Chrysin abrogates gibberellic acid-induced testicular oxidative stress and dysfunction via the regulation of antioxidants and steroidogenesis- and apoptosis-associated genes
Corresponding Author
Mohamed Mohamed Soliman
Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia
Correspondence
Mohamed Mohamed Soliman, Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia.
Email: [email protected]
Contribution: Conceptualization, Funding acquisition, Investigation, Methodology, Visualization
Search for more papers by this authorAdil Aldhahrani
Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia
Contribution: Formal analysis
Search for more papers by this authorHeba I. Ghamry
Department of Home Economics, College of Home Economics, King Khalid University, Abha, Saudi Arabia
Contribution: Resources, Validation
Search for more papers by this authorSarah Albogami
Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
Search for more papers by this authorGehan B. A. Youssef
Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Benha University, Benha, Egypt
Contribution: Data curation, Supervision, Visualization
Search for more papers by this authorHosny Kesba
Zoology and Agricultural Nematology Department, Faculty of Agriculture, Cairo University, Giza, Egypt
Contribution: Resources
Search for more papers by this authorMustafa Shukry
Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
Contribution: Data curation, Visualization, Writing - original draft
Search for more papers by this authorCorresponding Author
Mohamed Mohamed Soliman
Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia
Correspondence
Mohamed Mohamed Soliman, Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia.
Email: [email protected]
Contribution: Conceptualization, Funding acquisition, Investigation, Methodology, Visualization
Search for more papers by this authorAdil Aldhahrani
Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif, Saudi Arabia
Contribution: Formal analysis
Search for more papers by this authorHeba I. Ghamry
Department of Home Economics, College of Home Economics, King Khalid University, Abha, Saudi Arabia
Contribution: Resources, Validation
Search for more papers by this authorSarah Albogami
Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
Search for more papers by this authorGehan B. A. Youssef
Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Benha University, Benha, Egypt
Contribution: Data curation, Supervision, Visualization
Search for more papers by this authorHosny Kesba
Zoology and Agricultural Nematology Department, Faculty of Agriculture, Cairo University, Giza, Egypt
Contribution: Resources
Search for more papers by this authorMustafa Shukry
Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
Contribution: Data curation, Visualization, Writing - original draft
Search for more papers by this authorFunding information
This study was supported by the Taif University Researchers Supporting Project (TURSP-2020/09), Taif University, Taif, Saudi Arabia
Abstract
GA3 is widely used as a growth stimulant in agricultural regions. The long-term use of GA3 can cause organs damage. Chrysin is a flavonoid found in nature that is commonly used to treat organ toxicity. In this study, we examined the effect of chrysin on the testes function of GA3-affected rats. A total of 24 male Wistar rats were divided into 4 groups. Saline was given to the control group. The chrysin group was given orally 50 mg/kg/BW of chrysin in saline. The GA3 group received a daily oral gavage of GA3 (55 mg/kg/BW). The protective group (chrysin + GA3) was given chrysin and GA3 as those described in chrysin and GA3 groups. There were an increase in MDA levels in the serum and testicular tissue of GA3-treated group. Catalase, GSH, and SOD levels were all lowered in the GA3-treated rats. Chrysin dramatically reduced the harmful effects of GA3 by restoring reproductive hormone levels, altered sperm parameters, and antioxidant capabilities. Furthermore, GA3 reduced the quantitative expression of steroidogenesis genes StAR and 3-HSD, as well as Bcl2 genes, while it increased the apoptotic marker BAX; all were alleviated by the pre-administration of chrysin. The pre-administration of chrysin protected the GA3 group from spermatogenic vacuolation, interstitial edema, necrosis, and depletion. Chrysin inhibited oxidative stress and modulated antioxidant activity, as well as apoptosis-/anti-apoptosis-related mediators in the testes. Chrysin has the potential to repair GA3-induced testicular dysfunctions. This suggests that chrysin is preferable as a medication to mitigate GA3-induced oxidative damage in the testes.
Practical applications
Chrysin has the potential to repair GA3-induced testicular dysfunctions. This suggests that chrysin is preferable as a medication to mitigate GA3-induced oxidative damage in the testes.
CONFLICT OF INTEREST
The authors report no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
Data are available upon request.
REFERENCES
- Abdellaoui, K., Halima-Kamel, M. B., & Hamouda, M. H. B. (2009). Physiological effects of gibberellic acid on the reproductive potential of Locusta migratoria migratoria. Tunisian Journal of Plant Protection, 4, 67–76.
- Aksu, E. H., Kandemir, F. M., Küçükler, S., & Mahamadu, A. (2018). Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin. Journal of Biochemical and Molecular Toxicology, 32(11), e22201. https://doi.org/10.1002/jbt.22201
- Aksu, E. H., Özkaraca, M., Kandemir, F. M., Ömür, A. D., Eldutar, E., Küçükler, S., & Çomaklı, S. (2016). Mitigation of paracetamol-induced reproductive damage by chrysin in male rats via reducing oxidative stress. Andrologia, 48(10), 1145–1154. https://doi.org/10.1111/and.12553
- Ali, M., Amin, W., Nasr El-Din, W., & Anter, S. (2018). Possible ameliorative effect of Vitamin C on cerebellar toxicity induced by gibberellic acid during late pregnancy and early postnatal periods in albino rats. European Journal of Anatomy, 22, 345–354.
- Ali, N., Rashid, S., Nafees, S., Hasan, S. K., & Sultana, S. (2014). Beneficial effects of chrysin against methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis. Molecular and Cellular Biochemistry, 385(1), 215–223.
- Almeida, O., Conde, G., Crochemore, C., Demeneix, B., Fischer, D., Hassan, A., Meyer, M., Holsboer, F., & Michaelidis, T. (2000). Subtle shifts in the ratio between pro-and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate. The FASEB Journal, 14(5), 779–790.
- Alsemeh, A. E., Moawad, R. S., & Abdelfattah, E. R. (2019). Histological and biochemical changes induced by gibberellic acid in the livers of pregnant albino rats and their offspring: ameliorative effect of Nigella sativa. Anatomical Science International, 94(4), 307–323. https://doi.org/10.1007/s12565-019-00488-0
- Amann, R. P. (1982). Use of animal models for detecting specific alterations in reproduction. Fundamental and Applied Toxicology, 2(1), 13–26. https://doi.org/10.1016/s0272-0590(82)80059-6
- Anand, K. V., Anandhi, R., Pakkiyaraj, M., & Geraldine, P. (2011). Protective effect of chrysin on carbon tetrachloride (CCl4)—induced tissue injury in male Wistar rats. Toxicology and Industrial Health, 27(10), 923–933.
- Aty, O., & Masoud, R. (2016). Potential toxicity of plant growth regulator gibberellic acid (GA3) on the pancreatic structures and functions in the albino rat. Academia Anatomica International, 2(2), 11–26. https://doi.org/10.21276/aanat.2016.2.2.4
10.21276/aanat.2016.2.2.4 Google Scholar
- Bakr, S., Moussa, E., & Khater, E. S. (1999). Cytogenetic evaluation of gibberellin A3 in Swiss albino mice. J Union Arab Biol, 11, 345–351.
- Behairy, A., El-Sharkawy, N. I., Saber, T. M., Soliman, M. M., Metwally, M. M. M., El-Rahman, A., Ghada, I., Abd-Elhakim, Y. M., & El Deib, M. M. (2020). The modulatory role of vitamin C in boldenone undecylenate induced testicular oxidative damage and androgen receptor dysregulation in adult male rats. Antioxidants (Basel), 9(11), 1053. https://doi.org/10.3390/antiox9111053
- Celik, I., Tuluce, Y., & Isik, I. (2007). Evalution of toxicity of abcisic acid and gibberellic acid in rats: 50 days drinking water study. Journal of Enzyme Inhibition and Medicinal Chemistry, 22(2), 219–226.
- Chaari-Rkhis, A., Maalej, M., Messaoud, S. O., & Drira, N. (2006). In vitro vegetative growth and flowering of olive tree in response to GA3 treatment. African Journal of Biotechnology, 5(22), 2097–2302.
- Ciftci, O., Ozdemir, I., Aydin, M., & Beytur, A. (2012). Beneficial effects of chrysin on the reproductive system of adult male rats. Andrologia, 44(3), 181–186. https://doi.org/10.1111/j.1439-0272.2010.01127.x
- Cormier, M., Ghouili, F., Roumaud, P., Bauer, W., Touaibia, M., & Martin, L. J. (2018). Influences of flavones on cell viability and cAMP-dependent steroidogenic gene regulation in MA-10 Leydig cells. Cell Biology and Toxicology, 34(1), 23–38. https://doi.org/10.1007/s10565-017-9395-8
- Del Fabbro, L., Jesse, C. R., de Gomes, M. G., Borges Filho, C., Donato, F., Souza, L. C., Goes, A. R., Furian, A. F., & Boeira, S. P. (2019). The flavonoid chrysin protects against zearalenone induced reproductive toxicity in male mice. Toxicon, 165, 13–21. https://doi.org/10.1016/j.toxicon.2019.04.004
- El-Mofty, M. M., Sakr, S. A., Rizk, A. M., & Moussa, E. A. (1994). Carcinogenic effect of gibberellin A3 in Swiss albino mice. Nutrition and Cancer, 21(12), 183–190. https://doi.org/10.1080/01635589409514316
- Halliwell, B., & Gutteridge, J. M. (2015). Free radicals in biology and medicine. Oxford University Press.
10.1093/acprof:oso/9780198717478.001.0001 Google Scholar
- Hassan, H. A., El-Kholy, W. M., & Nour, S. E. (2014). Proanthocyanidin as a cytogenetic protective agent against adverse effects of plant growth regulators supplementation in rats. Cytotechnology, 66(4), 585–596. https://doi.org/10.1007/s10616-013-9607-x
- Hussein, W., Farahat, F., Abass, M., & Shehata, A. (2011). Hepatotoxic potential of gibberellic acid (GA(3)) in adult male albino rats. Life Science Journal, 8, 373–383.
- Ileriturk, M., Benzer, F., Aksu, E. H., Yildirim, S., Kandemir, F. M., Dogan, T., … Genc, A. (2021). Chrysin protects against testicular toxicity caused by lead acetate in rats with its antioxidant, anti-inflammatory, and antiapoptotic properties. Journal of Food Biochemistry, 45(2), e13593. https://doi.org/10.1111/jfbc.13593
- Jana, K., Yin, X., Schiffer, R. B., Chen, J. J., Pandey, A. K., Stocco, D. M., Grammas, P., & Wang, X. (2008). Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells. Journal of Endocrinology, 197(2), 315–323. https://doi.org/10.1677/joe-07-0282
- Ji, B., Wen, Z., Ni, C., Zhu, Q., Wang, Y., Li, X., Zhong, Y., & Ge, R. S. (2021). The production of testosterone and gene expression in neonatal testes of rats exposed to diisoheptyl phthalate during pregnancy is inhibited. Frontiers in Pharmacology, 12, 568311. https://doi.org/10.3389/fphar.2021.568311
- Jiang, J., Yao, S., Cai, H. H., Yang, P. H., & Cai, J. (2013). Synthesis and synergetic effects of chrysin-organogermanium (IV) complex as potential anti-oxidant. Bioorganic & Medicinal Chemistry Letters, 23(20), 5727–5732. https://doi.org/10.1016/j.bmcl.2013.07.073
- Kandhare, A. D., Shivakumar, V., Rajmane, A., Ghosh, P., & Bodhankar, S. L. (2014). Evaluation of the neuroprotective effect of chrysin via modulation of endogenous biomarkers in a rat model of spinal cord injury. Journal of Natural Medicines, 68(3), 586–603. https://doi.org/10.1007/s11418-014-0840-1
- Kasala, E. R., Bodduluru, L. N., Madana, R. M., Gogoi, R., & Barua, C. C. (2015). Chemopreventive and therapeutic potential of chrysin in cancer: Mechanistic perspectives. Toxicology Letters, 233(2), 214–225. https://doi.org/10.1016/j.toxlet.2015.01.008
- Khalaf, H. A., Arafat, E. A., & Ghoneim, F. M. (2019). A histological, immunohistochemical and biochemical study of the effects of pomegranate peel extracts on gibberellic acid induced oxidative stress in adult rat testes. Biotechnic & Histochemistry, 94(8), 569–582. https://doi.org/10.1080/10520295.2019.1602884
- Lafi, B., Chaâbane, M., Elwej, A., Grati, M., Jamoussi, K., Mnif, H., Boudawara, T., Ketata Bouaziz, H., & Zeghal, N. (2018). Effects of co-exposure to imidacloprid and gibberellic acid on redox status, kidney variables and histopathology in adult rats. Archives of Physiology and Biochemistry, 124(2), 175–184. https://doi.org/10.1080/13813455.2017.1371195
- Lamfon, H. (2013). Gibberellin A 3 induced ovarian toxicity and oxidative stress in albino rat. Archives des Sciences, 66, 148–155.
- Madacsi, J. P., Parrish, F. W., & McNaughton, J. L. (1988). Treatment of low-tannin sorghum grain for broiler feed. Animal Feed Science and Technology, 20(1), 69–78. https://doi.org/10.1016/0377-8401(88)90128-9
- Mahmoud, A. M., Hussein, O. E., Abd El-Twab, S. M., & Hozayen, W. G. (2019). Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARγ, and suppression of NF-κB/NLRP3 inflammasome axis. Food & Function, 10(8), 4593–4607.
- Mansour, D. F., Saleh, D. O., Ahmed-Farid, O. A., Rady, M., Bakeer, R. M., & Hashad, I. M. (2021). Ginkgo biloba extract (EGb 761) mitigates methotrexate-induced testicular insult in rats: Targeting oxidative stress, energy deficit and spermatogenesis. Biomedicine & Pharmacotherapy, 143, 112201. https://doi.org/10.1016/j.biopha.2021.112201
- Martin, L. J., & Touaibia, M. (2020). Improvement of testicular steroidogenesis using flavonoids and isoflavonoids for prevention of late-onset male hypogonadism. Antioxidants (Basel), 9(3), 237. https://doi.org/10.3390/antiox9030237
- Mohos, V., Fliszár-Nyúl, E., Schilli, G., Hetényi, C., Lemli, B., Kunsági-Máté, S., Bognár, B., & Poór, M. (2018). Interaction of chrysin and its main conjugated metabolites chrysin-7-sulfate and chrysin-7-glucuronide with serum albumin. International Journal of Molecular Sciences, 19(12), 4073. https://doi.org/10.3390/ijms19124073
- Morawietz, G., Ruehl-Fehlert, C., Kittel, B., Bube, A., Keane, K., Halm, S., Heuser, A., Hellmann, J., RITA Group, & NACAD Group. (2004). Revised guides for organ sampling and trimming in rats and mice—Part 3. A joint publication of the RITA and NACAD groups. Experimental and Toxicologic Pathology, 55(6), 433–449. https://doi.org/10.1078/0940-2993-00350
- Muthu, S., Pandurangan, M., Muthuviveganandavel, V., & Srikumar, K. (2011). Acute effect of gibberellic acid on serum enzymes and blood markers in male albino rats. International Journal of Drug Delivery, 1, 340–347.
- Muthuraman, P., & Srikumar, K. (2009). A comparative study on the effect of homobrassinolide and gibberellic acid on lipid peroxidation and antioxidant status in normal and diabetic rats. Journal of Enzyme Inhibition and Medicinal Chemistry, 24(5), 1122–1127. https://doi.org/10.1080/14756360802667563
- Nafees, S., Ahmad, S., Arjumand, W., Rashid, S., Ali, N., & Sultana, S. (2013). Carvacrol ameliorates thioacetamide-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in liver of Wistar rats. Human & Experimental Toxicology, 32(12), 1292–1304.
- Nasseh, O., Wilps, H., Rembold, H., & Krall, S. (1993). Biologically active compounds in Melia volkensii: Larval growth inhibitor and phase modulator against the desert locust Schistocerca gregaria (Forskal)(Orth., Cyrtacanthacrinae) 1. Journal of Applied Entomology, 116(1-5), 1–11.
- Nordmann, R., Ribière, C., & Rouach, H. (1992). Implication of free radical mechanisms in ethanol-induced cellular injury. Free Radical Biology and Medicine, 12(3), 219–240.
- Pushpavalli, G., Kalaiarasi, P., Veeramani, C., & Pugalendi, K. V. (2010). Effect of chrysin on hepatoprotective and antioxidant status in D-galactosamine-induced hepatitis in rats. European Journal of Pharmacology, 631(1-3), 36–41. https://doi.org/10.1016/j.ejphar.2009.12.031
- Ruehl-Fehlert, C., Kittel, B., Morawietz, G., Deslex, P., Keenan, C., Mahrt, C. R., Nolte, T., Robinson, M., Stuart, B. P., Deschl, U., RITA Group, & NACAD Group. (2003). Revised guides for organ sampling and trimming in rats and mice—part 1. Experimental and Toxicologic Pathology, 55(2-3), 91–106.
- Sayed, A. E. H., AbdAllah, E. A., Hamed, M., & Soliman, H. A. M. (2020). Hepato-nephrotoxicity in late juvenile of Oreochromis niloticus exposed to gibberellic acid: Ameliorative effect of Spirulina platensis. Pesticide Biochemistry and Physiology, 167, 104600. https://doi.org/10.1016/j.pestbp.2020.104600
- Slaoui, M., & Fiette, L. (2011). Histopathology procedures: from tissue sampling to histopathological evaluation. Methods in Molecular Biology, 691, 69–82. https://doi.org/10.1007/978-1-60761-849-2_4
- Soliman, H., Mantawy, M., & Hassan, H. (2009). Biochemical and molecular profiles of gibberellic acid exposed albino rats. Journal of American Science, 6(8), 224–229.
- Soliman, M. M., Aldhahrani, A., Gaber, A., Alsanie, W. F., Shukry, M., Mohamed, W. A., & Metwally, M. M. M. (2021a). Impacts of n-acetyl cysteine on gibberellic acid-induced hepatorenal dysfunction through modulation of pro-inflammatory cytokines, antifibrotic and antioxidant activity. Journal of Food Biochemistry, 45(4), e13706. https://doi.org/10.1111/jfbc.13706
- Soliman, M. M., Aldhahrani, A., Gaber, A., Alsanie, W. F., Shukry, M., Mohamed, W. A., Metwally, M. M. M., & Mohamed, A. A. (2021b). Impacts of n-acetyl cysteine on gibberellic acid-induced testicular dysfunction through regulation of inflammatory cytokines, steroid and antioxidant activity. Andrologia, 53(5), e14036. https://doi.org/10.1111/and.14036
- Sönmez, M., Türk, G., & Yüce, A. (2005). The effect of ascorbic acid supplementation on sperm quality, lipid peroxidation and testosterone levels of male Wistar rats. Theriogenology, 63(7), 2063–2072. https://doi.org/10.1016/j.theriogenology.2004.10.003
- Srinivasan, P., Nabi, B., & Srikumar, K. (2003). Gibberellic acid is an activator of gamma glutamyl transpeptidase. Asian Journal of Microbiology, Biotechnology and Environmental Sciences, 5, 499–504.
- Sterchi, D. L. (2008). Molecular pathology—In situ hybridization. Theory and practice of histological techniques ( 6th ed., pp. 537–558). https://doi.org/10.1016/B978-0-443-10279-0.50033-6
10.1016/B978-0-443-10279-0.50033-6 Google Scholar
- Sukhotnik, I., Nativ, O., Roitburt, A., Bejar, D., Coran, A. G., Mogilner, J. G., & Nativ, O. (2013). Methotrexate induces germ cell apoptosis and impairs spermatogenesis in a rat. Pediatric Surgery International, 29(2), 179–184.
- Thangarajan, S., Ramachandran, S., & Krishnamurthy, P. (2016). Chrysin exerts neuroprotective effects against 3-Nitropropionic acid induced behavioral despair—Mitochondrial dysfunction and striatal apoptosis via upregulating Bcl-2 gene and downregulating Bax—Bad genes in male wistar rats. Biomedicine & Pharmacotherapy, 84, 514–525.
- Troudi, A., Amara, I. B., Soudani, N., Samet, A. M., & Zeghal, N. (2011). Oxidative stress induced by gibberellic acid on kidney tissue of female rats and their progeny: Biochemical and histopathological studies. Journal of Physiology and Biochemistry, 67(3), 307–316.
- Troudi, A., Ben Amara, I., Soudani, N., Bouaziz, H., Boudawara, T., & Zeghal, N. (2011). Oxidative stress induced by gibberellic acid in bone of suckling rats. Ecotoxicology and Environmental Safety, 74(4), 643–649. https://doi.org/10.1016/j.ecoenv.2010.10.010
- Tülüce, Y., & Celik, I. (2006). Influence of subacute and subchronic treatment of abcisic acid and gibberellic acid on serum marker enzymes and erythrocyte and tissue antioxidant defense systems and lipid peroxidation in rats. Pesticide Biochemistry and Physiology, 86, 85–92. https://doi.org/10.1016/j.pestbp.2006.01.009
- Wolter, K. G., Hsu, Y.-T., Smith, C. L., Nechushtan, A., Xi, X.-G., & Youle, R. J. (1997). Movement of Bax from the cytosol to mitochondria during apoptosis. The Journal of Cell Biology, 139(5), 1281–1292.
- Yang, H., Jin, X., Lam, C. W. K., & Yan, S.-K. (2011). Oxidative stress and diabetes mellitus. Clinical Chemistry and Laboratory Medicine, 49(11), 1773–1782.
- Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., … Wang, X. (1997). Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science, 275(5303), 1129–1132.
