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Ezati, D., Vardiyan, R., Talebi, A. R., Anvari, M., & Pourentezari, M. (2020). L-Carnitine reduces the negative effects of formalin on sperm parameters, chromatin condensation and apoptosis in mice: An experimental study. International Journal of Reproductive BioMedicine (IJRM), 13(10), 837–846. https://doi.org/10.18502/ijrm.v13i10.7768
https://doi.org/10.18502/ijrm.v13i10.7768
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Daniyal Ezati
Daniyal Ezati
Department of Biology and Anatomy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
-
Reyhane Vardiyan
Reyhane Vardiyan
Department of Biology and Anatomy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
-
Ali Reza Talebi
Ali Reza Talebi
Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
-
Morteza Anvari
Morteza Anvari
Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
-
Majid Pourentezari
Majid Pourentezari
Department of Biology and Anatomy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Published Date
- Oct 14, 2020
L-Carnitine reduces the negative effects of formalin on sperm parameters, chromatin condensation and apoptosis in mice: An experimental study
Abstract
Background: Formalin is commonly applied as an antiseptic and tissue fixative. It has reactive molecules that lead to its cytotoxic effects. According to recent studies, formalin causes a change in the testicular and sperm structure and L-carnitine (LC) acts as an antioxidant to counteract its effects.
Objectives: This study aimed to investigate the protective effects of LC on the parameters, chromatin condensation and apoptosis of mice sperm exposed to formalin.
Materials and Methods: In this experimental study, 24 balb/c mice (25-40 gr ,10-12 wk) were divided into three groups (n = 8/each): group I without any injections or gavage; group II, received 10 mg/ kg formalin intraperitoneally (I.P); and group III was exposed to formalin and LC, where a dose of 10 mg/kg formalin was injected I.P daily and LC the dose of 100 mg/kg was kept in a solvent solution. After 31 days, the sperm examination was performed as follows: to evaluate chromatin and DNA quality of the sperm, we applied aniline blue (AB), toluidine blue (TB), chromomycin A3 (CMA3), and terminal transferase-mediated deoxy uridine triphosphate biotin end labeling (TUNEL) tests.
Results: Sperm parameters such as count, motility, morphology, and viability displayed a significant decrease in the formalin group. While the data exhibited a considerable augment in sperm parameters in the formalin + LC than the formalin and control groups (p < 0.001), significant differences were detected between groups with respect to TB staining, TUNEL test, CMA3 test and AB staining in the formalin and formalin + LC groups.
Conclusion: LC can reduce the negative effects of formalin on sperm parameters, chromatin stability, and percentage of apoptosis in an animal model.
Key words: Formalin, L-carnitine, Mice, Sperm chromatin, Apoptosis.
References
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[2] La Vignera S, Condorelli R, Vicari E, D’Agata R, Calogero AE. Diabetes mellitus and sperm parameters. J Androl 2012; 33: 145–153.
[3] Martino−Andrade AJ, Chahoud I. Reproductive toxicity of phthalate esters. Mol Nutr Food Res 2010; 54: 148–157.
[4] Golalipour MJ, Azarhoush R, Ghafari S, Gharravi AM, Fazeli SA, Davarian A. Formaldehyde exposure induces histopathological and morphometric changes in the rat testis. Folia Morphol 2007; 66: 167–171.
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[6] Vosoughi S, Khavanin A, Salehnia M, Mahabadi HA, Shahverdi A, Esmaeili V. Adverse effects of formaldehyde vapor on mouse sperm parameters and testicular tissue. Int J Fertil Steril 2013; 6: 250–267.
[7] Tajaddini Mahani S, Behnam B, Abbassi M, Asgari H, Nazmara Z, Shirinbayan P, et al. Tsga10 expression correlates with sperm profiles in the adult formalin−exposed mice. Andrologia 2016; 48: 1092–1099.
[8] Zhou DX, Qiu SD, Zhang J, Tian H, Wang HX. The protective effect of vitamin E against oxidative damage caused by formaldehyde in the testes of adult rats. Asian J Androl 2006; 8: 584–588.
[9] Ozen OA, Kus MA, Kus I, Alkoc OA, Songur A. Protective effects of melatonin against formaldehyde-induced oxidative damage and apoptosis in rat testes: an immunohistochemical and biochemical study. Syst Biol Reprod Med 2008; 54: 169–176.
[10] Afrigan L, Anarkooli IJ, Sohrabi D, Abdanipour A, Yazdinezhad A, Sayyar Z, et al. The effect of hydroethanolic extract of Matricaria chamomilla on the reproductive system of male rats exposed to formaldehyde. Andrologia 2019; 51: e13362.
[11] Zhou D, Zhang J, Wang H. Assessment of the potential reproductive toxicity of long-term exposure of adult male rats to low-dose formaldehyde. Toxicol Ind Health 2011; 27: 591–598.
[12] Wong VC, Cash HL, Morse JL, Lu S, Zhitkovich A. Sphase sensing of DNA-protein crosslinks triggers TopBP1- independent ATR activation and p53-mediated cell death by formaldehyde. Cell Cycle 2012; 11: 2526–2537.
[13] Tang BD, Wang X, Tang C, Zhang D, Wu SW, Li LN. Effect of formaldehyde on the reproductive toxicity in male Wistar rats. J Bengbu Med College 2018; 4: 187–195.
[14] Jedlinska-Krakowska M, Bomba G, Jakubowski K, Rotkiewicz T, Jana B, Penkowski A. Impact of oxidative stress and supplementation with vitamins E and C on testes morphology in rats. J Reprod Dev 2006; 52: 203–209.
[15] Yang HS, Han DK, Kim JR, Sim JC. Effects of α- tocopherol on cadmium-induced toxicity in rat testis and spermatogenesis. J Korean Med Sci 2006; 21: 445–451.
[16] Abdelrazik H, Sharma R, Mahfouz R, Agarwal A. Lcarnitine decreases DNA damage and improves the in vitro blastocyst development rate in mouse embryos. Fertil Steril 2009; 91: 589–596.
[17] Mongioi L, Calogero AE, Vicari E, Condorelli RA, Russo GI, Privitera S, et al. The role of carnitine in male infertility. Andrology 2016; 4: 800–807.
[18] Agarwal A, Said TM. Carnitines and male infertility. Reprod Biomed Online 2004; 8: 376–384.
[19] Vassiliadis S, Athanassakis I. A “conditionally essential” nutrient, L-carnitine, as a primary suspect in endometriosis. Fertil Steril 2011; 95: 2759–2760.
[20] İzgüt-Uysal VN, Ağaç A, Derin N. Effect of L-carnitine on carrageenan-induced inflammation in aged rats. Gerontology 2003; 49: 287–292.
[21] Khushboo M, Murthy MK, Devi MS, Sanjeev S, Ibrahim KS, Kumar NS, et al. Testicular toxicity and sperm quality following copper exposure in Wistar albino rats: ameliorative potentials of L-carnitine. Environ Sci Pollut Res Int 2018; 25: 1837–1862.
[22] Moretti S, Famularo G, Marcellini S, Boschini A, Santini G, Trinchieri V, et al. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal 2002; 4: 391–403.
[23] Khademi A, Alleyassin A, Agha-Hosseini M, Safdarian L, Saeidi Saeidabadi H, Pooyan O. The effect of LCarnitine on sperm parameters in patients candidated for intracytoplasmic sperm injection. Fertility Sterility 2005; 84: S212–S213.
[24] Onem G, Aral E, Enli Y, Oguz EO, Coskun E, Aybek H, et al. Neuroprotective effects of L-carnitine and vitamin E alone or in combination against ischemia-reperfusion injury in rats. J Surg Res 2006; 131: 124–130.
[25] Hegazy AA, Elsayed NE, Ahmad MM, Omar NM. Effect of formaldehyde on rat testis structure. Acad Anat Int 2017; 3: 15–23.
[26] Altun Z, Olgun Y, Ercetin P, Aktas S, Kirkim G, Serbetcioglu B, et al. Protective effect of acetyl−l−carnitine against cisplatin ototoxicity: role of apoptosis−related genes and pro−inflammatory cytokines. Cell Prolif 2014; 47: 72–80.
[27] Mangoli E, Talebi AR, Anvari M, Pourentezari M. Effects of experimentally-induced diabetes on sperm parameters and chromatin quality in mice. Iran J Reprod Med 2013; 11: 53–60.
[28] Talebi AR, Abbasi Sarcheshmeh A, Khalili MA, Tabibnejad N. Effects of ethanol consumption on chromatin condensation and DNA integrity of epididymal spermatozoa in rat. Alcohol 2011; 45: 403–409.
[29] Talebi AR, Khalili MA, Hossaini A. Assessment of nuclear DNA integrity of epididymal spermatozoa following experimental chronic spinal cord injury in the rat. Int J Androl 2007; 30: 163–169.
[30] Talebi AR, Moein MR, Tabibnejad N, Ghasemzadeh J. Effect of varicocele on chromatin condensation and DNA integrity of ejaculated spermatozoa using cytochemical tests. Andrologia 2008; 40: 245–251.
[31] Talebi AR, Vahidi S, Aflatoonian A, Ghasemi N, Ghasemzadeh J, Dehghani Firoozabadi R, et al. Cytochemical evaluation of sperm chromatin and DNA integrity in couples with unexplained recurrent spontaneous abortions. Andrologia 2012; 44 (Suppl.): 462–470.
[32] Pourentezari M, Talebi A, Abbasi A, Khalili MA, Mangoli E, Anvari M. Effects of acrylamide on sperm parameters, chromatin quality, and the level of blood testosterone in mice. Iran J Reprod Med 2014; 12: 335–342.
[33] Gandini L, Lombardo F, Paoli D, Caponecchia L, Familiari G, Verlengia C, et al. Study of apoptotic DNA fragmentation in human spermatozoa. Hum Reprod 2000; 15: 830–839.
[34] Cankut S, Dinc T, Cincik M, Ozturk G, Selam B. Evaluation of sperm DNA fragmentation via halosperm technique and TUNEL assay before and after cryopreservation. Reprod Sci 2019; 26: 1575–1581.
[35] Roshankhah S, Jalili C, Salahshoor MR. Effects of crocin on sperm parameters and seminiferous tubules in diabetic rats. Adv Biomed Res 2019; 8: 4–13.
[36] Moladoust H, Nasiri E, Gazor R, Mahdavi T, Ghorbani R, Rostampour M. Assessment of the protective impact of vitamin E on sex hormones and sperm parameters of formaldehyde-treated male rats: A preliminary investigation. Galen Medical Journal 2017; 6: 330–337.
[37] Aitken RJ. Reactive oxygen species as mediators of sperm capacitation and pathological damage. Mol Reprod Dev 2017; 84: 1039–1052.
[38] Zhu Z, Kawai T, Umehara T, Hoque SAM, Zeng W, Shimada M. Negative effects of ROS generated during linear sperm motility on gene expression and ATP generation in boar sperm mitochondria. Free Radic Biol Med 2019; 141: 159– 171.
[39] Fukushima T, Hamada Y, Komiyama M, Matsuno Y, Mori C, Horii I. Early changes in sperm motility, acrosome reaction, and gene expression of reproductive organs in rats treated with sulfasalazine. Reprod Toxicol 2007; 23: 153–157.
[40] Aziz N, Saleh RA, Sharma RK, Lewis-Jones I, Esfandiari N, Thomas Jr AJ, et al. Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index. Fertil Steril 2004; 81: 349–354.
[41] Baird DJ, Pascoe TJ, Zhou X, Hajibabaei M. Building freshwater macroinvertebrate DNA-barcode libraries from reference collection material: formalin preservation vs specimen age. Journal of the North American Benthological Society 2011; 30: 125–130.
[42] Köse E, Sarsılmaz M, Taş U, Kavaklı A, Türk G, Özlem Dabak D, et al. Rose oil inhalation protects against formaldehyde−induced testicular damage in rats. Andrologia 2012; 44 (Suppl.): 342–348.
[43] Alkan İ, Yüksel M, Canat HL, Atalay HA, Can O, Özveri H, et al. Superoxide anion production by the spermatozoa of men with varicocele: relationship with Varicocele grade and semen parameters. World J Men Health 2018; 36: 255–262.
[44] Sapmaz HI, Yıldız A, Polat A, Vardı N, Köse E, Tanbek K, et al. Protective efficacy of Nigella sativa oil against the harmful effects of formaldehyde on rat testicular tissue. Asian Pacific Journal of Tropical Biomedicine 2018; 8: 548–553.
[45] Duong A, Steinmaus C, McHale CM, Vaughan CP, Zhang L. Reproductive and developmental toxicity of formaldehyde: A systematic review. Mutat Res 2011; 728: 118–138.
[46] Yoshikawa K, Oshima Y, Inagaki A, Sakuragawa A. Determination of formaldehyde in water samples by high-performance liquid chromatography with Methyl acetoacetate derivatization. Bull Environ Contam Toxicol 2018; 101: 672–677.
[47] Tang M, Xie Y, Yi Y, Wang W. Effects of formaldehyde on germ cells of male mice. Wei Sheng Yan Jiu 2003; 32: 544–548.
[48] Levine H, Jørgensen N, Martino-Andrade A, Mendiola J, Weksler-Derri D, Mindlis I, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update 2017; 23: 646–659.
[49] Balercia G, Regoli F, Armeni T, Koverech A, Mantero F, Boscaro M. Placebo-controlled double-blind randomized trial on the use of L-carnitine, L-acetylcarnitine, or combined L-carnitine and L-acetylcarnitine in men with idiopathic asthenozoospermia. Fertil Steril 2005; 84: 662– 671.
[50] Cheah Y, Yang W. Functions of essential nutrition for high quality spermatogenesis. Advances in Bioscience and Biotechnology 2011; 2: 182–197.
[51] Banihani S, Sharma R, Bayachou M, Sabanegh E, Agarwal A. Human sperm DNA oxidation, motility and viability in the presence of l−carnitine during in vitro incubation and centrifugation. Andrologia 2012; 44 (Suppl.): 505–512.
[52] Hufana-Duran D, Duran PG, Monson R, Parrish J. Motility and membrane integrity of ejaculated bovine spermatozoa extended and cryopreserved in L-carnitine Tris-egg yolk extender. J ISSAAS 2017; 23: 56–67.
[53] Berni A, Meschini R, Filippi S, Palitti F, De Amicis A, Chessa L. L-carnitine enhances resistance to oxidative stress by reducing DNA damage in Ataxia telangiectasia cells. Mutat Res 2008; 650: 165–174.
[54] Zidan A, Hedya SE, Elfeky DM, Abdin AA. The possible anti-apoptotic and antioxidant effects of acetyl l-carnitine as an add-on therapy on a relapsing-remitting model of experimental autoimmune encephalomyelitis in rats. Biomed Pharmacother 2018; 103: 1302–1311.
[55] de Moraes MS, Guerreiro G, Sitta A, de Moura Coelho D, Manfredini V, Wajner M, et al. Oxidative damage in mitochondrial fatty acids oxidation disorders patients and the in vitro effect of l-carnitine on DNA damage induced by the accumulated metabolites. Arch Biochem Biophys 2020; 679: 108206: 3–7.
[2] La Vignera S, Condorelli R, Vicari E, D’Agata R, Calogero AE. Diabetes mellitus and sperm parameters. J Androl 2012; 33: 145–153.
[3] Martino−Andrade AJ, Chahoud I. Reproductive toxicity of phthalate esters. Mol Nutr Food Res 2010; 54: 148–157.
[4] Golalipour MJ, Azarhoush R, Ghafari S, Gharravi AM, Fazeli SA, Davarian A. Formaldehyde exposure induces histopathological and morphometric changes in the rat testis. Folia Morphol 2007; 66: 167–171.
[5] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Formaldehyde, 2-butoxyethanol and 1- tert-butoxypropan-2-ol. IARC Monogr Eval Carcinog Risks Hum 2006; 88: 1–487.
[6] Vosoughi S, Khavanin A, Salehnia M, Mahabadi HA, Shahverdi A, Esmaeili V. Adverse effects of formaldehyde vapor on mouse sperm parameters and testicular tissue. Int J Fertil Steril 2013; 6: 250–267.
[7] Tajaddini Mahani S, Behnam B, Abbassi M, Asgari H, Nazmara Z, Shirinbayan P, et al. Tsga10 expression correlates with sperm profiles in the adult formalin−exposed mice. Andrologia 2016; 48: 1092–1099.
[8] Zhou DX, Qiu SD, Zhang J, Tian H, Wang HX. The protective effect of vitamin E against oxidative damage caused by formaldehyde in the testes of adult rats. Asian J Androl 2006; 8: 584–588.
[9] Ozen OA, Kus MA, Kus I, Alkoc OA, Songur A. Protective effects of melatonin against formaldehyde-induced oxidative damage and apoptosis in rat testes: an immunohistochemical and biochemical study. Syst Biol Reprod Med 2008; 54: 169–176.
[10] Afrigan L, Anarkooli IJ, Sohrabi D, Abdanipour A, Yazdinezhad A, Sayyar Z, et al. The effect of hydroethanolic extract of Matricaria chamomilla on the reproductive system of male rats exposed to formaldehyde. Andrologia 2019; 51: e13362.
[11] Zhou D, Zhang J, Wang H. Assessment of the potential reproductive toxicity of long-term exposure of adult male rats to low-dose formaldehyde. Toxicol Ind Health 2011; 27: 591–598.
[12] Wong VC, Cash HL, Morse JL, Lu S, Zhitkovich A. Sphase sensing of DNA-protein crosslinks triggers TopBP1- independent ATR activation and p53-mediated cell death by formaldehyde. Cell Cycle 2012; 11: 2526–2537.
[13] Tang BD, Wang X, Tang C, Zhang D, Wu SW, Li LN. Effect of formaldehyde on the reproductive toxicity in male Wistar rats. J Bengbu Med College 2018; 4: 187–195.
[14] Jedlinska-Krakowska M, Bomba G, Jakubowski K, Rotkiewicz T, Jana B, Penkowski A. Impact of oxidative stress and supplementation with vitamins E and C on testes morphology in rats. J Reprod Dev 2006; 52: 203–209.
[15] Yang HS, Han DK, Kim JR, Sim JC. Effects of α- tocopherol on cadmium-induced toxicity in rat testis and spermatogenesis. J Korean Med Sci 2006; 21: 445–451.
[16] Abdelrazik H, Sharma R, Mahfouz R, Agarwal A. Lcarnitine decreases DNA damage and improves the in vitro blastocyst development rate in mouse embryos. Fertil Steril 2009; 91: 589–596.
[17] Mongioi L, Calogero AE, Vicari E, Condorelli RA, Russo GI, Privitera S, et al. The role of carnitine in male infertility. Andrology 2016; 4: 800–807.
[18] Agarwal A, Said TM. Carnitines and male infertility. Reprod Biomed Online 2004; 8: 376–384.
[19] Vassiliadis S, Athanassakis I. A “conditionally essential” nutrient, L-carnitine, as a primary suspect in endometriosis. Fertil Steril 2011; 95: 2759–2760.
[20] İzgüt-Uysal VN, Ağaç A, Derin N. Effect of L-carnitine on carrageenan-induced inflammation in aged rats. Gerontology 2003; 49: 287–292.
[21] Khushboo M, Murthy MK, Devi MS, Sanjeev S, Ibrahim KS, Kumar NS, et al. Testicular toxicity and sperm quality following copper exposure in Wistar albino rats: ameliorative potentials of L-carnitine. Environ Sci Pollut Res Int 2018; 25: 1837–1862.
[22] Moretti S, Famularo G, Marcellini S, Boschini A, Santini G, Trinchieri V, et al. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal 2002; 4: 391–403.
[23] Khademi A, Alleyassin A, Agha-Hosseini M, Safdarian L, Saeidi Saeidabadi H, Pooyan O. The effect of LCarnitine on sperm parameters in patients candidated for intracytoplasmic sperm injection. Fertility Sterility 2005; 84: S212–S213.
[24] Onem G, Aral E, Enli Y, Oguz EO, Coskun E, Aybek H, et al. Neuroprotective effects of L-carnitine and vitamin E alone or in combination against ischemia-reperfusion injury in rats. J Surg Res 2006; 131: 124–130.
[25] Hegazy AA, Elsayed NE, Ahmad MM, Omar NM. Effect of formaldehyde on rat testis structure. Acad Anat Int 2017; 3: 15–23.
[26] Altun Z, Olgun Y, Ercetin P, Aktas S, Kirkim G, Serbetcioglu B, et al. Protective effect of acetyl−l−carnitine against cisplatin ototoxicity: role of apoptosis−related genes and pro−inflammatory cytokines. Cell Prolif 2014; 47: 72–80.
[27] Mangoli E, Talebi AR, Anvari M, Pourentezari M. Effects of experimentally-induced diabetes on sperm parameters and chromatin quality in mice. Iran J Reprod Med 2013; 11: 53–60.
[28] Talebi AR, Abbasi Sarcheshmeh A, Khalili MA, Tabibnejad N. Effects of ethanol consumption on chromatin condensation and DNA integrity of epididymal spermatozoa in rat. Alcohol 2011; 45: 403–409.
[29] Talebi AR, Khalili MA, Hossaini A. Assessment of nuclear DNA integrity of epididymal spermatozoa following experimental chronic spinal cord injury in the rat. Int J Androl 2007; 30: 163–169.
[30] Talebi AR, Moein MR, Tabibnejad N, Ghasemzadeh J. Effect of varicocele on chromatin condensation and DNA integrity of ejaculated spermatozoa using cytochemical tests. Andrologia 2008; 40: 245–251.
[31] Talebi AR, Vahidi S, Aflatoonian A, Ghasemi N, Ghasemzadeh J, Dehghani Firoozabadi R, et al. Cytochemical evaluation of sperm chromatin and DNA integrity in couples with unexplained recurrent spontaneous abortions. Andrologia 2012; 44 (Suppl.): 462–470.
[32] Pourentezari M, Talebi A, Abbasi A, Khalili MA, Mangoli E, Anvari M. Effects of acrylamide on sperm parameters, chromatin quality, and the level of blood testosterone in mice. Iran J Reprod Med 2014; 12: 335–342.
[33] Gandini L, Lombardo F, Paoli D, Caponecchia L, Familiari G, Verlengia C, et al. Study of apoptotic DNA fragmentation in human spermatozoa. Hum Reprod 2000; 15: 830–839.
[34] Cankut S, Dinc T, Cincik M, Ozturk G, Selam B. Evaluation of sperm DNA fragmentation via halosperm technique and TUNEL assay before and after cryopreservation. Reprod Sci 2019; 26: 1575–1581.
[35] Roshankhah S, Jalili C, Salahshoor MR. Effects of crocin on sperm parameters and seminiferous tubules in diabetic rats. Adv Biomed Res 2019; 8: 4–13.
[36] Moladoust H, Nasiri E, Gazor R, Mahdavi T, Ghorbani R, Rostampour M. Assessment of the protective impact of vitamin E on sex hormones and sperm parameters of formaldehyde-treated male rats: A preliminary investigation. Galen Medical Journal 2017; 6: 330–337.
[37] Aitken RJ. Reactive oxygen species as mediators of sperm capacitation and pathological damage. Mol Reprod Dev 2017; 84: 1039–1052.
[38] Zhu Z, Kawai T, Umehara T, Hoque SAM, Zeng W, Shimada M. Negative effects of ROS generated during linear sperm motility on gene expression and ATP generation in boar sperm mitochondria. Free Radic Biol Med 2019; 141: 159– 171.
[39] Fukushima T, Hamada Y, Komiyama M, Matsuno Y, Mori C, Horii I. Early changes in sperm motility, acrosome reaction, and gene expression of reproductive organs in rats treated with sulfasalazine. Reprod Toxicol 2007; 23: 153–157.
[40] Aziz N, Saleh RA, Sharma RK, Lewis-Jones I, Esfandiari N, Thomas Jr AJ, et al. Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index. Fertil Steril 2004; 81: 349–354.
[41] Baird DJ, Pascoe TJ, Zhou X, Hajibabaei M. Building freshwater macroinvertebrate DNA-barcode libraries from reference collection material: formalin preservation vs specimen age. Journal of the North American Benthological Society 2011; 30: 125–130.
[42] Köse E, Sarsılmaz M, Taş U, Kavaklı A, Türk G, Özlem Dabak D, et al. Rose oil inhalation protects against formaldehyde−induced testicular damage in rats. Andrologia 2012; 44 (Suppl.): 342–348.
[43] Alkan İ, Yüksel M, Canat HL, Atalay HA, Can O, Özveri H, et al. Superoxide anion production by the spermatozoa of men with varicocele: relationship with Varicocele grade and semen parameters. World J Men Health 2018; 36: 255–262.
[44] Sapmaz HI, Yıldız A, Polat A, Vardı N, Köse E, Tanbek K, et al. Protective efficacy of Nigella sativa oil against the harmful effects of formaldehyde on rat testicular tissue. Asian Pacific Journal of Tropical Biomedicine 2018; 8: 548–553.
[45] Duong A, Steinmaus C, McHale CM, Vaughan CP, Zhang L. Reproductive and developmental toxicity of formaldehyde: A systematic review. Mutat Res 2011; 728: 118–138.
[46] Yoshikawa K, Oshima Y, Inagaki A, Sakuragawa A. Determination of formaldehyde in water samples by high-performance liquid chromatography with Methyl acetoacetate derivatization. Bull Environ Contam Toxicol 2018; 101: 672–677.
[47] Tang M, Xie Y, Yi Y, Wang W. Effects of formaldehyde on germ cells of male mice. Wei Sheng Yan Jiu 2003; 32: 544–548.
[48] Levine H, Jørgensen N, Martino-Andrade A, Mendiola J, Weksler-Derri D, Mindlis I, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update 2017; 23: 646–659.
[49] Balercia G, Regoli F, Armeni T, Koverech A, Mantero F, Boscaro M. Placebo-controlled double-blind randomized trial on the use of L-carnitine, L-acetylcarnitine, or combined L-carnitine and L-acetylcarnitine in men with idiopathic asthenozoospermia. Fertil Steril 2005; 84: 662– 671.
[50] Cheah Y, Yang W. Functions of essential nutrition for high quality spermatogenesis. Advances in Bioscience and Biotechnology 2011; 2: 182–197.
[51] Banihani S, Sharma R, Bayachou M, Sabanegh E, Agarwal A. Human sperm DNA oxidation, motility and viability in the presence of l−carnitine during in vitro incubation and centrifugation. Andrologia 2012; 44 (Suppl.): 505–512.
[52] Hufana-Duran D, Duran PG, Monson R, Parrish J. Motility and membrane integrity of ejaculated bovine spermatozoa extended and cryopreserved in L-carnitine Tris-egg yolk extender. J ISSAAS 2017; 23: 56–67.
[53] Berni A, Meschini R, Filippi S, Palitti F, De Amicis A, Chessa L. L-carnitine enhances resistance to oxidative stress by reducing DNA damage in Ataxia telangiectasia cells. Mutat Res 2008; 650: 165–174.
[54] Zidan A, Hedya SE, Elfeky DM, Abdin AA. The possible anti-apoptotic and antioxidant effects of acetyl l-carnitine as an add-on therapy on a relapsing-remitting model of experimental autoimmune encephalomyelitis in rats. Biomed Pharmacother 2018; 103: 1302–1311.
[55] de Moraes MS, Guerreiro G, Sitta A, de Moura Coelho D, Manfredini V, Wajner M, et al. Oxidative damage in mitochondrial fatty acids oxidation disorders patients and the in vitro effect of l-carnitine on DNA damage induced by the accumulated metabolites. Arch Biochem Biophys 2020; 679: 108206: 3–7.