{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:24:20Z","timestamp":1791300260399,"version":"4.1.0"},"reference-count":32,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5455","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2000,2,11]]},"abstract":"<jats:p>\n                    The deleterious effects of ethanol on the developing human brain are poorly understood. Here it is reported that ethanol, acting by a dual mechanism [blockade of\n                    <jats:italic>N<\/jats:italic>\n                    -methyl-\n                    <jats:sc>d<\/jats:sc>\n                    -aspartate (NMDA) glutamate receptors and excessive activation of GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptors], triggers widespread apoptotic neurodegeneration in the developing rat forebrain. Vulnerability coincides with the period of synaptogenesis, which in humans extends from the sixth month of gestation to several years after birth. During this period, transient ethanol exposure can delete millions of neurons from the developing brain. This can explain the reduced brain mass and neurobehavioral disturbances associated with human fetal alcohol syndrome.\n                  <\/jats:p>","DOI":"10.1126\/science.287.5455.1056","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:50:55Z","timestamp":1027749055000},"page":"1056-1060","source":"Crossref","is-referenced-by-count":1191,"title":["Ethanol-Induced Apoptotic Neurodegeneration and Fetal Alcohol Syndrome"],"prefix":"10.1126","volume":"287","author":[{"given":"Chrysanthy","family":"Ikonomidou","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Charite\u0301, Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Bittigau","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Charite\u0301, Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko J.","family":"Ishimaru","sequence":"additional","affiliation":[{"name":"Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyodku, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David F.","family":"Wozniak","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, 4940 Children's Place, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Charite\u0301, Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Genz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Charite\u0301, Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelon T.","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, 4940 Children's Place, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanya","family":"Stefovska","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Charite\u0301, Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Ho\u0308rster","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Charite\u0301, Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Tenkova","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, 4940 Children's Place, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krikor","family":"Dikranian","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, 4940 Children's Place, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Olney","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, 4940 Children's Place, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/S0140-6736(73)91092-1","author":"Jones K. 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K.","year":"1978","unstructured":"Clarren S. K., Smith D. W., N. Engl. J. Med. 298, 1063 (1978);","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_1_3_3","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1177\/002221949703000612","volume":"30","author":"Kerns K. A.","year":"1977","unstructured":"Kerns K. A., Don A., Mateer C. A., Streissguth A. P., J. Learn. Disab. 30, 685 (1977);","journal-title":"J. Learn. Disab."},{"key":"e_1_3_1_3_4","doi-asserted-by":"publisher","DOI":"10.1126\/science.6795717"},{"key":"e_1_3_1_3_5","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1176\/ajp.155.4.552","volume":"155","author":"Famy C.","year":"1998","unstructured":"Famy C., Streissguth A. P., Unis A. S., Am. J. Psychiatr. 155, 552 (1998).","journal-title":"Am. J. Psychiatr."},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.1998.tb03695.x"},{"key":"e_1_3_1_4_3","unstructured":"; C. L. Faingold P. N'Gouemo"},{"key":"e_1_3_1_4_4","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0301-0082(98)00027-6","volume":"55","author":"Riaz A.","year":"1998","unstructured":"Riaz A., Prog. Neurobiol. 55, 509 (1998);","journal-title":"Prog. Neurobiol."},{"key":"e_1_3_1_4_5","first-page":"768","volume":"284","author":"Sapp D. W.","year":"1998","unstructured":"Sapp D. W., Yeh H. H., J. Pharmacol. Exp. Ther. 284, 768 (1998).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_1_5_2","doi-asserted-by":"crossref","unstructured":"C. R. Goodlett and J. R. West in Maternal Substance Abuse and the Developing Nervous System I. Zagon and T. Slotkin Eds. (Academic Press San Diego CA 1992) pp. 45\u201375.","DOI":"10.1016\/B978-0-08-092667-4.50008-8"},{"key":"e_1_3_1_6_2","first-page":"423","volume":"7","author":"West J. R.","year":"1987","unstructured":"West J. 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R., Alcohol 7, 107 (1990);","journal-title":"Alcohol"},{"key":"e_1_3_1_9_4","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1111\/j.1530-0277.1995.tb01583.x","volume":"19","author":"Ryabinin A. E.","year":"1995","unstructured":"Ryabinin A. E., Cole M., Bloom F. E., Wilson M. C., Alcohol. Clin. Exp. Res. 19, 784 (1995).","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"e_1_3_1_10_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1126\/science.283.5398.70","volume":"283","author":"Ikonomidou C.","year":"1999","unstructured":"Ikonomidou C., et al., Science 283, 70 (1999).","journal-title":"Science"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2467382"},{"key":"e_1_3_1_11_3","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1111\/j.1471-4159.1989.tb07280.x","volume":"52","author":"Hoffman P. L.","year":"1989","unstructured":"Hoffman P. L., Rabe C. S., Moses F., Tabakoff B., J. Neurochem. 52, 1937 (1989).","journal-title":"J. Neurochem."},{"key":"e_1_3_1_12_2","unstructured":"Twenty-four hours after saline or ethanol treatment the immature rats were deeply anesthetized and perfused with aldehyde fixative and the brains were studied with the use of three histological methods: TUNEL DeOlmos silver impregnation and electron microscopy. The TUNEL method first described by Gavrieli et al. (12) detects a DNA fragmentation process that occurs typically in cells that are dying by an apoptotic mechanism. Thus it is useful for marking neurons that are undergoing experimentally induced apoptosis or neurons in the normal brain that are undergoing PCD. We have found (9 14) that DeOlmos silver impregnation (13) also stains neurons undergoing either experimentally induced apoptosis or PCD and that it reveals in the normal brain the same pattern of cells dying by PCD that is revealed by TUNEL. The DeOlmos silver method is more favorable for quantitative purposes because it more uniformly penetrates thick histological sections. Because neither TUNEL nor the DeOlmos method is specific for apoptosis (they are positive for apoptosis but also for at least some nonapoptotic cell death processes) it is necessary to establish the apoptosis diagnosis by ultrastructural analysis using as a reference standard the ultrastructural appearance of neurons undergoing PCD in the normal developing rat brain (14)."},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.119.3.493"},{"key":"e_1_3_1_14_2","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/0006-8993(71)90130-2","volume":"33","author":"DeOlmos J. S.","year":"1971","unstructured":"DeOlmos J. S., Ingram W. R., Brain Res. 33, 523 (1971).","journal-title":"Brain Res."},{"key":"e_1_3_1_15_2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/(SICI)1096-9861(19990614)408:4<461::AID-CNE2>3.0.CO;2-9","volume":"408","author":"Ishimaru M. J.","year":"1999","unstructured":"Ishimaru M. J., et al., J. Comp. Neurol. 408, 461 (1999).","journal-title":"J. Comp. Neurol."},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","unstructured":"A. H. Wyllie J. F. R. Kerr A. R. Currie Int. Rev. Cytol. 68 251 (1980).","DOI":"10.1016\/S0074-7696(08)62312-8"},{"key":"e_1_3_1_17_2","unstructured":"In the normal developing brain after neurons have differentiated migrated and are undergoing synaptogenesis spontaneous apoptotic neurodegeneration (PCD) occurs at a relatively low rate about 1% of the total neuronal population (9). To determine whether ethanol treatment induced a rate of apoptotic neurodegeneration exceeding the spontaneous rate in a given brain region we used an unbiased stereological disector method (17) to quantify the numerical density (neurons\/mm 3 ) of normal neurons in 70-\u03bcm Nissl-stained sections or of degenerating neurons in 70-\u03bcm sections stained by the DeOlmos silver method (13). A total of 8 to 10 disectors (0.05 mm by 0.05 mm disector height 0.07 mm) were used to sample each brain region. Counts were performed in a blinded manner. To establish the absolute numbers of degenerating neurons we identified boundaries of individual brain regions [thalamus dentate gyrus CA1 hippocampus subiculum caudate septum hypothalamus amygdala and frontoparietal cingulate retrosplenial temporal and pyriform\/entorhinal cortices according to G. Paxinos I. Tork L. H. Tecott K. L. Valentino Atlas of the Developing Rat Brain (Academic Press New York 1991)] in Nissl-stained sections. We used an image analysis system (IMAGE 1.54 National Institutes of Health) to facilitate volume determinations for each brain region. Multiplication of the volume of a given region by the numerical density of degenerating neurons in that region provided an estimate of total numbers of neurons deleted from each brain region by ethanol treatment. The regional values were summed to give a total for each brain and from these totals means (\u00b1SEM) were calculated separately for the brains in the ethanol- and saline-treated groups."},{"key":"e_1_3_1_18_2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0197-4580(93)90112-O","volume":"14","author":"West M. J.","year":"1993","unstructured":"West M. J., Neurobiol. Aging 14, 275 (1993);","journal-title":"Neurobiol. Aging"},{"key":"e_1_3_1_18_3","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/j.1699-0463.1988.tb05320.x","volume":"96","author":"Gundersen H. J. G.","year":"1988","unstructured":"Gundersen H. J. G., Bendtsen T. F., Korbo L., West M. J., APMIS 96, 379 (1988).","journal-title":"APMIS"},{"key":"e_1_3_1_19_2","unstructured":"In addition to GABAergic agents we tested 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2 3-dione (NBQX) an antagonist of non-NMDA glutamate receptors at a dose of 20 mg\/kg ip given at 0 75 and 150 min and at 8 hours ( n = 5); scopolamine hydrobromide an antagonist of cholinergic muscarinic receptors at a dose of 0.3 mg\/kg ip given at 0 4 and 8 hours ( n = 5); haloperidol an antagonist of dopamine receptors at a dose of 10 mg\/kg ip given at 0 and 8 hours ( n = 5); and l -dopa an agent that increases the availability of dopamine at dopamine receptors administered at 50 100 or 200 mg\/kg ip together with benserazide (dopamine decarboxylase inhibitor) at 14 28 or 56 mg\/kg ip ( n = 5 per dose). Finally because NMDA receptor\u2013activated ion channels are highly permeable to Ca 2+ ions we tested whether blockade of calcium influx via other routes (i.e. voltage-dependent Ca 2+ channels) may also cause apoptotic neurodegeneration in the brain. For this purpose we treated P7 rats with the Ca 2+ channel blockers nimodipine (50 mg\/kg ip at 0 and 8 hours; n = 6) or nifedipine (10 mg\/kg ip at 0 and 8 hours; n = 6). We examined the brains histologically 24 hours after each of these treatments. None of these agents reproduced the apoptosis-inducing action of NMDA antagonists."},{"key":"e_1_3_1_20_2","unstructured":"Supported in part by Deutsche Forschungsgemeinschaft grant Ik2\/2-1 Humboldt University grant 98-649 National Institute for Mental Health Research Scientist Award MH 38894 (J.W.O.) National Institute on Aging grant AG 11355 National Institute on Drug Abuse grant DA 05072 National Eye Institute grant EY 08089 and a National Alliance for Research on Schizophrenia and Depression Established Investigator Award (J.W.O.)."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.287.5455.1056","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T05:48:13Z","timestamp":1705124893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.287.5455.1056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,2,11]]},"references-count":32,"journal-issue":{"issue":"5455","published-print":{"date-parts":[[2000,2,11]]}},"alternative-id":["10.1126\/science.287.5455.1056"],"URL":"https:\/\/doi.org\/10.1126\/science.287.5455.1056","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,2,11]]}}}