Environmentally relevant levels of BDE-209 induces proteomic and phosphoproteomic reprogramming in murine melanoma cells

Polybrominated diphenyl ethers (PBDEs), notably decabromodiphenyl ether (BDE-209), are persistent organic pollutants widely used as flame retardants and frequently detected in electronic waste. Despite global restrictions, BDE-209 remains an environmental contaminant with bioaccumulative and potentially risk to human health. This study investigated the proteomic and phosphoproteomic effects of chronic concentration BDE-209 exposure in murine melanoma (B16-F1) cells, aiming to elucidate molecular mechanisms underlying pollutant-induced phenotypic changes of malignancy. Cells were exposed to environmentally relevant concentrations of BDE-209 (0.1 and 1 nM) for 15 days, selected based on levels previously reported in human biological samples and on prior in vitro and in vivo studies investigating chronic low-concentration exposure, followed by mass spectrometry-based analyses. A total of 3369 proteins and 4422 phosphosites were identified. BDE-209 exposure resulted in distinct proteomic signatures, including the exclusive expression in exposed cells of proteins such as PRKDC, and modulation of pathways involved in DNA repair, mRNA processing, and chromatin remodeling. PRKDC is a key kinase in DNA damage repair, and it has been associated with chemotherapy resistance and poor prognosis in several cancers, suggesting its potential as a prognostic biomarker in BDE-209-related tumor progression. Additionally, proteins involved in chromatin remodeling, SUMOylation, mRNA processing, and oncogenic signaling (e.g., YES1, DIMT1, UBE2V2) were induced. Phosphoproteomic analysis revealed differential phosphorylation of proteins linked to cancer progression, including TCOF1, IRF2BP2, and HDGFRP2. These findings demonstrate that even low-dose exposure to BDE-209 can modulate cellular signaling and promote malignancy-associated phenotypic changes, underscoring its potential role in worsening cancer prognosis and highlighting the broader health risks posed by persistent environmental contaminants.