title: From the Cover: 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 20 pM 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.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Streifel
authors.affiliation: Department of Pharmacology, School of Medicine, University of California-Davis, Davis, California 95616.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Dongren
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Linley
authors.initials: L
authors.lastname: Mangini
authors.affiliation: Department of Pharmacology, School of Medicine, University of California-Davis, Davis, California 95616.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000071446:Neuronal Outgrowth / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*
chemical_list: D055768:Halogenated Diphenyl Ethers; D019837:Ryanodine Receptor Calcium Release Channel; C511295:2,2',4,4'-tetrabromodiphenyl ether; C572625:2,2',4,5'-tetrabromodiphenyl ether
keywords: PBDE; axon; calcium signaling; developmental neurotoxicity; neuronal morphogenesis; ryanodine receptor.