From Screening-Level Profiling of Novel Brominated Flame Retardants to a Putative AOP-Informed Framework for...

The rapidly expanding use of novel brominated flame retardants (NBFRs), combined with limited knowledge of their effects, raises concerns regarding their potential hazards. To address this gap, screening-level toxicokinetic and toxicity profiling was first conducted for 27 environmentally prevalent NBFRs, followed by zebrafish verification using decabromodiphenyl ethane (DBDPE) as a representative compound. The study further integrated transcriptomic analysis and ferrostatin-1 (Fer-1) intervention to investigate whether ferroptosis is involved in DBDPE-induced neurodegeneration-related cognitive impairment within a putative adverse outcome pathway (AOP)-informed framework. Predictive toxicological analyses indicated that most investigated NBFRs shared similar toxicokinetic characteristics, with neurotoxicity and blood-brain barrier (BBB) toxicity identified as common predicted toxicity end points. In zebrafish, DBDPE caused BBB impairment, learning and memory deficits, amyloid-β dysregulation, and neuronal injury. Transcriptomic and molecular analyses suggested ferroptosis as one of the major affected processes, accompanied by downstream mitochondrial alterations. Furthermore, in male zebrafish, Fer-1 markedly alleviated DBDPE-induced cognitive impairment and most ferroptosis- and mitochondria-related changes. Collectively, our findings support a putative AOP-informed mechanistic framework for DBDPE-induced neurodegeneration-related cognitive impairment. While the in vivo experimental verification is limited to DBDPE, the predictive profiling provides mainly screening-level indications to support future hazard identification and risk assessment for the broader NBFR class.