New insights into polycyclic aromatic hydrocarbons: Phenanthrene targets ribosomes to induce neuronal apoptosis.

The environmental pollutant polycyclic aromatic hydrocarbons (PAHs) are abundant in the environment due to large-scale industrial production and can induce toxic effects in multiple systems. Phenanthrene (Phe) is the major PAHs in environmental sources. However, it remains unknown whether Phe exposure induced brain injury in zebrafish was related to ribotoxic stress, apoptosis and energy metabolism. In this study, 100 zebrafish (Danio rerio) were exposed to Phe in the water environment at environmental relevant concentrations for 28 days. By deploying molecular dynamics simulations, RNA sequencing (RNA-seq), western blotting (WB), immunofluorescence (IF) staining, immunohistochemistry (IHC), and other methods, we showed that Phe exposure induce neuron DNA damage and directly bind and disrupt ribosomal structure to induce ribotoxic stress, leading to the activation of MAP kinase signaling pathway phosphorylation (p38/JNK). In addition, the ribotoxic stress further induced the activation of p53 and the marked upregulation of pro-apoptotic genes (Caspase-9, Caspase-3, Bax, Cytc, puma, Bak) to trigger apoptosis, disrupting components of the electron transport chain (ubiquinone oxidoreductase (Complex I) and cytochrome c oxidase (Complex IV), and eventually causing brain injury. These results suggest that the Phe exposure induced ribotoxic stress, energy metabolism perturbation and neuronal apoptosis via damaging ribosomes and DNA. In summary, Phe exposure could cause neurobehavioral deficits in zebrafish, cause strong neurotoxicity, and induce brain injury. This study provides novel insights on the mechanisms of PAHs toxicity.