Journal article
PCB 136 Atropselectively Alters Morphometric and Functional Parameters of Neuronal Connectivity in Cultured Rat Hippocampal Neurons via Ryanodine Receptor-Dependent Mechanisms
Toxicological sciences, Vol.138(2), pp.379-392
04/01/2014
DOI: 10.1093/toxsci/kft334
PMCID: PMC4007107
PMID: 24385416
Abstract
Editor's Highlight:
Polychlorinated biphenyls (PCBs) have been banned since 1977 in the U.S. With over 200 different congeners based on the multiple positions for chlorination, PCBs exhibit a wide range of health effects. Some of the congeners that appear to be more persistent in human tissues are chiral. As if having over 200 different combinations of chlorination wasn't sufficiently complex, these chiral congeners, termed atropisomers, display unique neuronal effects. As shown by Yang and coworkers, one such atropisomer, (-)PCB 136 (2,2′, 3,3′, 6,6′, hexachlorobiphenyl), promotes dendritic arborization in hippocampal neurons, while its (+) atropisomer does not. These actions appear to be mediated by the ryanodine receptor. The atropisomer-selective effects add a new layer of complexity to our understanding of PCB congeners and their effects on the brain. Given the past widespread use of these compounds, their ability to persist in human tissue, and the demonstrable effects on neuronal function, it would be wise to further examine the effects of PCBs in neurodevelopmental and neurodegenerative diseases. —Gary W. Miller
We recently demonstrated that polychlorinated biphenyl (PCB) congeners with multiple
ortho
chlorine substitutions sensitize ryanodine receptors (RyRs), and this activity promotes Ca
2+
-dependent dendritic growth in cultured neurons. Many
ortho
-substituted congeners display axial chirality, and we previously reported that the chiral congener PCB 136 (2,2′,3,3′,6,6′-hexachlorobiphenyl) atropselectively sensitizes RyRs. Here, we test the hypothesis that PCB 136 atropisomers differentially alter dendritic growth and other parameters of neuronal connectivity influenced by RyR activity. (−)-PCB 136, which potently sensitizes RyRs, enhances dendritic growth in primary cultures of rat hippocampal neurons, whereas (+)-PCB 136, which lacks RyR activity, has no effect on dendritic growth. The dendrite-promoting activity of (−)-PCB 136 is observed at concentrations ranging from 0.1 to 100nM and is blocked by pharmacologic RyR antagonism. Neither atropisomer alters axonal growth or cell viability. Quantification of PCB 136 atropisomers in hippocampal cultures indicates that atropselective effects on dendritic growth are not due to differential partitioning of atropisomers into cultured cells. Imaging of hippocampal neurons loaded with Ca
2+
-sensitive dye demonstrates that (−)-PCB 136 but not (+)-PCB 136 increases the frequency of spontaneous Ca
2+
oscillations. Similarly, (−)-PCB 136 but not (+)-PCB 136 increases the activity of hippocampal neurons plated on microelectrode arrays. These data support the hypothesis that atropselective effects on RyR activity translate into atropselective effects of PCB 136 atropisomers on neuronal connectivity, and suggest that the variable atropisomeric enrichment of chiral PCBs observed in the human population may be a significant determinant of individual susceptibility for adverse neurodevelopmental outcomes following PCB exposure.
Details
- Title: Subtitle
- PCB 136 Atropselectively Alters Morphometric and Functional Parameters of Neuronal Connectivity in Cultured Rat Hippocampal Neurons via Ryanodine Receptor-Dependent Mechanisms
- Creators
- Dongren Yang - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616Izabela Kania-Korwel - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242Atefeh Ghogha - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616Hao Chen - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616Marianna Stamou - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616Diptiman D Bose - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616Isaac N Pessah - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242Pamela J Lein - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616
- Resource Type
- Journal article
- Publication Details
- Toxicological sciences, Vol.138(2), pp.379-392
- DOI
- 10.1093/toxsci/kft334
- PMID
- 24385416
- PMCID
- PMC4007107
- NLM abbreviation
- Toxicol Sci
- ISSN
- 1096-6080
- eISSN
- 1096-0929
- Publisher
- Oxford University Press
- Comment
- This article was the Editor’s Highlight in the April 2014 issue of Toxicological Sciences.
- Language
- English
- Date published
- 04/01/2014
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984000924602771
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