Developmental neurotoxic effects of organophosphate flame retardants (OPFRs) across different life stages and the central role of pioneer transcription factors Neurog2/Ascl1 during the embryonic period.

In contemporary consumer products markets, organophosphorus flame retardants (OPFRs) are widely used, associated with non-carcinogenic health risks and exhibit multisystem toxicity. Based on the endocrine-disrupting properties, which are combined with the endocrine system's susceptibility and interaction with the nervous system during early developmental stages, developmental neurotoxicity (DNT) has been increasingly reported in epidemiological studies. Unfortunately, their toxic mechanisms remain unclear. Given the highly stage specific nature of neurogenesis-related gene expression across life stages, these mechanisms are highly time- and stage-dependent. This study employed network toxicology methods and machine learning algorithms to reveal that OPFRs cause abnormal protein translation during late embryonic neurogenesis by disrupting the expression of ribosome-associated genes-Rpl9, Rps21, Rps23, Rps28, and Rps29. Combining network toxicology with mouse cohort transcriptomics revealed that OPFRs induce DNT during early larval neurogenesis by disrupting the expression of pioneer transcription factors Neurog2 and Ascl1. Therefore, ribosome-associated genes and pioneer transcription factors can serve as sensitive candidate biomarkers in the mode of DNT action of OPFRs.