Prediction of neurotoxic potency of hazardous substances with a modular in vitro test battery.
Neurotoxic action was investigated on different model nervous systems linked to a modular in vitro test battery. Voltage operated potassium channels and glutamate operated ion channels expressed in oocytes of the clawed frog Xenopus laevis by injection of cRNA (cloned RNA) or mRNA, respectively, as well as isolated neurons and isolated neuronal networks from the buccal ganglia of the snail Helix pomatia, were used as consecutive modules of different complexity. Lead (Pb2+) was chosen as a known neurotoxic model substance to evaluate the suitability of the test battery to predict the neurotoxic potency of hazardous substances, to establish dose-response relationships, and to investigate the basic mechanisms involved in neurotoxicity. All modules delivered consistent results: potassium currents were reduced by lead with a threshold concentration of 0.1 mumol/l. Membrane currents elicited by the glutamate receptor agonists kainate were decreased by lead with a threshold concentration below 0.1 mumol/l, while currents elicited by the agonist AMPA were not affected. Action potentials generated by the isolated B4 snail neuron showed a decrease of potential amplitude and a prolongation of potential duration after application of lead. The neuronal network controlling the feeding activities of the snail reacted with a decrease of the frequency of the spontaneously generated feeding depolarisations, thus showing the direct neurotoxic effect of lead on body functions and behaviour.
Binding
N
N
Institut für Arbeitsmedizin, Westfälischen Wilhelms-Universität Münster, Germany.
Madeja
M
M
Musshoff
U
U
Neidt
U
U
Altrup
U
U
Speckmann
E J
EJ
Witting
U
U
D000818:Animals; D015386:Hazardous Substances / Q000633:toxicity*; D006372:Helix, Snails; D066298:In Vitro Techniques; D007854:Lead / Q000633:toxicity; D009422:Nervous System Diseases / Q000139:chemically induced*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D018675:Toxicity Tests / Q000379:methods*; D014982:Xenopus laevis
D015386:Hazardous Substances; D015221:Potassium Channels; D007854:Lead