title: The sea urchin embryo, an invertebrate model for mammalian developmental neurotoxicity, reveals multiple neurotransmitter mechanisms for effects of chlorpyrifos: therapeutic interventions and a comparison with the monoamine depleter, reserpine.
abstract: Lower organisms show promise for the screening of neurotoxicants that might target mammalian brain development. Sea urchins use neurotransmitters as embryonic growth regulatory signals, so that adverse effects on neural substrates for mammalian brain development can be studied in this simple organism. We compared the effects of the organophosphate insecticide, chlorpyrifos in sea urchin embryos with those of the monoamine depleter, reserpine, so as to investigate multiple neurotransmitter mechanisms involved in developmental toxicity and to evaluate different therapeutic interventions corresponding to each neurotransmitter system. Whereas reserpine interfered with all stages of embryonic development, the effects of chlorpyrifos did not emerge until the mid-blastula stage. After that point, the effects of the two agents were similar. Treatment with membrane permeable analogs of the monoamine neurotransmitters, serotonin and dopamine, prevented the adverse effects of either chlorpyrifos or reserpine, despite the fact that chlorpyrifos works simultaneously through actions on acetylcholine, monoamines and other neurotransmitter pathways. This suggests that different neurotransmitters, converging on the same downstream signaling events, could work together or in parallel to offset the developmental disruption caused by exposure to disparate agents. We tested this hypothesis by evaluating membrane permeable analogs of acetylcholine and cannabinoids, both of which proved effective against chlorpyrifos- or reserpine-induced teratogenesis. Invertebrate test systems can provide both a screening procedure for mammalian neuroteratogenesis and may uncover novel mechanisms underlying developmental vulnerability as well as possible therapeutic approaches to prevent teratogenesis.
authors.affiliation: N.K. Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Gennady A
authors.initials: GA
authors.lastname: Buznikov
authors.forename: Lyudmila A
authors.initials: LA
authors.lastname: Nikitina
authors.forename: Ljubisa M
authors.initials: LM
authors.lastname: Rakić
authors.forename: Ivan
authors.initials: I
authors.lastname: Milosević
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Bezuglov
authors.forename: Jean M
authors.initials: JM
authors.lastname: Lauder
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000633:toxicity*; D000818:Animals; D004390:Chlorpyrifos / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004625:Embryo, Nonmammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D018377:Neurotransmitter Agents / Q000627:therapeutic use; D012110:Reserpine / Q000633:toxicity*; D012617:Sea Urchins / Q000196:embryology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D007306:Insecticides; D018377:Neurotransmitter Agents; D012110:Reserpine; D004390:Chlorpyrifos