Teratogenic effects of silymarin on mouse fetuses

Document Type : Original Research Article

Authors

1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Anatomy, Birjand University of Medical Sciences, Birjand, Iran

4 Department of Pathology, Imam-Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

5 Pharmaceutical Research Center, Pharmacy school, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract


Objective: Silybum marianum has been used for centuries in herbal medicine for treatment of liver diseases. Currently, there is no data available on the possible effects of silymarin on fetal development. This study aimed to investigate the teratogenic effect of silymarin on BALB/c mice fetuses.
Materials and Methods: A total of 40 pregnant mice were divided into 4 groups of 10 mice each. Three groups received silymarin at three different doses of 50, 100 and 200 mg/kg/day during gestational days (GDs). The control group received normal saline and tween (solvent). Dams were sacrificed on GD 18 and all fetuses were examined for gross malformations, size and body weight. Malformed fetuses were double stained with alizarin red and alcian blue.
Results: Silymarin administration at all doses resulted in reduction of the mean fetal body weights. The abnormalities included limb, vertebral column and craniofacial malformations. Craniofacial malformations were the most common abnormalities, but they were not observed in a dose-dependent manner. The percentage of fetal resorption significantly increased (up to 15%) in all treatment groups.
Conclusion: Based on our results, silymarin, especially at high doses can lead to fetal resorption, intrauterine growth retardation and limb, vertebral column and craniofacial abnormalities. More precise studies should be conducted about the teratogenic effects of herbal medicine investigating the underlying mechanisms. Thus, caution should be taken when administering S. marianum to pregnant woman.

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References

Afshar, M, Moallem S A, Mohammadpour A H, Shiravi A, Jalalian S M,Golalipour J. 2010. Teratogenic effects of carbamazepine on embryonic eye development in pregnant mice. Cutan Ocul Toxicol, 29: 10-15.
Ahmadi-Ashtiani, H, Allameh A, Rastegar H, Soleimani M,Barkhordari E. 2012. Inhibition of cyclooxygenase-2 and inducible nitric oxide synthase by silymarin in proliferating mesenchymal stem cells: comparison with glutathione modifiers. J Nat Med, 66: 85-94.
Ahmadi-ashtiani, H, Rezazadeh S, Safipourian K, Afraz K, Khaki A,Rastegar H. 2010. Study the Effects of Oral Administration of Silymarin in Preventing Consequences of Ethanol on Liver during Pregnancy. J Med Plants, 9: 143-150.
Badawy, G, El-Sayyad H L,Al-Shahar E E. 2011. Maternal and neonatal toxicities induced by three antirheumatic drugs in albino rats. J Am Sci, 7: 783-793.
Burdan, F, Dudka J, Szumilo J, Korobowicz A,Klepacz L. 2003. Prenatal effects of DuP-697-the irreversible, highly selective cyclooxygenase-2 inhibitor. Reprod Toxicol, 17: 413-419.
Burdan, F, Pliszczynska-Steuden M, Rozylo-Kalinowska I, Chalas A, Rozylo T K, Staroslawska E, Klepacz R,Szumilo J. 2011. Developmental outcome after exposure to cyclooxygenase inhibitors during pregnancy and lactation. Reprod Toxicol, 32: 407-417.
Burdan, F, Szumilo J,Klepacz R. 2009. Maternal toxicity of nonsteroidal anti-inflammatory drugs as an important factor affecting prenatal development. Reprod Toxicol, 28: 239-244.
Campos, R, Garrido A, Guerra R,Valenzuela A. 1989. Silibinin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55: 417-419.
Chan, L Y, Chiu P Y, Siu S S,Lau T K. 2001. A study of diclofenac-induced teratogenicity during organogenesis using a whole rat embryo culture model. Hum Reprod, 16: 2390-2393.
Etemad, L, Jafarian A H,Moallem S A. . Pathogenesis of Pregabalin-Induced Limb Defects in Mouse Embryos. J Pharm Pharm Sci, 18: 882 - 889.
Fraschini, F, Demartini G,Esposti D. . Pharmacology of Silymarin. Clin Drug Investig, 22: 51-65.
Fukushima, R, Kanamori S, Hirashiba M, Hishikawa A, Muranaka R I, Kaneto M, Nakamura K,Kato I. . Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reprod Toxicol, 24: 310-316.
Giannola, C, Buogo F, Forestiere G, Scaffidi L, Ferrigno V,Scaffidi A. 1985. A two-center study on the effects of silymarin in pregnant women and adult patients with so-called minor hepatic insufficiency. Clin Ter, 114: 129-135.
Gilroy, D W, Tomlinson A, Greenslade K, Seed M P,Willoughby D A. 1998. The effects of cyclooxygenase 2 inhibitors on cartilage erosion and bone loss in a model of Mycobacterium tuberculosis-induced monoarticular arthritis in the rat. Inflammation, 22: 509-519.
Karimi, G, Vahabzadeh M, Lari P, Rashedinia M,Moshiri M. 2011. Silymarin, a promising pharmacological agent for treatment of diseases. Iran J Basic Med Sci, 14: 308-317.
Kasim, M J, Zheen A A, Intesar T N,Saad Abdul R H. 2009. Dose-dependent anti-inflammatory effect of silymarin in experimental animal model of chronic inflammation. Iraqi J Pharm Sci, 3: 242-247.
Kaur, A K, Wahi A K, Brijesh K, Bhandari A,Prasad N. 2011. Milk thistle (Silybum marianum): A review. IJPRD 3: 1-10.
Kimmel, C A,Trammell C. 1981. A rapid procedure for routine double staining of cartilage and bone in fetal and adult animals. Stain Technol, 56: 271-273.
Mahabady, M K,Varzi H N. 2011. Prophylactic Effects of Silymarin and Vitamin E on Cyclophosphamide-Induced Skeletal Malformations in Rat Embryos. World Appl Sci J, 12: 636-641.
Malekinejad, H, Taheri-Broujerdi M, Moradi M,Tabatabaie S H. 2011. Silymarin potentiates the antinociceptive effect of morphine in mice. Phytother Res, 25: 250-255.
Mallikarjuna, G, Dhanalakshmi S, Singh R P, Agarwal C,Agarwal R. 2004. Silibinin protects against photocarcinogenesis via modulation of cell cycle regulators, mitogen-activated protein kinases, and Akt signaling. Cancer Res, 64: 6349-6356.
Metcalfe, A D, Hunter H R, Bloor D J, Lieberman B A, Picton H M, Leese H J, Kimber S J,Brison D R. 2004. Expression of 11 members of the BCL-2 family of apoptosis regulatory molecules during human preimplantation embryo development and fragmentation. Mol Reprod Dev, 68: 35-50.
Muriel, P, Garciapina T, Perez-Alvarez V,Mourelle M. 1992. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol 12: 439-442.
Nwadinigwe, C U,Anyaehie U E. 2007. Effects of cyclooxygenase inhibitors on bone and cartilage metabolism. Niger J Med, 16: 290-294.
Polyak, S J, Ferenci P,Pawlotsky J M. 2013. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology, 57: 1262-1271.
Pradhan, S C,Girish C. 2006. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res, 124: 491-504.
Sharma, m, Anwer T, Pillai K K, Haque S H, A K Najmi A K,Sultana Y. 2008. Silymarin, a flavonoid antioxidant, protects streptozotocin-induced lipid peroxidation and β-Cell damage in rat pancreas. Orient Pharm Exp Med, 8: 146-153.
Sorní, C, Sánchez R, Pellicer P,Andrés J P. 2005. Leflunomide: assessing teratogenic risk during the first trimester of pregnancy. Farm Hospital, 29: 265-268.
Torchinsky, A, Fein A,Toder V. 2005. Teratogen-Induced Apoptotic Cell Death: Does the Apoptotic Machinery Act As a Protector of Embryos Exposed to Teratogens? Birth Defects Res C, 75: 353-361.
Urban, M. 2000. COX-2 specific inhibitors offer improved advantages over traditional NSAIDs. Orthopedics, 23: S761-764.
Woo, S M, Min K J, Kim S, Park  J W, Kim D E, Chun K S, Kim Y H, Lee T J, Kim S H, Choi Y H, Chang J S,Kwon T K. 2014. Silibinin induces apoptosis of HT29 colon carcinoma cells through early growth response-1 (EGR-1)-mediated non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) up-regulation. Chem Biol Interact, 25: 36-43.
Avicenna Journal of Phytomedicine
Volume 6, Issue 5
September and October 2016
Pages 542-549

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