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Role of Apoptosis in Retinoic Acid-Induced Cleft Palate

Choi, Jong Woo MD; Park, Hyung Woo MD, PhD; Kwon, Yoon Jeong PhD; Park, Beyoung Yoon MD, PhD

doi: 10.1097/SCS.0b013e318208ba10
Original Articles

Purpose: Although the mechanism by which retinoic acid (RA) induces cleft palate has been intensely investigated, some controversies remain. Some researchers argue that RA inhibits apoptosis, resulting in a failure of palatal shelves to fuse, whereas others propose that RA disrupts elevation or retards the growth of palatal shelves. This study investigated the mechanism underlying RA-induced formation of cleft palate in the rat, focusing mainly on the role of apoptosis.

Methods: Using an RA-induced cleft palate model of Sprague-Dawley rats described in our previous study, we examined a total of 92 embryos. Retinoic acid was injected intraperitoneally in experimental group animals on embryonic day 11 (D11), a time when our previous study indicated that RA-induced cleft palate was maximally developed. Control animals were treated with normal saline mixed with sesame oil. Timed pregnant rats were killed by an overdose of ether on D13, D14, D15, D16, and D17, and 8 sections were prepared from the anterior to the posterior of the palate. Growth of palatal shelves was evaluated histologically by examining sections stained with hematoxylin-eosin, periodic acid-Schiff, trichrome, and cresyl violet. Differences in apoptosis were monitored using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays.

Results: Histologic examinations revealed underdevelopment of palatal shelves in the experimental group compared with the control group. In the RA-treated group, the overall process of palatal shelf development was delayed 1 day, and palatal elevation was observed. In hard-palate areas of both groups, apoptosis was maximal immediately after the fusion of palatal shelves. In the soft-palate areas, the saline-treated group showed fusion of palatal shelves, whereas the RA-treated group showed retarded growth of palatal shelves that resulted in failure of palatal fusion. Moreover, apoptosis occurred before palatal contact.

Conclusions: Apoptotic manifestations did not differ between RA-induced cleft palates and control palates, suggesting that apoptosis makes a minimal contribution to the cleft palate formed in response to RA. Instead, growth retardation of the palatal shelves appears to play a major role in RA-induced cleft palate.

From the Department of Plastic and Reconstructive Surgery, Ulsan University, College of Medicine, Asan Medical Center, Yonsei University, College of Medicine, Severance Hospital, Seoul, Korea.

Received April 19, 2010.

Accepted for publication November 14, 2010.

Address correspondence and reprint requests to Jong-Woo Choi, MD, Department of Plastic & Reconstructive Surgery, University of Ulsan College of Medicine, Asan Medical Center, 388-1 PungNap-2Dong SongPaGu, Seoul, Korea 138-736; E-mail:

The authors report no conflicts of interest.

© 2011 Mutaz B. Habal, MD