Structure-Activity Relationship of Lower Chlorinated Biphenyls and Their Human-Relevant Metabolites for Astrocyte Toxicity

Authors

• Neha Paranjape, Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States.
• Laura E. Dean, Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242, United States.
• Andres Martinez, Department of Civil and Environmental Engineering, IIHR-Hydroscience & Engineering, University of Iowa, Iowa City, Iowa 52242, United States.
• Ronald B. Tjalkens, Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80521, United States.
• Hans-Joachim Lehmler, Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242, United States.
• Jonathan A. Doorn, Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States.

Document Type

Article

Abstract

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.

Medical Subject Headings

Mice; Humans; Rats; Animals; Polychlorinated Biphenyls (toxicity, metabolism); Astrocytes (metabolism); Rats, Sprague-Dawley; Mice, Inbred C57BL; Structure-Activity Relationship

Publication Date

6-19-2023

Publication Title

Chemical research in toxicology

E-ISSN

1520-5010

Volume

36

Issue

6

First Page

971

Last Page

981

PubMed ID

37279407

Digital Object Identifier (DOI)

10.1021/acs.chemrestox.3c00095

Recommended Citation

Paranjape, Neha; Dean, Laura E.; Martinez, Andres; Tjalkens, Ronald B.; Lehmler, Hans-Joachim; and Doorn, Jonathan A., "Structure-Activity Relationship of Lower Chlorinated Biphenyls and Their Human-Relevant Metabolites for Astrocyte Toxicity" (2023). Translational Neuroscience. 2568.
https://scholar.barrowneuro.org/neurobiology/2568