Predicted Versus Observed Activity of PCB Mixtures Toward the Ryanodine Receptor

Justin A. Griffin; Xueshu Li; Hans-Joachim Lehmler; Erika B. Holland

doi:10.1101/2023.08.22.554299

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Predicted Versus Observed Activity of PCB Mixtures Toward the Ryanodine Receptor

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Predicted Versus Observed Activity of PCB Mixtures Toward the Ryanodine Receptor

Justin A. Griffin, Xueshu Li, Hans-Joachim Lehmler and Erika B. Holland

bioRxiv

Cold Spring Harbor Laboratory

08/23/2023

DOI: 10.1101/2023.08.22.554299

PMCID: PMC10473618

PMID: 37662381

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https://doi.org/10.1101/2023.08.22.554299View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Non-dioxin-like polychlorinated biphenyls (NDL PCBs) alter the activity of the ryanodine receptor (RyR), and this activity is linked to developmental neurotoxicity. Most work to date has focused on the activity of single congeners rather than relevant mixtures. The current study assessed the RyR activity of single congeners or binary, tertiary, and complex PCB mixtures. Observed mixture activity was then compared to the expected activity calculated using the concentration addition (CA) model or a RyR-specific neurotoxic equivalency scheme (rNEQ). The predictions of the CA model were consistent with the observed activity of binary mixtures at the lower portion of the concentration-response curve, supporting the additivity of RyR1 active PCBs. Findings also show that minimally active congeners can compete for the RyR1 binding site, and congeners that do not activate the RyR1 do not interfere with the activity of a full agonist. Complex PCB mixtures that mimic PCB profiles detected in indoor air, fish tissue, and the serum of mothers and children activated the RyR1 and displayed similar efficacy and potency regardless of varying congener profiles. Neither the CA model nor the rNEQ perfectly predicted the observed activity of complex mixtures, but predictions were often within one magnitude of change from the observed response. Importantly, PCB mixtures approximating profiles found in environmental samples or human serum displayed RyR1 activity at concentrations reported in published research. The work presented will aid in the development of risk assessment platforms for NDL PCBs, and similar compounds, towards RyR1 activation and related neurotoxicity.

Details

Title: Subtitle: Predicted Versus Observed Activity of PCB Mixtures Toward the Ryanodine Receptor
Creators: Justin A. Griffin
Xueshu Li - University of Iowa
Hans-Joachim Lehmler - University of Iowa
Erika B. Holland - California State University, Long Beach
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2023.08.22.554299
PMID: 37662381
PMCID: PMC10473618
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 08/23/2023
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute
Record Identifier: 9984461800702771

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