Mitochondria under fire: toxicological mechanisms of brominated flame retardants.

Abstract

Brominated flame retardants (BFRs) are ubiquitous and persistent environmental contaminants owing to their extensive use in consumer products. Although linked to various adverse health effects, the underlying molecular mechanisms remain complex. This review consolidates scientific evidence positioning mitochondria as a central target of BFR toxicity, unraveling the pathways that drive cellular damage. The analysis revealed that BFRs converge on the fundamental mechanisms of mitochondrial injury. They consistently impair bioenergetics by disrupting the electron transport chain and uncoupling oxidative phosphorylation, leading to ATP depletion and collapse of the mitochondrial membrane potential (ΔΨm). This energetic failure triggers a surge in reactive oxygen species, overwhelming antioxidant defenses, and causing severe oxidative damage. Beyond these common effects, this review highlights remarkable mechanistic plasticity. Tetrabromobisphenol A can induce distinct cell death programs, including apoptosis, necroptosis, and ferroptosis, depending on the cellular context of the study. Furthermore, BFR biotransformation can yield metabolites such as hydroxylated polybrominated diphenyl ethers (PBDEs) that exhibit significantly greater toxicity than their parent compounds. Finally, mitochondrial dysfunction is a central hub that orchestrates cellular damage by BFRs. This is critically highlighted by the replacement of BDE-209 with decabromodiphenyl ethane, a regrettable substitution, where the new compound shares similar mitotoxic mechanisms and has become a widespread pollutant. This underscores the urgent need for a paradigm shift toward mechanism-based risk assessment to prevent future cycles of hazardous chemical replacements and to guide the design of genuinely safer alternatives.