The effects of Coenzyme Q10, Fullerene C60, α–Lipoic Acid on reproductive system of pubertal male rats exposed to Bisphenol A
Abstract
Bisphenol A is widely recognized as a significant toxic environmental contaminant globally, primarily due to its extensive industrial and commercial applications. The current study aimed to evaluate the potential of Coenzyme Q10, Carbon–60 fullerene and α–Lipoic Acid, which are known for their significant antioxidant capacity, to reduce the reproductive toxic effects induced by Bisphenol A in male rats. A total of sixty prepubertal male Sprague Dawley rats were assigned to eight experimental groups. The substances were applied by oral gavage at dose–adjusted levels, dissolved in olive oil and/or water, once per day for a duration of seven weeks. The rats were decapitated 24 hours subsequent to the final application thereafter blood and testicular tissues were taken for analysis. The exposure of Bisphenol A resulted in significant elevation in serum and testicular malondialdehyde level and significant reduction in the level of antioxidant enzymes. Epididymal sperm concentration and motility were considerably lower in the Bisphenol A–exposed group against the control group. Marked histopathological changes were evident in the testicular tissue, characterized by degeneration and a notable decrease in germinal cell. It was determined that administration of Coenzyme Q10 and α–Lipoic Acid significantly prevented Bisphenol A–induced oxidative stress and associated complications such as testicular dysfunction and the decreased epididymal sperm quality. In conclusion, Bisphenol A negatively affected the reproductive system biochemically, histologically and reproductively in male rats; Coenzyme Q10, Carbon-60 fullerene, and α–Lipoic Acid alleviated these negative effects.
Downloads
References
Ribeiro E, Ladeira C, Viegas S. Occupational exposure to bisphenol A (BPA): a reality that still needs to be unveiled. Toxics [Internet]. 2017; 5(3):22. doi: https://doi.org/p5rp DOI: https://doi.org/10.3390/toxics5030022
Murata M, Kang J–H. Bisphenol A (BPA) and cell signaling pathways. Biotechnol. Adv. [Internet]. 2018; 36(1):311–327. doi: https://doi.org/gc2nrz DOI: https://doi.org/10.1016/j.biotechadv.2017.12.002
Welshons WV, Thayer KA, Judy BM, Taylor JA, Curran EM, vom Saal FS. Large effects from small exposures. I. Mechanisms for endocrine–disrupting chemicals with estrogenic activity. Environ. Health Perspect. [Internet]. 2003; 111(8):994–1006. doi: https://doi.org/dksw5j DOI: https://doi.org/10.1289/ehp.5494
Moriyama K, Tagami T, Akamizu T, Usui T, Saijo M, Kanamoto N, Hataya Y, Shimatsu A, Kuzuya H, Nakao K. Thyroid hormone action is disrupted by bisphenol A as an antagonist. J. Clin. Endocrinol. Metab. [Internet]. 2002; 87(11):5185–5190. doi: https://doi.org/bptspv DOI: https://doi.org/10.1210/jc.2002-020209
Michałowicz J. Bisphenol A–sources, toxicity and biotransformation. Environ. Toxicol. Pharmacol. [Internet]. 2014; 37(2):738–758. doi: https://doi.org/f52s66 DOI: https://doi.org/10.1016/j.etap.2014.02.003
Murphy MP. How mitochondria produce reactive oxygen species. Biochem. J. [Internet]. 2009; 417(1):1–13. doi: https://doi.org/dfv9mv DOI: https://doi.org/10.1042/BJ20081386
Anet A, Olakkaran S, Purayil AK, Puttaswamygowda GH. Bisphenol A induced oxidative stress mediated genotoxicity in Drosophila melanogaster. J. Hazard. Mater. [Internet]. 2019; 370:42–53. doi: https://doi.org/gv378c DOI: https://doi.org/10.1016/j.jhazmat.2018.07.050
Varela–López A, Giampieri F, Battino M, Quiles JL. Coenzyme Q and its role in the dietary therapy against aging. Molecules [Internet]. 2016; 21(3):373. doi: https://doi.org/f8nn8b DOI: https://doi.org/10.3390/molecules21030373
Crane FL. Biochemical functions of coenzyme Q10. J. Am. Coll. Nutr. [Internet]. 2001; 20(6):591–598. doi: https://doi.org/gjtdzs DOI: https://doi.org/10.1080/07315724.2001.10719063
Tirabassi G, Vignini A, Tiano L, Buldreghini E, Bruge F, Silvestri S, Orlando P, D’Aniello A, Mazzanti L, Lenzi A, Balercia G. Protective effects of coenzyme Q 10 and aspartic acid on oxidative stress and DNA damage in subjects affected by idiopathic asthenozoospermia. Endocrine. [Internet]. 2015; 49:549–552. doi: https://doi.org/p5rw DOI: https://doi.org/10.1007/s12020-014-0432-6
Andrievsky GV, Bruskov VI, Tykhomyrov AA, Gudkov SV. Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostructures in vitro and in vivo. Free Radic. Biol. Med. [Internet]. 2009; 47(6):786–793. doi: https://doi.org/fsbt2x DOI: https://doi.org/10.1016/j.freeradbiomed.2009.06.016
Bal R, Türk G, Tuzcu M, Yilmaz O, Ozercan I, Kuloglu T, Gür S, Nedzvetsky VS, Tykhomyrov AA, Andrievsky GV, Baydas G, Naziroglu M. Protective effects of nanostructures of hydrated C60 fullerene on reproductive function in streptozotocin– diabetic male rats. Toxicology [Internet]. 2011; 282(3):69–81. doi: https://doi.org/bxjt56 DOI: https://doi.org/10.1016/j.tox.2010.12.003
El–Beshbishy HA, Aly HA, El–Shafey M. Lipoic acid mitigates bisphenol A–induced testicular mitochondrial toxicity in rats. Toxicol. Ind. Health. [Internet]. 2013; 29(10):875–887. doi: https://doi.org/p5rz DOI: https://doi.org/10.1177/0748233712446728
Korenbrot CC, Huhtaniemi IT, Weiner RI. Preputial separation as an external sign of pubertal development in the male rat. Biol. Reprod. [Internet]. 1977; 17(2):298–303. doi: https://doi.org/cvdkcz DOI: https://doi.org/10.1095/biolreprod17.2.298
Aydoğan M, Korkmaz A, Barlas N, Kolankaya D. Pro–oxidant effect of vitamin C coadministration with bisphenol A, nonylphenol, and octylphenol on the reproductive tract of male rats. Drug Chem. Toxicol. [Internet]. 2010; 33(2):193–203. doi: https://doi.org/dhdm2n DOI: https://doi.org/10.3109/01480540903286468
Güleş Ö, Kum Ş, Yildiz M, Boyacioğlu M, Ahmad E, Naseer Z, Ülker E. Protective effect of coenzyme Q10 against bisphenol–A– induced toxicity in the rat testes. Toxicol. Ind. Health. [Internet]. 2019; 35(7):466–481. doi: https://doi.org/p5r5 DOI: https://doi.org/10.1177/0748233719862475
Shila S, Subathra M, Devi MA, Panneerselvam C. Arsenic intoxication–induced reduction of glutathione level and of the activity of related enzymes in rat brain regions: reversal by DL–α–lipoic acid. Arch. Toxicol. [Internet]. 2005; 79:140–146. doi: https://doi.org/dqcwbg DOI: https://doi.org/10.1007/s00204-004-0614-8
Türk G, Ateşşahin A, Sönmez M, Yüce A, Çeribaşi AO. Lycopene protects against cyclosporine A–induced testicular toxicity in rats. Theriogenology. [Internet]. 2007; 67(4):778–785. doi: https://doi.org/fxghnh DOI: https://doi.org/10.1016/j.theriogenology.2006.10.013
Sönmez M, Türk G, Yüce A. The effect of ascorbic acid supplementation on sperm quality, lipid peroxidation and testosterone levels of male Wistar rats. Theriogenology. [Internet]. 2005; 63(7):2063–2072. doi: https://doi.org/cn6kn5 DOI: https://doi.org/10.1016/j.theriogenology.2004.10.003
Moska N, Murray E, Wakefield P, Matson P. The staining pattern of human sperm with Diff Quik: relationship with sperm head morphology and a sperm chromatin structure assay (SCSA). Reprod. Biol. [Internet]. 2011; 11(1):55–59. doi: https://doi.org/p5r6 DOI: https://doi.org/10.1016/S1642-431X(12)60064-3
Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal. Biochem. [Internet]. 1966; 16(2):359–364. doi: https://doi.org/b96rpj DOI: https://doi.org/10.1016/0003-2697(66)90167-9
Sedlak J, Lindsay RH. Estimation of total, protein–bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. [Internet]. 1968; 25(1):192–205. doi: https://doi.org/csbsfm DOI: https://doi.org/10.1016/0003-2697(68)90092-4
Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium–deficient rat liver. Biochem. Biophys. Res. Commun. [Internet]. 1976; 71(4):952–958. doi: https://doi.org/d3vv59 DOI: https://doi.org/10.1016/0006-291X(76)90747-6
Goth L. A simple method for determination of serum catalase activity and revision of reference range. Clin. Chim. Acta [Internet]. 1991; 196(2–3):143–151. doi: https://doi.org/fthsdb DOI: https://doi.org/10.1016/0009-8981(91)90067-M
Johnsen SG. Testicular biopsy score count – a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones [Internet]. 1970; 1(1):2–25. doi: https://doi.org/bvxfrs DOI: https://doi.org/10.1159/000178170
Jahnukainen K, Chrysis D, Hou M, Parvinen M, Eksborg S, Söder O. Increased apoptosis occurring during the first wave of spermatogenesis is stage–specific and primarily affects midpachytene spermatocytes in the rat testis. Biol. Reprod. [Internet]. 2004; 70(2):290–296. doi: https://doi.org/cjk3gk DOI: https://doi.org/10.1095/biolreprod.103.018390
Saillenfait AM, Ndiaye D, Sabaté JP, Denis F, Antoine G, Robert A, Rouiller–Fabre V, Moison D. Evaluation of the effects of deltamethrin on the fetal rat testis. J. Appl. Toxicol. [Internet]. 2016; 36(11):1505–1515. doi: https://doi.org/f86cm3 DOI: https://doi.org/10.1002/jat.3310
Adibnia E, Razi M, Malekinejad H. Zearalenone and 17 β–estradiol induced damages in male rats reproduction potential; evidence for ERα and ERβ receptors expression and steroidogenesis. Toxicon. [Internet]. 2016; 120:133–146. doi: https://doi.org/f84432 DOI: https://doi.org/10.1016/j.toxicon.2016.08.009
Chitra K, Rao KR, Mathur P. Effect of bisphenol A and co– administration of bisphenol A and vitamin C on epididymis of adult rats: a histological and biochemical study. Asian J. Androl. [Internet]. 2003 [cited May 15, 2025]; 5(3):203–208. Available in: https://goo.su/ns11m
Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser–Kuntz DR, vom Saal FS. In vivo effects of bisphenol A in laboratory rodent studies. Reprod. Toxicol. [Internet]. 2007; 24(2):199–224. doi: https://doi.org/bbp9c4 DOI: https://doi.org/10.1016/j.reprotox.2007.06.004
Liu C, Duan W, Li R, Xu S, Zhang L, Chen C, He M, Lu Y, Wu H, Pi H, Luo X, Zhang Y, Zhong M, Yu Z, Zhou Z. Exposure to bisphenol A disrupts meiotic progression during spermatogenesis in adult rats through estrogen–like activity. Cell Death Dis. [Internet]. 2013; 4(6):e676. doi: https://doi.org/p5sc DOI: https://doi.org/10.1038/cddis.2013.203
Balercia G, Mancini A, Paggi F, Tiano L, Pontecorvi A, Boscaro M, Lenzi A, Littarru GP. Coenzyme Q 10 and male infertility. J. Endocrinol. Invest. [Internet]. 2009; 32(7):626–632. doi: https://doi.org/p5sd DOI: https://doi.org/10.1007/BF03346521
Gámez JM, Penalba R, Cardoso N, Ponzo O, Carbone S, Pandolfi M, Scacchi P, Reynoso R. Low dose of bisphenol A impairs the reproductive axis of prepuberal male rats. J. Physiol. Biochem. [Internet]. 2014; 70(1):239–246. doi: https://doi.org/f5vbt5 DOI: https://doi.org/10.1007/s13105-013-0298-8
Desdoits–Lethimonier C, Lesné L, Gaudriault P, Zalko D, Antignac J–P, Deceuninck Y, Platel C, Dejucq–Rainsford N, Mazaud–Guittot S, Jégou B. Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis. Hum. Reprod. [Internet]. 2017; 32(7):1465–1473. doi: https://doi.org/gqgk3v DOI: https://doi.org/10.1093/humrep/dex093
Nadjarzadeh A, Shidfar F, Amirjannati N, Vafa MR, Motevalian SA, Gohari MR, Nazeri Kakhki SA, Akhondi MM, Sadeghi MR. Effect of Coenzyme Q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double–blind randomised clinical trial. Andrologia [Internet]. 2014; 46(2):177–183. doi: https://doi.org/f5r7d8 DOI: https://doi.org/10.1111/and.12062
Ahmadvand H, Tavafi M, Khosrowbeygi A. Amelioration of altered antioxidant enzymes activity and glomerulosclerosis by coenzyme Q10 in alloxan–induced diabetic rats. J. Diabetes Complicat. [Internet]. 2012; 26(6):476–482. doi: https://doi.org/f4fnnh DOI: https://doi.org/10.1016/j.jdiacomp.2012.06.004
Kim MY, Kim EJ, Kim Y–N, Choi C, Lee B–H. Effects of α– lipoic acid and L–carnosine supplementation on antioxidant activities and lipid profiles in rats. Nutr. Res. Pract. [Internet]. 2011; 5(5):421–428. doi: https://doi.org/d62dhw DOI: https://doi.org/10.4162/nrp.2011.5.5.421
Sena CM, Nunes E, Louro T, Proença T, Fernandes R, Boarder MR, Seiça RM. Effects of α–lipoic acid on endothelial function in aged diabetic and high–fat fed rats. Br. J. Pharmacol. [Internet]. 2008; 153(5):894–906. doi: https://doi.org/dtczc6 DOI: https://doi.org/10.1038/sj.bjp.0707474
Ateşşahin A, Türk G, Yilmaz S, Sönmez M, Sakin F, Çeribasi AO. Modulatory effects of lycopene and ellagic acid on reproductive dysfunction induced by polychlorinated biphenyl (Aroclor 1254) in male rats. Basic Clin. Pharmacol. Toxicol. [Internet]. 2010; 106(6):479–489. doi: https://doi.org/cttzz6 DOI: https://doi.org/10.1111/j.1742-7843.2009.00529.x
Oltval ZN, Milliman CL, Korsmeyer SJ. Bcl–2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death. Cell [Internet]. 1993; 74(4):609–619. doi: https://doi.org/bk8kvd DOI: https://doi.org/10.1016/0092-8674(93)90509-O
Caglayan C, Kandemir FM, Ayna A, Gür C, Küçükler S, Darendelioğlu E. Neuroprotective effects of 18β–glycyrrhetinic acid against bisphenol A–induced neurotoxicity in rats: involvement of neuronal apoptosis, endoplasmic reticulum stress and JAK1/STAT1 signaling pathway. Metab. Brain Dis. [Internet]. 2022; 37(6):1931–1940. doi: https://doi.org/p5sp DOI: https://doi.org/10.1007/s11011-022-01027-z
Wang P, Luo C, Li Q, Chen S, Hu Y. Mitochondrion–mediated apoptosis is involved in reproductive damage caused by BPA in male rats. Environ. Toxicol. Pharmacol. [Internet]. 2014; 38(3):1025–1033. doi: https://doi.org/f6vt9z DOI: https://doi.org/10.1016/j.etap.2014.10.018
Wang R–S, Yeh S, Tzeng C–R, Chang C. Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell–specific androgen receptor knockout mice. Endocr. Rev. [Internet]. 2009; 30(2):119–132. doi: https://doi.org/fj2pf7 DOI: https://doi.org/10.1210/er.2008-0025
Teng C, Goodwin B, Shockley K, Xia M, Huang R, Norris J, Merrick BA, Jetten AM, Austin CP, Tice RR. Bisphenol A affects androgen receptor function via multiple mechanisms. Chem. Biol. Interact. [Internet]. 2013; 203(3):556–564. doi: https://doi.org/p5sq DOI: https://doi.org/10.1016/j.cbi.2013.03.013
Lee HJ, Chattopadhyay S, Gong EY, Ahn RS, Lee K. Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor. Toxicol. Sci. [Internet]. 2003; 75(1):40–46. doi: https://doi.org/bqtbwj DOI: https://doi.org/10.1093/toxsci/kfg150
