title: Structure-activity relationship of non-coplanar polychlorinated biphenyls toward skeletal muscle ryanodine receptors in rainbow trout (Oncorhynchus mykiss).
abstract: Research addressing the health impacts of polychlorinated biphenyls (PCBs) has primarily focused on the effects of coplanar, or dioxin-like (DL), congeners, which is especially true for research assessing impacts in fish species. Ortho substituted non-coplanar, termed non-dioxin-like (NDL), PCBs have received less attention. In mammals, NDL PCBs enhance the activity of ryanodine receptors (RyR), calcium release channels necessary for engaging excitation-contraction (EC) coupling in striated muscle. We utilized in vitro receptor binding analysis to determine whether NDL PCB congeners detected in aquatic environments alter the activity of RyR isoform 1 (RyR1) found in the skeletal muscle of rainbow trout. Congeners 52, 95, 136, and149 were the most efficacious leading to an increase in receptor activity that was approximately 250% greater than that found under solvent control conditions. Other environmentally relevant congeners, namely PCB 153, 151 and 101, which all contain two or more chlorines in the ortho-position, enhanced receptor activity by greater than 160% of baseline. The mono-ortho congeners or the non-ortho PCB 77 had negligible impact on the RyR1. When combined, in binary or environmentally relevant mixtures, congeners shown to enhance receptor activity appeared to display additivity and when the active PCB 95 was present with the non-active congener PCB 77 the impact on receptor activity was reduced from 250% to 230%. The important role of the RyR and the demonstrated additive nature of NDL congeners toward altering channel function calls for further investigation into the ecological implications of altered RyR function in fish with high PCB burdens.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA. ebholland@ucdavis.edu
authors.forename: Erika B
authors.initials: EB
authors.lastname: Fritsch
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000818:Animals; D018482:Muscle, Skeletal / Q000187:drug effects*; D017686:Oncorhynchus mykiss / Q000502:physiology*; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014874:Water Pollutants, Chemical / Q000737:chemistry / Q000633:toxicity*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D014874:Water Pollutants, Chemical; D011078:Polychlorinated Biphenyls
keywords: Calcium signaling; Halogenated compound mixtures; Muscle contraction; Non-dioxin-like polychlorinated biphenyls; Relative potency scheme; Ryanodine receptor