The estuarine ecological environment faces significant threats from contaminants of emerging concern (CECs); yet, the risk posed by CECs to resident organisms remains poorly understood. Here, we employed tiered toxicity testing to investigate the adverse effects and potential mechanisms of tris (1-chloro-2-propyl) phosphate (TCPP) on the early life stages of an estuarine fish, Mugilogobius chulae. TCPP affected the development of M. chulae embryos, including survival, morphology, hatching, and behavior. A concentration-dependent transcriptomic analysis showed that TCPP disrupted 12 neurodevelopment-related KEGG pathways in M. chulae embryos, with five of the 30 % top-ranked pathways related to neurotransmitter signaling. Besides the cholinergic synapse signaling pathway, the glutamatergic signaling pathway (including NMDAR and AMPAR subtypes) may also mediate TCPP-induced neurodevelopmental toxicity. The NMDAR subtype GRIN2B was downregulated at high concentrations. Molecular dynamics simulations revealed a strong interaction between TCPP and GRIN2B, with TCPP binding to the residues Ile153 and Ile188. The results suggest that NMDARs play a crucial role in TCPP-induced neurodevelopmental toxicity toward M. chulae. AOP network analysis predicted that TCPP may impact cognitive functions and memory. Our study provides a novel testing strategy for identifying the mechanisms of toxicity of CECs, a crucial component of ecological risk assessment.
Keywords: Concentration-dependent transcriptome; Estuarine ecological risk; Glutamatergic signaling pathway; Neurodevelopmental toxicity; New approach methodologies.
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