100s—General Toxicology P101: North American Graduate Fellowship Recipient: Toxicity of Polychlorinated Biphenyls and their Human-relevant Metabolites in Astroglial Cells

Exposure to polychlorinated biphenyls (PCBs) correlates with developmental neurotoxicity and, recently, with neurodegenerative disorders. However, the underlying mechanisms remain unknown. Because normal brain function is largely astrocyte dependent, we hypothesize that astrocytes play an important role in PCB-mediated neurotoxicity. We assessed the toxicity of four PCB congeners, 4-chlorobiphenyl (PCB3), 3,3’-dichlorobiphenyl (PCB11), 2,3’,4-trichlorobiphenyl (PCB25) and 2,2’,5,5’-tetrachlorobiphenyl (PCB52) and their corresponding human-relevant hydroxylated and sulfated metabolites, in C6 cells (rat glioma cell line) or primary glial cells (from C57BL/6 mice) exposed to test compounds at a concentration range of 0.5 to 50 μM for 24 h. The MTT assay was employed to determine cell viability, also in the absence and presence of 100 μM dopamine. Reactive oxygen species (ROS) generation was analyzed using fluorescent probes, MitoSox Red and CellRox Green in C6 cells. PCB52 and both its metabolites were the most toxic in C6 cells at LC50 concentrations of 8.4 μM (PCB52), 2.2 μM (4-OH-PCB52) and 8.8 μM (4-PCB52-sulfate) thus, further studies were focused on these compounds. ROS was generated at concentrations of PCB 52 and its metabolites much below the LC50 concentrations and was largely mitochondria-targeted. The presence of dopamine significantly increased cell viability in C6 cells exposed to 4-PCB52-sulfate but not other test compounds. PCB52 and 4-OH-PCB52 were similarly cytotoxic to primary glia as observed in C6 cells. These findings suggest that key cellular processes in astrocytes are impaired in a structuredependent manner following PCB exposure. Future studies will assess the functional implications of these findings in PCB-mediated neurotoxicity.