From exposure models to multi-organ toxicity of 6PPD-quinone in mice: A mini-review

Emerging evidence positions 6PPD-quinone (6PPD-Q) as a global environmental contaminant, with confirmed toxicity to various species and widespread detection in human biological samples. Despite these observations, toxicological understanding of 6PPD-Q in mammals remains fragmented and inconsistent. Therefore, this review integrates current evidence from murine models within an "exposure-toxicokinetics-organ toxicity" framework, revealing exposure route-dependent toxicokinetics and toxicological outcomes. Moreover, 6PPD-Q perturbs lipid metabolism, mitochondrial function, and immune homeostasis mechanistically. Crucially, evidence suggests sex-dependent differences in the toxicological profile of 6PPD-Q; males tend to display higher peak concentrations and faster clearance, whereas females show prolonged systemic retention and reproductive toxicities. However, the majority of this toxicological evidence has been obtained from high-dose or artificial exposure paradigms, sex-dependent susceptibility and the molecular-to-systemic integration of inter-organ crosstalk are insufficiently addressed. Future research should, therefore, prioritize physiologically or environmentally relevant chronic-exposure models, integrating physiologically based pharmacokinetic (PBPK) modeling with multi-omics approaches to better delineate inter-organ axis mechanism. Such an approach will be of great importance to transform descriptive toxicology into predictive, preventive science with direct environmental and public health impact.