Zhang_2024_Environ.Toxicol.Pharmacol_110_104528

Isopropylate Triphenyl Phosphate (IPPP), a novel organophosphorus flame retardant, has become a widespread environmental pollutant. However, the toxic effects and mechanisms of IPPP remain unclear. In this study, we evaluated the neurodevelopmental toxicity effects of IPPP on zebrafish embryonic development, neurobehavior, and physiological and transcriptomic changes. The results showed that IPPP induced adverse developments such as low survival rates and hatching rates, decreased body length and eye distance, and also led to increased heart rates and embryonic malformation rates. The developmental defects mainly included typical pericardial edema, eye deformities, and a reduction in the number of newborn neurons. Mitochondrial energy metabolism disorders and apoptosis of cardiomyocytes may be responsible for heart malformation. Behavioral results showed that IPPP caused abnormal changes in swimming speed, total swimming distance and trajectory, and showed a low-dose effect. In addition, the decreased activity of neurotransmitters such as acetylcholinesterase (AchE) and dopamine (DA), and the changes in genes related to the central nervous system (CNS) and metabolism pathway may be the causes of neurodevelopmental toxicity of IPPP. Meanwhile, IPPP induced oxidative stress and apoptosis, and changed the ATPase activity of zebrafish larvae by altering nuclear factor erythroid2-related factor 2 (Nrf2) and mitochondrial signaling pathways, respectively. Transcriptome sequencing results indicated that Cytochrome P450 and drug metabolism, Energy metabolism-related pathways, Glutathione metabolism, Retinoid acid (RA) and REDOX signaling pathways were significantly enriched, and most of the genes in these pathways were up-regulated after IPPP treatment, which may be new targets for IPPP-induced neurodevelopment. In summary, the results of this study provide an important reference for a comprehensive assessment of the toxic effects and health risks of the new pollutant IPPP.