The sea urchin embryo as a model for mammalian developmental neurotoxicity: ontogenesis of the high-affinity choline transporter and its role in cholinergic trophic activity.
Embryonic development in the sea urchin requires trophic actions of the same neurotransmitters that participate in mammalian brain assembly. We evaluated the development of the high-affinity choline transporter, which controls acetylcholine synthesis. A variety of developmental neurotoxicants affect this transporter in mammalian brain. [3H]Hemicholinium-3 binding to the transporter was found in the cell membrane fraction at stages from the unfertilized egg to pluteus, with a binding affinity comparable with that seen in mammalian brain. Over the course of development, the concentration of transporter sites rose more than 3-fold, achieving concentrations comparable with those of cholinergically enriched mammalian brain regions. Dimethylaminoethanol (DMAE), a competitive inhibitor of choline transport, elicited dysmorphology beginning at the mid-blastula stage, with anomalies beginning progressively later as the concentration of DMAE was lowered. Pretreatment, cotreatment, or delayed treatment with acetylcholine or choline prevented the adverse effects of DMAE. Because acetylcholine was protective at a lower threshold, the DMAE-induced defects were most likely mediated by its effects on acetylcholine synthesis. Transient removal of the hyaline layer enabled a charged transport inhibitor, hemicholinium-3, to penetrate sufficiently to elicit similar anomalies, which were again prevented by acetylcholine or choline. These results indicate that the developing sea urchin possesses a high-affinity choline transporter analogous to that found in the mammalian brain, and, as in mammals, the functioning of this transporter plays a key role in the developmental, trophic activity of acetylcholine. The sea urchin model may thus be useful in high-throughput screening of suspected developmental neurotoxicants.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710-3813, USA.
Dan
D
Qiao
Lyudmila A
LA
Nikitina
Gennady A
GA
Buznikov
Jean M
JM
Lauder
Frederic J
FJ
Seidler
Theodore A
TA
Slotkin
D000109:Acetylcholine / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000633:toxicity; D002462:Cell Membrane / Q000502:physiology; D002794:Choline / Q000378:metabolism; D003642:Deanol / Q000633:toxicity; D004195:Disease Models, Animal; D047108:Embryonic Development; D006426:Hemicholinium 3 / Q000494:pharmacology; D006801:Humans; D008322:Mammals; D026901:Membrane Transport Proteins / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology / Q000506:poisoning; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D012617:Sea Urchins / Q000196:embryology*
D000928:Antidepressive Agents; D026901:Membrane Transport Proteins; D009498:Neurotoxins; D014179:Neurotransmitter Uptake Inhibitors; C065637:choline transporter; D003642:Deanol; D006426:Hemicholinium 3; D002794:Choline; D000109:Acetylcholine