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Effects of Spirulina on Cyclophosphamide-Induced Ovarian Toxicity in Rats: Biochemical and Histomorphometric Evaluation of the Ovary

DOI: 10.1155/2013/764262

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Cyclophosphamide (Cyc) is known to cause ovotoxicity and infertility in women. Our aim is to investigate the possible ovotoxic effects of Cyc and possible antioxidant and protective effects of blue-green algae, Spirulina (Sp), in rat ovaries. Eighteen rats were given: group I ( , control); group II ( , CP), a single dose Cyc; group III ( , Sp+Cyc), 7 days Sp+single dose Cyc. Tissue malondialdehyde (MDA) levels, superoxide dismutase (SOD), and catalase (CAT) activities are assessed biochemically. Normal and atretic primordial and primary follicle counts for all sections obtained for each ovary are calculated. Mean number of follicle counts for each group are compared. In Sp+Cyc group, tissue MDA levels were significantly lower than those in the CP and higher than those in the C group ( + ). Tissue SOD activity was significantly higher in Sp+Cyc group than that in the CP group and lower than that in the C group ( + ). No statistically significant difference was found between the ovarian CAT activities in any group. Histomorphometrically, there was also no significant difference between the mean numbers of normal and atretic small follicle counts. Our results suggest that single dose Cyc has adverse effects on oxidant status of the ovaries and Sp has protective effects in Cyc-induced ovotoxicity. 1. Background Cyclophosphamide (Cyc), one of the most effective alkylating agents, is associated with the greatest risk of female infertility [1, 2]. This is mostly attributed to ovarian toxicity and is thought to be strongly related to the cumulative doses of Cyc [1]. Reproductive functions deteriorate by rapid depletion of the oocyte reserve mediated by apoptotic cell death and ovarian atrophy with disappearance of resting primordial follicles [3] and also growing follicles [4] in humans. In other words, apoptosis, which physiologically is an essential event for ovarian function [5] and development of this organ, would become harmful when the ovary is exposed to Cyc [6]. The toxic metabolites of Cyc and the drug itself also interfere with intracellular antioxidation systems which play an important role in detoxifying the reactive oxygen species (ROS) [7]. Superoxide dismutase (SOD), which converts the superoxide anion to hydrogen peroxide, plays a central role in antioxidation reactions [8]. Catalase (CAT), another antioxidant enzyme, catalyzes exclusively the decomposition of hydrogen peroxide to water and oxygen without an electron donor [8]. It is also shown that the lipid peroxidation in ovaries increases in oxidative stress conditions such as ischemia [9].


[1]  F. Tomao, G. P. Spinelli, P. B. Panici, L. Frati, and S. Tomao, “Ovarian function, reproduction and strategies for fertility preservation after breast cancer,” Critical Reviews in Oncology/Hematology, vol. 76, no. 1, pp. 1–12, 2010.
[2]  S. J. Lee, L. R. Schover, A. H. Partridge et al., “American Society of Clinical Oncology recommendations on fertility preservation in cancer patients,” Journal of Clinical Oncology, vol. 24, no. 18, pp. 2917–2931, 2006.
[3]  R. M. Chapman, “Effect of cytotoxic therapy on sexuality and gonadal function,” Seminars in Oncology, vol. 9, no. 1, pp. 84–94, 1982.
[4]  M. E. Clowse, S. C. Copland, T. C. Hsieh et al., “Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's),” Arthritis Care & Research, vol. 63, no. 12, pp. 1777–1781, 2011.
[5]  K. Shkolnik, A. Tadmor, S. Ben-Dor, N. Nevo, D. Galiani, and N. Dekel, “Reactive oxygen species are indispensable in ovulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 4, pp. 1462–1467, 2011.
[6]  P. J. Devine, S. D. Perreault, and U. Luderer, “Roles of reactive oxygen species and antioxidants in ovarian toxicity,” Biology of Reproduction, vol. 86, no. 2, pp. 1–10, 2012.
[7]  M. Tsai-Turton, B. T. Luong, Y. Tan, and U. Luderer, “Cyclophosphamide-induced apoptosis in COV434 human granulosa cells involves oxidative stress and glutathione depletion,” Toxicological Sciences, vol. 98, no. 1, pp. 216–230, 2007.
[8]  J. Fujii, Y. Iuchi, and F. Okada, “Fundamental roles of reactive oxygen species and protective mechanisms in the female reproductive system,” Reproductive Biology and Endocrinology, vol. 3, p. 43, 2005.
[9]  U. Isaoglu, M. Yilmaz, M. Calik et al., “Biochemical and histopathologic investigation of the protective effect of disulfiram in ischemia-induced ovarian damage,” Gynecological Endocrinology, vol. 28, no. 2, pp. 143–147, 2012.
[10]  S. Bozkurt, D. C. Arikan, E. B. Kurutas et al., “Selenium has a protective effect on ischemia/reperfusion injury in a rat ovay model: biochemical and histopathologic evaluation,” Journal of Pediatric Surgery, vol. 47, no. 9, pp. 1735–1741, 2012.
[11]  J. L. Tilly and K. I. Tilly, “Inhibitors of oxidative stress mimic the ability of follicle-stimulating hormone to suppress apoptosis in cultured rat ovarian follicles,” Endocrinology, vol. 136, no. 1, pp. 242–252, 1995.
[12]  A. Belay, “The potential application of Spirulina (Arthrospira) as a nutritional and therapeutic supplement in health management,” Journal of the American Nutraceutical Association, vol. 5, no. 2, pp. 27–49, 2002.
[13]  T. Karaca and N. Simsek, “Effects of spirulina on the number of ovary mast cells in lead-induced toxicity in rats,” Phytotherapy Research, vol. 21, no. 1, pp. 44–46, 2007.
[14]  G. Chamorro-Cevallos, L. Gardu?o-Siciliano, B. L. Barrón, E. Madrigal-Bujaidar, D. E. Cruz-Vega, and N. Pages, “Chemoprotective effect of Spirulina (Arthrospira) against cyclophosphamide-induced mutagenicity in mice,” Food and Chemical Toxicology, vol. 46, no. 2, pp. 567–574, 2008.
[15]  B. J. Davis and J. J. Heindel, “Ovarian toxicants: multiple mechanisms of action,” in Reproductive and Developmental Toxicology, K. S. Korach, Ed., pp. 373–395, Marcel Dekker, New York, NY, USA, 1998.
[16]  D. Meirow, H. Lewis, D. Nugent, and M. Epstein, “Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool,” Human Reproduction, vol. 14, no. 7, pp. 1903–1907, 1999.
[17]  J. L. Tilly, “Ovarian follicle counts-not as simple as 1, 2, 3,” Reproductive Biology and Endocrinology, vol. 1, p. 11, 2003.
[18]  Y. Xiang, J. Xu, L. Li et al., “Calorie restriction increases primordial follicle reserve in mature female chemotherapy-treated rats,” Gene, vol. 493, no. 1, pp. 77–82, 2012.
[19]  E. S. Sills, M. M. Alper, and A. P. H. Walsh, “Ovarian reserve screening in infertility: practical applications and theoretical directions for research,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 146, no. 1, pp. 30–36, 2009.
[20]  S. K. Petrillo, P. Desmeules, T. Q. Truong, and P. J. Devine, “Detection of DNA damage in oocytes of small ovarian follicles following phosphoramide mustard exposures of cultured rodent ovaries in vitro,” Toxicology and Applied Pharmacology, vol. 253, no. 2, pp. 94–102, 2011.
[21]  D. R. Plowchalk and D. R. Mattison, “Phosphoramide mustard is responsible for the ovarian toxicity of cyclophosphamide,” Toxicology and Applied Pharmacology, vol. 107, no. 3, pp. 472–481, 1991.
[22]  P. Desmeules and P. J. Devine, “Characterizing the ovotoxicity of cyclophosphamide metabolites on cultured mouse ovaries,” Toxicological Sciences, vol. 90, no. 2, pp. 500–509, 2006.
[23]  L. Luo, D. Z. Yang, Z. Wang, Q. X. Zhang, Y. Q. Mo, and N. DI, “Cyclophosphamide-induced ovarian damage and stem cell factor expression in rat ovaries,” Nan Fang Yi Ke Da Xue Xue Bao, vol. 27, no. 10, pp. 1476–1479, 2007.
[24]  S. G. Lopez and U. Luderer, “Effects of cyclophosphamide and buthionine sulfoximine on ovarian glutathione and apoptosis,” Free Radical Biology and Medicine, vol. 36, no. 11, pp. 1366–1377, 2004.
[25]  M. R. Hussein, “Apoptosis in the ovary: molecular mechanisms,” Human Reproduction Update, vol. 11, no. 2, pp. 162–178, 2005.
[26]  D. L. Boone and B. K. Tsang, “Caspase-3 in the rat ovary: localization and possible role in follicular atresia and luteal regression,” Biology of Reproduction, vol. 58, no. 6, pp. 1533–1539, 1998.
[27]  S. Y. Lee, J. Y. Lee, S. J. Oh, H. C. Kim, and S. K. Kim, “Expression of hepatic and ovarian antioxidant enzymes during estrous cycle in rats,” Toxicology Letters, vol. 212, no. 3, pp. 329–336, 2012.
[28]  B. D. Lawenda, K. M. Kelly, E. J. Ladas, S. M. Sagar, A. Vickers, and J. B. Blumberg, “Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?” Journal of the National Cancer Institute, vol. 100, no. 11, pp. 773–783, 2008.
[29]  K. N. Prasad and W. C. Cole, “Antioxidants in cancer therapy,” Journal of Clinical Oncology, vol. 24, no. 6, pp. 8–9, 2006.


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