enrichment analysis is consistent with core target enrichment analysis. Taken together, this study provides novel evidence for the association between OPFRs exposure and neuroaxonal injury in adults and uncovers the underlying mechanisms of TBP-induced neurotoxicity.