Regrettable Substitutions: Halogenated Flame Retardants TDCPP and TDBPP Exploit the ATF3/SLC7A11 Axis to Trigger Ferroptotic Renal Filtration

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and tris(2,3-dibromopropyl) phosphate (TDBPP) are widely detected organophosphate flame retardants and environmental contaminants; however, the molecular mechanisms underlying their nephrotoxicity remain poorly defined. In this study, zebrafish larvae were used to evaluate TDCPP/TDBPP-induced renal injury, whereas HEK-293T cells were employed as an in vitro system to investigate ferroptosis-associated cellular responses and ATF3-related regulation. TDCPP and TDBPP exposure induced pronounced renal malformations and impaired filtration function in zebrafish larvae. Mechanistically, exposed cells and larvae exhibited hallmark features of ferroptosis-associated injury, including intracellular iron accumulation, excessive reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial shrinkage, and lysosomal dysfunction. TDCPP/TDBPP exposure also markedly upregulated activating transcription factor 3 (ATF3) while concomitantly suppressing the SLC7A11/GPX4 antioxidant defense axis. ChIP-qPCR analysis revealed increased enrichment of ATF3 at the SLC7A11 promoter following exposure, suggesting that SLC7A11 may serve as a direct transcriptional regulatory target involved in ATF3-mediated pathway disruption. Pharmacological intervention with the ferroptosis inhibitor ferrostatin-1 (Fer-1) markedly attenuated TDCPP/TDBPP-induced renal injury, oxidative stress, organelle dysfunction, and ferroptosis-associated molecular alterations. Furthermore, ATF3 loss- and gain-of-function experiments in HEK-293T cells showed that ATF3 knockdown markedly attenuated, whereas ATF3 overexpression exacerbated, TDCPP/TDBPP-induced ferroptosis-associated cellular responses. Collectively, these findings demonstrate TDCPP/TDBPP-induced renal injury in zebrafish larvae and support the involvement of the ATF3/SLC7A11/GPX4 axis in ferroptosis-associated cellular responses to these compounds. This study provides a mechanistic basis for assessing the health risks associated with exposure to organophosphate flame retardants.