Sex-related differences in procarbazine-induced cleft palate and microgenia and the anti-teratogenic effect of prenatal folic acid supplementation in rats

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Summary

Sex-related differences in the frequency of cleft palates and microgenia in rat fetuses prenatally treated with procarbazine (200 mg/kg on day 14 of gestation (GD14), group 1), and the anti-teratogenic effect of prenatal folic acid supplementation (4 mg/kg on GD14 through GD17, group 2) were studied in LEW.1A rats. In group 1, complete clefts were observed in 69% of the male and in 36% of the female fetuses while incomplete clefts (present only in the hard palate) were exhibited by 31% of the males and 43% of the females. Microgenia occurred in all males but only in 64% of the female fetuses. In group 2, the prenatal folic acid supplementation significantly reduced the occurrence frequency of complete clefts to 9% in males and to 0% in females. In contrast, incomplete clefts increased to 82% in males and 91% in females. Microgenias were reduced to 73% and 57% in male and female fetuses, respectively. Since incomplete clefts present in the hard palate are assumed to be residues of spontaneous intra-uterine repair processes of exogenously induced complete palatal clefts, we conclude that prenatal supplementation with folic acid at a dose of 4 mg/kg promotes the intra-uterine repair of cleft palates and offers a partial protection against procarbazine teratogenicity. Furthermore, it is deduced that gender-specific differences exist in the susceptibility to procarbazine and in the anti-teratogenic effect of folic acid on procarbazine-induced microgenia.

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      In general, an exogenous stimulus is needed for these conditions to become manifest (Gabka, 1981). Numerous experimental and clinical studies have been performed to investigate reduction of the manifestation rate of these craniofacial malformations by supplementation with B vitamins (Schubert et al., 2002; Schubert and Krost, 2006), multivitamins (Czeizel, 1993; Botto et al., 2002), and/or folic acid (Malek et al., 2003; Bienengräber et al., 2001; Tolarová and Harris, 1995), beginning before fertilization and during the first trimester of pregnancy. Cleft lip with or without cleft palate (CL/P) and cleft palate (CP) have an evident and constant difference in sex ratios in human beings.

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