Carnosine and Histidine Supplementation Blunt Lead-Induced Reproductive Toxicity through Antioxidative and Mitochondria-Dependent Mechanisms
Lead (Pb)-induced reproductive toxicity is a well-characterized adverse effect associated with this heavy metal. It has been found that Pb exposure is associated with altered spermatogenesis, increased testicular degeneration, and pathological sperm alterations. On the other hand, it has been reported that Pb-induced reproductive toxicity is associated with increased reactive oxygen species (ROS) formation and diminished antioxidant capacity in the reproductive system. Hence, administration of antioxidants as protective agents might be of value against Pb-induced reproductive toxicity. This study was designed to investigate whether carnosine (CAR) and histidine (HIS) supplementation would mitigate the Pb-induced reproductive toxicity in male rats. Animals received Pb (20 mg/kg/day, oral, 14 consecutive days) alone or in combination with CAR (250 and 500 mg/kg/day, oral, 14 consecutive days) or HIS (250 and 500 mg/kg/day, oral, 14 consecutive days). Pb toxicity was evident in the reproductive system by a significant increase in tissue markers of oxidative stress along with severe histopathological changes, seminal tubule damage, tubular desquamation, low spermatogenesis index, poor sperm parameters, and impaired sperm mitochondrial function. It was found that CAR and HIS supplementation blunted the Pb-induced oxidative stress and mitochondrial dysfunction in the rat reproductive system. Thereby, antioxidative and mitochondria-protective properties serve as primary mechanisms for CAR and HIS against Pb-induced reproductive toxicity.
KeywordsHeavy metals Infertility Oxidative stress Peptide Protective
The authors gratefully acknowledge the Pharmaceutical Sciences Research Center and the Vice Chancellor for Research, Shiraz University of Medical Sciences for the financial support (grant no. 95-01-36-11290).
Compliance with Ethical Standards
The rats were killed according to an animal protocol that was approved by the Institutional Animal Ethics Committee of Shiraz University of Medicine (Shiraz, Iran; no. 11290).
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 2.Yu Y, Han Y, Niu R, Wang J, Manthari RK, Ommati MM et al (2017) Ameliorative effect of VE, IGF-I, and hCG on the fluoride-induced testosterone release suppression in mice Leydig cells via the up-regulation of Star and Cyp11a expression. Biol Trace Elem Res 181:95–103PubMedPubMedCentralGoogle Scholar
- 20.Wang J, Yang Z, Zhu H, Lin L, Liu Z (2012) Lead-induced oxidative stress and protective effect of naringenin on testis tissues of rats. CNKI 19:2012–2019Google Scholar
- 23.Ma L, Liu J-Y, Dong J-X, Xiao Q, Zhao J, Jiang F-L (2017) Toxicity of Pb2+ on rat liver mitochondria induced by oxidative stress and mitochondrial permeability transition. Toxicol Res 6:822–830Google Scholar
- 27.Roberts PR, Zaloga GP (2000) Cardiovascular effects of carnosine. Biochemistry (Mosc) 65:856–861Google Scholar
- 30.Fu H, Katsumura Y, Lin M, Muroya Y, Hata K, Fujii K et al (2009) Free radical scavenging and radioprotective effects of carnosine and anserine. Radiat Phys Chem 78:1192–1197Google Scholar
- 34.Aldini G, Granata P, Carini M (2002) Detoxification of cytotoxic alpha,beta-unsaturated aldehydes by carnosine: characterization of conjugated adducts by electrospray ionization tandem mass spectrometry and detection by liquid chromatography/mass spectrometry in rat skeletal muscle. J Mass Spectrom 37:1219–1228PubMedPubMedCentralGoogle Scholar
- 36.Aydın AF, Küçükgergin C, Çoban J, Doğan-Ekici I, Doğru-Abbasoğlu S, Uysal M et al (2018) Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D-galactose-induced aged rats. Andrologia 50. https://doi.org/10.1111/and.12939
- 46.Farshid AA, Tamaddonfard E, Belasius MS, Hamzeh-Gooshchi N et al (2009) Histopathological comparison of the effects of histidine and ketotifen in a rat model of colitis. Bull Vet Inst Pulawy 53:795–800Google Scholar
- 48.Ommati MM, Zamiri MJ, Akhlaghi A, Atashi H, Jafarzadeh MR, Rezvani MR et al (2013) Seminal characteristics, sperm fatty acids, and blood biochemical attributes in breeder roosters orally administered with sage (Salvia officinalis) extract. Anim Prod Sci 53:548–554Google Scholar
- 49.Fonseca JF, Torres CAA, Maffili VV, Borges AM, Santos ADF, Rodrigues MT et al (2005) The hypoosmotic swelling test in fresh goat spermatozoa. Anim Reprod 2:139–144Google Scholar
- 50.Ommati MM, Heidari R, Zamiri MJ, Shojaee S, Akhlaghi A, Sabouri S (2017) Association of open field behavior with blood and semen characteristics in roosters: as an alternative animal model. Int Androl. https://doi.org/10.1016/j.androl.2017.02.002
- 54.Niknahad H, Jamshidzadeh A, Heidari R, Abdoli N, Ommati MM, Jafari F et al (2016) The postulated hepatotoxic metabolite of methimazole causes mitochondrial dysfunction and energy metabolism disturbances in liver. Pharm Sci 22:217–226Google Scholar
- 58.Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Esfandiari A, Azarpira N et al (2018) Dithiothreitol supplementation mitigates hepatic and renal injury in bile duct ligated mice: potential application in the treatment of cholestasis-associated complications. Biomed Pharmacother 99:1022–1032PubMedPubMedCentralGoogle Scholar
- 60.Jamshidzadeh A, Niknahad H, Heidari R, Zarei M, Ommati MM, Khodaei F (2017) Carnosine protects brain mitochondria under hyperammonemic conditions: relevance to hepatic encephalopathy treatment. PharmaNutrition 5:58–63Google Scholar
- 64.Katalinic V, Modun D, Music I, Boban M (2005) Gender differences in antioxidant capacity of rat tissues determined by 2,2′-azinobis (3-ethylbenzothiazoline 6-sulfonate; ABTS) and ferric reducing antioxidant power (FRAP) assays. Comp Biochem Physiol 140:47–52Google Scholar
- 65.Heidari R, Moezi L, Asadi B, Ommati MM, Azarpira N (2017) Hepatoprotective effect of boldine in a bile duct ligated rat model of cholestasis/cirrhosis. PharmaNutrition 5:109–117Google Scholar
- 66.Heidari R, Jamshidzadeh A, Niknahad H, Safari F, Azizi H, Abdoli N et al (2016) The hepatoprotection provided by taurine and glycine against antineoplastic drugs induced liver injury in an ex vivo model of normothermic recirculating isolated perfused rat liver. Trends Pharmacol Sci 2:59–76Google Scholar
- 69.Kianifard D, Sadrkhanlou R-A, Hasanzadeh S (2011) The histological, histomorphometrical and histochemical changes of testicular tissue in the metformin treated and untreated streptozotocin-induced adult diabetic rats. Vet Res Forum 3:13–24Google Scholar
- 83.Kukreja RC, Loesser KE, Kearns AA, Naseem SA, Hess ML (1993) Protective effects of histidine during ischemia-reperfusion in isolated perfused rat hearts. Am J Phys 264:H1370–H1H81Google Scholar
- 85.Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu S-S (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Phys 287:C817–CC33Google Scholar
- 86.Schaffer SW, Suleiman MS (2010) Mitochondria: the dynamic organelle. Springer Science & Business Media, New York 359 pGoogle Scholar
- 90.Leberman R, Rabin BR (1959) Metal complexes of histidine. Trans Faraday Soc 55:1660–1670Google Scholar
- 91.Sundberg RJ, Martin RB (1974) Interactions of histidine and other imidazole derivatives with transition metal ions in chemical and biological systems. Chem Rev 74:471–517Google Scholar