Induction of Testicular Damage by Daily Methamphetamine Administration in Rats




Ji-Fan Lin;Yi-Hsuan Lin;Po-Cheng Liao;Yi-Chia Lin;Te-Fu Tsai;Kuang-Yu Chou;Hung-En Chen;Shiow-Chwen Tsai;Thomas I-Sheng Hwang

Key Words

antioxidant enzymes ; apoptosis ; methamphetamine ; oxidative stress ; testosterone


The Chinese Journal of Physiology

Volume or Term/Year and Month of Publication

57卷1期(2014 / 02 / 28)

Page #

19 - 30

Content Language


English Abstract

Methamphetamine (METH)-induced brain damage and apoptosis within the central nervous system are well documented. This study was conducted to investigate the toxic effects of daily METH administration on the testes in a rat model. Male Sprague-Dawley rats (5 weeks old, ~100 g, n = 64) were divided into two groups and treated with vehicle (saline, control) or METH (10 mg/kg) for 15, 30, 60 and 90 days. The results showed that daily administration of METH decreased the body, testicular and epididymis weights as well as the serum levels of total testosterone. The increased apoptotic index (Bad/Bcl2 expression ratio) and levels of cleaved caspase-3 indicated that apoptosis had occurred in the testes of the METH-treated rats. The oxidative stress levels increased as the reduced and oxidized glutathione (GSH/GSSG) ratio decreased. The overall sperm counts decreased at 15 and 90 days, whereas morphologically abnormal sperm counts increased at 30, 60 and 90 days in the METH-treated rats. This study demonstrates that daily exposure to METH significantly reduced the number and quality of sperm in rats. The underlying pathophysiological mechanisms likely include the reduction of serum testosterone levels and the increase of oxidative stress and apoptosis in the rat testes.

Topic Category 醫藥衛生 > 基礎醫學
  1. Emre, M.H.,Aktay, G.,Polat, A.,Vardt, N.(2007).Effects of benzo(a)pyrene and ethanol on oxidative stress of brain, lung tissues and lung morphology in rats.Chinese J. Physiol.,50,143-148.
  2. Kiray, M.,Bagriyanik, H.A.,Pekcetin, C.,Ergur, B.U.,Uysal, N.(2008).Protective effects of deprenyl in transient cerebral ischemia in rats.Chinese J. Physiol.,51,275-281.
  3. Yang, C.H.,Lin, C.Y.,Yang, J.H.,Liou, S.Y.,Li, P.C.,Chien, C.T.(2009).Supplementary catechins attenuate cooking-oil-fumes-induced oxidative stress in rat lung.Chinese J. Physiol.,52,151-159.
  4. Alavi, S.H.,Taghavi, M.M.,Moallem, S.A.(2008).Evaluation of effects of methamphetamine repeated dosing on proliferation and apoptosis of rat germ cells.Syst. Biol. Reprod. Med.,54,85-91.
  5. Beers, R.F., Jr.,Sizer, I.W.(1952).A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase.J. Biol. Chem.,195,133-140.
  6. Beitia, G.,Cobreros, A.,Sainz, L.,Cenarruzabeitia, E.(2000).Ecstasy-induced toxicity in rat liver.Liver,20,8-15.
  7. Bittner, S.E.,Wagner, G.C.,Aigner, T.G.,Seiden, L.S.(1981).Effects of a high-dose treatment of methamphetamine on caudate dopamine and anorexia in rats.Pharmacol. Biochem. Behav.,14,481-486.
  8. Cadet, J.L.,Sheng, P.,All, S.,Rothman, R.,Carlson, E.,Epstein, C.(1994).Attenuation of methamphetamine-induced neurotoxicity in copper/zinc superoxide dismutase transgenic mice.J. Neurochem.,62,380-383.
  9. Christ, G.J.,Lerner, S.E.,Kim, D.C.,Melman, A.(1995).Endothelin-1 as a putative modulator of erectile dysfunction: I. Characteristics of contraction of isolated corporal tissue strips.J. Urol.,153,1998-2003.
  10. Cook, C.E.,Jeffcoat, A.R.,Sadler, B.M.,Hill, J.M.,Voyksner, R.D.,Pugh, D.E.,White, W.R.,Perez-Reyes, M.(1992).Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans.Drug Metab. Dispos.,20,856-862.
  11. Davidson, C.,Gow, A.J.,Lee, T.H.,Ellinwood, E.H.(2001).Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment.Brain Res. Rev.,36,1-22.
  12. Erkkila, K.,Henriksen, K.,Hirvonen, V.,Rannikko, S.,Salo, J.,Parvinen, M.,Dunkel, L.(1997).Testosterone regulates apoptosis in adult human seminiferous tubules in vitro.J. Clin. Endocrinol. Metab.,82,2314-2321.
  13. Griffith, O.W.(1980).Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine.Anal. Biochem.,106,207-212.
  14. He, S.Y.,Matoba, R.,Fujitani, N.,Sodesaki, K.I.,Onishi, S.(1996).Cardiac muscle lesions associated with chronic administration of methamphetamine in rats.Am. J. Forensic Med. Pathol.,17,155-162.
  15. Henriksen, K.,Hakovirta, H.,Parvinen, M.(1995).Testosterone inhibits and induces apoptosis in rat seminiferous tubules in a stage-specific manner: in situ quantification in squash preparations after administration of ethane dimethane sulfonate.Endocrinology,136,3285-3291.
  16. Huang, C.C.,Lin, T.J.,Lu, Y.F.,Chen, C.C.,Huang, C.Y.,Lin, W.T.(2009).Protective effects of L-arginine supplementation against exhaustive exercise-induced oxidative stress in young rat tissues.Chinese J. Physiol.,52,306-315.
  17. Ignarro, L.J.,Cirino, G.,Casini, A.,Napoli, C.(1999).Nitric oxide as a signaling molecule in the vascular system: an overview.J. Cardiovasc. Pharmacol.,34,879-886.
  18. Jayanthi, S.,Ladenheim, B.,Cadet, J.L.(1998).Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidation in copper/zinc-superoxide dismutase transgenic mice.Ann. N. Y. Acad. Sci.,844,92-102.
  19. Kalant, H.(2001).The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs.CMAJ,165,917-928.
  20. Kaye, S.,McKetin, R.,Duflou, J.,Darke, S.(2007).Methamphetamine and cardiovascular pathology: a review of the evidence.Addiction,102,1204-1211.
  21. Kuriyama, K.,Kitamura, T.,Yokoi, R.,Hayashi, M.,Kobayashi, K.,Kuroda, J.,Tsujii, H.(2005).Evaluation of testicular toxicity and sperm morphology in rats treated with methyl methanesulphonate (MMS).J. Reprod. Dev.,51,657-667.
  22. Lin, J.F.,Lin, Y.C.,Lin, Y.H.,Tsai, T.F.,Chou, K.Y.,Chen, H.E.,Hwang, T.I.(2011).Zoledronic acid induces autophagic cell death in human prostate cancer cells.J. Urol.,185,1490-1496.
  23. Melo, P.,Zanon-Moreno, V.,Alves, C.J.,Magalhaes, A.,Tavares, M.A.(2010).Pinazo-Duran, M.D. and Moradas-Ferreira, P. Oxidative stress response in the adult rat retina and plasma after repeated administration of methamphetamine.Neurochem. Int.,56,431-436.
  24. Miller, M.A.(ed.),Kozel, N.J.(ed.)(1991).Methamphetamine Abuse: Epidemiologic Issues and Implications.Rockville, MD:National Institute on Drug Abuse.
  25. Mirecki, A.,Fitzmaurice, P.,Ang, L.,Kalasinsky, K.S.,Peretti, F.J.,Aiken, S.S.,Wickham, D.J.,Sherwin, A.,Nobrega, J.N.,Forman, H.J.,Kish, S.J.(2004).Brain antioxidant systems in human methamphetamine users.J. Neurochem.,89,1396-1408.
  26. Mori, T.,Ito, S.,Kita, T.,Narita, M.,Suzuki, T.,Matsubayashi, K.,Sawaguchi, T.(2007).Oxidative stress in methamphetamine-induced self-injurious behavior in mice.Behav. Pharmacol.,18,239-249.
  27. Nandi, S.,Banerjee, P.P.,Zirkin, B.R.(1999).Germ cell apoptosis in the testes of Sprague Dawley rats following testosterone withdrawal by ethane 1,2-dimethanesulfonate administration: relationship to Fas?.Biol. Reprod.,61,70-75.
  28. Nudmamud-Thanoi, S.,Thanoi, S.(2011).Methamphetamine induces abnormal sperm morphology, low sperm concentration and apoptosis in the testis of male rats.Andrologia,43,278-282.
  29. Peltola, V.,Huhtaniemi, I.,Ahotupa, M.(1992).Antioxidant enzyme activity in the maturing rat testis.J. Androl.,13,450-455.
  30. Pereira, C.V.,Nadanaciva, S.,Oliveira, P.J.,Will, Y.(2012).The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo.Expert Opin. Drug Metab. Toxicol.,8,219-237.
  31. Pontes, H.,Duarte, J.A.,de Pinho, P.G.,Soares, M.E.,Fernandes, E.,Dinis-Oliveira, R.J.,Sousa, C.,Silva, R.,Carmo, H.,Casal, S.,Remião, F.,Carvalho, F.,Bastos, M.L.(2008).Chronic exposure to ethanol exacerbates MDMA-induced hyperthermia and exposes liver to severe MDMA-induced toxicity in CD1 mice.Toxicology,252,64-71.
  32. Rawson, R.A.,Anglin, M.D.,Ling, W.(2001).Will the methamphetamine problem go away?.J. Addict. Dis.,21,5-19.
  33. Roll, J.M.(Editor)(2009).Methamphetamine Addiction: From Basic Science to Treatment.New York:Guilford.
  34. Roth, L.W.,Richards, R.K.,Shemano, I.,Morphis, B.B.(1954).A comparison of the analeptic, circulatory and other properties of D- and L-desoxyephedrine.Arch. Int. Pharmacodyn. Ther.,98,362-368.
  35. Roveri, A.,Casasco, A.,Maiorino, M.,Dalan, P.,Calligaro, A.,Ursini, F.(1992).Phospholipid hydroperoxide glutathione peroxidase of rat testis. Gonadotropin dependence and immunocytochemical identification.J. Biol. Chem.,267,6142-6146.
  36. Schaiberger, P.H.,Kennedy, T.C.,Miller, F.C.,Gal, J.,Petty, T.L.(1993).Pulmonary hypertension associated with long-term inhalation of "crank" methamphetamine.Chest,104,614-616.
  37. Tietze, F.(1969).Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues.Anal. Biochem.,27,502-522.
  38. Tsai, S.C.,Chen, J.J.,Chiao, Y.C.,Lu, C.C.,Lin, H.,Yeh, J.Y.,Lo, M.J.,Kau, M.M.,Wang, S.W.,Wang, P.S.(1997).The role of cyclic AMP production, calcium channel activation and enzyme activities in the inhibition of testosterone secretion by amphetamine.Brit. J. Pharmacol.,122,949-955.
  39. Tsai, S.C.,Chiao, Y.C.,Lu, C.C.,Doong, M.L.,Chen, Y.H.,Shih, H.C.,Liaw, C.,Wang, S.W.,Wang, P.S.(1996).Inhibition by amphetamine of testosterone secretion through a mechanism involving an increase of cyclic AMP production in rat testes.Brit. J. Pharmacol.,118,984-988.
  40. Tsai, S.C.,Lu, C.C.,Lin, C.S.,Wang, P.S.(2003).Antisteroidogenic actions of hydrogen peroxide on rat Leydig cells.J. Cell. Biochem.,90,1276-1286.
  41. Volkow, N.D.,Fowler, J.S.,Wang, G.J.,Shumay, E.,Telang, F.,Thanos, P.K.,Alexoff, D.(2010).Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications.PLoS One,5,e15269.
  42. Yamamoto, B.K.,Moszczynska, A.,Gudelsky, G.A.(2010).Amphetamine toxicities: classical and emerging mechanisms.Ann. N. Y. Acad. Sci.,1187,101-121.
  43. Yamamoto, Y.,Yamamoto, K.,Abiru, H.,Fukui, Y.,Shiota, K.(1995).Effects of methamphetamine on rat embryos cultured in vitro.Biol. Neonate,68,33-38.
  44. Yamamoto, Y.,Yamamoto, K.,Hayase, T.(1999).Effect of methamphetamine on male mice fertility.J. Obstet. Gynaecol. Res.,25,353-358.
  45. Yamamoto, Y.,Yamamoto, K.,Hayase, T.,Abiru, H.,Shiota, K.,Mori, C.(2002).Methamphetamine induces apoptosis in seminiferous tubules in male mice testis.Toxicol. Appl. Pharmacol.,178,155-160.
Times Cited
  1. Wu, Li-Yi,Tzang, Bor-Show,Lin, Hsou-Lin,Kao, Tseng-Wei,Huang, Chih-Yang,Hsu, Tsai-Ching,Chiu, Chun-Ching,Chen, Li-Jeng(2015).Attenuated Effects of Deep-Sea Water on Hepatic Apoptosis in STZ-Induced Diabetic Rats.中國生理學雜誌,58(3),197-205.
  2. Yeh, Ching-Ying,Tzeng, Chii-Ruey,Li, Ching-Jen,Han, Bor-Cheng,Chien, Ling-Chu,Chen, Ruey-Yu(2016).Decline in Semen Quality in Men in Northern Taiwan between 2001 and 2010.中國生理學雜誌,59(6),355-365.
  3. Yeh, Ching-Ying,Tzeng, Chii-Ruey,Li, Ching-Jen,Han, Bor-Cheng,Chien, Ling-Chu,Chen, Ruey-Yu(2016).Decline in Semen Quality in Men in Northern Taiwan between 2001 and 2010.中國生理學雜誌,59(6),355-365.