BDE-47 and BDE-49 inhibit axonal growth in primary rat hippocampal neuron-glia co-cultures via ryanodine receptor-dependent mechanisms

Hao Chen, Karin M. Streifel, Vikrant Singh, Dongren Yang, Linley Mangini, Heike Wulff, Pamela J Lein

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with adverse neurodevelopmental outcomes in children and preclinical models; however, the mechanisms by which PBDEs cause developmental neurotoxicity remain speculative. The structural similarity between PBDEs and nondioxin-like (NDL) polychlorinated biphenyls (PCBs) suggests shared toxicological properties. Consistent with this, both NDL PCBs and PBDEs have been shown to stabilize ryanodine receptors (RyRs) in the open configuration. NDL PCB effects on RyR activity are causally linked to increased dendritic arborization, but whether PBDEs similarly enhance dendritic growth is not known. In this study, we quantified the effects of individual PBDE congeners on not only dendritic but also axonal growth since both are regulated by RyR-dependent mechanisms, and both are critical determinants of neuronal connectivity. Neuronal-glial co-cultures dissociated from the neonatal rat hippocampus were exposed to BDE-47 or BDE-49 in the culture medium. At concentrations ranging from 20pM to 2 μM, neither PBDE congener altered dendritic arborization. In contrast, at concentrations ≥ 200 pM, both congeners delayed neuronal polarization resulting in significant inhibition of axonal outgrowth during the first few days in vitro. The axon inhibitory effects of these PBDE congeners occurred independent of cytotoxicity, and were blocked by pharmacological antagonism of RyR or siRNA knockdown of RyR2. These results demonstrate that the molecular and cellular mechanisms by which PBDEs interfere with neurodevelopment overlap with but are distinct from those of NDL PCBs, and suggest that altered patterns of neuronal connectivity may contribute to the developmental neurotoxicity of PBDEs.

Original languageEnglish (US)
Article numberkfw259
Pages (from-to)375-386
Number of pages12
JournalToxicological Sciences
Volume156
Issue number2
DOIs
StatePublished - Apr 1 2017

Fingerprint

Halogenated Diphenyl Ethers
Ryanodine Receptor Calcium Release Channel
Coculture Techniques
Neuroglia
Neurons
Rats
Growth
Polychlorinated Biphenyls
Neuronal Plasticity
2,2',4,4'-tetrabromodiphenyl ether
2,2',4,5'-tetrabromodiphenyl ether
Cytotoxicity
Toxicology
Small Interfering RNA
Axons
Culture Media
Hippocampus

Keywords

  • Axon
  • Calcium signaling
  • Developmental neurotoxicity
  • Neuronal morphogenesis
  • PBDE
  • Ryanodine receptor

ASJC Scopus subject areas

  • Toxicology

Cite this

BDE-47 and BDE-49 inhibit axonal growth in primary rat hippocampal neuron-glia co-cultures via ryanodine receptor-dependent mechanisms. / Chen, Hao; Streifel, Karin M.; Singh, Vikrant; Yang, Dongren; Mangini, Linley; Wulff, Heike; Lein, Pamela J.

In: Toxicological Sciences, Vol. 156, No. 2, kfw259, 01.04.2017, p. 375-386.

Research output: Contribution to journalArticle

Chen, Hao ; Streifel, Karin M. ; Singh, Vikrant ; Yang, Dongren ; Mangini, Linley ; Wulff, Heike ; Lein, Pamela J. / BDE-47 and BDE-49 inhibit axonal growth in primary rat hippocampal neuron-glia co-cultures via ryanodine receptor-dependent mechanisms. In: Toxicological Sciences. 2017 ; Vol. 156, No. 2. pp. 375-386.
@article{1ade95b54331467798a594011454632e,
title = "BDE-47 and BDE-49 inhibit axonal growth in primary rat hippocampal neuron-glia co-cultures via ryanodine receptor-dependent mechanisms",
abstract = "Polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with adverse neurodevelopmental outcomes in children and preclinical models; however, the mechanisms by which PBDEs cause developmental neurotoxicity remain speculative. The structural similarity between PBDEs and nondioxin-like (NDL) polychlorinated biphenyls (PCBs) suggests shared toxicological properties. Consistent with this, both NDL PCBs and PBDEs have been shown to stabilize ryanodine receptors (RyRs) in the open configuration. NDL PCB effects on RyR activity are causally linked to increased dendritic arborization, but whether PBDEs similarly enhance dendritic growth is not known. In this study, we quantified the effects of individual PBDE congeners on not only dendritic but also axonal growth since both are regulated by RyR-dependent mechanisms, and both are critical determinants of neuronal connectivity. Neuronal-glial co-cultures dissociated from the neonatal rat hippocampus were exposed to BDE-47 or BDE-49 in the culture medium. At concentrations ranging from 20pM to 2 μM, neither PBDE congener altered dendritic arborization. In contrast, at concentrations ≥ 200 pM, both congeners delayed neuronal polarization resulting in significant inhibition of axonal outgrowth during the first few days in vitro. The axon inhibitory effects of these PBDE congeners occurred independent of cytotoxicity, and were blocked by pharmacological antagonism of RyR or siRNA knockdown of RyR2. These results demonstrate that the molecular and cellular mechanisms by which PBDEs interfere with neurodevelopment overlap with but are distinct from those of NDL PCBs, and suggest that altered patterns of neuronal connectivity may contribute to the developmental neurotoxicity of PBDEs.",
keywords = "Axon, Calcium signaling, Developmental neurotoxicity, Neuronal morphogenesis, PBDE, Ryanodine receptor",
author = "Hao Chen and Streifel, {Karin M.} and Vikrant Singh and Dongren Yang and Linley Mangini and Heike Wulff and Lein, {Pamela J}",
year = "2017",
month = "4",
day = "1",
doi = "10.1093/toxsci/kfw259",
language = "English (US)",
volume = "156",
pages = "375--386",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - BDE-47 and BDE-49 inhibit axonal growth in primary rat hippocampal neuron-glia co-cultures via ryanodine receptor-dependent mechanisms

AU - Chen, Hao

AU - Streifel, Karin M.

AU - Singh, Vikrant

AU - Yang, Dongren

AU - Mangini, Linley

AU - Wulff, Heike

AU - Lein, Pamela J

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with adverse neurodevelopmental outcomes in children and preclinical models; however, the mechanisms by which PBDEs cause developmental neurotoxicity remain speculative. The structural similarity between PBDEs and nondioxin-like (NDL) polychlorinated biphenyls (PCBs) suggests shared toxicological properties. Consistent with this, both NDL PCBs and PBDEs have been shown to stabilize ryanodine receptors (RyRs) in the open configuration. NDL PCB effects on RyR activity are causally linked to increased dendritic arborization, but whether PBDEs similarly enhance dendritic growth is not known. In this study, we quantified the effects of individual PBDE congeners on not only dendritic but also axonal growth since both are regulated by RyR-dependent mechanisms, and both are critical determinants of neuronal connectivity. Neuronal-glial co-cultures dissociated from the neonatal rat hippocampus were exposed to BDE-47 or BDE-49 in the culture medium. At concentrations ranging from 20pM to 2 μM, neither PBDE congener altered dendritic arborization. In contrast, at concentrations ≥ 200 pM, both congeners delayed neuronal polarization resulting in significant inhibition of axonal outgrowth during the first few days in vitro. The axon inhibitory effects of these PBDE congeners occurred independent of cytotoxicity, and were blocked by pharmacological antagonism of RyR or siRNA knockdown of RyR2. These results demonstrate that the molecular and cellular mechanisms by which PBDEs interfere with neurodevelopment overlap with but are distinct from those of NDL PCBs, and suggest that altered patterns of neuronal connectivity may contribute to the developmental neurotoxicity of PBDEs.

AB - Polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with adverse neurodevelopmental outcomes in children and preclinical models; however, the mechanisms by which PBDEs cause developmental neurotoxicity remain speculative. The structural similarity between PBDEs and nondioxin-like (NDL) polychlorinated biphenyls (PCBs) suggests shared toxicological properties. Consistent with this, both NDL PCBs and PBDEs have been shown to stabilize ryanodine receptors (RyRs) in the open configuration. NDL PCB effects on RyR activity are causally linked to increased dendritic arborization, but whether PBDEs similarly enhance dendritic growth is not known. In this study, we quantified the effects of individual PBDE congeners on not only dendritic but also axonal growth since both are regulated by RyR-dependent mechanisms, and both are critical determinants of neuronal connectivity. Neuronal-glial co-cultures dissociated from the neonatal rat hippocampus were exposed to BDE-47 or BDE-49 in the culture medium. At concentrations ranging from 20pM to 2 μM, neither PBDE congener altered dendritic arborization. In contrast, at concentrations ≥ 200 pM, both congeners delayed neuronal polarization resulting in significant inhibition of axonal outgrowth during the first few days in vitro. The axon inhibitory effects of these PBDE congeners occurred independent of cytotoxicity, and were blocked by pharmacological antagonism of RyR or siRNA knockdown of RyR2. These results demonstrate that the molecular and cellular mechanisms by which PBDEs interfere with neurodevelopment overlap with but are distinct from those of NDL PCBs, and suggest that altered patterns of neuronal connectivity may contribute to the developmental neurotoxicity of PBDEs.

KW - Axon

KW - Calcium signaling

KW - Developmental neurotoxicity

KW - Neuronal morphogenesis

KW - PBDE

KW - Ryanodine receptor

UR - http://www.scopus.com/inward/record.url?scp=85017169715&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017169715&partnerID=8YFLogxK

U2 - 10.1093/toxsci/kfw259

DO - 10.1093/toxsci/kfw259

M3 - Article

C2 - 28003438

AN - SCOPUS:85017169715

VL - 156

SP - 375

EP - 386

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 2

M1 - kfw259

ER -