Directly Reprogrammed Neurons as a Tool to Assess Neurotoxicity of the Contaminant 4‑Hydroxy-2′,3,5,5′-tetrachlorobiphenyl (4′OH-CB72) in Melon-Headed Whales

Whales accumulate high levels of environmental pollutants. Exposure to polychlorinated biphenyls (PCBs) and their metabolites (OH-PCBs) could be linked to abnormal behavior, which may lead to mass stranding of marine mammals. Whales may thus suffer from adverse effects such as neuronal dysfunction, yet testing the neurotoxicity of these compounds has never been feasible for these species. This study established neurons chemically reprogrammed from fibroblasts of mass stranded melon-headed whales (Peponocephala electra) and used them for in vitro neurotoxicity assays. Exposure to 4-hydroxy-2′,3,5,5′-tetrachlorobiphenyl (4′OH-CB72), a metabolite of PCBs, caused apoptosis in the reprogrammed neurons. Transcriptome analysis of 4′OH-CB72-treated whale neurons showed altered expressions of genes associated with oxidative phosphorylation, chromatin degradation, axonal transport, and neurodegenerative diseases. These results suggest that 4′OH-CB72 exposure may induce neurodegeneration through disrupted apoptotic processes. A comparison of the results with human reprogrammed neurons revealed the specific effects on the whale neurons. Our noninvasive approach using fibroblast-derived neurons is useful for hazard and risk assessments of neurotoxicity in whales.