Study of the effects of Persistent organic pollutants (POPs) on Dictyostelium genome for the identification of genes and proteins susceptible to their carcinogenic action

Persistent organic pollutants (POPs) are a class of chemicals characterized by their resistance to degradation. This persistence poses significant health risks to living organisms. Among them, Polychlorinated biphenyls (PCBs) can disrupt several biological processes, including oxidative stress, iron metabolism and critical signalling pathways, due to their biphenyl structure with varying chlorine substitutions. While their toxic effects in mammalian systems are well documented, their impact on non-mammalian models such as Dictyostelium discoideum remains underexplored. Given that Dictyostelium is widely used in toxicity studies, investigating its response to PCBs exposure may provide further insight into the molecular mechanism underlying PCBs toxicity. In this study, we employ a multi-model approach, analysing the cellular effects of PCB 138 and PCB 153 on both Dictyostelium and human THP-1 cells. Our findings demonstrate that PCBs significantly alter growth and development in Dictyostelium cells, leading to reduced proliferation rate and the formation of smaller fruiting bodies during differentiation. Notably, marked changes in gene expression related to iron homeostasis are observed in both Dictyostelium e TPH-1 cells, highlighting a potential evolutionary conserved response to PCBs. Furthermore, oxidative stress assays, proteomic analysis and mitochondrial analysis collectively support the hypothesis that oxidative stress could be a mechanism through which PCBs exert their toxic effect. PCBs exposure also induces gene expression changes in cAMP signalling, a pathway fundamental for Dictyostelium development and differentiation. Despite the evolutionary distance between the two models, Dictyostelium exhibits ancestral mechanism of PCB response, reinforcing its suitability as an effective model for studying PCBs toxicity. During the period at the Drug Discovery and Clinic s.r.l., a new inhibitor (Meds433) of dihydroorotate dehydrogenase (DHODH), a key enzyme involved in the pyrimidines biosynthesis pathway, was tested on different leukemic cell lines. In fact, DHODH recently became a new therapeutic target due to the fast-proliferating nature of cancer cells, which strongly relay on de novo pyrimidines biosynthesis. According to company policies and secrecy of data, these results cannot be shown in this thesis.