ArticleEnvironmental health perspectives2011
Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity.
Article in Environmental health perspectives, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 48 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
- Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence.Journal of toxicology and environmental health. Part B, Critical reviews · 2018Pooled it
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- Early Life PBDE Flame Retardant Exposures Cause Neurobehavioral Alterations in Fish That Persist into Adulthood and Vary by Sex and Route of Exposure.Environmental science & technology · 2025Article
- Cumulative risk assessment as the pathway to public health protection for behavioral neurotoxicity.Neurotoxicology · 2025Review
- Predicted versus observed activity of PCB mixtures toward the ryanodine receptor.Neurotoxicology · 2024Article
- Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food.EFSA journal. European Food Safety Authority · 2024Article
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- Gene×environment interactions in autism spectrum disorders.Current topics in developmental biology · 2023Review
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- Persistent organic pollutants at the synapse: Shared phenotypes and converging mechanisms of developmental neurotoxicity.Developmental neurobiology · 2021Review
- Non-dioxin-like polychlorinated biphenyl neurotoxic equivalents found in environmental and human samples.Regulatory toxicology and pharmacology : RTP · 2021Article
- Environmental neurotoxic pollutants: review.Environmental science and pollution research international · 2020Review
- Polybrominated diphenyl ether (PBDE) and poly- and perfluoroalkyl substance (PFAS) exposures during pregnancy and maternal depression.Environment international · 2020Article
- Neurotoxicity of polychlorinated biphenyls and related organohalogens.Acta neuropathologica · 2019Review
- Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- A Prospective Study of Environmental Exposures and Early Biomarkers in Autism Spectrum Disorder: Design, Protocols, and Preliminary Data from the MARBLES Study.Environmental health perspectives · 2018Article
- The chemical cue tetrabromopyrrole induces rapid cellular stress and mortality in phytoplankton.Scientific reports · 2018Article
- Organohalogens Naturally Biosynthesized in Marine Environments and Produced as Disinfection Byproducts Alter Sarco/Endoplasmic Reticulum CaEnvironmental science & technology · 2018Article
- From the Cover: BDE-47 and BDE-49 Inhibit Axonal Growth in Primary Rat Hippocampal Neuron-Glia Co-Cultures via Ryanodine Receptor-Dependent Mechanisms.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundPolybrominated diphenyl ethers (PBDEs) are widely used flame retardants that bioaccumulate in human tissues. Their neurotoxicity involves dysregulation of calcium ion (Ca(2+))signaling; however, specific mechanisms have yet to be defined.
objectiveWe aimed to define the structure-activity relationship (SAR) for PBDEs and their metabolites toward ryanodine receptors type 1 (RyR1) and type 2 (RyR2) and to determine whether it predicts neurotoxicity.
methodsWe analyzed [3H]ryanodine binding, microsomal Ca(2+) fluxes, cellular measurements of Ca(2+) homeostasis, and neurotoxicity to define mechanisms and specificity of PBDE-mediated Ca(2+) dysregulation.
resultsPBDEs possessing two ortho-bromine substituents and lacking at least one para-bromine substituent (e.g., BDE-49) activate RyR1 and RyR2 with greater efficacy than corresponding congeners with two para-bromine substitutions (e.g., BDE-47). Addition of a methoxy group in the free para position reduces the activity of parent PBDEs. The hydroxylated BDEs 6-OH-BDE-47 and 4´-OH-BDE-49 are biphasic RyR modulators. Pretreatment of HEK293 cells (derived from human embryonic kidney cells) expressing either RyR1 or RyR2 with BDE-49 (250 nM) sensitized Ca2+ flux triggered by RyR agonists, whereas BDE-47 (250 nM) had negligible activity. The divergent activity of BDE-49, BDE-47, and 6-OH-BDE-47 toward RyRs predicted neurotoxicity in cultures of cortical neurons.
conclusionsWe found that PBDEs are potent modulators of RyR1 and RyR2. A stringent SAR at the ortho and para position determined whether a congener enhanced, inhibited, or exerted nonmonotonic actions toward RyRs. These results identify a convergent molecular target of PBDEs previously identified for noncoplanar polychlorinated biphenyls (PCBs) that predicts their cellular neurotoxicity and therefore could be a useful tool in risk assessment of PBDEs and related compounds.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.