Abstract
The mechanisms underlying the acute neurophysiological and behavioral effects of volatile organic compounds (VOCs) remain to be elucidated. However, the function of neuronal ion channels is perturbed by VOCs. The present study examined effects of toluene (TOL), trichloroethylene (TCE), and perchloroethylene (PERC) on whole-cell calcium current (ICa) in nerve growth factor-differentiated pheochromocytoma (PC12) cells. All three VOCs affected ICa in a reversible, concentration-dependent manner. At +10-mV test potentials, VOCs inhibited ICa, whereas at test potentials of –20 and –10 mV, they potentiated it. The order of potency for inhibition (IC50) was PERC (270 μM) > TOL (720 μM) > TCE (1525 μM). VOCs also changed ICa inactivation kinetics from a single- to double-exponential function. Voltage-ramp experiments suggested that VOCs shifted ICa activation in a hyperpolarizing direction; this was confirmed by calculating the half-maximal voltage of activation (V1/2,act) in the absence and presence of VOCs using the Boltzman equation. V1/2, act was shifted from approximately –2 mV in control to –11, –12, and –16 mV by TOL, TCE, and PERC, respectively. Similarly, VOCs shifted the half-maximal voltage of steady-state inactivation (V1/2, inact) from approximately –16 mV in control to –32, –35, and –20 mV in the presence of TOL, TCE, and PERC, respectively. Inhibition of ICa by TOL was confirmed in primary cultures of cortical neurons, where 827 μM TOL inhibited current by 61%. These data demonstrate that VOCs perturb voltage-sensitive Ca2+ channel function in neurons, an effect that could contribute to the acute neurotoxicity of these compounds.
Footnotes
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Preliminary results were presented at the 32nd Annual Meeting of the Society for Neuroscience; 2002 November 2–7; and at the 42nd Annual Meeting of the Society of Toxicology; 2003 March 9–13; and have been published in abstract form [Program 437.28, in 2002 Abstract Viewer/Itinerary Planner, Society for Neuroscience, Washington, DC, 2002. CD-ROM, and in Toxicol Sci (2003) 72 (Suppl 1):266]. The information in this document has been funded wholly by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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doi:10.1124/jpet.105.090027.
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ABBREVIATIONS: VOC, volatile organic compound; TOL, toluene; TCE, 1,1,1-trichloroethylene; PERC, perchloroethylene, 1,1,2,2-tetrachloroethylene; CNS, central nervous system; VSCC, voltage-sensitive calcium channel; VSSC, voltage-sensitive sodium channel; NMDA, N-methyl-d-aspartate; NGF, nerve growth factor; GVIA, ω-conotoxin GVIA; DMEM, Dulbecco's modified Eagle's medium; ICa, whole-cell Ca2+ current; TTX, tetrodotoxin; ANOVA, analysis of variance; I/V, current-voltage.
- Received June 2, 2005.
- Accepted August 15, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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