title: Volatile organic compounds inhibit human and rat neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
abstract: The relative sensitivity of rats and humans to volatile organic compounds (VOCs) such as toluene (TOL) and perchloroethylene (PERC) is unknown and adds to uncertainty in assessing risks for human exposures to VOCs. Recent studies have suggested that ion channels, including nicotinic acetylcholine receptors (nAChRs), are targets of TOL effects. However, studies comparing TOL effects on human and rat ligand-gated ion channels have not been conducted. To examine potential toxicodynamic differences between these species, the sensitivity of human and rat nAChRs to TOL was assessed. Since PERC has similar effects, in vivo, to TOL, effects of PERC on nAChR function were also examined. Two-electrode voltage-clamp techniques were utilized to measure acetylcholine-induced currents in neuronal nAChRs (alpha4beta2, alpha3beta2, and alpha7) expressed in Xenopus oocytes. PERC (0.065 mM) inhibited alpha7 nAChR currents by 60.1 +/- 4.0% (human, n = 7) and 40 +/- 3.5% (rat, n = 5), and inhibited alpha4beta2 nAChR currents by 42.0 +/- 5.2% (human, n = 6) and 52.2 +/- 5.5% (rat, n = 8). Likewise, alpha3beta2 nAChRs were significantly inhibited by 62.2 +/- 3.8% (human, n = 7) and 62.4 +/- 4.3% (rat, n = 8) in the presence of 0.065 mM PERC. TOL also inhibited both rat and human alpha7, alpha4beta2, and alpha3beta2 nAChRs. Statistical analysis indicated that although there was not a species (human vs. rat) difference with PERC (0.0015-0.065 mM) or TOL (0.03-0.9 mM) inhibition of alpha7, alpha4beta2, or alpha3beta2 nAChRs, all receptor types were more sensitive to PERC than TOL. These results demonstrate that human and rat nACh receptors represent a sensitive target for VOCs. This toxicodynamic information will help decrease the uncertainty associated with animal to human extrapolations in the risk assessment of VOCs.
authors.affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Ambuja S
authors.initials: AS
authors.lastname: Bale
authors.forename: Connie A
authors.initials: CA
authors.lastname: Meacham
authors.forename: Vernon A
authors.initials: VA
authors.lastname: Benignus
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bushnell
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D013750:Tetrachloroethylene / Q000032:analysis / Q000633:toxicity*; D014050:Toluene / Q000032:analysis / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods; D014835:Volatilization; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C419362:nicotinic receptor alpha3beta2; C403531:nicotinic receptor alpha4beta2; D014050:Toluene; D013750:Tetrachloroethylene