Neurobehavioral teratogenicity of sarin in an avian model.
Nerve gas organophosphates like sarin are likely to be used in urban terrorism, leading to widespread exposures of pregnant women and young children. Here, we established a model for sarin neurobehavioral teratogenicity in the developing chick so as to explore the consequences of apparently subtoxic sarin exposure and the mechanisms underlying synaptic and behavioral deficits. Chicken eggs were injected with sarin (2, 6 and 12 microg/kg) on incubation days 2 and 6, treatments that did not decrease hatching and did not evoke dysmorphology. After hatching the chicks were tested for filial imprinting and neurochemical markers known to be critical for imprinting. Imprinting was reduced at 2 and 6 microg/kg but not at the highest dose. Acetylcholinesterase and choline acetyltransferase were unaffected but sarin reduced the concentration of the high-affinity choline transporter, the rate-limiting factor in acetylcholine utilization. The concentration of PKC isoforms was assessed in the imprinting-related intermediate part of the medial hyperstriatum ventrale, the region most closely associated with cholinergic function in imprinting behavior. Sarin reduced the concentration of all isoforms (alpha, beta, gamma) with a similar, biphasic dose-response curve to that seen for behavioral performance, a relationship noted in previous work with organophosphate pesticides. Our results indicate that otherwise subtoxic exposures to sarin produce neurodevelopmental deficits; since we utilized a chick model, which is devoid of maternal confounds that are present in mammalian development, the adverse effects of sarin are mediated directly in the developing organism.
Yanai
Joseph
J
The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research, Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. yanai@md.huji.ac.il
Pinkas
Adi
A
Seidler
Frederic J
FJ
Ryde
Ian T
IT
Van der Zee
Eddy A
EA
Slotkin
Theodore A
TA
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002642:Chick Embryo / Q000187:drug effects*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005260:Female; D007173:Imprinting, Psychological / Q000187:drug effects*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D023421:Models, Animal; D011493:Protein Kinase C / Q000378:metabolism; D011897:Random Allocation; D012524:Sarin / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*
D002619:Chemical Warfare Agents; D026901:Membrane Transport Proteins; D013723:Teratogens; C065637:choline transporter; D012524:Sarin; D002795:Choline O-Acetyltransferase; D011493:Protein Kinase C; D000110:Acetylcholinesterase