Exploring the underlying molecular mechanism of tri(1,3-dichloropropyl) phosphate-induced neurodevelopmental toxicity via thyroid hormone disruption in zebrafish by multi-omics analysis

Tri(1,3-dichloropropyl) phosphate (TDCPP) is widespread in the environment as a typical thyroid hormone-disrupting chemical. Here, we aimed to explore the toxicological mechanisms of the thyroid hormone-disrupting effects induced by TDCPP in zebrafish embryos/larvae using multi-omics analysis. The results showed that TDCPP (400 and 600 µg/L) induced phenotypic alteration and thyroid hormone imbalance in zebrafish larvae. It resulted in behavioral abnormalities during zebrafish embryonic development, suggesting that this chemical might exhibit neurodevelopmental toxicity. Transcriptomic and proteomic analysis provided consistent evidence at the gene and protein levels that neurodevelopmental disorders were significantly enhanced by TDCPP exposure (p < 0.05). Additionally, multi-omics data indicated that membrane thyroid hormone receptor (mTR)-mediated non-genomic pathways, including cell communication (ECM-receptor interactions, focal adhesion, etc.) and signal transduction pathways (MAPK signaling pathway, calcium signaling pathway, neuroactive ligand-receptor interaction pathway, etc.), were significantly disturbed (p < 0.05) and might contribute to the neurodevelopmental toxicity induced by TDCPP. Therefore, behavioral abnormalities and neurodevelopmental disorders might be important phenotypic characteristics of TDCPP-induced thyroid hormone disruption, and mTR-mediated non-genomic networks might participate in the disruptive effects of this chemical. This study provides new insights into the toxicological mechanisms of TDCPP-induced thyroid hormone disruption and proposes a theoretical basis for risk management of this chemical.