Dictyostelium exhibits PCB-induced impairment of proliferation, development and stress response, emerging as model for conserved environmental toxicity.

Persistent Organic Pollutants, such as polychlorinated biphenyls (PCBs), are environmental pollutants for their resistance to degradation and adverse health effects. Despite extensive toxicological data in mammalian system, the use of alternative models such as Dictyostelium discoideum offers an opportunity to dissect evolutionarily conserved molecular mechanisms underlying pollutant-induced cellular dysfunction. In this study, we used Dictyostelium to investigate the effects of PCB 138 and PCB 153 revealing, for the first time, a direct impairment of both growth and multicellular development. PCBs exposure reduced cell proliferation and led to the formation of smaller fruiting bodies. These phenotypic effects were accompanied by altered expression of iron-regulatory genes, including upregulation of abcb7 and ferroportin, and downregulation of ferritin, consistent with intracellular iron depletion confirmed by calcein assay. We used THP-1 human cells to confirm the effect of PCBs on hamp gene, supporting the relevance of iron homeostasis as a target pathway. In Dictyostelium, iron imbalance was associated with increased ROS levels, downregulation of superoxide dismutase genes, and altered mitochondrial morphology. Under starvation, PCBs-treated cells also showed transcriptional upregulation of key development genes involved in cAMP signaling (acaA, carA, regA, gtaC), while proteomic analysis revealed changes in proteins linked to cell adhesion, stress response, and development. Together these findings support a model in which PCBs induce iron efflux, oxidative stress, and disruption of developmental signaling, ultimately both proliferation and morphogenesis. This study highlights the potential of Dictyostelium discoideum as a sensitive and cost-effective model to uncover conserved cellular responses to environmental pollutants.