Phenol exposure promotes tumor-related signaling and blood vessel formation through the extracellular signal-regulated kinase/p38/hypoxia-inducible factor-1α pathway in cellular and zebrafish models.

Phenol is a common aquatic contaminant originating from industrial discharge, plastics, and personal care products, and is frequently detected due to its high solubility and environmental persistence. Although its acute toxicity is well documented, the effects of phenol at environmentally relevant concentrations on cellular mechanisms linked to tumor progression remain underexplored. In this study, we investigated the impact of phenol exposure (0-125 μM) on cancer-related cellular behaviors using B16F10 melanoma and LL2 lung carcinoma cells, as well as zebrafish xenograft models, which serve as an integrated aquatic toxicology platform. Phenol exposure activated extracellular signal-regulated kinase (ERK) and p38 pathways, upregulated hypoxia-inducible factor 1α (HIF-1α), increased vascular endothelial growth factor (VEGF) expression, and induced epithelial-mesenchymal transition (EMT). These molecular events collectively enhanced tumor cell migration and angiogenesis both in vitro and in vivo. Our findings provide mechanistic evidence that environmentally relevant phenol exposure can modulate conserved stress and signaling pathways associated with tumor-related phenotypes. This work underscores the importance of combining molecular biomarkers with aquatic vertebrate models to assess the ecological and toxicological risks of persistent organic pollutants such as phenol.