Structure-Activity Relationship of Lower Chlorinated Biphenyls and Their Human-Relevant Metabolites for Astrocyte Toxicity.
Neha ParanjapeLaura E DeanAndres MartinezRonald B TjalkensHans-Joachim LehmlerJonathan A DoornPublished in: Chemical research in toxicology (2023)
Exposure to polychlorinated biphenyls (PCBs) is associated with developmental neurotoxicity and neurodegenerative disorders; however, the underlying mechanisms of pathogenesis are unknown. Existing literature has focused mainly on using neurons as a model system to study mechanisms of PCB-mediated neurotoxicity, overlooking the role of glial cells, such as astrocytes. As normal brain function is largely astrocyte-dependent, we hypothesize that astrocytes play an important role in PCB-mediated injury to neurons. We assessed the toxicity of two commercial PCB mixtures, Aroclor 1016 and Aroclor 1254, and a non-Aroclor PCB mixture found in residential air called the Cabinet mixture, all of which contain lower chlorinated PCBs (LC-PCBs) found in indoor and outdoor air. We further assessed the toxicity of five abundant airborne LC-PCBs and their corresponding human-relevant metabolites in vitro models of astrocytes, namely, the C6 cell line and primary astrocytes isolated from Sprague-Dawley rats and C57BL/6 mice. PCB52 and its human-relevant hydroxylated and sulfated metabolites were found to be the most toxic compounds. No significant sex-dependent cell viability differences were observed in rat primary astrocytes. Based on the equilibrium partitioning model, it was predicted that the partitioning of LC-PCBs and their corresponding metabolites in biotic and abiotic compartments of the cell culture system is structure-dependent and that the observed toxicity is consistent with this prediction. This study, for the first time, shows that astrocytes are sensitive targets of LC-PCBs and their human-relevant metabolites and that further research to identify mechanistic targets of PCB exposure in glial cells is necessary.
Keyphrases
- endothelial cells
- ms ms
- oxidative stress
- induced apoptosis
- pluripotent stem cells
- induced pluripotent stem cells
- simultaneous determination
- particulate matter
- mass spectrometry
- polycyclic aromatic hydrocarbons
- high resolution
- cell cycle arrest
- spinal cord
- type diabetes
- insulin resistance
- health risk
- liquid chromatography
- subarachnoid hemorrhage
- ionic liquid
- transcription factor
- high fat diet induced
- blood brain barrier