Chronic low level polychlorinated biphenyls (PCB) exposures remain a significant public health concern since results from epidemiological studies indicate PCB burden is associated with immune system dysfunction, cardiovascular disease, and impairment of the developing nervous system. Of these various adverse health effects, developmental neurotoxicity has emerged as a particularly vulnerable endpoint in PCB toxicity. Arguably the most pervasive biological effects of PCBs could be mediated by their ability to alter the spatial and temporal fidelity of Ca 2+ signals through one or more receptor mediated processes. This review will focus on our current knowledge of the structure and function of ryanodine receptors (RyRs) in muscle and nerve cells and how PCBs and related non-coplanar structures alter these functions. The molecular and cellular mechanisms by which noncoplanar PCBs and related structures alter local and global Ca 2+ signaling properties and the possible short and long-term consequences of these perturbations on neurodevelopment and neurodegeneration are reviewed. Dioxin-like and non-dioxin-like PCBs Occurrence and concerns to public healthPolychlorinated biphenyls (PCBs) are synthetic chlorinated aromatic hydrocarbons that are non-flammable, chemically stable and have high boiling points. In the United States, PCBs were synthesized and marketed primarily as Aroclor® mixtures whose degree of chlorination was identified by a four-digit designation (e.g., 1248, 1254, 1260, etc.), with the first two digits identifying the mixture as PCBs and the last two digits identifying the percent of chlorine used during synthesis. A higher degree of PCB chlorination increases melting point and lipophilicity, whereas lower chlorination increases vapor pressure and water solubility. Similar PCB mixtures were synthesized worldwide and identified under several trade names such as Clophen® and Kanechlor®. PCB mixtures, especially those of intermediate chlorination, such as Aroclor 1248 and Aroclor 1254, were widely used in several industries for their insulation and heat dissipating properties. PCBs were also broadly incorporated into a variety of common products such as pesticide extenders, plastics, varnishes, adhesives, carbonless copy paper, newsprint, fluorescent light ballasts and caulking compounds (Ross, 2004).By 1977, when PCBs were banned, more than 600,000 tons were manufactured in the United States, and global production is estimated at over 1.5 million tons (Breivik, Sweetman, Pacyna, & Jones, 2002). Because of their extensive industrial use and chemical stability, PCBs have Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the conten...

BackgroundConcerns have been raised about the biological and toxicologic effects of the antimicrobials triclocarban (TCC) and triclosan (TCS) in personal care products. Few studies have evaluated their biological activities in mammalian cells to assess their potential for adverse effects.ObjectivesIn this study, we assessed the activity of TCC, its analogs, and TCS in in vitro nuclear-receptor–responsive and calcium signaling bioassays.Materials and methodsWe determined the biological activities of the compounds in in vitro, cell-based, and nuclear-receptor–responsive bioassays for receptors for aryl hydrocarbon (AhR), estrogen (ER), androgen (AR), and ryanodine (RyR1).ResultsSome carbanilide compounds, including TCC (1–10 μM), enhanced estradiol (E2)-dependent or testosterone-dependent activation of ER- and AR-responsive gene expression up to 2.5-fold but exhibited little or no agonistic activity alone. Some carbanilides and TCS exhibited weak agonistic and/or antagonistic activity in the AhR-responsive bioassay. TCS exhibited antagonistic activity in both ER- and AR-responsive bioassays. TCS (0.1–10 μM) significantly enhanced the binding of [3H]ryanodine to RyR1 and caused elevation of resting cytosolic [Ca2+] in primary skeletal myotubes, but carbanilides had no effect.ConclusionsCarbanilides, including TCC, enhanced hormone-dependent induction of ER- and AR-dependent gene expression but had little agonist activity, suggesting a new mechanism of action of endocrine-disrupting compounds. TCS, structurally similar to noncoplanar ortho-substituted poly-chlorinated biphenyls, exhibited weak AhR activity but interacted with RyR1 and stimulated Ca2+ mobilization. These observations have potential implications for human and animal health. Further investigations are needed into the biological and toxicologic effects of TCC, its analogs, and TCS.

Store-operated Ca 2+ entry (SOCE) occurs in diverse cell types in response to depletion of Ca 2+ within the endoplasmic/sarcoplasmic reticulum and functions both to refill these stores and to shape cytoplasmic Ca 2+ transients. Here we report that in addition to conventional SOCE, skeletal myotubes display a physiological mechanism that we term excitation-coupled Ca 2+ entry (ECCE). ECCE is rapidly initiated by membrane depolarization. Like excitation-contraction coupling, ECCE is absent in both dyspedic myotubes that lack the skeletal muscle-type ryanodine receptor 1 and dysgenic myotubes that lack the dihydropyridine receptor (DHPR), and is independent of the DHPR l -type Ca 2+ current. Unlike classic SOCE, ECCE does not depend on sarcoplasmic reticulum Ca 2+ release. Indeed, ECCE produces a large Ca 2+ entry in response to physiological stimuli that do not produce substantial store depletion and depends on interactions among three different Ca 2+ channels: the DHPR, ryanodine receptor 1, and a Ca 2+ entry channel with properties corresponding to those of store-operated Ca 2+ channels. ECCE may provide a fundamental means to rapidly maintain Ca 2+ stores and control important aspects of Ca 2+ signaling in both muscle and nonmuscle cells.