PROTECTIVE EFFECT OF HYDROALCOHOLIC EXTRACT FROM PSIDIUM GUAJAVA LEAVES ON BPA-INDUCED REPRODUCTIVE TOXICITY IN FEMALE RATS
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Abstract
Background: Psidium guajavaL. is a well-known plant traditionally used within the Pakistani community to address reproductive system irregularities. This study aims to assess the impact of various fractions of P. guajava L., derived from its hydroalcoholic extract, on female reproductive impairments induced by Bisphenol A (BPA).
Design: Animal study.
Setting: Conducted within animal and laboratory facilities at a university.
Animals: Eighty adult female Sprague Dawley rats.
Methods: The crude extract of the plant underwent acute and subacute toxicity studies to determine its safety profile. The extract was then subjected to activity-guided fractionation using solvents of differing polarities, including hexane, dichloromethane, and water. Dichloromethane and aqueous soluble fractions were used for pharmacological evaluations, while hexane-soluble fractions were omitted due to inadequate quantity. Eighty rats were divided into different groups based on the administered fraction. P. guajava L. leaves' hydroalcoholic extract and its fractions, along with Bisphenol A and the vehicle, were administered orally via gavage for six consecutive weeks. GC–MS analysis was conducted to detect and identify the plant's constituents responsible for its pharmacological effects. Main Outcome Measures: Parameters assessed included daily vaginal smears, gonadotropin and sexual-steroid hormone levels, as well as ovarian histopathology.
Results: Toxicity tests revealed the safety of the extract, with no mortality observed at doses as high as 5g/kg for P. GuajavaL. BPA-exposed animals exhibited disruptions in their estrous cycles, endocrine alterations, and adverse histopathological and morphological changes in rat ovaries. Animals treated with BPA in conjunction with ethanol-water extract displayed a dose-dependent reproductive protective effect in rats. Data from this study indicated that the plant's crude extract significantly increased the number of rats with normal estrous cycles, reduced the number of atretic follicles (as evidenced by histopathological examination of ovaries), and normalized levels of gonadotropin hormones (FSH and LH) and sexual steroid hormones (Estradiol and Progesterone), with the highest efficacy at 500 mg/kg for P. guajavaLethanol and water extract. GC-MS analysis of P. guajavaLethanol and water extract confirmed the presence of gallic acid, chlorogenic acid (CGA), caffeic acid, catechin, epicatechin, epigallocatechin, and rutin in the plant's extract.Notably, published studies have reported the protective effects of rutin, gallic acid, and Kaempferol on reproductive disorders.
Conclusions: The data generated from this study underscore the valuable role of P. guajava L. in managing female reproductive system disorders. It is further concluded that no singular chemical entity can account for the reported pharmacological effects, as numerous phytochemicals have been identified in the plant, as revealed by the investigations mentioned above. Therefore, further research into the isolation of pure active principles and the elucidation of their precise mechanisms of reproductive protective and curative action is warranted.
References
2. Pivonello, C., Muscogiuri, G., Nardone, A., Garifalos, F., Provvisiero, D. P., Verde, N., ... & Colao, A. (2020). Bisphenol A: An emerging threat to female fertility. Reproductive Biology and Endocrinology, 18, 22. doi: 10.1186/s12958-019-0558-8.
3. La Rocca, C., Tait, S., Guerranti, C., Busani, L., Ciardo, F., Bergamasco, B., ... & Lucente, C. (2014). Exposure to endocrine disrupters and nuclear receptor gene expression in infertile and fertile women from different Italian areas. International Journal of Environmental Research and Public Health, 11, 10146-10164. doi: 10.3390/ijerph111010146.
4. Tachibana, T., Wakimoto, Y., Nakamuta, N., Phichitraslip, T., Wakitani, S., Kusakabe, K., ... & Hondo, E. (2007). Effects of bisphenol A (BPA) on placentation and survival of the neonates in mice. Journal of Reproduction and Development, 53, 509-514. doi: 10.1262/jrd.18171.
5. Honma, S., Suzuki, A., Buchanan, D. L., Katsu, Y., Watanabe, H., & Iguchi, T. (2002). Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction. Reproductive Toxicology, 16, 117-122. doi: 10.1016/S0890-6238(02)00006-0.
6. Lawson, C., Gieske, M., Murdoch, B., Ye, P., Li, Y., Hassold, T., & Hunt, P. A. (2011). Gene expression in the fetal mouse ovary is altered by exposure to low doses of bisphenol A. Biology of Reproduction, 84, 79-86. doi: 10.1095/biolreprod.110.084814.
7. Rodríguez, H. A., Santambrosio, N., Santamaría, C. G., Muñoz-de-Toro, M., & Luque, E. H. (2010). Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary. Reproductive Toxicology, 30, 550-557. doi: 10.1016/j.reprotox.2010.07.008.
8. Sugiura-Ogasawara, M., Ozaki, Y., Sonta, S., Makino, T., & Suzumori, K. (2005). Exposure to bisphenol A is associated with recurrent miscarriage. Human Reproduction, 20, 2325-2329. doi: 10.1093/humrep/deh888.
9. Mínguez-Alarcón, L., Gaskins, A. J., Chiu, Y. H., Williams, P. L., Ehrlich, S., Chavarro, J. E., ... & Hauser, R. (2015). Urinary bisphenol A concentrations and association with in vitro fertilization outcomes among women from a fertility clinic. Human Reproduction, 30, 2120-2128. doi: 10.1093/humrep/dev183.
10. Vahedi, M., Saeedi, A., Poorbaghi, S. L., Sepehrimanesh, M., & Fattahi, M. (2016). Metabolic and endocrine effects of bisphenol A exposure in market seller women with polycystic ovary syndrome. Environmental Science and Pollution Research International, 23, 23546-23550. doi: 10.1007/s11356-016-7573-5.
11. Shen, Y., Zheng, Y., Jiang, J., Liu, Y., Luo, X., Shen, Z., ... & Sun, Z. (2015). Higher urinary bisphenol A concentration is associated with unexplained recurrent miscarriage risk: Evidence from a case-control study in eastern China. PLoS ONE, 10(6), e0127886. doi: 10.1371/journal.pone.0127886.
12. Flores, G., Wu, S. B., Negrin, A., Kennelly, E. J. (2015). Chemical composition and antioxidant activity of seven cultivars of guava (Psidium guajava) fruits. Food Chemistry, 170, 327-335. doi: 10.1016/j.foodchem.2014.08.063.
13. Naseer, S., Hussain, S., Naeem, N., Pervaiz, M., & Rahman, M. (2018). The phytochemistry and medicinal value of Psidium guajava (guava). Clinical Phytoscience, 4, 32. doi: 10.1186/s40816-018-0094-7.
14. Nantitanon, W., Yotsawimonwat, S., & Okonogi, S. (2010). Factors influencing antioxidant activities and total phenolic content of guava leaf extract. LWT - Food Science and Technology, 43, 1095-1103. doi: 10.1016/j.lwt.2010.03.002.
15. Gutiérrez, R. M. P., Mitchell, S., & Solis, R. V. (2008). Psidium guajava: A review of its traditional uses, phytochemistry, and pharmacology. Journal of Ethnopharmacology, 117, 1-27. doi: 10.1016/j.jep.2008.01.025.
16. Tariq, A., Adnan, M., Iqbal, A., Sadia, S., Fan, Y., Nazar, A., ... & Khan, A. L. (2018). Ethnopharmacology and toxicology of Pakistani medicinal plants used to treat gynecological complaints and sexually transmitted infections. South African Journal of Botany, 114, 132-149. doi: 10.1016/j.sajb.2017.09.012.
17. Alamgeer, Chabert, P., Akhtar, M. S., Jabeen, Q., Delecolle, J., Heintz, D., Garo, E. and Oak, M. H. (2016). Endothelium-independent vasorelaxant effect of a Berberis orthobotrys root extract via inhibition of phosphodiesterases in the porcine coronary artery. Phytomedicine., 23(8): 793-799.
18. Mayasari, A., Suryawan, A., Christita, M., Simamora, A. T. J., Abinawanto, A., Suryanda, A., & Bowolaksono, A. (2018). Vaginal swab cytology aplication to determine the estrus cycle of lowland anoa (bubalus depressicornis, smith, 1927) in captivity. MATEC Web of Conferences, 197, 06008.
19. Akhila JS, Shyamjith D, Alwar M. Acute toxicity studies and determination of median lethal dose. Current science 2007:917
20. Roy, C. K., Kamath, J. V., & Asad, M. (2006). Hepatoprotective activity of Psidium guajava Linn. leaf extract. Indian Journal of Experimental Biology, 44(4), 305-311. PMID: 16629373.
21. Atanasov, A. G. et al. Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol. Adv. 33, 1582–1614 (2015). Article CAS PubMed PubMed Central Google Scholar
22. Harvey, A. L., Edrada-Ebel, R. & Quinn, R. J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 14, 111–129 (2015).
23. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661 (2016).ArticleCASPubMedGoogle Scholar
24. Waltenberger, B., Mocan, A., Šmejkal, K., Heiss, E. H. E. H. & Atanasov, A. A. G. A. G. Natural products to counteract the epidemic of cardiovascular and metabolic disorders. Molecules 21, 807 (2016).ArticlePubMed CentralCASGoogle Scholar
25. Tintore, M., Vidal-Jordana, A. & Sastre-Garriga, J. Treatment of multiple sclerosis — success from bench to bedside. Nat. Rev. Neurol. 15, 53–58 (2019).ArticleCASPubMedGoogle Scholar
26. Yang, Y., Wei, S., Zhang, B., & Li, W. (2021). Recent progress in environmental toxins-induced cardiotoxicity and protective potential of natural products. Frontiers in Pharmacology, 12, 699193. doi: 10.3389/fphar.2021.699193. [PMC free article] [PubMed] [CrossRef]
27. Adewale, H. B., Jefferson, W. N., Newbold, R. R., & Patisaul, H. B. (2009). Neonatal bisphenol-A exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin-releasing hormone neurons. Biology of Reproduction, 81(4), 690-699. doi: 10.1095/biolreprod.109.078261. [PMC free article] [PubMed] [CrossRef]
28. Markey, C. M., Coombs, M. A., Sonnenschein, C., & Soto, A. M. (2003). Mammalian development in a changing environment: Exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evolution and Development, 5(1), 67-75. doi: 10.1046/j.1525-142X.2003.03011.x. [PubMed] [CrossRef]
29. Rubin, B. S., Murray, M. K., Damassa, D. A., King, J. C., & Soto, A. M. (2001). Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environmental Health Perspectives, 109(7), 675-680. doi: 10.1289/ehp.01109675. [PMC free article] [PubMed] [CrossRef]
30. Howdeshell, K. L., Hotchkiss, A. K., Thayer, K. A., Vandenbergh, J. G., vom Saal, F. S., & Vandenbergh, J. G. (1999). Exposure to bisphenol A advances puberty. Nature, 401(6755), 763-764. doi: 10.1038/44517. [PubMed] [CrossRef]
31. Mendoza-Rodriguez, C. A., Garcia-Guzman, M., Baranda-Avila, N., Morimoto, S., Perrot-Applanat, M., & Cerbon, M. (2011). Administration of bisphenol A to dams during the perinatal period modifies molecular and morphological reproductive parameters of the offspring. Reproductive Toxicology, 31(2), 177-183. doi: 10.1016/j.reprotox.2010.10.013. [PubMed] [CrossRef]
32. Fernandez, M., Bianchi, M., Lux-Lantos, V., & Libertun, C. (2009). Neonatal exposure to bisphenol A alters reproductive parameters and gonadotropin-releasing hormone signaling in female rats. Environmental Health Perspectives, 117(5), 757-762. doi: 10.1289/ehp.0800267. [PMC free article] [PubMed] [CrossRef]
33. Nikaido Y, Yoshizawa K, Danbara N, Tsujita-Kyutoku M, Yuri T, Uehara N, Tsubura A. Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring. Reprod Toxicol. 2004;18(6):803–811. doi: 10.1016/j.reprotox.2004.05.002. [PubMed] [CrossRef] [Google Scholar]
34. Oke, J. M., & Hamburger, O. (2002). Screening of some Nigerian medicinal plants for antoxidant activity using 2, 2, Diphenyl-Picryl-Hydrazyl radical, 5, 77–79.
35. Oladimeji, O. S., Lawal, O. A., & Ogundimu, E. O. (2014). Anti-oxidants levels in female rats administered pro-fertility ethanolic leave extract of byrsocarpus coccineus. European Scientific Journal, 10(15), 349–363.
36. Rajan, R. K., M, S. S. K., & Balaji, B. (2017). Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (DCOS) model through anti-androgenic mechanism. Pharmaceutical Biology, 55(1), 242–251.
37. Jahan, S., Munir, F., Razak, S., Mehboob, A., Ain, Q. U., Ullah, H., Afsar, T., Shaheen, G., & Almajwal, A. (2016). Ameliorative effects of rutin against metabolic, biochemical and hormonal disturbances in polycystic ovary syndrome in rats. Journal of Ovarian Research, 9(1).
38. Rotimi, D., Ojo, O. A., Emmanuel, B. A., Ojo, A. B., Elebiyo, T. C., Nwonuma, C. O., & Oluba, O. M. (2021). Protective impacts of gallic acid against cadmium-induced oxidative toxicity in the ovary of rats. Comparative Clinical Pathology, 30(3), 453–460.
39. Mendonca, E. M. F. T. (2013). Kaempferol Exhibits Progestogenic Effects in Ovariectomized Rats. Journal of Steroids & Hormonal Science, 05(03).
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Maryam Khan
College of Pharmacy, University of Sargodha, Pakistan,
Phone no: +923338602060
Hafiz M. Irfan
College of Pharmacy, University of Sargodha, 40100 Sargodha, Pakistan
Taseer Ahmed Khan
The Department of Physiology, University of Karachi, 75270 Karachi, Pakistan.