Organophosphate Flame Retardants Disrupt Autism-Relevant Gene Networks Across Development: A Cross-Species Multi-Omics Study

Organophosphate flame retardants (OPFRs) are widely used environmental contaminants with suspected developmental neurotoxicity, yet their stage-specific molecular impacts and potential relevance to autism spectrum disorder (ASD) remain poorly defined. We integrated transcriptomic and lipidomic analyses from two rat models to investigate OPFR-induced disruption across early neurodevelopment. In dataset GSE148266, fetal forebrain and placenta were analyzed following in utero OPFR exposure; in dataset GSE211430, neonatal cortical RNA-seq and lipidomics were profiled after postnatal exposure to triphenyl phosphate and isopropylated triaryl phosphate (1000 μg/day; n = 10/sex/group). Differential expression (DESeq2; FDR <0.05), pathway enrichment (GSEA), and multi-omics integration (DIABLO; |r| > 0.9) were performed. Fetal exposure altered 191 genes (144 mapped to human orthologues), including ASD-relevant genes such as ADNP, BRAF, and MAPK3, with enrichment in spliceosome (NES = 2.39), cell-cycle regulation (NES = 2.26), and suppressed Toll-like/NOD-like immune signaling (NES = -2.06). Postnatal exposure disrupted 34 genes and 12 lipids, notably PC(15:0_16:0) and TG(18:1_20:1_20:1), which correlated with synaptic and immune-related genes. Eighteen neonatal DEGs overlapped with human ASD cortical transcriptomes, and integrated analysis revealed shared neurotransmission networks across developmental stages. These findings demonstrate that OPFRs disrupt conserved neurodevelopmental gene networks in a stage-specific manner. The convergence of transcriptomic and lipidomic signals with ASD-relevant features supports further investigation of OPFRs as candidate environmental risk factors and highlights molecular pathways for future biomarker and toxicity studies.