Treatment of pregnant Sprague-Dawley rats with retinoic acid or etretinate pregnancy day 8.5 to 9.0 resulted in craniofacial defects in 100% of the embryos. A morphologic investigation of the malformations occurring in the ear was performed. Outer ears were missing, microtic, low-placed, and dorsally situated. External acoustic meatus was short or absent. Middle ear structures were delayed in differentiation, middle ear ossicle primordia were hypoplastic and malformed, the stapedial artery and facial nerve were hypoplastic, and their relation to the stapes was variable. In the inner ear, the otic capsule was thick, the cochlea had fewer turns and the semicircular ducts showed poor differentiation.
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References
1.
LammerEJChenDTHoarRM. Retinoic acid embryopathy. N Engl J Med1985; 313:837–41.
2.
BenkePJ. The isotretinoin teratogen syndrome. JAMA1984; 251:3267–9.
3.
HappleRTaupeYBounameauxYFischT. Teratogene Wirkung von Etretinat beim Menschen. Dtsch Med Wochenschr1984; 109:1476–80.
4.
ShenefeltRE. Morphogenesis of malformations in hamsters caused by retinoic acid: Relations to dose and stage at treatment. Teratology1972; 5:103–18.
5.
WileyMJCauwenbergsPTaylorIM. Effects of retinoic acid on the development of the facial skeleton in hamsters: Early changes involving cranial neural crest cells. Acta Anat1983; 116:180–92.
6.
GranströmGKullaa-MikkonenA. Studies on craniofacial malformations of experimental first and second branchial arch syndromes. Scand J Plast Reconstr Surg1990; 24:3–12.
7.
GeelenJAE. Hypervitaminosis A induced teratogenesis. CRC Crit Rev Toxicol1979; 6:351–75.
8.
ColburnWAVaneFMShorterHJ. Pharmacokinetics of isotretinoin and its major blood metabolite following a single oral dose to man. Eur J Clin Pharmacol1983; 24:689–94.
9.
NordlindKThybergJ. In vitro effects of 13-cis-retinoic acid and etretinate on DNA synthesis and fine structure of guinea pig and human lymphoid cells. Int Arch Allergy Appl Immunol1983; 71:363–7.
10.
EschenbruchMOttoAMde AsuaLJ. Retinoic acid enhances the initiation of DNA synthesis stimulated by prostaglandin F2α in Swiss 3T3 cells. Cell Biol Int Rep1982; 6:961–7.
11.
EdwardsMKSMcBurneyMW. The concentration of retinoic acid determines the differentiated cell types formed by a teratocarcinoma cell line. Dev Biol1983; 98:187–91.
12.
RosaFW. Teratogenicity of isotretinoin. Lancet1983; 2:513.
13.
FDA Drug Bulletin1983; 13:21–2.
14.
ParavicinUBusslingerA. Etretinate and isotretinoin, two retinoids with different pharmacokinetic profiles. In: ConcliffeWJMillerAJ, eds. Retinoid therapy. Lancaster, England: MTP Press, 1984: 11–34.
15.
HummlerHSchupbachME. Studies in reproductive toxicology and mutagenicity with Ro 10-9359. In: FarberEMGrupperCPolanoMK, eds. Retinoids: Advances in basic research and therapy. Berlin: Springer-Verlag, 1981: 49–58.
16.
HamiltonWJBoydJDMossmanHW. Human embryology. London: Williams and Wilkins, 1978: 509–16.
17.
McCredieJ. Thalidomide and congenital charcots joints. Lancet1973; ii:1058–61.
18.
McCredieJ. Embryological neuropathy: A hypothesis of neural injury as the pathogenesis of congenital malformations. Med J Aust1974; 1:159–63.
19.
JohnstonMC. The neural crest in abnormalities of the face and brain. In: BergsmaA, ed. Morphogenesis and malformations of the face and brain. New York: Liss Co., 1975: 1–18.
20.
JohnstonMCMorrisGMKushnerDC. Abnormal organogenesis of facial structures. In: WilsonMFraserG, eds. Handbook of teratology. Vol. 2 — Mechanisms and pathogenesis. New York: Plenum Press, 1977: 421–51.
21.
GrabowskiCT. Physiological changes in the blood stream of chick embryos exposed to teratogenic doses of hypoxia. Dev Biol1966; 13:199–213.
22.
PoswilloDE. Hemorrhage in development of the face. Birth Defects1975; 11:61–81.
23.
PoswilloDE. Orofacial malformations. Proc R Soc Med1974; 67:343–9.
GranströmGKullaa-MikkonenAZellinG. Malformations of the maxillofacial region induced by retinoids in an experimental system. Int J Oral Maxillofac Surg1990; 19:167–71.
