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.

doi:10.1093/toxsci/kfw259

Cited by 20 publications

(31 citation statements)

References 73 publications

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“…Cells were fixed with 4% paraformaldehyde for 20 min on DIV 9 and immunostained as described (Chen et al, 2017a). Briefly, after fixation, cells were washed with phosphate buffered saline (PBS; 3.6 mM disodium phosphate, 1.4 mM monosodium phosphate, 150 mM sodium chloride, pH 7.2) and permeabilized with 0.1% Triton X-100 (Sigma-Aldrich) in PBS for 5 min, incubated in blocking buffer containing 10% bovine serum albumin (Sigma-Aldrich) and 5% goat serum (Vector Laboratories, Burlingame, California) in PBS for 1 h and coincubated overnight at 4 C with antibodies targeting MAP2B (1:1000, AB5622, Millipore, Burlington, Massachusetts) to label neurons and glial fibrillary acidic protein (GFAP, 1:1000, no.…”

Section: Immunocytochemistrymentioning

confidence: 99%

Sex-Dependent Effects of 2,2′,3,5′,6-Pentachlorobiphenyl on Dendritic Arborization of Primary Mouse Neurons

Keil

Sethi

Lein

2018

Toxicological Sciences

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Early life exposures to environmental contaminants are implicated in the pathogenesis of many neurodevelopmental disorders (NDDs). These disorders often display sex biases, but whether environmental neurotoxicants act in a sex-dependent manner to modify neurodevelopment is largely unknown. Since altered dendritic morphology is associated with many NDDs, we tested the hypothesis that male and female primary mouse neurons are differentially susceptible to the dendrite-promoting activity of 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95). Hippocampal and cortical neuron-glia co-cultures were exposed to vehicle (0.1% dimethylsulfoxide) or PCB 95 (100 fM–1 μM) from day in vitro 7–9. As determined by Sholl analysis, PCB 95-enhanced dendritic growth in female but not male hippocampal and cortical neurons. In contrast, both male and female neurons responded to bicuculline with increased dendritic complexity. Detailed morphometric analyses confirmed that PCB 95 effects on the number and length of primary and nonprimary dendrites varied depending on sex, brain region and PCB concentration, and that female neurons responded more consistently with increased dendritic growth and at lower concentrations of PCB 95 than their male counterparts. Exposure to PCB 95 did not alter cell viability or the ratio of neurons to glia in cultures of either sex. These results demonstrate that cultured female mouse hippocampal and cortical neurons are more sensitive than male neurons to the dendrite-promoting activity of PCB 95, and suggest that mechanisms underlying PCB 95-induced dendritic growth are sex-dependent. These data highlight the importance of sex in neuronal responses to environmental neurotoxicants.

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Section: Immunocytochemistrymentioning

confidence: 99%

Sex-Dependent Effects of 2,2′,3,5′,6-Pentachlorobiphenyl on Dendritic Arborization of Primary Mouse Neurons

Keil

Sethi

Lein

2018

Toxicological Sciences

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“…All these findings argue against a single mechanism of action underlying the developmental neurotoxicity of brominated or organophosphate flame retardants, e.g. thyroid disruption or actions at ryanodine receptors (Chen et al 2017). …”

Section: Discussionmentioning

confidence: 99%

Brominated and organophosphate flame retardants target different neurodevelopmental stages, characterized with embryonic neural stem cells and neuronotypic PC12 cells

et al. 2017

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In addition to their activity as endocrine disruptors, brominated and organophosphate flame retardants are suspected to be developmental neurotoxicants, although identifying their specific mechanisms for that activity has been elusive. In the current study, we evaluated the effects of several flame retardants on neurodifferentiation using two in vitro models that assess distinct “decision nodes” in neural cell development: embryonic rat neural stem cells (NSCs), which evaluate the origination of neurons and glia from precursors, and rat neuronotypic PC12 cells, which characterize a later stage where cells committed to a neuronal phenotype undergo neurite outgrowth and neurotransmitter specification. In NSCs, both brominated and organophosphate flame retardants diverted the phenotype in favor of glia and away from formation of neurons, leading to an increased glia/neuron ratio, a common hallmark of the in vivo effects of neurotoxicants. For this early decision node, the brominated flame retardants were far more potent than the organophosphates. In PC12 cells, the brominated flame retardants were far less effective, whereas tris (1,3-dichloro-2-propyl) phosphate, an organophosphate, was more effective. Thus, the two classes of flame retardants differentially impact the two distinct vulnerable periods of neurodifferentiation. Furthermore, the effects on neurodifferentiation were separable from outright cytotoxicity, an important requirement in establishing a specific effect of these agents on neural cell development. These results reinforce the likelihood that flame retardants act as developmental neurotoxicants via direct effects on neural cell differentiation, over and above other activities that can impact nervous system development, such as endocrine disruption.

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“…Several studies have indicated that the neurotoxic activities of NDL PCBs, PBDEs and their hydroxylated metabolites are additive, and that a dose addition model for estimating risk may be appropriate [34,71]. However, unlike NDL PCBs, which selectively alter dendritic complexity, neuronal-glial co-cultures from rat hippocampus exposed to BDE-47 or BDE-49 exhibited delayed neuronal polarization resulting in significant inhibition of axonal outgrowth during 1 3 the first few days in vitro, but no later influences on dendritic complexity [24]. Interestingly, the axon inhibitory effects of these PBDEs were blocked by pharmacological antagonism of RyR or siRNA knockdown of RyR2, indicating common molecular mechanisms affecting two distinct developmental processes of neuronal connectivity.…”

Section: Are Pcbs the Tip Of The Ndl-pop Iceberg?mentioning

confidence: 99%

Neurotoxicity of polychlorinated biphenyls and related organohalogens

et al. 2019

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Halogenated organic compounds are pervasive in natural and built environments. Despite restrictions on the production of many of these compounds in most parts of the world through the Stockholm Convention on Persistent Organic Pollutants (POPs), many "legacy" compounds, including polychlorinated biphenyls (PCBs), are routinely detected in human tissues where they continue to pose significant health risks to highly exposed and susceptible populations. A major concern is developmental neurotoxicity, although impacts on neurodegenerative outcomes have also been noted. Here, we review human studies of prenatal and adult exposures to PCBs and describe the state of knowledge regarding outcomes across domains related to cognition (e.g., IQ, language, memory, learning), attention, behavioral regulation and executive function, and social behavior, including traits related to attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). We also review current understanding of molecular mechanisms underpinning these associations, with a focus on dopaminergic neurotransmission, thyroid hormone disruption, calcium dyshomeostasis, and oxidative stress. Finally, we briefly consider contemporary sources of organohalogens that may pose human health risks via mechanisms of neurotoxicity common to those ascribed to PCBs.

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BDE-47 and BDE-49 Inhibit Axonal Growth in Primary Rat Hippocampal Neuron-Glia Co-Cultures via Ryanodine Receptor-Dependent Mechanisms

Cited by 20 publications

References 73 publications

Sex-Dependent Effects of 2,2′,3,5′,6-Pentachlorobiphenyl on Dendritic Arborization of Primary Mouse Neurons

Sex-Dependent Effects of 2,2′,3,5′,6-Pentachlorobiphenyl on Dendritic Arborization of Primary Mouse Neurons

Brominated and organophosphate flame retardants target different neurodevelopmental stages, characterized with embryonic neural stem cells and neuronotypic PC12 cells

Neurotoxicity of polychlorinated biphenyls and related organohalogens

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