Eur J Anat, 9 (1): 1-16 (2005)

Palatal abnormalities in the developing rat induced by retinoic acid

Gunston E., Emmanouil-Nikoloussi E.-N., Moxham B.J.

Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom; Laboratory of Histology-Embryology and Anthropology, Faculty of Medicine, Aristotle University of Thessaloniki, Greece; Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3US, United Kingdom

ABSTRACT Palatogenesis is a complex developmental process that requires two main events: elevation and then fusion of the palatal shelves. These processes are disrupted by teratogens such as retinoic acid (RA) and genetic defects, resulting in various malformations (including cleft palate). Using histological and immunohistochemical techniques, the effects of different isomers of RA, administered in various concentrations to pregnant rats on different gestational days (GD), were assessed from observations of the state of palatal development on GD 18 in foetuses without exencephaly. Varying degrees of clefting of the palate were observed, from failure of elevation of the palatal shelves to failure of fusion in the midline. This study shows that all-trans-RA is the most teratogenic RA isomer in terms of rat palatal abnormalities. It also supports previous findings that the timing of administration of all-trans-RA is more critical than the concentration, with treatment between GD 10 and 10.5 having the most severe effects. Previous histological studies also suggested that RA is associated with the appearance of ectopic cartilages within the developing palate of foetuses showing exencephaly. In this investigation, immunohistochemical labelling of the foetal material with antibodies that recognise epitopes present in link proteins 1, 2, and 3 (8A4), chondroitin-4-sulphate stubs (2B6), and G1 and chondroitin sulphate attachments (7D1) present in aggrecan (associated with hyaluronan in cartilage) showed no signs of ectopic cartilage formation within the palate at GD18. Internal controls of the cartilages of the nasal septum, vomeronasal cartilage, and Merkel's cartilage labelled intensely and appeared morphologically normal.

Keywords: aggrecan, chondroitin 4 sulfate, chondroitin sulfate, epitope, etretin, hyaluronic acid, isotretinoin, link protein, retinoic acid, teratogenic agent, animal experiment, animal model, animal tissue, article, cartilage, cleft palate, concentration response, controlled study, craniofacial development, drug effect, ectopic tissue, exencephaly, female, fetus, gestational age, histopathology, immunohistochemistry, isomer, nonhuman, nose septum, palate malformation, rat, rat strain, teratogenicity, vomeronasal organ