Skip to main content
SpringerLink
Log in

Assessment of the reproductive toxicity of inhalation exposure to ethyl tertiary butyl ether in male mice with normal, low active and inactive ALDH2

  • Reproductive Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

No data are available regarding aldehyde dehydrogenase 2 (ALDH2) polymorphisms related to the reproductive toxicity possibly caused by ethyl tertiary butyl ether (ETBE). In this study, two inhalation experiments were performed in Aldh2 knockout (KO), heterogeneous (HT) and wild type (WT) C57BL/6 male mice exposed to ETBE, and the data about general toxicity, testicular histopathology, sperm head numbers, sperm motility and sperm DNA damage were collected. The results showed that the 13-week exposure to 0, 500, 1,750 and 5,000 ppm ETBE significantly decreased sperm motility and increased levels of sperm DNA strand breaks and 8-hydroxy-deoxyguanosine in both WT and KO mice, the effects were found in 1,750 and 5,000 ppm groups of WT mice, and all of the three exposed groups of KO mice compared to the corresponding control; furthermore, ETBE also caused decrease in the relative weights of testes and epididymides, the slight atrophy of seminiferous tubules of testis and reduction in sperm numbers of KO mice exposed to ≥500 ppm. In the experiment of exposure to lower concentrations of ETBE (0, 50, 200 and 500 ppm) for 9 weeks, the remarkable effects of ETBE on sperm head numbers, sperm motility and sperm DNA damage were further observed in KO and HT mice exposed to 200 ppm ETBE, but not in WT mice. Our findings suggested that only exposure to high concentrations of ETBE might result in reproductive toxicity in mice with normal active ALDH2, while low active and inactive ALDH2 enzyme significantly enhanced the ETBE-induced reproductive toxicity in mice, even exposed to low concentrations of ETBE, mainly due to the accumulation of acetaldehyde as a primary metabolite of ETBE.

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
Fig. 6

Similar content being viewed by others

Abbreviations

ETBE:

Ethyl tertiary butyl ether

AA:

Acetaldehyde

ALDH2:

Aldehyde dehydrogenase 2

WT:

Wild type

HT:

Heterogeneous

KO:

Knockout

TBA:

Tertiary butyl alcohol

MPD:

2-Methyl-1,2-propanediol

MTBE:

Methyl tertiary butyl ether

IARC:

International Agency for Research on Cancer

hOGG1:

8-Hydroxyguanine DNA-glycosylase

8-OH-dG:

8-Hydroxy-deoxyguanosine

References

  • Aitken J, Fisher H (1994) Reactive oxygen species generation and human spermatozoa: the balance of benefit and risk. BioEssays 16:259–267

    Article  CAS  PubMed  Google Scholar 

  • Aitken RJ, Krausz C (2001) Oxidative stress, DNA damage and the Y chromosome. Reproduction 122:497–506

    Article  CAS  PubMed  Google Scholar 

  • Aitken RJ, Baker MA, Sawyer D (2003) Oxidative stress in the male germ line and its role in the aetiology of male infertility and genetic disease. Reprod Biomed Online 7:65–70

    Article  CAS  PubMed  Google Scholar 

  • Aitken RJ, Koopman P, Lewis SE (2004) Seeds of concern. Nature 432:48–52

    Article  CAS  PubMed  Google Scholar 

  • Bevan C, Tyl RW, Neeper-Bradley TL, Fisher LC, Panson RD, Douglas JF, Andrews LS (1997) Developmental toxicity evaluation of methyl tertiary-butyl ether (MTBE) by inhalation in mice and rabbits. J Appl Toxicol 17(Suppl 1):S21–S29

    Article  CAS  PubMed  Google Scholar 

  • Brennan P, Lewis S, Hashibe M, Bell DA, Boffetta P, Bouchardy C, Caporaso N, Chen C, Coutelle C, Diehl SR, Hayes RB, Olshan AF, Schwartz SM, Sturgis EM, Wei Q, Zavras AI, Benhamou S (2004) Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review. Am J Epidemiol 159:1–16

    Article  PubMed  Google Scholar 

  • Conaway CC, Schroeder RE, Snyder NK (1985) Teratology evaluation of methyl tertiary butyl ether in rats and mice. J Toxicol Environ Health 16:797–809

    Article  CAS  PubMed  Google Scholar 

  • Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214

    Article  CAS  PubMed  Google Scholar 

  • de Peyster A (2010) Ethyl t-butyl ether: review of reproductive and developmental toxicity. Birth Defects Res B Dev Reprod Toxicol 89:239–263

    PubMed  Google Scholar 

  • de Peyster A, Stanard B, Westover C (2009) Effect of ETBE on reproductive steroids in male rats and rat Leydig cell cultures. Toxicol Lett 190:74–80

    Article  PubMed  Google Scholar 

  • Donnelly ET, McClure N, Lewis SE (1999) The effect of ascorbate and alpha-tocopherol supplementation in vitro on DNA integrity and hydrogen peroxide-induced DNA damage in human spermatozoa. Mutagenesis 14:505–512

    Article  CAS  PubMed  Google Scholar 

  • Faulkner TP, Wiechart JD, Hartman DM, Hussain AS (1989) The effects of prenatal tertiary butanol administration in CBA/J and C57BL/6 J mice. Life Sci 45:1989–1995

    Article  CAS  PubMed  Google Scholar 

  • Gaoua W (2003) Ethyl tertiary butyl ether (ETBE), CAS No. 637-92-3: Reproduction/developmental toxicity dose-range finding/probe study by the oral (gavage) route in two strains of rat. CIT Study No. 24168 RSR. Unpublished study for Totalfinaelf on behalf of the ETBE Producers’ Consortium

  • Genesca A, Caballin MR, Miro R, Benet J, Germa JR, Egozcue J (1992) Repair of human sperm chromosome aberrations in the hamster egg. Hum Genet 89:181–186

    Article  CAS  PubMed  Google Scholar 

  • Hagiwara A, Doi Y, Imai N, Nakashima H, Ono T, Kawabe M, Furukawa F, Tamano S, Nagano K, Fukushima S (2011) Medium-term multi-organ carcinogenesis bioassay of ethyl tertiary-butyl ether in rats. Toxicology 289:160–166

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa K, Kawamoto T, Kunugita N, Tsukiyama T, Okamoto K, Yoshida A, Nakayama K (2000) Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse. FEBS Lett 476:306–311

    Article  CAS  PubMed  Google Scholar 

  • Latendresse JR, Warbrittion AR, Jonassen H, Creasy DM (2002) Fixation of testes and eyes using a modified Davidson’s fluid: comparison with Bouin’s fluid and conventional Davidson’s fluid. Toxicol Pathol 30:524–533

    Article  PubMed  Google Scholar 

  • Le Gal A, Dreano Y, Gervasi PG, Berthou F (2001) Human cytochrome P450 2A6 is the major enzyme involved in the metabolism of three alkoxyethers used as oxyfuels. Toxicol Lett 124:47–58

    Article  PubMed  Google Scholar 

  • Lewis SE (2007) Is sperm evaluation useful in predicting human fertility? Reproduction 134:31–40

    Article  CAS  PubMed  Google Scholar 

  • Lewis SE, Agbaje IM (2008) Using the alkaline comet assay in prognostic tests for male infertility and assisted reproductive technology outcomes. Mutagenesis 23:163–170

    Article  CAS  PubMed  Google Scholar 

  • Lewis SE, Agbaje I, Alvarez J (2008) Sperm DNA tests as useful adjuncts to semen analysis. Syst Biol Reprod Med 54:111–125

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Kobayashi M, Inagaki H, Hirata Y, Hirata K, Shimizu T, Wang RS, Suda M, Kawamoto T, Nakajima T, Kawada T (2011) Effects of subchronic inhalation exposure to ethyl tertiary butyl ether on splenocytes in mice. Int J Immunopathol Pharmacol 24:837–847

    CAS  PubMed  Google Scholar 

  • McGregor D (2010) Tertiary-butanol: a toxicological review. Crit Rev Toxicol 40:697–727

    Article  CAS  PubMed  Google Scholar 

  • Meamar M, Zribi N, Cambi M, Tamburrino L, Marchiani S, Filimberti E, Fino MG, Biggeri A, Menezo Y, Forti G, Baldi E, Muratori M (2012) Sperm DNA fragmentation induced by cryopreservation: new insights and effect of a natural extract from Opuntia ficus-indica. Fertil Steril 98:326–333

    Article  CAS  PubMed  Google Scholar 

  • Medinsky MA, Wolf DC, Cattley RC, Wong B, Janszen DB, Farris GM, Wright GA, Bond JA (1999) Effects of a thirteen-week inhalation exposure to ethyl tertiary butyl ether on fischer-344 rats and CD-1 mice. Toxicol Sci 51:108–118

    Article  CAS  PubMed  Google Scholar 

  • Niemela O, Parkkila S, Bradford B, Iimuro Y, Pasanen M, Thurman RG (2002) Effect of Kupffer cell inactivation on ethanol-induced protein adducts in the liver. Free Radic Biol Med 33:350–355

    Article  CAS  PubMed  Google Scholar 

  • Novitskiy G, Traore K, Wang L, Trush MA, Mezey E (2006) Effects of ethanol and acetaldehyde on reactive oxygen species production in rat hepatic stellate cells. Alcohol Clin Exp Res 30:1429–1435

    Article  CAS  PubMed  Google Scholar 

  • O’Brien PJ, Siraki AG, Shangari N (2005) Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. Crit Rev Toxicol 35:609–662

    Article  PubMed  Google Scholar 

  • Ollero M, Gil-Guzman E, Lopez MC, Sharma RK, Agarwal A, Larson K, Evenson D, Thomas AJ Jr, Alvarez JG (2001) Characterization of subsets of human spermatozoa at different stages of maturation: implications in the diagnosis and treatment of male infertility. Hum Reprod 16:1912–1921

    Article  CAS  PubMed  Google Scholar 

  • Saito A, Sasaki T, Kasai T, Katagiri T, Nishizawa T, Noguchi T, Aiso S, Nagano K, Fukushima S (2013) Hepatotumorigenicity of ethyl tertiary-butyl ether with 2-year inhalation exposure in F344 rats. Arch Toxicol 87:905–914

    Article  CAS  PubMed  Google Scholar 

  • Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V (2009) A review of human carcinogens—part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 10:1033–1034

    Article  PubMed  Google Scholar 

  • Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7:599–612

    Article  CAS  PubMed  Google Scholar 

  • Sgambato A, Iavicoli I, De Paola B, Bianchino G, Boninsegna A, Bergamaschi A, Pietroiusti A, Cittadini A (2009) Differential toxic effects of methyl tertiary butyl ether and tert-butanol on rat fibroblasts in vitro. Toxicol Ind Health 25:141–151

    Article  CAS  PubMed  Google Scholar 

  • Simon L, Brunborg G, Stevenson M, Lutton D, McManus J, Lewis SE (2010) Clinical significance of sperm DNA damage in assisted reproduction outcome. Hum Reprod 25:1594–1608

    Article  CAS  PubMed  Google Scholar 

  • Simon L, Lutton D, McManus J, Lewis SE (2011) Sperm DNA damage measured by the alkaline Comet assay as an independent predictor of male infertility and in vitro fertilization success. Fertil Steril 95:652–657

    Article  PubMed  Google Scholar 

  • Smith CC, O’Donovan MR, Martin EA (2006) hOGG1 recognizes oxidative damage using the comet assay with greater specificity than FPG or ENDOIII. Mutagenesis 21:185–190

    Article  CAS  PubMed  Google Scholar 

  • Stanard B, Westover C, Hirakawa B, Gonzalez J, and de Peyster A (2003) Effect of ethyl t-butyl ether (ETBE) on testosterone in male rats. Toxicologist 72:S1, Abstract 644. Toxicologist

  • Thomson LK, Fleming SD, Aitken RJ, De Iuliis GN, Zieschang JA, Clark AM (2009) Cryopreservation-induced human sperm DNA damage is predominantly mediated by oxidative stress rather than apoptosis. Hum Reprod 24:2061–2070

    Article  CAS  PubMed  Google Scholar 

  • Wang M, McIntee EJ, Cheng G, Shi Y, Villalta PW, Hecht SS (2000) Identification of DNA adducts of acetaldehyde. Chem Res Toxicol 13:1149–1157

    Article  CAS  PubMed  Google Scholar 

  • Weng Z, Suda M, Ohtani K, Mei N, Kawamoto T, Nakajima T, Wang RS (2011) Aldh2 knockout mice were more sensitive to DNA damage in leukocytes due to ethyl tertiary butyl ether exposure. Ind Health 49:396–399

    Article  CAS  PubMed  Google Scholar 

  • Weng Z, Suda M, Ohtani K, Mei N, Kawamoto T, Nakajima T, Wang RS (2012) Differential genotoxic effects of subchronic exposure to ethyl tertiary butyl ether in the livers of Aldh2 knockout and wild-type mice. Arch Toxicol 86:675–682

    Article  CAS  PubMed  Google Scholar 

  • Weng Z, Suda M, Ohtani K, Mei N, Kawamoto T, Nakajima T, Wang RS (2013) Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice. Toxicology 311:107–114

    Article  CAS  PubMed  Google Scholar 

  • Yamaki K, Yoshino S (2009) Inhibition of IgE-induced mast cell activation by ethyl tertiary-butyl ether, a bioethanol-derived fuel oxygenate. J Pharm Pharmacol 61:1243–1248

    Article  CAS  PubMed  Google Scholar 

  • Yuan Y, Wang HF, Sun HF, Du HF, Xu LH, Liu YF, Ding XF, Fu DP, Liu KX (2007) Adduction of DNA with MTBE and TBA in mice studied by accelerator mass spectrometry. Environ Toxicol 22:630–635

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Ms. S. Watanabe for her assistance in the manipulation of the animals, and Dr. R. Hojo for her helps in the experiments. This work was supported by grant-in-aid for project research from the Japan National Institute of Occupational Safety and Health, Japan (P21-03).

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Author notes

  1. Zuquan Weng

    Present address: Division of System Biology, National Center for Toxicological Research, Jefferson, AR, 72079, USA

Authors and Affiliations

  1. Japan National Institute of Occupational Safety and Health, Kawasaki, Japan

    Zuquan Weng, Katsumi Ohtani, Megumi Suda, Yukie Yanagiba & Rui-Sheng Wang

  2. Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Japan

    Toshihiro Kawamoto

  3. College of Life and Health Sciences, Chubu University, Nagoya, Japan

    Tamie Nakajima

  4. Division of Health Effects Research, National Institute of Occupational Safety and Health, 6-21-1 Nagao, Kawasaki, 214-8585, Japan

    Rui-Sheng Wang

Authors
  1. Zuquan Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katsumi Ohtani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Megumi Suda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yukie Yanagiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshihiro Kawamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tamie Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rui-Sheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rui-Sheng Wang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPT 583 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weng, Z., Ohtani, K., Suda, M. et al. Assessment of the reproductive toxicity of inhalation exposure to ethyl tertiary butyl ether in male mice with normal, low active and inactive ALDH2. Arch Toxicol 88, 1007–1021 (2014). https://doi.org/10.1007/s00204-014-1192-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-014-1192-z

Keywords

Search

Navigation