beneath the table to the abstract. Use the Word Count cmd under Utilites menu for counting Significance The cellular events leading to birth defects following exposure to an environmental agent are largely unknown. However, recent technological advances in molecular and cellular biology have provided new tools to study the pathogenesis and mechanisms of teratogen-induced dysmorphogenesis. Objectives The present study was carried out to study the molecular/cellular consequences of embryonic exposure to a known human teratogen, 13-cis retinoic acid (cRA, isotretinoin, Accutane) in the cynomolgus monkey. We have previously demonstrated that the human cRA syndrome can be modeled in this species due to striking similarities in malformations, teratogenic dose, and sensitive period during early pregnancy. Results The hallmark defects of the cRA syndrome in the cynomolgus model are external (auricle) and middle (malleus, incus and zygomatic arch) ear malformations which occur at relatively the same incidence. Immunohistochemistry using antibodies to cellular retinoic acid binding protein-1 on embryos exposed to teratogenic doses of cRA showed abnormal migration patterns of cranial neural crest cells which contribute to the pharyngeal arches and cranial nerves/ganglia. Scanning electron microscopy indicated hypoplasia and/or abnormal development of the first and second pharyngeal arches. Neurofilament immunohistochemistry indicated fusion of the facial (V) and glossopharyngeal (IX) cranial nerves. These observed alterations are likely to be a pathogenic event underlying the cRA-induced malformations of the external and middle ears which are derived from the mesenchymal derivatives of neural crest cells which populate the first two pharyngeal arches. Future Directions Use of additional molecular markers combined with morphometry to study gross and histological alterations in cerebellar development after cRA exposure. KEY WORDS retinoids, birth defects, cranial nerves, neural crest cells FUNDING NIH Grant No. RR00169 and F. Hoffmann-La Roche PUBLICATIONS Makori, N., Peterson, P.E., Blankenship, T.N., Dillard-Telm, L., Hummler, H., and Hendrickx, A.G. Effects of 13-cis-retinoic acid on hindbrain and craniofacial morphogenesis in long-tailed macaques (Macaca fascicularis). J. Med. Primatol. 27:210-219, 1998. Hendrickx, A.G. and Peterson, P.E. """"""""Neural Crest Cell Migration"""""""" pp. 225-243. In Handbook of Developmental Neurotoxicology (Slikker, W.J., Jr. and Chang, W., eds). Academic Press, 1998. Makori, N., X. Wei, P.E. Peterson, and A.G. Hendrickx. Hoxb-1 and Krox-20 immunolocalization in abnormally developing hindbrain of macaque embryos exposed to 13-cis-retinoic acid. Teratology 57(4/5) 224, 1998 (abstract). Wei, X., P. Peterson, N. Makori, H. Hummler, and A.G. Hendrickx. Retinoic acid embryopathy characterized by ear duplication in a primate model. Teratology 57 (4/5):192, 1998 (abstract).
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