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Cited by 136Toxic Organic Pollutants ImpactNeuroscience and Neuropharmacology ResearchEffects and risks of endocrine disrupting chemicals

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PCB-95 Promotes Dendritic Growth via Ryanodine Receptor–Dependent Mechanisms

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Wayman, Gary A., Yang, Dongren, Bose, Diptiman D., Lesiak, Adam, Ledoux, Veronica, Bruun, Donald, Pessah, Isaac N., Lein, Pamela J.·2012·Environmental Health Perspectives
DOI 10.1289/ehp.1104832PMC PMC3404670
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Abstract

Background: Aroclor 1254 (A1254) interferes with normal dendritic growth and plasticity in the developing rodent brain, but the mechanism(s) mediating this effect have yet to be established. Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) enhance the activity of ryanodine receptor (RyR) calcium ion (Ca2+) channels, which play a central role in regulating the spatiotemporal dynamics of intracellular Ca2+ signaling. Ca2+ signaling is a predominant factor in shaping dendritic arbors, but whether PCB potentiation of RyR activity influences dendritic growth is not known. Objective: We determined whether RyR activity is required for PCB effects on dendritic growth. Methods and Results: Golgi analysis of hippocampi from weanling rats confirmed that developmental exposure via the maternal diet to NDL PCB-95 (2,2´,3,5´6-pentachlorobiphenyl), a potent RyR potentiator, phenocopies the dendrite-promoting effects of A1254. Dendritic growth in dissociated cultures of primary hippocampal neurons and in hippocampal slice cultures is similarly enhanced by PCB-95 but not by PCB-66 (2,3,4´,4-tetrachlorobiphenyl), a congener with negligible effects on RyR activity. The dendrite-promoting effects of PCB-95 are evident at concentrations as low as 2 pM and are inhibited by either pharmacologic blockade or siRNA knockdown of RyRs. Conclusions: Our findings demonstrate that environmentally relevant levels of NDL PCBs modulate neuronal connectivity via RyR-dependent effects on dendritic arborization. In addition, these findings identify RyR channel dysregulation as a novel mechanism contributing to dysmorphic dendritogenesis associated with heritable and environmentally triggered neurodevelopmental disorders.

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Figure 1 PCBs enhance dendritic growth in vivo. (A) Representative camera lucida images and (B) Sholl analyses of the basilar dendritic arbor of Golgi-stained CA1 pyramidal neurons from PD31 weanling rats exposed throughout gestation and lactation to vehicle or A1254 in the maternal diet (n = 45 neurons per group). (C) Sholl analyses of the basilar dendritic arbor of Golgi-stained pyramidal neurons from PD38 weanling rats exposed throughout gestation and lactation to vehicle or PCB-95 in the maternal diet (n = 60 neurons per group). *p < 0.05 relative to vehicle control.
Figure 1 PCBs enhance dendritic growth in vivo. (A) Representative camera lucida images and (B) Sholl analyses of the basilar dendritic arbor of Golgi-stained CA1 pyramidal neurons from PD31 weanling rats exposed throughout gestation and lactation to vehicle or A1254 in the maternal diet (n = 45 neurons per group). (C) Sholl analyses of the basilar dendritic arbor of Golgi-stained pyramidal neurons from PD38 weanling rats exposed throughout gestation and lactation to vehicle or PCB-95 in the maternal diet (n = 60 neurons per group). *p < 0.05 relative to vehicle control.CC0 · PubMed Central
Figure 2 RyR expression in cultured hippocampal neurons. (A) Representative blots and densitometric analyses of membrane fractions from rat hippocampal cultures harvested at 2, 7, and 12 DIV, and probed with RyR1- or RyR2-selective monoclonal antibodies and a monoclonal antibody for α-tubulin. Densitometric data are presented as the pixel intensity of the RyR-immunoreactive band normalized to the pixel intensity of the α-tubulin immunoreactive band in the same sample. Expression of RyR1 and RyR2 at 7 and 12 DIV was verified in cultures derived from two separate dissections. “Brain” indicates membranes prepared from adult (2- to 4-month-old) mouse hippocampi. (B) Fluorescent photomicrograph illustrating subcellular localization of RyR immunoreactivity (red) and phalloidin reactivity (green) in a 21-DIV mouse hippocampal neuron. Bar = 5 μM.
Figure 2 RyR expression in cultured hippocampal neurons. (A) Representative blots and densitometric analyses of membrane fractions from rat hippocampal cultures harvested at 2, 7, and 12 DIV, and probed with RyR1- or RyR2-selective monoclonal antibodies and a monoclonal antibody for α-tubulin. Densitometric data are presented as the pixel intensity of the RyR-immunoreactive band normalized to the pixel intensity of the α-tubulin immunoreactive band in the same sample. Expression of RyR1 and RyR2 at 7 and 12 DIV was verified in cultures derived from two separate dissections. “Brain” indicates membranes prepared from adult (2- to 4-month-old) mouse hippocampi. (B) Fluorescent photomicrograph illustrating subcellular localization of RyR immunoreactivity (red) and phalloidin reactivity (green) in a 21-DIV mouse hippocampal neuron. Bar = 5 μM.CC0 · PubMed Central
Figure 3 PCB-95 enhances dendritic growth in cultured hippocampal neurons. (A) Representative photomicrographs of 9-DIV hippocampal neurons expressing MAP2B-EGFP after 48-hr exposure to vehicle (control) or PCB-95 (2 nM). (B) Concentration-dependent effect of PCB-95 on dendritic length and branching (determined as the number of dendritic termini per neuron) in GFP+ neurons. Data presented as mean ± SE (n = 30 neurons from three to four independent cultures per group). #p < 0.001 relative to vehicle control.
Figure 3 PCB-95 enhances dendritic growth in cultured hippocampal neurons. (A) Representative photomicrographs of 9-DIV hippocampal neurons expressing MAP2B-EGFP after 48-hr exposure to vehicle (control) or PCB-95 (2 nM). (B) Concentration-dependent effect of PCB-95 on dendritic length and branching (determined as the number of dendritic termini per neuron) in GFP+ neurons. Data presented as mean ± SE (n = 30 neurons from three to four independent cultures per group). #p < 0.001 relative to vehicle control.CC0 · PubMed Central
Figure 4 In vitro PCB-induced dendritic growth requires RyR activity. PCB-95 (200 nM), but not PCB-66 (200 nM), increased dendritic length (A) and branching (B) in primary cultures of dissociated hippocampal neurons (9 DIV), and this effect was blocked by the RyR antagonist FLA365 (10 µM) (–, without, +, with FLA365). (C) PCB-95, but not PCB-66, significantly enhanced dendritic arborization of TFP+ neurons in hippocampal slice cultures, and this effect was blocked by FLA365. Data presented as mean ± SE (n = 35–50 neurons from three to four independent cultures per group). *p < 0.05, **p < 0.01, and #p < 0.001 relative to vehicle control. †p < 0.01 relative to PCB-95 in the absence of FLA365.
Figure 4 In vitro PCB-induced dendritic growth requires RyR activity. PCB-95 (200 nM), but not PCB-66 (200 nM), increased dendritic length (A) and branching (B) in primary cultures of dissociated hippocampal neurons (9 DIV), and this effect was blocked by the RyR antagonist FLA365 (10 µM) (–, without, +, with FLA365). (C) PCB-95, but not PCB-66, significantly enhanced dendritic arborization of TFP+ neurons in hippocampal slice cultures, and this effect was blocked by FLA365. Data presented as mean ± SE (n = 35–50 neurons from three to four independent cultures per group). *p < 0.05, **p < 0.01, and #p < 0.001 relative to vehicle control. †p < 0.01 relative to PCB-95 in the absence of FLA365.CC0 · PubMed Central
Figure 5 RyR-specific siRNA blocks PCB-induced dendritic growth in vitro. (A) Representative photomicrographs of 9-DIV hippocampal neurons transfected with MAP2B-EGFP alone or in combination with RyR siRNA before 48-hr treatment with vehicle or PCB-95 (200 nM). Expression of RyR1- or RyR2-specific siRNA, but not scrambled siRNA, blocked PCB-95 effects on dendritic length (B) and branching (C). Data presented as mean ± SE (n = 30 neurons from three independent cultures per group). **p < 0.01 relative to vehicle control. ‡p < 0.001 relative to untransfected (control) PCB-95–treated hippocampal neurons.
Figure 5 RyR-specific siRNA blocks PCB-induced dendritic growth in vitro. (A) Representative photomicrographs of 9-DIV hippocampal neurons transfected with MAP2B-EGFP alone or in combination with RyR siRNA before 48-hr treatment with vehicle or PCB-95 (200 nM). Expression of RyR1- or RyR2-specific siRNA, but not scrambled siRNA, blocked PCB-95 effects on dendritic length (B) and branching (C). Data presented as mean ± SE (n = 30 neurons from three independent cultures per group). **p < 0.01 relative to vehicle control. ‡p < 0.001 relative to untransfected (control) PCB-95–treated hippocampal neurons.CC0 · PubMed Central

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Metadata

Authors
Wayman, G. A., Yang, D., Bose, D. D., Lesiak, A., Ledoux, V., Bruun, D., Pessah, I. N., & Lein, P. J.
Affiliations
  • Washington State University (US)
  • University of California, Davis (US)
  • Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington, USA
  • Oregon Health & Science University (US)
Corresponding author
Lein, Pamela J.
ORCID
Venue
Environmental Health Perspectives
Publisher
American Chemical Society (ACS)
Published
2012-04-25
Volume
120
Issue
7
Pages
997-1002
ISSN
  • 0091-6765 (ISSN-L)
  • 1552-9924
DOI
10.1289/ehp.1104832
PMC
PMC3404670
OpenAlex
W2057153652
Cited by
136
References
59
Citations by year
2026: 7 · 2025: 2 · 2024: 6 · 2023: 10 · 2022: 11 · 2021: 6 · 2020: 12 · 2019: 14 · 2018: 12 · 2017: 12 · 2016: 8 · 2015: 3 · 2014: 12 · 2013: 15 · 2012: 5
FWCI
7.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Environmental Health Perspectives (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Environmental Protection Agency (R-829388, R-833292, R01 ES014901, ES011269)
  • Hope for Depression Research Foundation
  • National Institutes of Health (ES04699, ES014901, ES011269)
  • National Institute of Mental Health (R01MH086032)
  • National Institute of Environmental Health Sciences (P42-ES-04699, P42ES004699, R01ES017425, P01ES011269, R01ES014901, T32ES007060)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Keywords
PCB 95, non-dioxin-like polychlorinated biphenyls, ryanodine receptor, dendritic growth, dendritic branching, calcium signaling, Aroclor 1254, hippocampal neurons, neurodevelopmental disorders, developmental neurotoxicity, PCB congeners, maternal dietary exposure
MeSH terms
Animals, Cells, Cultured, Dendrites, Hippocampus, Neurons, Polychlorinated Biphenyls, Ryanodine Receptor Calcium Release Channel, Rats

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