Abstract
Neuronal vulnerability to ethanol may be non-specific, i.e., vulnerability may be conferred by the developmental state of the population or by the site of derivation. To address these issues, the effect of developmental exposure to ethanol on three brainstem nuclei; the trigeminal motor (MoV), facial motor (MoVII) and medial superior olivary (MSO) nuclei was determined. MoVII and MSO are generated at the same time and from the same rhombomere, r4. MoV is generated earlier from r2. Macaca nemestrina were exposed to ethanol or a control solution one day per week for six or 24 weeks of gestation. Brainstems of the mature offspring were sectioned and stained. The number of neurons and volume of each nucleus were determined stereologically. Neuron number was lower in MoV and MSO following exposure to ethanol whereas MoVII appeared unaffected. No significant effects of ethanol exposure were seen on the volume and weight of the brainstem, or the volume of the individual nuclei. These findings show that ethanol differentially affects brainstem nuclei in a targeted, rather than non-specific, manner. Furthermore, they show that serious ethanol-induced neurological deficits can be present without gross morphological changes.
Similar content being viewed by others
References
Abel, E. L. (1995) Update on incidence of FAS: FAS is not an equal opportunity birth defect. Neurotoxicology & Teratology 17, 437–443.
Abel, E.L. & Sokol, R. J. (1986) Fetal alcohol syndrome is now leading cause of mental retardation. Lancet 2, 1222.
Altman, J. & Bayer, S. A. (1980a) Development of the brain stem in the rat. IV. Thymidine-radiographic study of the time of origin of neurons in the pontine region. Journal of Comparative Neurology 194, 905–929.
Altman, J. & Bayer, S. A. (1980b) Development of the brain stem in the rat. III. Thymidine-radiographic study of the time of origin of neurons of the vestibular and auditory nuclei of the upper medulla. Journal of Comparative Neurology 194, 877–904.
Altman, J. & Bayer, S. A. (1980c) Development of the brain stem in the rat. II. Thymidine-radiographic study of the time of origin of neurons of the upper medulla, excluding the vestibular and auditory nuclei. Journal of Comparative Neurology 194, 37–56.
Astley, S. J., Magnuson, S. I., Omnell, L. M. & Clarren, S. K. (1999) Fetal alcohol syndrome: Changes in craniofacial form with age, cognition, and timing of ethanol exposure in the macaque. Teratology 59, 163–172.
Barron, S., Kelly, S. J. & Riley, E. P. (1991) Neonatal alcohol exposure alters suckling behavior in neonatal rat pups. Pharmacology, Biochemistry & Behavior 39, 423–427.
Bass, A. H. & Baker, R. (1997) Phenotypic specification of hindbrain rhombomeres and the origins of rhythmic circuits in vertebrates. Brain, Behavior & Evolution 50 (Suppl. 1), 3–16.
Berman, R. F., Beare, D. J., Church, M. W. & Abel, E. L. (1992) Audiogenic seizure susceptibility and auditory brainstem responses in rats prenatally exposed to alcohol. Alcoholism: Clinical & Experimental Research 16, 490–498.
Bhave, S. V. & Hoffman, P. L. (1997) Ethanol promotes apoptosis in cerebellar granule cells by inhibiting the trophic effect of NMDA. Journal of Neurochemistry 68, 578–586.
Boillee, S., Cadusseau, J., Coulpier, M., Grannec, G. & Junier, M. P. (2001) Transforming growth factor alpha:Apromoter of motoneuron survival of potential biological relevance. Journal of Neuroscience 21, 7079–7088.
Brown, M., Keynes, R. & Lumsden, A. (2001) The Developing Brain. New York: Oxford University Press Inc.
Byrd, K. E., Stein, S. T., Sokoloff, A. J. & Shankar, K. (1990) Craniofacial alterations following electrolytic lesions of the trigeminal motor nucleus in actively growing rats. American Journal of Anatomy 189, 93–110.
Cartwright, M. M. & Smith, S. M. (1995) Increased cell death and reduced neural crest cell numbers in ethanol-exposed embryos: Partial basis for the fetal alcohol syndrome phenotype. Alcoholism: Clinical & Experimental Research 19, 378–386.
Cartwright, M. M., Tessmer, L. L. & Smith, S. M. (1998) Ethanol-induced neural crest apoptosis is coincident with their endogenous death, but is mechanistically distinct. Alcoholism: Clinical & Experimental Research 22, 142–149.
Cheema, Z. F., West, J. R. & Miranda, R. C. (2000) Ethanol induces Fas/Apo [apoptosis]-1 mRNA and cell suicide in the developing cerebral cortex. Alcoholism: Clinical & Experimental Research 24, 535–543.
Chen, J. S., Driscoll, C. D. & Riley, E. P. (1982) Ontogeny of suckling behavior in rats prenatally exposed to alcohol. Teratology 26, 145–153.
Chisaka, O., Musci, T. S. & Capecchi, M. R. (1992) Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature 355, 516–520.
Church, M. W. (1987) Chronic in utero alcohol exposure affects auditory function in rats and in humans. Alcohol 4, 231–239.
Church, M. W., Abel, E. L., Kaltenbach, J. A. & Overbeck, G. W. (1996) Effects of prenatal alcohol exposure and aging on auditory function in the rat: Preliminary results. Alcoholism: Clinical & Experimental Research 20, 172–179.
Church, M. W., Eldis, F., Blakley, B. W. & Bawle, E. V. (1997) Hearing, language, speech, vestibular, and dentofacial disorders in fetal alcohol syndrome. Alcoholism: Clinical & Experimental Research 21, 227–237.
Clarren, S. K., Alvord, E. C. JR., Sumi, S. M., Streissguth, A. P. & Smith, D. W. (1978) Brain malformations related to prenatal exposure to ethanol. Journal of Pediatrics 92, 64–67.
Clarren, S. K. & Astley, S. J. (1992) Pregnancy outcomes after weekly oral administration of ethanol during gestation in the pig-tailed macaque: Comparing early gestational exposure to full gestational exposure. Teratology 45, 1–9.
Debelek, K. A. & Smith, S. M. (2000) Avian genetic background modulates the neural crest apoptosis induced by ethanol exposure. Alcoholism: Clinical & Experimental Research 24, 307–314.
Dunty, W. C. JR., Chen, S. Y., Zucker, R. M., Dehart, D. B. & Sulik, K. K. (2001) Selective vulnerability of embryonic cell populations to ethanol-induced apoptosis: Implications for alcohol-related birth defects and neurodevelopmental disorder. Alcoholism: Clinical & Experimental Research 25, 1523–1535.
Goodlett, C. R. & Eilers, A. T. (1997) Alcohol-induced Purkinje cell loss with a single binge exposure in neonatal rats: A stereological study of temporal windows of vulnerability. Alcoholism: Clinical & Experimental Research 21, 738–744.
Goodlett, C. R., Peterson, S. D., Lundahl, K. R. & Pearlman, A. D. (1997) Binge-like alcohol exposure of neonatal rats via intragastric intubation induces both Purkinje cell loss and cortical astrogliosis. Alcoholism: Clinical & Experimental Research 21, 1010–1017.
Gundersen, H. J. G., Bagger, P., Bendtsen, T. F., Evans, S. M., Korbo, L., Marcussen, N., Moller, A., Nielsen, K., Nyengaard, J. R., Pakkenberg, B., Sorensen, F. B., Vesterby, A. & West, M. J. (1988) The new stereological tools: Disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96, 857–881.
Gundersen, H. J. G. & Jensen, E. B. (1987) The efficiency of systematic sampling in stereology and its prediction. Journal of Microscopy 147, 229–263.
Hamre, K. M. & West, J. R. (1993) The effects of the timing of ethanol exposure during the brain growth spurt on the number of cerebellar Purkinje and granule cell nuclear profiles. Alcoholism: Clinical & Experimental Research 17, 610–622.
Harris, S. R., Mackay, L. L. & Osborn, J. A. (1995) Autistic behaviors in offspring of mothers abusing alcohol and other drugs: A series of case reports. Alcoholism: Clinical & Experimental Research 19, 660–665.
Jacobs, J. S. & Miller, M. W. (2001) Proliferation and death of cultured fetal neocortical neurons: Effects of ethanol on the dynamics of cell growth. Journal of Neurocytology 30, 391–401.
Jones, K. L. & Smith, D. W. (1973) Recognition of the fetal alcohol syndrome in early infancy. Lancet 2, 999–1001.
Jones, K. L. & Smith, D. W. (1975) The fetal alcohol syndrome. Teratology 12, 1–10.
Jones, K. L., Smith, D. W., Ulleland, C. H. & Streissguth, A. P. (1973) Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1, 1267.
Kotch, L. E. & Sulik, K. K. (1992) Experimental fetal alcohol syndrome: Proposed pathogenic basis for a variety of associated facial and brain anomalies. American Journal of Medical Genetics 44, 168–176.
Lemoine, P. H., Harousseau, H., Borteyru, J.-P. & Menuet, J.-C. (1968) Les enfants de parents alcooliques: Anomalies observées. A propos de 127 cas. Ouest Medicine 21, 476–482.
Luo, J. & Miller, M. W. (1998) Effects of ethanol on growth factor-mediated proliferation of neural cells. Brain Research Reviews 27, 157–167.
Luo, J. & Miller, M. W. (1999a) Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: Site of ethanol action. Journal of Neuroscience 19, 10014–10025.
Luo, J. & Miller, M. W. (1999b) Transforming growth factor beta1-regulated cell proliferation and expression of neural cell adhesion molecule in B104 neuroblastoma cells: Differential effects of ethanol. Journal of Neurochemistry 72, 2286–2293.
Maier, S. E., Chen, W.J., Miller, J. A. & West, J. R. (1997) Fetal alcohol exposure and temporal vulnerability regional differences in alcohol-induced microencephaly as a function of the timing of binge-like alcohol exposure during rat brain development. Alcoholism: Clinical & Experimental Research 21, 1418–1428.
Maier, S. E., Miller, J. A. & West, J. R. (1999) Prenatal binge-like alcohol exposure in the rat results in region-specific deficits in brain growth. Neurotoxicology & Teratology 21, 285–291.
Marcussen, B. L., Goodlett, C. R., Mahoney, J. C. & West, J. R. (1994) Developing rat Purkinje cells are more vulnerable to alcohol-induced depletion during differentiation than during neurogenesis. Alcohol 11, 147–156.
Miller, M. W. (1986) Effects of alcohol on the generation and migration of cerebral cortical neurons. Science 233, 1308–1311.
Miller, M. W. (1987) Effect of prenatal exposure to alcohol on the distribution and time of origin of corticospinal neurons in the rat. Journal of Comparative Neurology 257, 372–382.
Miller, M. W. (1988) Effect of prenatal exposure to ethanol on the development of cerebral cortex: I. Neuronal generation. Alcoholism: Clinical & Experimental Research 12, 440–449.
Miller, M. W. (1989) Effects of prenatal exposure to ethanol on neocortical development: II. Cell proliferation in the ventricular and subventricular zones of the rat. Journal of Comparative Neurology 287, 326–338.
Miller, M. W. (1992) Effects of prenatal exposure to ethanol on cell proliferation and neuronal migration. In Development of the Central Nervous System: Effects of Alcohol and Opiates (edited by Miller, M. W.) pp. 47–69. NewYork: Wiley-Liss.
Miller, M. W. (1993) Migration of cortical neurons is altered by gestational exposure to ethanol. Alcoholism: Clinical & Experimental Research 17, 304–314.
Miller, M. W. (1995a) Effect of pre-or postnatal exposure to ethanol on the total number of neurons in the principal sensory nucleus of the trigeminal nerve: Cell proliferation and neuronal death. Alcoholism: Clinical & Experimental Research 19, 1359–1363.
Miller, M. W. (1995b) Generation of neuronos in the rat dentate gyrus and hippocampus: Effects of prenatal and postnatal treatment with ethanol. Alcoholism: Clinical & Experimental Research 19, 1500–1509.
Miller, M. W. (1996a) Effect of early exposure to ethanol on the protein and DNA contents of specific brain regions in the rat. Brain Research 734, 286–294.
Miller, M. W. (1996b) Limited ethanol exposure selectively alters the proliferation of precursor cells in the cerebral cortex. Alcoholism: Clinical & Experimental Research 20, 139–143.
Miller, M. W. (1997) Effects of prenatal exposure to ethanol on callosal projection neurons in rat somatosensory cortex. Brain Research 766, 121–128.
Miller, M. W. (1999) A longitudinal study of the effects of prenatal ethanol exposure on neuronal acquisition and death in the principal sensory nucleus of the trigeminal nerve: Interaction with changes induced by transection of the infraorbital nerve. Journal of Neurocytology 28, 999–1015.
Miller, M. W., Astley, S. J. & Clarren, S. K. (1999) Number of axons in the corpus callosum of the mature Macaca nemestrina: Increases caused by prenatal exposure to ethanol. Journal of Comparative Neurology 412, 123–131.
Miller, M. W. & Muller, S. J. (1989) Structure and histogenesis of the principal sensory nucleus of the trigeminal nerve: Effects of prenatal exposure to ethanol. Journal of Comparative Neurology 282, 570–580.
Miller, M. W. & Nowakowski, R. S. (1991) Effect of prenatal exposure to ethanol on the cell cycle kinetics and growth fraction in the proliferative zones of fetal rat cerebral cortex. Alcoholism: Clinical & Experimental Research 15, 229–232.
Mooney, S. M. & Miller, M. W. (1999) Ethanol and neuronal death in the developing brain. Recent Research Developments in Neurochemistry 2, 573–586.
Mooney, S. M., Napper, R. M. & West, J. R. (1996) Long-term effect of postnatal alcohol exposure on the number of cells in the neocortex of the rat: A stereological study. Alcoholism: Clinical & Experimental Research 20, 615–623.
Nanson, J. L. (1992) Autism in fetal alcohol syndrome: A report of six cases. Alcoholism: Clinical & Experimental Research 16, 558–565.
Napper, R. M. & West, J. R. (1995) Permanent neuronal cell loss in the inferior olive of adult rats exposed to alcohol during the brain growth spurt: A stereological investigation. Alcoholism: Clinical & Experimental Research 19, 1321–1326.
Paxinos, G., Huang, X.-F. & Toga, A. W. (2000) The Rhesus Monkey Brain in Stereotaxic Coordinates. San Diego: Academic Press.
Pierce, D. R., Serbus, D. C. & Light, K. E. (1993) Intragastric intubation of alcohol during postnatal development of rats results in selective cell loss in the cerebellum. Alcoholism: Clinical & Experimental Research 17, 1275–1280.
Ramachandran, V., Perez, A., Chen, J., Senthil, D., Schenker, S. & Henderson, G. I. (2001) In utero ethanol exposure causes mitochondrial dysfunction, which can result in apoptotic cell death in fetal brain: A potential role for 4-hydroxynonenal. Alcoholism: Clinical & Experimental Research 25, 862–871.
Rockwood, G. A. & Riley, E. P. (1986) Suckling deficits in rats exposed to alcohol in utero. Teratology 33, 145–151.
Rodier, P. M., Ingram, J. L., Tisdale, B., Nelson, S. & Romano, J. (1996) Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei. Journal of Comparative Neurology 370, 247–261.
Rossig, C., Wasser, S. & Oppermann, P. (1994) Audiologic manifestations in fetal alcohol syndrome assessed by brainstem auditory-evoked potentials. Neuropediatrics 25, 245–249.
Seabold, G. K., Luo, J. & Miller, M. W. (1998) Effect of ethanol on neurotrophin-mediated cell survival and receptor expression in cultures of cortical neurons. Developmental Brain Research 108, 139–145.
Sulik, K. K. & Johnston, M. C. (1983) Sequence of developmental alterations following acute ethanol exposure in mice: Craniofacial features of the fetal alcohol syndrome. American Journal of Anatomy 166, 257–269.
Vigliecca, N. S., Ferreyra Moyano, H. & Molina, J. C. (1986) Acute prenatal alcohol exposure in rats: A behavioral study. Acta Physiologica et Pharmacologica Latinoamericana 36, 463–472.
Zajac, C. S., Bunger, P. C. & Moore, J. C. (1989) Changes in red nucleus neuronal development following maternal alcohol exposure. Teratology 40, 567–570.
Rights and permissions
About this article
Cite this article
Mooney, S.M., Miller, M.W. Episodic exposure to ethanol during development differentially affects brainstem nuclei in the macaque. J Neurocytol 30, 973–982 (2001). https://doi.org/10.1023/A:1021832522701
Issue Date:
DOI: https://doi.org/10.1023/A:1021832522701