Structure-activity relationship of selected meta- and para-hydroxylated non-dioxin like polychlorinated biphenyls: from single RyR1 channels to muscle dysfunction.

Non-dioxin like polychlorinated biphenyls (NDL-PCBs) are legacy environmental contaminants with contemporary unintentional sources. NDL-PCBs interact with ryanodine receptors (RyRs), Ca(2+) channels of sarcoplasmic/endoplasmic reticulum (SR/ER) that regulate excitation-contraction coupling (ECC) and Ca(2+)-dependent cell signaling in muscle. Activities of 4 chiral congeners PCB91, 95, 132, and 149 and their respective 4- and 5-hydroxy (-OH) derivatives toward rabbit skeletal muscle ryanodine receptor (RyR1) are investigated using [(3)H]ryanodine binding and SR Ca(2+) flux analyses. Although 5-OH metabolites have comparable activity to their respective parent in both assays, 4-OH derivatives are unable to trigger Ca(2+) release from SR microsomes in the presence of Ca(2+)-ATPase activity. PCB95 and derivatives are investigated using single channel voltage-clamp and primary murine embryonic muscle cells (myotubes). Like PCB95, 5-OH-PCB95 quickly and persistently increases channel open probability (p o > .9) by stabilizing the full-open channel state, whereas 4-OH-PCB95 transiently enhances p o. Ca(2+) imaging of myotubes loaded with Fluo-4 show that acute exposure to PCB95 (5 µM) potentiates ECC and caffeine responses and partially depletes SR Ca(2+) stores. Exposure to 5-OH-PCB95 (5 µM) increases cytoplasmic Ca(2+), leading to rapid ECC failure in 50% of myotubes with the remainder retaining negligible responses. 4-OH-PCB95 neither increases baseline Ca(2+) nor causes ECC failure but depresses ECC and caffeine responses by 50%. With longer (3h) exposure to 300 nM PCB95, 5-OH-PCB95, or 4-OH-PCB95 decreases the number of ECC responsive myotubes by 22%, 81%, and 51% compared with control by depleting SR Ca(2+) and/or uncoupling ECC. NDL-PCBs and their 5-OH and 4-OH metabolites differentially influence RyR1 channel activity and ECC in embryonic skeletal muscle.

[1]  Andres Martinez,et al.  Record of PCB congeners, sorbents and potential toxicity in core samples in Indiana Harbor and Ship Canal. , 2011, Chemosphere.

[2]  P. Thorne,et al.  PCBs and OH-PCBs in serum from children and mothers in urban and rural U.S. communities. , 2013, Environmental science & technology.

[3]  P. Apostoli,et al.  Persistent organochlorine compounds in fetal and maternal tissues: evaluation of their potential influence on several indicators of fetal growth and health. , 2011, The Science of the total environment.

[4]  Charles S Wong,et al.  Chiral polychlorinated biphenyl transport, metabolism, and distribution: a review. , 2010, Environmental science & technology.

[5]  K. Hornbuckle,et al.  Inadvertent Polychlorinated Biphenyls in Commercial Paint Pigments† , 2009, Environmental science & technology.

[6]  J. Parrott,et al.  Assessment of the health status of wild fish from the wheatley Harbour area of Concern, Ontario, Canada , 2012, Environmental toxicology and chemistry.

[7]  E. Stuenkel,et al.  Stimulation of oscillatory uterine contraction by the PCB mixture Aroclor 1242 may involve increased [Ca2+]i through voltage-operated calcium channels. , 1999, Toxicology and applied pharmacology.

[8]  K. Storey,et al.  Bound and determined: a computer program for making buffers of defined ion concentrations. , 1992, Analytical biochemistry.

[9]  G. Johnson,et al.  Polychlorinated biphenyl (PCB) exposure assessment by multivariate statistical analysis of serum congener profiles in an adult Native American population. , 2005, Environmental research.

[10]  K. Beam,et al.  Impaired gating of an L-Type Ca(2+) channel carrying a mutation linked to malignant hyperthermia. , 2013, Biophysical journal.

[11]  A. Bergman,et al.  Selective retention of hydroxylated PCB metabolites in blood. , 1994, Environmental health perspectives.

[12]  A. Marks,et al.  Ryanodine receptor studies using genetically engineered mice , 2010, FEBS letters.

[13]  D. Costa,et al.  Polychlorinated Biphenyls and Polybrominated Diphenyl Ethers in Galapagos Sea Lions (Zalophus wollebaeki) , 2009, Environmental toxicology and chemistry.

[14]  T. Crawford,et al.  Selenoprotein N is required for ryanodine receptor calcium release channel activity in human and zebrafish muscle , 2008, Proceedings of the National Academy of Sciences.

[15]  Charles S Wong,et al.  Chiral polychlorinated biphenyls are biotransformed enantioselectively by mammalian cytochrome P-450 isozymes to form hydroxylated metabolites. , 2009, Environmental science & technology.

[16]  Pamela J Lein,et al.  Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity. , 2010, Pharmacology & therapeutics.

[17]  Pamela J. Lein,et al.  PCB-95 Modulates the Calcium-Dependent Signaling Pathway Responsible for Activity-Dependent Dendritic Growth , 2012, Environmental health perspectives.

[18]  C. Viero,et al.  Intracellular Ca2+ regulation in rat motoneurons during development. , 2006, Cell calcium.

[19]  C. Ward,et al.  Enhanced Excitation-Coupled Calcium Entry in Myotubes Expressing Malignant Hyperthermia Mutation R163C Is Attenuated by Dantrolene , 2008, Molecular Pharmacology.

[20]  R. Ashworth,et al.  Ryanodine receptors, a family of intracellular calcium ion channels, are expressed throughout early vertebrate development , 2011, BMC Research Notes.

[21]  M. Stamou,et al.  2,2',3,5',6-Pentachlorobiphenyl (PCB 95) and its hydroxylated metabolites are enantiomerically enriched in female mice. , 2012, Environmental science & technology.

[22]  E. Jaimovich,et al.  NFAT activation by membrane potential follows a calcium pathway distinct from other activity-related transcription factors in skeletal muscle cells. , 2008, American journal of physiology. Cell physiology.

[23]  Diptiman D. Bose,et al.  Enantiomeric specificity of (-)-2,2',3,3',6,6'-hexachlorobiphenyl toward ryanodine receptor types 1 and 2. , 2009, Chemical research in toxicology.

[24]  P. Beaune,et al.  Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues , 2007, Pharmacogenetics and genomics.

[25]  A. Bergman,et al.  Chiral PCB methyl sulfones in rat tissues after exposure to technical PCBs. , 2002, Environmental science & technology.

[26]  M. Theroux,et al.  Core myopathies and malignant hyperthermia susceptibility: a review , 2013, Paediatric anaesthesia.

[27]  M. Duffel,et al.  Synthesis of Sterically Hindered Polychlorinated Biphenyl Derivatives. , 2011, Synthesis.

[28]  M. Peters-Golden,et al.  Stimulation of pregnant rat uterine contraction by the polychlorinated biphenyl (PCB) mixture aroclor 1242 may be mediated by arachidonic acid release through activation of phospholipase A2 enzymes. , 1999, The Journal of pharmacology and experimental therapeutics.

[29]  S. Schantz,et al.  Formulation and characterization of an experimental PCB mixture designed to mimic human exposure from contaminated fish. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[30]  Pamela J. Lein,et al.  Developmental Exposure to Polychlorinated Biphenyls Interferes with Experience-Dependent Dendritic Plasticity and Ryanodine Receptor Expression in Weanling Rats , 2008, Environmental health perspectives.

[31]  A. Marks,et al.  Ryanodine receptor channelopathies , 2010, Pflügers Archiv - European Journal of Physiology.

[32]  B. Seo,et al.  Long-term effects of developmental exposure to 2,2',3,5',6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding. , 1997, Neurotoxicology.

[33]  M. Duffel,et al.  2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is enantioselectively oxidized to hydroxylated metabolites by rat liver microsomes. , 2011, Chemical research in toxicology.

[34]  E. Budtz-Jørgensen,et al.  Neurobehavioral deficits at age 7 years associated with prenatal exposure to toxicants from maternal seafood diet. , 2012, Neurotoxicology and teratology.

[35]  P. Allen,et al.  Coordinated Movement of Cytoplasmic and Transmembrane Domains of RyR1 upon Gating , 2009, PLoS biology.

[36]  J. Jacobson,et al.  Determinants of polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), and dichlorodiphenyl trichloroethane (DDT) levels in the sera of young children. , 1989, American journal of public health.

[37]  J. Casida,et al.  Ca2+-activated ryanodine binding: mechanisms of sensitivity and intensity modulation by Mg2+, caffeine, and adenine nucleotides. , 1987, Molecular pharmacology.

[38]  C. Schreiner,et al.  Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex , 2007, Proceedings of the National Academy of Sciences.

[39]  Kyong-Tai Kim,et al.  Effects of Polychlorinated Biphenyl 19 (2,2′,6‐Trichlorobiphenyl) on Contraction, Ca2+ Transient, and Ca2+ Current of Cardiac Myocytes , 2001, Journal of cardiovascular pharmacology.

[40]  Andres Martinez,et al.  Spatial distribution of chlordanes and PCB congeners in soil in Cedar Rapids, Iowa, USA. , 2012, Environmental pollution.

[41]  Hui Dong,et al.  The effect of the structure of polychlorinated biphenyls on their hydroxylation, oxidation, and glutathionyl conjugation reactions. , 2013, Biomedical and environmental sciences : BES.

[42]  K. Beam,et al.  Restoration of excitation—contraction coupling and slow calcium current in dysgenic muscle by dihydropyridine receptor complementary DNA , 1988, Nature.

[43]  T. Shiomi,et al.  Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. , 2011, Cell metabolism.

[44]  G. Pavlath,et al.  Activation and cellular localization of the cyclosporine A-sensitive transcription factor NF-AT in skeletal muscle cells. , 1998, Molecular biology of the cell.

[45]  Hanh T. Nguyen,et al.  Enhanced dihydropyridine receptor channel activity in the presence of ryanodine receptor , 1996, Nature.

[46]  F. Hu,et al.  Persistent Organic Pollutants and Type 2 Diabetes: A Prospective Analysis in the Nurses’ Health Study and Meta-analysis , 2012, Environmental health perspectives.

[47]  M. Molinaro,et al.  Polychlorobiphenyls inhibit skeletal muscle differentiation in culture. , 2001, Toxicology and applied pharmacology.

[48]  S. Fleischer,et al.  Preparation and morphology of sarcoplasmic reticulum terminal cisternae from rabbit skeletal muscle , 1984, The Journal of cell biology.

[49]  K. Beam,et al.  Triclosan impairs excitation–contraction coupling and Ca2+ dynamics in striated muscle , 2012, Proceedings of the National Academy of Sciences.

[50]  T. Albertson,et al.  Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1). , 2006, Chemical research in toxicology.

[51]  L. Hovander,et al.  Identification of Hydroxylated PCB Metabolites and Other Phenolic Halogenated Pollutants in Human Blood Plasma , 2002, Archives of environmental contamination and toxicology.

[52]  Libera Berghella,et al.  Molecular control of neuromuscular junction development , 2011, Journal of cachexia, sarcopenia and muscle.

[53]  H. Lehmler,et al.  Enantioselective disposition of PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl) in C57BL/6 mice after oral and intraperitoneal administration. , 2007, Chirality.

[54]  Pamela J. Lein,et al.  PCB-95 Promotes Dendritic Growth via Ryanodine Receptor–Dependent Mechanisms , 2012, Environmental health perspectives.

[55]  Y. L. Guo,et al.  Early development of Yu-Cheng children born seven to twelve years after the Taiwan PCB outbreak. , 1994, Chemosphere.

[56]  V. Felipo,et al.  Differential long-term effects of developmental exposure to polychlorinated biphenyls 52, 138 or 180 on motor activity and neurotransmission. Gender dependence and mechanisms involved , 2011, Neurochemistry International.