Protective effect of maternal vitamin E supplementation on phenytoin-induced teratogenicity in rat pups

Year 2015, Volume: 9 Issue: 1, 1 - 12, 20.06.2015

Tarek M. Essa Attia M. Gabr Abd Elrahman E. Mohamed Abdelraheim M. A. Meki

https://doi.org/10.2399/ana.14.045

Abstract

Objectives: Phenytoin teratogenicity is induced by embryonic hypoxia as a result of generation of reactive oxygen species. Antioxidants are effective in treating conditions associated with oxidative damage. This study investigated the possible protective effect of vitamin E maternal supplementation on oxidative damage, and the morphological and morphometric changes induced by phenytoin in pups.

Methods: Five groups of female rats were utilized. All the treatments were injected intraperitoneal. Groups I and II were injected with saline and olive oil, respectively. Group III was injected with vitamin E (0.5 g/kg BW/day) from day one to day 20 of gestation. Group IV was injected with phenytoin (150 mg/kg BW/day) from day 6 to day 18 of gestation. Group V was injected with
phenytoin and vitamin E. The N-acetyl D-glucosaminidase, malondialdehyde, and glutathione were determined as markers of tissue damage. The skeletons of pups were examined after staining with alizarin red-S.

Results: Phenytoin significantly increased oxidative stress indices in maternal plasma and tissues and in pup tissues. This was associated with a significant decrease in the weight, length and number of pups. Moreover, there were maxillary hypoplasia and skeletal anomalies. Co-administration of vitamin E with phenytoin reduced oxidative damage with significant increase in the weight, length and number of pups. Reduction in maxillary hypoplasia and skeletal anomalies were observed.

Conclusion: Vitamin E maternal supplementation has significant effect in the reduction of the anomalies induced by phenytoin in pups. 

Keywords

maxillary hypoplasia, oxidative stress, phenytoin, rats, skeletal anomalies

References

• Wells PG, McCallum GP, Chen CS, Henderson JT, Lee CJ, Perstin J, Preston TJ, Wiley MJ, Wong AW. Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmen- tal deficits, and cancer. Toxicol Sci 2009;108:4–18.
• Thompson J, Doi T, Power E, Balasubramanian I, Puri P, Bannigan J. Evidence against a direct role for oxidative stress in cadmium- induced axial malformation in the chick embryo. Toxicol Appl Pharmacol 2010;243:390–8.
• Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. In J Biochem Cell Biol 2007;39:44–84.
• Hansen JM, Harris KK, Philbert MA, Harris C. Thalidomide modulates nuclear redox status and preferentially depletes glu- tathione in rabbit limb versus rat limb. J Pharmacol Exp Ther 2002;300:768–76.
• Wells PG, Kim PM, Laposa RR, Nicol ChJ, Parman T, Winn LM. Oxidative damage in chemical teratogenesis. Mutat Res 1997; 396:65–78.
• Ono H, Sakamoto A, Sakura N. Plasma total glutathione concentra- tions in epileptic patients taking anticonvulsants. Clin Chim Acta 2000;298:135–43.
• Mahle C, Dasgupta A. Decreased total antioxidant capacity and elevated lipid hydroperoxide concentrations in sera of epileptic patients receiving phenytoin. Life Sci 1997;61:437–43.
• Winn LM, Kim PM, Nickoloff JA. Oxidative stress-induced homol- ogous recombination as a novel mechanism for phenytoin-initiated toxicity. J Pharmacol Exp Ther 2003;306:523–37.
• Navarova J, Ujhazy E, Dubovicky M, Mach M. Phenytoin induced oxidative stress in pre-and postnatal rat development – Effect of vitamin E on selective biochemical variables. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2005;149:325–8.
• Bhuller Y, Jeng W, Wells PG. Variable in vivo embryoprotective role for ataxia-telangiectasia-mutated against constitutive and pheny- toin-enhanced oxidative stress in atm knockout mice. Toxicol Sci 2006;93:146–55.
• Owoeye O, Adedara IA, Bakare OS, Adeyemo OA, Egun C, Farombi EO. Kolaviron and vitamin E ameliorate hematotoxicity and oxida- tive stress in brains of prepubertal rats treated with an anticonvulsant phenytoin. Toxicol Mech Methods 2014;24:353–61.
• Owoeye O, Adedara IA, Adeyemo OA, Bakare OS, Egun C, Farombi EO. Modulatory role of kolaviron in phenytoin-induced hepatic and testicular dysfunctions in Wistar rats. J Diet Suppl 2015;12:105–17.
• Soysal H, Unur E, Duzler A, Karaca O, Ekinci N. Effects of intraperitoneal administration of the phenytoin on the skeletal sys- tem of rat fetus. Seizure 2011;20:187–193.
• Giavini E, Menegola E. Gene-teratogen chemically induced inter- actions in congenital malformations. Biol Neonate 2004;85:73–81.
• Webster WS, Howe AM, Abela D, Oakes DJ. The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin. Curr Pharm Des 2006;12:1431–48.
• Abela D, Howe AM, Oakes DA, Webster WS. Maternal antioxi- dant supplementation does not reduce the incidence of phenytoin- induced cleft lip and related malformations in rats. Birth Defects Res B Dev Reprod Toxicol 2005;74:201–6.
• Nilson MF, Ritchie H, Webster WS. The effect on rat embryonic heart rate of Na+, K+, and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age. Birth Defects Res B Dev Peprod Toxicol 2013;98:416–27.
• Danielsson BR, Azarbayjani F, Skold AC, Webster WS. Initiation of phenytoin teratogenesis: pharmacologically induced embryonic bradycardia and arrhythmia resulting in hypoxia and possible free radical damage at reoxygenation. Teratology 1997;4:271–81.
• Sun J, Chen Y, Li M, Ge Z. Role of antioxidant enzyme on ioniz- ing radiation resistance. Free Rad Biol Med 1998;24:586–93.
• Kappus H, Diplock AT. Tolerance and safety of vitamin E: a tox- icological position report. Free Rad Biol Med 1992;13:55–74.
• Cohen-Kerem R, Koren G. Antioxidants and fetal protection against ethanol teratogenicity. I. Review of the experimental data and implications to humans. Neurotoxicol Teratol 2003;25:1–9.
• Sastre J, Asens M, Rodrigo F, Pallardo FV, Vento M, Vina J. Antioxidant administration to the mother prevents oxidative stress associated with birth in the neonatal rat. Life Sci 1994;54:2055–9.
• Turgut M, Baflaran O, Cekmen M, Karatafl F, Kurt A, Aygün AD. Oxidant and antioxidant levels in preterm newborns with idiopath- ic hyperbilirubinaemia. J Paediatr Child Health 2004;40:633–7.
• Rugh R. The mouse: its reproduction and development. 2nd ed. Minneapolis (MN): Burgess Publishing Company; 1968. p. 269–99.
• Smerdely P, Pitsiavas V, Boyages SC. Methimazole inhibits FTRL-5 thyroid cell proliferation by inducing-S-phase arrest of cell cycle. Endocrinology 1993;133:2403–6.
• Patton J, Kaufman H. Timing of ossification of limb bones and growth rates of various long bones of the fore and hind limbs of the prenatal and early postnatal laboratory mouse. J Anat 1995;186: 175–85.
• Ronning O, Kantoma T. The growth pattern of the clavicle in the rat. J Anat 1988;159:173–9.
• Culling CFA. Handbook of histopathological and histochemical techniques. 3rd ed. London: Butterworths; 1974.
• Erdogan D, Kadıo¤lu D, Peker T. Demostration of congenital anomalies in the joints of the forelimbs and hindlimbs caused by sev- eral pharmacological agents. Anat Histol Embryol 1996;25:263–7.
• Young AD, Phipps DE, Astroff AB. Large-scale double staining of rat fetal skeletons using alizarin red S and alcian blue. Teratology 2000;61:273–6.
• Duzler A, Cakır A. [Postnatal development of the thoracic limb bones in New Zealand rabbit.] Ankara Üniversitesi Veteriner Fakültesi Dergisi 2003;50:165–72. [Turkish]
• Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measure- ment with the Folin phenol reagent. J Biol Chem 1951;193:265–75.
• Thayer WS. Serum lipid peroxides in rats treated chronically with adriamycin. Biochem Pharmacol 1984;33:2259–63.
• Dutta P, Seirafi J, Halpin D, Pinto J, Rivlin R. Acute ethanol expo- sure alters hepatic glutathione metabolism in riboflavin deficiency. Alcohol 1995;12:43–7.
• Winn LM, Wells PG. Evidence for embryonic prostaglandin H syn- thase-catalyzed bioactivation and reactive oxygen species mediated oxidation of cellular macromolecules in phenytoin and benzo[a] pyrene teratogenesis. Free Radic Biol Med 1997;22:607–21.
• Kehrer JP, Lund LG. Cellular reducing equivalents and oxidative stress. Free Radical Biol Med 1994;17:65–75.
• Dubovicky M, Ujhazy E, Kovacovsk P, Navarova J, Jurani M, Šoltés L. Effect of melatonin on eurobehavioral dysfunctions induced by intrauterine hypoxia in rats. Cent Eur J Public Health 2004;12 Suppl:S23–5.
• Navarova J, Ujhazy E, Dubovicky M, Mach M. Effect of melatonin on biochemical variables induced by phenytoin in organs of moth- ers, foetuses and offsprings of rats. Cent Eur J Public Health 2004;12 Suppl:S67–9.
• Ujhazy E, Mach M, Dubovicky M, Navarova J, Soltes L, Juranek I, Brucknerova I, Zeman M. Effect of melatonin and stobadine on maternal and embryofoetal toxicity in rats due to intrauterine hypoxia induced by phenytoin administration. Cent Eur J Public Health 2004;12 Suppl:S83–6.
• Reeta KH, Mehla J, Gupta YK. Curcumin is protective against phenytoin-induced cognitive impairment and oxidative stress in rats. Brain Research 2009;1301:52–60.
• Liu CS, Wu HM, Kao SH, Wei YH. Phenytoin-mediated oxida- tive stress in serum of female epileptics: a possible pathogenesis in the fetal hydantoin syndrome. Hum Exp Toxicol 1997;16:177–81.
• Wellfelt K, Skold AC, Wallin A, Danielsson BR. Teratogenicity of the class III antiarrhythmic drug almokalant: role of hypoxia and reactive oxygen species. Reprod Toxicol 1999;13:93–101.
• Pennell PB. Pregnancy in women who have epilepsy. Neurol Clin 2004;22:799–820.
• Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, Mawer G, Pennell PB, Smith JC, Wolff MC; NEAD Study Group. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006;67:407–12.
• Ata MM, Sullivan FM. Effect of prenatal phenytoin treatment on postnatal development Br J Pharmacol 1977;59:494P.
• Eluma FO, Sucheston ME, Hayes TG, Paulson RB. Teratogenic effects of dosage levels and time of administration of carpamazepine, sodium valproate and diphenylhydantoin on craniofacial development in the CD-1 mouse fetus. J Craniofac Gen Dev Biol 1984;4:191–210.
• Hicks HE, Spalding PM, Banes AJ. The water, DNA, collagen and noncollagen protein contents in embryos after maternal adminis- tration of a teratogenic dose of phenytoin. Toxicol Lett 1985;25: 41–6.
• Hansen DK, Billings RE. Effect of route of administration on phenytoin teratogenicity in A/J mice. J Craniofac Gen Dev Biol 1986;6:131–8.
• Sulik KK, Johnston MC, Ambrose LJ, Dorgan D. Phenytoin dilan- tin-induced cleft lip and palate in A/J mice: a scanning and transmis- sion electron microscopic study. Anat Rec 1979;195:243–55.
• Millicovsky G, Johnston MC. Maternal hypoxia greatly reduces the incidence of phenytoin-induced cleft lip and palate in A/J mice. Science 1981;212:671–72.
• Millicovsky G, Johnston MC. Hyperoxia and hypoxia in pregnan- cy: simple experimental manipulation alters the incidence of cleft lip and palate in Cl/Fr mice. Proc Natl Acad Sci U S A 1981;78:5722–23.
• Sullivan FM, Mcelhatton PR. Teratogenic activity of the antiepileptic drugs phenobarbital. phenytoin and primidone in mice. Toxicol Appl Pharmacol 1975;34:271–82.
• Harbison RD, Becker BA. Diphenylhydantoin teratogenicity in rats. Toxicol Appl Pharmacol 1972;22:193–200.
• Hanson JW. Teratogen update: fetal hydantoin effects. Teratology 1986;33:349–53.
• Kim SH, Lee IC, Baek HS, Lim JH, Moon C, Shin DH, Kim SH, Park SC, Kim JC. Dose-response effects of diphenylhydantoin on pregnant dams and embryo-fetal development in rats. Birth Defects Res B Dev Reprod Toxicol 2012;95:337–45.
• Mansoor MA, Sewelam AS, Abdul Rahman MM, Sabry MA. A model for the study of induced skeletal anomalies in albino rat fetuses. J Am Sci 2014;10:181–90.
• Wong M, Wells PG. Modulation of embryonic glutathione reduc- tase and phenytoin teratogenicity by 1, 3-bis(2-chloroethyl)-1- nitrosourea. J Pharmacol Exp Ther 1989;250:336–42.
• Winn LM, Wells PG. Maternal administration of superoxide dis- mutase and catalase in phenytoin teratogenicity. Free Rad Biol Med 1999;26:266–74.
• Capper JL, Wilkinson RG, Kasapidou E, Pattinson SE, Mackenzie AM, Sinclair LA. The effect of dietary vitamin E and fatty acid sup- plementation of pregnant and lactating ewes on placental and mam- mary transfer of vitamin E to the lamb. Br J Nutr 2005;93:549–57.
• Boskovic R, Gargaun L, Oren D, Djulus J, Koren G. Pregnancy out- come following high doses of Vitamin E supplementation. Reprod Toxicol 2005;20:85–8. Correspondence to: Tarek Mohamed Essa, MD Department of Anatomy, Faculty of Medicine, Alexandria University, Alexandria, Egypt Phone: [phone] e-mail: [e-mail] Conflict of interest statement: No conflicts declared.
• This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC
• ND0) Licence (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any
• medium, provided the original work is properly cited. Please cite this article as: Essa TM, Gabr AM, Mohamed AEE, Meki AMA. Protective effect of mater
• nal vitamin E supplementation on phenytoin-induced teratogenicity in rat pups. Anatomy 2015;9(1):1–12.