title: PCB 136 atropselectively alters morphometric and functional parameters of neuronal connectivity in cultured rat hippocampal neurons via ryanodine receptor-dependent mechanisms.
abstract: We recently demonstrated that polychlorinated biphenyl (PCB) congeners with multiple ortho chlorine substitutions sensitize ryanodine receptors (RyRs), and this activity promotes Ca²⁺-dependent dendritic growth in cultured neurons. Many ortho-substituted congeners display axial chirality, and we previously reported that the chiral congener PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl) atropselectively sensitizes RyRs. Here, we test the hypothesis that PCB 136 atropisomers differentially alter dendritic growth and other parameters of neuronal connectivity influenced by RyR activity. (-)-PCB 136, which potently sensitizes RyRs, enhances dendritic growth in primary cultures of rat hippocampal neurons, whereas (+)-PCB 136, which lacks RyR activity, has no effect on dendritic growth. The dendrite-promoting activity of (-)-PCB 136 is observed at concentrations ranging from 0.1 to 100 nM and is blocked by pharmacologic RyR antagonism. Neither atropisomer alters axonal growth or cell viability. Quantification of PCB 136 atropisomers in hippocampal cultures indicates that atropselective effects on dendritic growth are not due to differential partitioning of atropisomers into cultured cells. Imaging of hippocampal neurons loaded with Ca²⁺-sensitive dye demonstrates that (-)-PCB 136 but not (+)-PCB 136 increases the frequency of spontaneous Ca²⁺ oscillations. Similarly, (-)-PCB 136 but not (+)-PCB 136 increases the activity of hippocampal neurons plated on microelectrode arrays. These data support the hypothesis that atropselective effects on RyR activity translate into atropselective effects of PCB 136 atropisomers on neuronal connectivity, and suggest that the variable atropisomeric enrichment of chiral PCBs observed in the human population may be a significant determinant of individual susceptibility for adverse neurodevelopmental outcomes following PCB exposure.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616.
authors.forename: Dongren
authors.initials: D
authors.lastname: Yang
authors.forename: Izabela
authors.initials: I
authors.lastname: Kania-Korwel
authors.forename: Atefeh
authors.initials: A
authors.lastname: Ghogha
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Marianna
authors.initials: M
authors.lastname: Stamou
authors.forename: Diptiman D
authors.initials: DD
authors.lastname: Bose
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
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; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D020439:Growth Cones / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D004785:Environmental Pollutants; D019837:Ryanodine Receptor Calcium Release Channel; D011078:Polychlorinated Biphenyls; C010498:2,3,6,2',3',6'-hexachlorobiphenyl
keywords: atropselectivity; chirality; dendritic growth; developmental neurotoxicity; neuronal connectivity; polychlorinated biphenyls; ryanodine receptor