Journal article
Predicted versus observed activity of PCB mixtures toward the ryanodine receptor
Neurotoxicology (Park Forest South), Vol.100, pp.25-34
12/07/2023
DOI: 10.1016/j.neuro.2023.12.003
PMCID: PMC10842331
PMID: 38065417
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 toward RyR1 activation and related neurotoxicity.
Details
- Title: Subtitle
- Predicted versus observed activity of PCB mixtures toward the ryanodine receptor
- Creators
- Justin A Griffin - California State University, Long BeachXueshu Li - University of IowaHans-Joachim Lehmler - University of IowaErika B Holland - California State University, Long Beach
- Resource Type
- Journal article
- Publication Details
- Neurotoxicology (Park Forest South), Vol.100, pp.25-34
- DOI
- 10.1016/j.neuro.2023.12.003
- PMID
- 38065417
- PMCID
- PMC10842331
- NLM abbreviation
- Neurotoxicology
- eISSN
- 1872-9711
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: 1SC3GM132033–01A1, 8RL5GM118978–02, 8TL4GM118980–02, 8UL1GM118979–02, P30ES005605, P42ES013661, R25GM071638; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences; DOI: 10.13039/100019336, name: Program for Education and Research in Biotechnology, California State University
- Language
- English
- Date published
- 12/07/2023
- Academic Unit
- Occupational and Environmental Health; Iowa Superfund Research Program
- Record Identifier
- 9984530376802771
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