Skip to main content

Advertisement

SpringerLink
Log in

Protective effect of alpha-lipoic acid on di-(2-ethylhexyl) phthalate-induced testicular toxicity in mice

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Phthalates are synthetic chemicals, widely used as plasticizers due to their flexibility in plastics. Human populations may be exposed to phthalates through direct contact or environmental contamination. Most studies have focused on the effects of phthalates on the reproductive tract and have classified these compounds as endocrine disruptors. In this study, we aimed to investigate the possible oxidative damage induced by di-(2-ethylhexyl) phthalate (DEHP) in the mouse testis and to evaluate the regulatory effects of alpha-lipoic acid (LA). For this purpose, forty male mice were divided into four experimental groups. Group I received normal saline (2 mL/kg; p.o.) and corn oil (5 mL/kg; p.o.) as the control group, group II received DEHP (2 g/kg; p.o.), group III received DEHP and LA (20 mg/kg; p.o.), and group IV was treated with LA alone; treatments continued for 2 weeks. The glutathione level (GSH), as well as glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities, was determined in mice. In addition, serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured. Nitric oxide (NO) level, malondialdehyde (MDA) level, sperm characteristics, and histological changes of the testes were also evaluated. The results showed that 2 g/kg of DEHP could significantly decrease the sperm motility. Based on our findings, DEHP significantly reduced the production and count of sperms; these toxic effects were associated with alterations in the serum hormone levels. In the DEHP group, a significant reduction was reported in the serum testosterone, FSH, and LH levels. LA improved DEHP-induced changes in hormonal levels and sperm index. According to our findings, treatment with DEHP triggered histopathological changes and oxidative stress, which were normalized by LA pretreatment. In conclusion, DEHP disrupts the testicular function in rats, at least partly through induction of oxidative stress. On the other hand, LA exhibits potential protective effects on testicular toxicity induced by DEHP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abd-Ellah M, Aly H, Mokhlis H, Abdel-Aziz AJH (2016) Quercetin attenuates di-(2-ethylhexyl) phthalate-induced testicular toxicity in adult rats. Toxicology 35:232–243

    CAS  Google Scholar 

  • Aebi H (1984). Catalase in vitro. 105, 121–6

  • Al-Azawi T, Asker MH (2017): Alpha lipoic acid role on pituitary testicular function in mice treated with Nitrofurantoin or Methotrexate.  J. Entomol. Zool. Stud 5, 74–78

  • Arivazhagan P, Panneerselvam C (2000) Effect of DL-α-lipoic acid on neural antioxidants in aged rats. J Pharmacol Res 42:219–222

    Article  CAS  Google Scholar 

  • Bahrami N, Goudarzi M, Hosseinzadeh A, Sabbagh S, Reiter RJ, Mehrzadi S (2018a) Evaluating the protective effects of melatonin on di (2-ethylhexyl) phthalate-induced testicular injury in adult mice. Biomed Pharmacother 108:515–523

    Article  CAS  Google Scholar 

  • Bahrami N, Mehrzadi S, Goudarzi M, Mansouri E, Fatemi I (2018b) Lycopene abrogates di-(2-ethylhexyl) phthalate induced testicular injury by modulating oxidative, endocrine and inflammatory changes in mice. Life Sci 207:265–271

    Article  CAS  Google Scholar 

  • Bansal AK, Bilaspuri GS (2011) Impacts of oxidative stress and antioxidants on semen functions. Vet Med Int 2011:686137

    Article  Google Scholar 

  • Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, Berentshtein E, Tritschler H, Müller MJD (1997) Advanced glycation end product-induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells. Diabetes 46:1481–1490

    Article  CAS  Google Scholar 

  • Bist R, Bhatt DK (2009) The evaluation of effect of alpha-lipoic acid and vitamin E on the lipid peroxidation, gamma-amino butyric acid and serotonin level in the brain of mice (Mus musculus) acutely intoxicated with lindane. J Neurol Sci 276:99–102

    Article  CAS  Google Scholar 

  • Botelho GG, Bufalo AC, Boareto AC, Muller JC, Morais RN, Martino-Andrade AJ, Lemos KR, Dalsenter PRJAoec, toxicology (2009) Vitamin C and resveratrol supplementation to rat dams treated with di (2-ethylhexyl) phthalate: impact on reproductive and oxidative stress end points in male offspring. Arch Environ Contam Toxicol 57:785–793

    Article  CAS  Google Scholar 

  • Boussoum M, Belhaneche-bemsemera NJRSdMLLI (2016): Gas chromatography–mass spectrometry determination of the migration of phthalate plasticisers from polyvinyl chloride in food aliments 2352, 9954

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  Google Scholar 

  • Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310

    Article  CAS  Google Scholar 

  • Cai Q-Y, Mo C-H, Wu Q-T, Katsoyiannis A, Zeng Q-Y (2008) The status of soil contamination by semivolatile organic chemicals (SVOCs) in China: a review. Sci Total Environ 389:209–224

    Article  CAS  Google Scholar 

  • Collodel G, Moretti E, Micheli L, Menchiari A, Moltoni L, Cerretani D (2015) Semen characteristics and malondialdehyde levels in men with different reproductive problems. Andrology 3:280–286

    Article  CAS  Google Scholar 

  • Dobrzynska MM (2016) Phthalates-widespread occurrence and the effect on male gametes. Part 1. General characteristics, sources and human exposure. Rocz Panstw Zakl Hig 67(2):97–103

    CAS  Google Scholar 

  • El-Beshbishy HA, Aly HA, El-Shafey M (2013) Lipoic acid mitigates bisphenol A-induced testicular mitochondrial toxicity in rats. Toxicol Ind Health 29:875–887

    Article  CAS  Google Scholar 

  • El-Fattah AAA, Fahim AT, Sadik NAH, Ali BMJG (2016) Resveratrol and curcumin ameliorate di-(2-ethylhexyl) phthalate induced testicular injury in rats. Gen Comp Endocrinol 225:45–54

    Article  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  CAS  Google Scholar 

  • Erkekoglu P, Rachidi W, Yuzugullu OG, Giray B, Favier A, Ozturk M, Hincal FJT (2010) Evaluation of cytotoxicity and oxidative DNA damaging effects of di (2-ethylhexyl)-phthalate (DEHP) and mono (2-ethylhexyl)-phthalate (MEHP) on MA-10 Leydig cells and protection by selenium. Toxicol Appl Pharmacol 248:52–62

    Article  CAS  Google Scholar 

  • Erkekoglu P, Giray B, Rachidi W, Hininger-Favier I, Roussel AM, Favier A, Hincal F (2014) Effects of di (2-ethylhexyl) phthalate on testicular oxidant/antioxidant status in selenium-deficient and selenium-supplemented rats. Environ Toxicol 29:98–107

    Article  CAS  Google Scholar 

  • Erkekoğlu P, Rachidi W, De Rosa V, Giray B, Favier A, Hıncal F (2010) Protective effect of selenium supplementation on the genotoxicity of di (2-ethylhexyl) phthalate and mono (2-ethylhexyl) phthalate treatment in LNCaP cells. Free Radic Biol Med 49:559–566

    Article  Google Scholar 

  • Evans JL, Goldfine ID (2000) α-Lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther 2:401–413

    Article  CAS  Google Scholar 

  • Evans JL, Maddux BA, Goldfine ID (2005) The molecular basis for oxidative stress-induced insulin resistance. 7:1040–1052

  • Gawish AM (2010): The protective role of alpha lipoic acid against pesticides induced testicular toxicity. (Histopathological and Histochemical Studies). 7, 117–124

  • Gomes MB, Negrato CA (2014) Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 6:80

    Article  Google Scholar 

  • Güleş Ö, Eren Ü (2016) Protective role of alpha lipoic acid against polychlorobiphenyl (Aroclor 1254)-induced testicular toxicity in rats. Rom J Morphol Embryol 57:451–459

    Google Scholar 

  • Hess RA, Gist DH, Bunick D, Lubahn DB, Farrell A, Bahr J, Cooke GL, Greene (1997) Estrogen receptor (alpha and beta) expression in the excurrent ducts of the adult male rat reproductive tract. J Androl 602–611

  • Hirai S, Naito M, Kuramasu M, Ogawa Y, Terayama H, Qu N, Hatayama N, Hayashi S, Itoh M (2015) Low-dose exposure to di-(2-ethylhexyl) phthalate DEHP increases susceptibility to testicular autoimmunity in mice. Reprod Biol 15:163–171

    Article  Google Scholar 

  • Kasahara E, Miyoshi M, Konaka R, Hiramoto K, Sasaki J, Tokuda M, Nakano Y, Inoue M (2002) Role of oxidative stress in germ cell apoptosis induced by di (2-ethylhexyl) phthalate. Biochem J 365:849–856

    Article  CAS  Google Scholar 

  • Koniecki D, Wang R, Moody RP, Zhu J (2011): Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure 111, 329–336

  • Latini G, Verrotti A, De Felice C, (2004): Di-2-ethylhexyl phthalate and endocrine disruption: a review. 4, 37–40

  • Lebda M, Gad S, Gaafar HJ (2014): Effects of lipoic acid on acrylamide induced testicular damage 26, 208

  • Li X, Fang EF, Scheibye-Knudsen M, Cui H, Qiu L, Li J, He Y, Huang J, Bohr VA, Ng T (2014a): Di-(2-ethylhexyl) phthalate inhibits DNA replication leading to hyperPARylation, SIRT1 attenuation, and mitochondrial dysfunction in the testis. 4, 6434

  • Li Y-W, Cai Q-Y, Mo C-H, Zeng Q-Y, Lü H, Li Q-S, Xu GS (2014b) Plant uptake and enhanced dissipation of di (2-ethylhexyl) phthalate (DEHP) in spiked soils by different plant species. Int J Phytoremediation 16:609–620

    Article  CAS  Google Scholar 

  • Lin H, Ge R-S, Chen G-R, Hu G-X, Dong L, Lian Q-Q, Hardy DO, Sottas CM, Li X-K, Hardy MP (2008): Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero 105, 7218–7222

  • Liu K, Lehmann KP, Sar M, Young SS, Gaido KW (2005): Gene expression profiling following in utero exposure to phthalate esters reveals new gene targets in the etiology of testicular dysgenesis 73, 180–192

  • Moini H, Packer L, Saris N-E (2002): Antioxidant and prooxidant activities of α-lipoic acid and dihydrolipoic acid 182, 84–90

  • Naito M, Terayama H, Hirai S, Qu N, Lustig L, Itoh MJ (2012): Experimental autoimmune orchitis as a model of immunological male infertility 45, 185–189

  • Noriega NC, Howdeshell KL, Furr J, Lambright CR, Wilson VS, Gray Jr L (2009): Pubertal administration of DEHP delays puberty, suppresses testosterone production, and inhibits reproductive tract development in male Sprague-Dawley and Long-Evans rats. 111, 163–178

  • Odabasoglu F, Halici Z, Aygun H, Halici M, Atalay F, Cakir A, Cadirci E, Bayir Y, Suleyman HJ(2011): α-Lipoic acid has anti-inflammatory and anti-oxidative properties: an experimental study in rats with carrageenan-induced acute and cotton pellet-induced chronic inflammations. 105, 31–43

  • Othman AI, Edrees GM, El-Missiry MA, Ali DA, Aboel-Nour M, Dabdoub BR (2016): Melatonin controlled apoptosis and protected the testes and sperm quality against bisphenol A-induced oxidative toxicity 32, 1537–1549

  • Ozbal S, Ergur BU, Erbil G, Tekmen I, Bagrıyanık A, Cavdar ZJTSWJ (2012): The effects of α-lipoic acid against testicular ischemia-reperfusion injury in rats 2012

  • Packer L, Witt EH, Tritschler HJ (1995): Alpha-lipoic acid as a biological antioxidant 19, 227–250

  • Papadopoulou AA, Katsoura MH, Chatzikonstantinou A, Kyriakou E, Polydera AC, Tzakos AG, Stamatis H (2013): Enzymatic hybridization of α-lipoic acid with bioactive compounds in ionic solvents 136, 41–48

  • Parks LG, Ostby JS, Lambright CR, Abbott BD, Klinefelter GR, Barlow NJ, Gray Jr L (2000): The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat 58, 339–349

  • Park SJD, Habeebu M, Klaassen CD (2002) Testicular toxicity of di-(2-ethylhexyl) phthalate in young Sprague–Dawley rats. Toxicology 171(2):105–115

    Article  CAS  Google Scholar 

  • Prathima P, Venkaiah K, Pavani R, Daveedu T, Munikumar M, Gobinath M, Valli M, Sainath SB (2017) α-lipoic acid inhibits oxidative stress in testis and attenuates testicular toxicity in rats exposed to carbimazole during embryonic period. Toxicol Rep 4:373–381

    Article  CAS  Google Scholar 

  • Pınar N, Çakırca G, Özgür T, Kaplan M (2018) The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats. Biomed Pharmacother 97:1486–1492

    Article  Google Scholar 

  • Saad EI, El-Gowilly SM, Sherhaa MO, Bistawroos AE (2010) Role of oxidative stress and nitric oxide in the protective effects of α-lipoic acid and aminoguanidine against isoniazid–rifampicin-induced hepatotoxicity in rats. Food Chem Toxicol 48:1869–1875

    Article  CAS  Google Scholar 

  • Saleh HM, El-Sayed YS, Naser SM, Eltahawy AS, Onoda A, Umezawa M (2017) Efficacy of α-lipoic acid against cadmium toxicity on metal ion and oxidative imbalance, and expression of metallothionein and antioxidant genes in rabbit brain. Environ Sci Pollut Res Int 24:24593–24601

    Article  CAS  Google Scholar 

  • Shamsi M, Venkatesh S, Kumar R, Gupta N, Malhotra N, Singh N, Mittal S, Arora S, Arya D, Talwar P (2010) Antioxidant levels in blood and seminal plasma and their impact on sperm parameters in infertile men. Indian J Biochem Biophys 47:38–43

    CAS  Google Scholar 

  • Simoni M, Weinbauer GF, Gromoll J, Nieschlag E (1999) Role of FSH in male gonadal function. Ann Endocrinol (Paris) 60:102–106

    CAS  Google Scholar 

  • Sitton A, Schmid MG, Gübitz G, Aboul-Enein HY (2004) Determination of lipoic acid in dietary supplement preparations by capillary electrophoresis. J Biochem Biophys Methods 61:119–124

    Article  CAS  Google Scholar 

  • Staples CA, Peterson DR, Parkerton TF, Adams WJ (1997) The environmental fate of phthalate esters: a literature review. Chemosphere. 35:667–749

    Article  CAS  Google Scholar 

  • Tang X, Tong K, Zhu L, Fu G, Chang W, Zhou T, Zhang Z, Tong L, Zhang L, Shi YJM, Toxicology C (2016): Di-2-ethylhexyl phthalate induced oxidative damage involving FasL-associated apoptotic pathway in mouse spermatogenic GC-2spd cells. 12, 381-389

  • Tracey WR, Linden J, Peach MJ, Johns RA (1990) : Comparison of spectrophotometric and biological assays for nitric oxide (NO) and endothelium-derived relaxing factor (EDRF): nonspecificity of the diazotization reaction for NO and failure to detect EDRF. 252, 922−928

  • Tretter L, Adam-Vizi V (2005): Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress 360, 2335–2345

  • Wang W, Craig ZR, Basavarajappa MS, Gupta RK, Flaws JA, (2012): Di (2-ethylhexyl) phthalate inhibits growth of mouse ovarian antral follicles through an oxidative stress pathway. 258, 288–295

  • Wong A, Dukic-Stefanovic S, Gasic-Milenkovic J, Schinzel R, Wiesinger H, Riederer P, Münch GJ (2001): Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia 14, 1961–1967

  • Xu J, Lu Q, de Toledo RA, Shim HJIB, (2017): Degradation of di-2-ethylhexyl phthalate (DEHP) by an indigenous isolate Acinetobacter sp. SN13. 117, 205–214

  • Yang G, Zhang T, Gao S, Guo Z, Wan H, Luo W et al (2007) Distribution of phthalic acid esters in agricultural soils in typical regions of Guangdong Province. J Appl Ecol 18:2308–2312

    CAS  Google Scholar 

  • Zare Z, Mohammadi M, Eimani H, Shafaroudi MM (2011) Prevention of di (2-ethylhexyl) phthalate-induced testicular disturbance in mice by co-administration of L-carnitine. Int J Fertil Steril 5:186

    Google Scholar 

  • Zeng F, Cui K, Xie Z, Wu L, Liu M, Sun G et al (2008) Phthalate esters (PAEs): emerging organic contaminants in agricultural soils in peri-urban areas around Guangzhou. China Environ Pollut 156:425–434

    Article  CAS  Google Scholar 

  • Zeng F, Cui K, Xie Z, Wu L, Luo D, Chen L, Lin Y, Liu M, Sun G (2009) Distribution of phthalate esters in urban soils of subtropical city, Guangzhou. China J Hazard Mater 164:1171–1178

    Article  CAS  Google Scholar 

  • Zeng Q, Mo C, Cai Q, Wu Q (2006) Possible pathways through which phthalic acid esters (PAEs) are accumulated in radish plants (Raphanus sativus). Acta Sci Circumst 26:10–16

    CAS  Google Scholar 

Download references

Funding

This study was funded by Deputy of Research of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (grant number MPRC-9616).

Author information

Authors and Affiliations

  1. Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mehdi Goudarzi & Hadi Kalantar

  2. Shoushtar Faculty of Medical Sciences, Shoushtar, Iran

    Mojtaba Haghi Karamallah & Mojtaba Kalantar

  3. Nab’a Al-Hayat Health Research Center, Nab’a Al-Hayat Foundation for Medical Sciences and Health Care, Najaf, Iraq

    Alireza Malayeri

  4. Department of Pharmacology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Alireza Malayeri

  5. Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Esrafil Mansouri

Authors
  1. Mehdi Goudarzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mojtaba Haghi Karamallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alireza Malayeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mojtaba Kalantar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Esrafil Mansouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hadi Kalantar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors discussed the results and contributed to the final manuscript.

Corresponding author

Correspondence to Hadi Kalantar.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Additional information

Responsible editor: Mohamed Abdel-Daim

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goudarzi, M., Haghi Karamallah, M., Malayeri, A. et al. Protective effect of alpha-lipoic acid on di-(2-ethylhexyl) phthalate-induced testicular toxicity in mice. Environ Sci Pollut Res 27, 13670–13678 (2020). https://doi.org/10.1007/s11356-020-07817-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-020-07817-1

Keywords

Search

Navigation