Department of Anatomy, Meram Medical Faculty, Selcuk University, Konya, Turkey Investigation of Developmental Toxicity and Teratogenicity of Macrolide Antibiotics in Cultured Rat Embryos A. K. Karabulut 1 *, I. I. Uysal 1 , H. Acar 2 and Z. Fazliogullari 1 Address of authors: Departments of 1 Anatomy and 2 Medical Genetics, Meram Medical Faculty, Selcuk University, Konya 42080, Turkey; *Corresponding author: Tel.: 00 90 332 223 71 17; fax: 00 90 332 223 61 81; e-mail: akkarabulut@yahoo.com With 6 figures and 1 table Received September 2007; accepted for publication December 2007 Summary Macrolides are considered to be one of the safest anti-infec- tive groups in clinical use, with severe adverse reactions being rare. However, there are limited data about their embryo- toxicity and teratogenicity. We aimed to investigate and compare the effects of these agents on embryonic growth and development. Rat embryos were cultured in vitro for 48 h in rat serum. Whole rat serum was used as a culture medium for the control group while different concentrations of spiramycin and azithromycin (1.25–6.25 lg/ml), and clarithromycin (2.5– 30 lg/ml) were added to rat serum for the experimental groups. Dose-dependent effects of macrolides on embryonic developmental parameters were compared using morpholo- gical methods. Embryos were evaluated for the presence of any malformations. After morphological examination of the embryos, total DNA was extracted from the cells using standard procedures to determine fragmentation of nuclear DNA of embryonic cells. When compared with the control embryos, the macrolides significantly decreased all growth and developmental parameters dose dependently. While clarith- romycin was found to cause more developmental toxicity than spiramycin and azithromycin, azitromycin was determined to have more teratogenicity potential. Compared with controls, there was no difference regarding the fragmentation of nuclear DNA of all the agents used. According to these results, when the toxic and teratogenic potential of the used agents compared, because of the lower toxic and teratogenic effects observed with spiramycin, this agent may be preferred for parturients. Introduction Macrolides are an old and well-established class of antimic- robial agents that account for 10–15% of the worldwide oral antibiotic market (Periti et al., 1993). These agents play an important role in the management of infectious diseases (Blondeau et al., 2002). Erythromycin, which was introduced over 50 years ago, was the first macrolide to be used clinically especially as an alternative agent in the treatment of the patients with allergy to beta-lactam agents (Zhanel et al., 2001; Blondeau et al., 2002). However, the pharmacokinetic and adverse events profile of erythromycin MORPHOLOGICAL SCORE 0 10 20 30 40 50 60 WRS 1.25 2.5 3.75 5 6.25 * ** ** *** ** ** SOMITE NUMBER 0 5 10 15 20 25 30 WRS 1.25 2.5 3.75 5 6.25 *** ** ** * YOLK SAC DIAMETER (mm) 0 0.5 1 1.5 2 2.5 3 3.5 WRS 1.25 2.5 3.75 5 6.25 *** ** ** ** CROWN RUMP LENGTH (mm) 0 0.5 1 1.5 2 2.5 3 3.5 WRS 1.25 2.5 3.75 5 6.25 * * *** * Fig. 1. Embryonic growth and development in the presence of spiramycin (lg/ml). Values are mean ± SEM. Asterisks indicate significant difference from control values at *P < 0.05, ** P < 0.01, *** P < 0.001. Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag Anat. Histol. Embryol. 37, 369–375 (2008) doi: 10.1111/j.1439-0264.2008.00861.x ISSN 0340–2096