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. 2015 Jun 18;28(4):272–280. doi: 10.3967/bes2015.038

Grape Seed Proanthocyanidin Extract Alleviates Arsenic-induced Oxidative Reproductive Toxicity in Male Mice

Shu Gang LI 1,∧, Yu Song DING 1,∧, Qiang NIU 1, Shang Zhi XU 1, Li Juan PANG 1, Ru Lin MA 1, Ming Xia JING 1, Gang Ling FENG 1, Jia Ming LIU 1, Shu Xia GUO 1,*
PMCID: PMC7135117  PMID: 25966753

Abstract

Objective

To determine the ability of grape seed proanthocyanidin extract (GSPE) in alleviating arsenic-induced reproductive toxicity.

Methods

Sixty male Kunming mice received the following treatments by gavage: normal saline solution (control); arsenic trioxide (ATO; 4 mg/kg); GSPE (400 mg/kg); ATO+GSPE (100 mg/kg); ATO+GSPE (200 mg/kg) and ATO+GSPE (400 mg/kg). Thereafter, the mice were sacrificed and weighed, and the testis was examined for pathological changes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO1), glutathione S-transferase (GST), NAD(P)H dehydrogenase, and quinone 1 (NQO1) expression in the testis was detected by real-time PCR. Superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability (T-AOC), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed.

Results

ATO-treated mice showed a significantly decreased sperm count and testis somatic index and activity levels of SOD, GSH, and T-AOC than control group. Compared to the ATO-treated group, ATO +GSPE group showed recovery of the measured parameters. Mice treated with ATO+high-dose GSPE showed the highest level of mRNA expression of Nrf2, HO, NQO1, and GST.

Conclusions

GSPE alleviates oxidative stress damage in mouse testis by activating Nrf2 signaling, thus counteracting arsenic-induced reproductive toxicity.

Key words: Grape seed proanthocyanidin extract, Arsenic, Reproductive toxicity, Nrf2 signaling

Biographies

Biographical notes of the first authors: LI Shu Gang, male, born in 1979, PhD, associate professor, majoring in arsenic and health

DING Yu Song, male, born in 1979, PhD, associate professor, majoring in health toxicology.

Footnotes

This work was supported by a grant from the Xinjiang Production and Construction Corps (2014BA039) and Shihezi University grant (RCZX201112).

References

  • 1.National Research Council . Arsenic in Drinking Water. National Academy Press; Washington DC: 1999. pp. 4–9. [Google Scholar]
  • 2.ATSDR . Toxicological Profile for Arsenic. Agency for Toxic Substances and Disease Registry; Atlanta: 1999. pp. 3–6. [PubMed] [Google Scholar]
  • 3.Abernathy CO, Liu YP, Longfellow D. Arsenic: health effects, mechanisms of actions, and research issues. Environ Health Perspect. 1999;107:593–597. doi: 10.1289/ehp.99107593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Smith AH, Hopenhayn-Rich C, Bates MN. Cancer risks from arsenic in drinking water. Environ Health Perspect. 1992;97:259–267. doi: 10.1289/ehp.9297259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Biswas R, Poddar S, Mukherjee A. Investigation on the genotoxic effects of long-term administration of sodium arsenite in bone marrow and testicular cells in vivo using the comet assay. J Environ Pathol Toxicol Oncol. 2007;26:29–37. doi: 10.1615/jenvironpatholtoxicoloncol.v26.i1.40. [DOI] [PubMed] [Google Scholar]
  • 6.Sarkar M, Chaudhuri GR, Chattopadhyay A. Effect of sodium arsenite on spermatogenesis, plasma gonadotrophins and testosterone in rats. Asian J Androl. 2003;5:27–31. [PubMed] [Google Scholar]
  • 7.Jana K, Jana S, Samanta PK. Effects of chronic exposure to sodium arsenite on hypothalamic-pituitary-testicular activities in adult rats: possible an estrogenic mode of action. Reprod Biol Endocrinol. 2006;9:1–13. doi: 10.1186/1477-7827-4-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Sanghamitra S, Hazra J, Upadhyay SN. Arsenic induced toxicity on testicular tissue of mice. Indian J Physiol Pharmacol. 2008;52:84–90. [PubMed] [Google Scholar]
  • 9.Leke RJ, Oduma JA, Bassol-Mayagoitia S. Regional and geographical variations in infertility: effects of environmental, cultural, and socioeconomic factors. Environ Health Perspect. 1993;101:73–80. doi: 10.1289/ehp.93101s273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Hsieh FI, Hwang TS, Hsieh YC. Risk of erectile dysfunction induced by arsenic exposure through well water consumption in Taiwan. Environ Health Perspect. 2008;116:532–536. doi: 10.1289/ehp.10930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Xu W, Bao H, Liu F. Environmental exposure to arsenic may reduce human semen quality: associations derived from a Chinese cross-sectional study. Environ Health. 2012;11:46–49. doi: 10.1186/1476-069X-11-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Naujokas MF, Anderson B, Ahsan H. The Broad Scope of Health Effects from Chronic Arsenic Exposure: Update on a Worldwide Public Health Problem. Environ Health Perspect. 2013;121:295–302. doi: 10.1289/ehp.1205875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Choi J, Ou JH. Mechanisms of Liver Injury III Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol. 2006;290:847–851. doi: 10.1152/ajpgi.00522.2005. [DOI] [PubMed] [Google Scholar]
  • 14.Das S, Santra A, Lahiri S. Implications of oxidative stress and hepatic cytokine (TNF-α and IL-6) response in the pathogenesis of hepatic collagenesis in chronic arsenic toxicity. Toxicol Appl Pharmacol. 2005;204:18–26. doi: 10.1016/j.taap.2004.08.010. [DOI] [PubMed] [Google Scholar]
  • 15.Ghatak S, Biswas A, Dhali GK. Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice. Toxicol Appl Pharmacol. 2011;251:59–69. doi: 10.1016/j.taap.2010.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Ding WX, Ni HM, Francesca DD. Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes. Hepatology. 2004;40:403–413. doi: 10.1002/hep.20310. [DOI] [PubMed] [Google Scholar]
  • 17.Hall MN, Niedzwiecki M, Liu X. Chronic Arsenic Exposure and Blood Glutathione and Glutathione Disulfide Concentrations in Bangladeshi Adults. Environ Health Perspect. 2013;121:1068–1074. doi: 10.1289/ehp.1205727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Banerjee M, Banerjee N, Ghosh P. Evaluation of the Serum Catalase and Myeloperoxidase Activity in the Chronic Arsenic Exposed Individuals and Concomitant Cytogenetic Damage. Toxicol. Appl. Pharmacol. 2010;249:47–54. doi: 10.1016/j.taap.2010.08.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Bagchi D, Garg A, Krohn RL. Oxygen free radical scavenging abilities of vitamins C and E and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol. 1997;95:179–189. [PubMed] [Google Scholar]
  • 20.Bagchi D, Sen CK, Ray SD. Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract. Mutat. Res. 2003;21:523–524. doi: 10.1016/s0027-5107(02)00324-x. [DOI] [PubMed] [Google Scholar]
  • 21.Asl MN, Hosseinzadeh H. Review of the pharmacological effects of vitis vinifera (grape) and its bioactive compounds. Phytotherapy Res. 2009;10:1002–1006. doi: 10.1002/ptr.2761. [DOI] [PubMed] [Google Scholar]
  • 22.El-Ashmawy IM, Saleh A, Salama OM. Effects of marjoram volatile oil and grape seed extract on ethanol toxicity in male rats. Basic Clin Pharmacol Toxicol. 2007;101:320–327. doi: 10.1111/j.1742-7835.2007.00125.x. [DOI] [PubMed] [Google Scholar]
  • 23.Prasain JK, Peng N, Dai Y. Liquid chromatography tandem mass spectrometry identification of proanthocyanidins in rat plasma after oral administration of grape seed extract. Phytomedicine. 2009;16:233–243. doi: 10.1016/j.phymed.2008.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Nassiri-Asl M, Hosseinzadeh H. Review of the pharmacological effects of Vitis vinifera (Grape) and its bioactive compounds. Phytother Res. 2009;23:1197–1204. doi: 10.1002/ptr.2761. [DOI] [PubMed] [Google Scholar]
  • 25.Dulundu E, Ozel Y, Topaloglu U. Grape seed extract reduces oxidative stress and fibrosis in experimental biliary obstruction. J Gastroenterol Hepatol. 2007;22:885–892. doi: 10.1111/j.1440-1746.2007.04875.x. [DOI] [PubMed] [Google Scholar]
  • 26.Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–13295. doi: 10.1074/jbc.R900010200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Cuadrado A, Moreno-Murciano P, Pedraza-Chaverri J. The transcription factor Nrf2 as a new therapeutic target in Parkinson’s disease. Expert Opin Ther Targets. 2009;13:319–329. doi: 10.1517/13543780802716501. [DOI] [PubMed] [Google Scholar]
  • 28.Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci. 2009;34:176–188. doi: 10.1016/j.tibs.2008.12.008. [DOI] [PubMed] [Google Scholar]
  • 29.Liu Q, Zhang H, Smeester L. The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010;3:37–41. doi: 10.1186/1755-8794-3-37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Mitchell AM, Li C, Samulskia RJ. Arsenic trioxide stabilizes accumulations of adeno-associated virus virions at the perinuclear region, increasing transduction In Vitro and In Vivo. J Virol. 2013;87:4571–4583. doi: 10.1128/JVI.03443-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Xia Y, Hao G, Yang Y. Study on reproductive and immune toxicity of male rats exposed to As2O3. J Hygiene Res. 2009;38:720–722. [PubMed] [Google Scholar]
  • 32.Zhu LM, Yuan P, Zhang BB. Antagonism of Procyanidins on Semicarbazide induced Reproductive Toxicity in Male Mice. Prac Prev Med. 2012;19:165–168. [Google Scholar]
  • 33.Nahas S, Hondt HA, Abdou HA. Chromosome aberrations in spermatogonia and sperm abnormalities in curacron-treated mice. Mutat Res. 1989;222:409–414. doi: 10.1016/0165-1218(89)90116-x. [DOI] [PubMed] [Google Scholar]
  • 34.Okamura A, Kamijima M, Shibata E. A comprehensive evaluation of testicular toxicity of dichlorvos in wistar rats. Toxicology. 2005;213:129–137. doi: 10.1016/j.tox.2005.05.015. [DOI] [PubMed] [Google Scholar]
  • 35.Bancroft D, Stevens A, Turmer R. Theory and Practice of Histological Technique. 4th ed. Churchill Living Stone; Edinburgh: 1996. pp. 36–42. [Google Scholar]
  • 36.Balboni A, Gallina L, Palladini A. A real-time PCR assay for bat SARS-like coronavirus detection and its application to Italian greater horseshoe bat faecal sample surveys. Scientific World Journal. 2012;12:989–994. doi: 10.1100/2012/989514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Chow SK, Chan JY, Fung KP. Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells. J Endocrinol. 2004;182:325–337. doi: 10.1677/joe.0.1820325. [DOI] [PubMed] [Google Scholar]
  • 38.Uckun FM, Liu XP, D'Cruz OJ. Human sperm immobilizing activity of aminophenyl arsenic acid and its N-substituted quinazoline, pyrimidine, and purine derivatives: protective effect of glutathione. Reprod Toxicol. 2002;16:57–64. doi: 10.1016/s0890-6238(01)00195-2. [DOI] [PubMed] [Google Scholar]
  • 39.Omura M, Hirata M, Tanaka A. Testicular toxicity evaluation of arsenic-containing binary compound semiconductors, gallium arsenide and indium arsenide, in hamsters. Toxicol Lett. 1996;89:123–129. doi: 10.1016/s0378-4274(96)03796-4. [DOI] [PubMed] [Google Scholar]
  • 40.Turner TT, Lysiak JL. Oxidative stress: A common factor in testicular dysfunctions. J Androl. 2008;29:488–498. doi: 10.2164/jandrol.108.005132. [DOI] [PubMed] [Google Scholar]
  • 41.Yousef MI, Salama AF. Propolis protection from reproductive toxicity caused by aluminium chloride in male rats. Food Chem Toxicol. 2009;47:1168–1175. doi: 10.1016/j.fct.2009.02.006. [DOI] [PubMed] [Google Scholar]
  • 42.Sharma G, Tyagi AK, Singh RP. Synergistic anti-cancer effect of grape seed extract and conventional cytotoxic agent doxorubicin against human breast carcinoma cells. Breast Cancer Res Treat. 2004;85:1–12. doi: 10.1023/B:BREA.0000020991.55659.59. [DOI] [PubMed] [Google Scholar]
  • 43.Hala AHK, Inas ZAA, Gehan MK. Grape seed extract alleviate reproductive toxicity caused by aluminium chloride in male rats. J Am Sci. 2010;6:1200–1209. [Google Scholar]
  • 44.Caillet S, Salmiéri S, Lacroix M. Evaluation of free radical-scavenging properties of commercial grape phenol extracts by a fast colorimetric method. Food Chem. 2006;95:1–8. [Google Scholar]
  • 45.Faria A, Calhau C, de Freitas V. Procyanidins as antioxidants and tumor cell growth modulators. J Agric Food Chem. 2006;54:2392–2397. doi: 10.1021/jf0526487. [DOI] [PubMed] [Google Scholar]
  • 46.Higgins LG, Kelleher MO, Eggleston IM. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. Toxicol Appl Pharmacol. 2009;237:267–280. doi: 10.1016/j.taap.2009.03.005. [DOI] [PubMed] [Google Scholar]
  • 47.Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116. doi: 10.1146/annurev.pharmtox.46.120604.141046. [DOI] [PubMed] [Google Scholar]
  • 48.Villeneuve NF, Lau A, Zhang DD. Regulation of the nrf2-keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal. 2010;13:1699–1712. doi: 10.1089/ars.2010.3211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38:769–789. doi: 10.1080/03602530600971974. [DOI] [PubMed] [Google Scholar]

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