Lipid metabolism disruption as a conserved early response to Benzophenone-1: Pathway sensitivity profiling via...

Benzophenone-1 (BP-1), a widely used benzophenone-type UV filter in personal care products, has garnered global attention owing to its ubiquitous environmental occurrence and multiple adverse effects. However, its early molecular responses associated with molecular initiating events (MIEs) remain poorly understood. In this study, a dose-dependent yeast functional genomics approach (DYFGA) was employed to explore disturbed biological pathways, which were prioritized based on their point of departure (POD) induced by BP-1 at environmentally relevant concentrations, with these results further validated in HepG2 cell lines. Our results demonstrated that the BP-1-induced pathway-level POD (POD_PATH: 3.152 μg/L) was more sensitive than the gene-level POD (POD_DRG: 10.646 μg/L), both of which were much more sensitive than apical endpoint, as determined by the half-inhibitory concentration (IC₅₀: 49.47 mg/L). Quantitative POD calculation based on KEGG pathway showed that the most sensitive altered pathway was lipid metabolism, followed by DNA replication, DNA damage and repair, cell cycle, and oxidative phosphorylation. Subsequently, we determined that the phenotypic-based no observed effect concentrations (NOECs) perturbed by BP-1 were 0.625 mg/L (lipid metabolism), 2.5 mg/L (DNA replication, DNA damage, and cell cycle), and 5 mg/L (oxidative stress) by human cell lines. A significant positive correlation was observed between these NOEC values and the DYFGA-derived POD. Overall, this study not only validated the DYFGA as a robust and effective tool for identifying early-sensitive biological pathways perturbed by chemicals, but also pinpointed lipid metabolism as the conserved primary molecular response induced by BP-1, providing critical insights for the environmental risk assessment of BP-1 and its structural analogues.