Archives of Toxicology

, Volume 92, Issue 1, pp 289–299 | Cite as

Oxidative inactivation of the endogenous antioxidant protein DJ-1 by the food contaminants 3-MCPD and 2-MCPD

  • Thorsten Buhrke
  • Linn Voss
  • Anja Briese
  • Heike Stephanowitz
  • Eberhard Krause
  • Albert Braeuning
  • Alfonso Lampen
Molecular Toxicology


3-Chloro-1,2-propanediol (3-MCPD) and 2-chloro-1,3-propanediol (2-MCPD) are heat-induced food contaminants being present either as free substances or as fatty acid esters in numerous foods. 3-MCPD was classified to be possibly carcinogenic to humans (category 2B) with kidney and testis being the primary target organs according to animal studies. A previous 28-day oral feeding study with rats revealed that the endogenous antioxidant protein DJ-1 was strongly deregulated at the protein level in kidney, liver, and testis of the experimental animals that had been treated either with 3-MCPD, 2-MCPD or their dipalmitate esters. Here we show that this deregulation is due to the oxidation of a conserved, redox-active cysteine residue (Cys106) of DJ-1 to a cysteine sulfonic acid which is equivalent to loss of function of DJ-1. Irreversible oxidation of DJ-1 is associated with a number of oxidative stress-related diseases such as Parkinson, cancer, and type II diabetes. It is assumed that 3-MCPD or 2-MCPD do not directly oxidize DJ-1, but that these substances induce the formation of reactive oxygen species (ROS) which in turn trigger DJ-1 oxidation. The implications of 3-MCPD/2-MCPD-mediated ROS formation in vivo for the ongoing risk assessment of these compounds as well as the potential of oxidized DJ-1 to serve as a novel effect biomarker for 3-MCPD/2-MCPD toxicity are being discussed.


2-MCPD 3-MCPD Cysteine oxidation DJ-1 Oxidative stress 



We thank Christine Meckert and Linda Brandenburger for technical assistance. This work was funded by the German Federal Institute for Risk Assessment (Project 1322-523).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abraham K, Appel KE, Berger-Preiss E et al (2013) Relative oral bioavailability of 3-MCPD from 3-MCPD fatty acid esters in rats. Arch Toxicol 87(4):649–659. doi: 10.1007/s00204-012-0970-8 CrossRefPubMedGoogle Scholar
  2. Andres S, Appel KE, Lampen A (2013) Toxicology, occurrence and risk characterisation of the chloropropanols in food: 2-monochloro-1,3-propanediol, 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol. Food Chem Toxicol 58:467–478. doi: 10.1016/j.fct.2013.05.024 CrossRefPubMedGoogle Scholar
  3. Ariga H (2015) Common mechanisms of onset of cancer and neurodegenerative diseases. Biol Pharm Bull 38(6):795–808. doi: 10.1248/bpb.b15-00125 CrossRefPubMedGoogle Scholar
  4. Ariga H, Takahashi-Niki K, Kato I et al (2013) Neuroprotective function of DJ-1 in Parkinson’s disease. Oxid Med Cell Longev. doi: 10.1155/2013/683920 PubMedPubMedCentralGoogle Scholar
  5. Bakhiya N, Abraham K, Gurtler R, Appel KE, Lampen A (2011) Toxicological assessment of 3-chloropropane-1,2-diol and glycidol fatty acid esters in food. Mol Nutr Food Res 55(4):509–521. doi: 10.1002/mnfr.201000550 CrossRefPubMedGoogle Scholar
  6. Bandopadhyay R, Kingsbury AE, Cookson MR et al (2004) The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 127(Pt 2):420–430. doi: 10.1093/brain/awh054 CrossRefPubMedGoogle Scholar
  7. Barocelli E, Corradi A, Mutti A, Petronini PG (2011) Comparison between 3-MCPD and its palmitic esters in a 90-day toxicological study. Sci Rep CFP/EFSA/CONTAM/2009/01.
  8. Blackinton J, Lakshminarasimhan M, Thomas KJ et al (2009) Formation of a stabilized cysteine sulfinic acid is critical for the mitochondrial function of the parkinsonism protein DJ-1. J Biol Chem 284(10):6476–6485. doi: 10.1074/jbc.M806599200 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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 72:248–254CrossRefPubMedGoogle Scholar
  10. Braeuning A, Sawada S, Oberemm A, Lampen A (2015) Analysis of 3-MCPD- and 3-MCPD dipalmitate-induced proteomic changes in rat liver. Food Chem Toxicol 86:374–384. doi: 10.1016/j.fct.2015.11.010 CrossRefPubMedGoogle Scholar
  11. Buhrke T, Weisshaar R, Lampen A (2011) Absorption and metabolism of the food contaminant 3-chloro-1,2-propanediol (3-MCPD) and its fatty acid esters by human intestinal Caco-2 cells. Arch Toxicol 85(10):1201–1208. doi: 10.1007/s00204-011-0657-6 CrossRefPubMedGoogle Scholar
  12. Buhrke T, Frenzel F, Kuhlmann J, Lampen A (2015) 2-Chloro-1,3-propanediol (2-MCPD) and its fatty acid esters: cytotoxicity, metabolism, and transport by human intestinal Caco-2 cells. Arch Toxicol 89(12):2243–2251. doi: 10.1007/s00204-014-1395-3 CrossRefPubMedGoogle Scholar
  13. Cavanagh JB, Nolan CC, Seville MP (1993) The neurotoxicity of alpha-chlorohydrin in rats and mice: I. Evolution of the cellular changes. Neuropathol Appl Neurobiol 19(3):240–252CrossRefPubMedGoogle Scholar
  14. Chan JY, Chan SH (2015) Activation of endogenous antioxidants as a common therapeutic strategy against cancer, neurodegeneration and cardiovascular diseases: a lesson learnt from DJ-1. Pharmacol Ther 156:69–74. doi: 10.1016/j.pharmthera.2015.09.005 CrossRefPubMedGoogle Scholar
  15. Cho WS, Han BS, Lee H et al (2008a) Subchronic toxicity study of 3-monochloropropane-1,2-diol administered by drinking water to B6C3F1 mice. Food Chem Toxicol 46(5):1666–1673. doi: 10.1016/j.fct.2007.12.030 CrossRefPubMedGoogle Scholar
  16. Cho WS, Han BS, Nam KT et al (2008b) Carcinogenicity study of 3-monochloropropane-1,2-diol in Sprague–Dawley rats. Food Chem Toxicol 46(9):3172–3177. doi: 10.1016/j.fct.2008.07.003 CrossRefPubMedGoogle Scholar
  17. Choi J, Sullards MC, Olzmann JA et al (2006) Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 281(16):10816–10824. doi: 10.1074/jbc.M509079200 CrossRefPubMedPubMedCentralGoogle Scholar
  18. EFSA (2016) Risks for human health related to the presence of 3- and 2-monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food. EFSA Journal 14(5):4426. Available at
  19. El Ramy R, Ould Elhkim M, Lezmi S, Poul JM (2007) Evaluation of the genotoxic potential of 3-monochloropropane-1,2-diol (3-MCPD) and its metabolites, glycidol and beta-chlorolactic acid, using the single cell gel/comet assay. Food Chem Toxicol 45(1):41–48. doi: 10.1016/j.fct.2006.07.014 CrossRefPubMedGoogle Scholar
  20. Ford WC, Waites GM (1982) Activities of various 6-chloro-6-deoxysugars and (S) alpha-chlorohydrin in producing spermatocoeles in rats and paralysis in mice and in inhibiting glucose metabolism in bull spermatozoa in vitro. J Reprod Fertil 65(1):177–183CrossRefPubMedGoogle Scholar
  21. Frenzel F, Buhrke T, Wenzel I, Andrack J, Hielscher J, Lampen A (2017) Use of in silico models for prioritization of heat-induced food contaminants in mutagenicity and carcinogenicity testing. Arch Toxicol. doi: 10.1007/s00204-016-1924-3 Google Scholar
  22. Grosse Y, Baan R, Secretan-Lauby B et al (2011) Carcinogenicity of chemicals in industrial and consumer products, food contaminants and flavourings, and water chlorination byproducts. Lancet Oncol 12(4):328–329CrossRefPubMedGoogle Scholar
  23. Hamlet CG, Sadd PA (2009) In: Richard DRL, Stadler H (eds) Chloropropanols and chloroesters. Wiley, Hoboken, pp 175–214Google Scholar
  24. Henderson CJ, Cameron AR, Chatham L, Stanley LA, Wolf CR (2015) Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability. Toxicol Sci 145:138–148CrossRefPubMedPubMedCentralGoogle Scholar
  25. JECFA (2016) Eighty-third meeting of the Joint FAO/WHO Expert Committee on Food Additives. JECFA/83/SC; summary and conclusions are available online:
  26. Jeong J, Jung Y, Na S et al (2011) Novel oxidative modifications in redox-active cysteine residues. Mol Cell Proteomics. doi: 10.1074/mcp.M110.000513 PubMedCentralGoogle Scholar
  27. Jones AR (1983) Antifertility actions of alpha-chlorohydrin in the male. Aust J Biol Sci 36(4):333–350CrossRefPubMedGoogle Scholar
  28. Jones AR, Milton DH, Murcott C (1978) The oxidative metabolism of alpha-chlorohydrin in the male rat and the formation of spermatocoeles. Xenobiotica 8(9):573–582. doi: 10.3109/00498257809061257 CrossRefPubMedGoogle Scholar
  29. Jones AR, Gadiel P, Stevenson D (1981) The fate of oxalic acid in the Wistar rat. Xenobiotica 11(6):385–390CrossRefPubMedGoogle Scholar
  30. Kim K, Song C, Park Y et al (2004) 3-monochloropropane-1,2-diol does not cause neurotoxicity in vitro or neurobehavioral deficits in rats. Neurotoxicology 25(3):377–385. doi: 10.1016/j.neuro.2003.08.004 CrossRefPubMedGoogle Scholar
  31. Kim HJ, Ha S, Lee HY, Lee KJ (2015) ROSics: chemistry and proteomics of cysteine modifications in redox biology. Mass Spectrom Rev 34(2):184–208. doi: 10.1002/mas.21430 CrossRefPubMedGoogle Scholar
  32. Kinumi T, Kimata J, Taira T, Ariga H, Niki E (2004) Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells. Biochem Biophys Res Commun 317(3):722–728. doi: 10.1016/j.bbrc.2004.03.110 CrossRefPubMedGoogle Scholar
  33. Kuhlmann J (2011) Determination of bound 2,3-epoxy-1-propanol (glycidol) and bound monochloropropanediol (MCPD) in refined oils. Eur J Lipid Sci Technol 113(3):335–344. doi: 10.1002/ejlt.201000313 CrossRefGoogle Scholar
  34. Kwack SJ, Kim SS, Choi YW et al (2004) Mechanism of antifertility in male rats treated with 3-monochloro-1,2-propanediol (3-MCPD). J Toxicol Environ Health A 67(23–24):2001–2011. doi: 10.1080/15287390490514651 CrossRefPubMedGoogle Scholar
  35. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685CrossRefPubMedGoogle Scholar
  36. Lee SJ, Kim SJ, Kim IK et al (2003) Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain. J Biol Chem 278:44552–44559. doi: 10.1074/jbc.M304517200 CrossRefPubMedGoogle Scholar
  37. Lee JY, Song J, Kwon K et al (2012) Human DJ-1 and its homologs are novel glyoxalases. Hum Mol Gen 21:3215–3225. doi: 10.1093/hmg/dds155 CrossRefPubMedGoogle Scholar
  38. Lee BS, Park SJ, Kim YB et al (2015) A 28-day oral gavage toxicity study of 3-monochloropropane-1,2-diol (3-MCPD) in CB6F1-non-Tg rasH2 mice. Food Chem Toxicol 86:95–103. doi: 10.1016/j.fct.2015.09.019 CrossRefPubMedGoogle Scholar
  39. Li HM, Taira T, Maita C, Ariga H, Iguchi-Ariga SM (2006) Protection against nonylphenol-induced cell death by DJ-1 in cultured Japanese medaka (Oryzias latipes) cells. Toxicology 228(2–3):229–238. doi: 10.1016/j.tox.2006.08.040 CrossRefPubMedGoogle Scholar
  40. Onami S, Cho YM, Toyoda T et al (2014) Absence of in vivo genotoxicity of 3-monochloropropane-1,2-diol and associated fatty acid esters in a 4-week comprehensive toxicity study using F344 gpt delta rats. Mutagenesis 29(4):295–302. doi: 10.1093/mutage/geu018 CrossRefPubMedGoogle Scholar
  41. Ooe H, Taira T, Iguchi-Ariga SM, Ariga H (2005) Induction of reactive oxygen species by bisphenol A and abrogation of bisphenol A-induced cell injury by DJ-1. Toxicol Sci 88(1):114–126. doi: 10.1093/toxsci/kfi278 CrossRefPubMedGoogle Scholar
  42. Rabilloud T (2000) Detecting proteins separated by 2-D gel electrophoresis. Anal Chem 72(1):48A–55ACrossRefPubMedGoogle Scholar
  43. Richarme G, Mihoub M, Dairou J et al (2015) Parkisonism-associated protein DJ-1/Park7 is a major protein deglycase that repairs methylglyoxal- and glyoxal-glycated cysteine, arginine, and lysine residues. J Biol Chem 290:1885–1897. doi: 10.1074/jbc.M114.597815 CrossRefPubMedGoogle Scholar
  44. Robjohns S, Marshall R, Fellows M, Kowalczyk G (2003) In vivo genotoxicity studies with 3-monochloropropan-1,2-diol. Mutagenesis 18(5):401–404CrossRefPubMedGoogle Scholar
  45. Sajjad MU, Green EW, Miller-Fleming L et al (2014) DJ-1 modulates aggregation and pathogenesis in models of Huntington’s disease. Hum Mol Genet 23(3):755–766. doi: 10.1093/hmg/ddt466 CrossRefPubMedGoogle Scholar
  46. Sawada S, Oberemm A, Buhrke T et al (2015) Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate toxicity in rat testis. Food Chem Toxicol 83:84–92. doi: 10.1016/j.fct.2015.06.002 CrossRefPubMedGoogle Scholar
  47. Sawada S, Oberemm A, Buhrke T, Merschenz J, Braeuning A, Lampen A (2016) Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate-induced toxicity in rat kidney. Arch Toxicol 90(6):1437–1448. doi: 10.1007/s00204-015-1576-8 CrossRefPubMedGoogle Scholar
  48. Scharmach E, Buhrke T, Lichtenstein D, Lampen A (2012) Perfluorooctanoic acid affects the activity of the hepatocyte nuclear factor 4 alpha (HNF4alpha). Toxicol Lett 212(2):106–112. doi: 10.1016/j.toxlet.2012.05.007 CrossRefPubMedGoogle Scholar
  49. Schilter B, Scholz G, Seefelder W (2011) Fatty acid esters of chloropropanols and related compounds in food: toxicological aspects. Eur J Lipid Sci Technol 113(3):309–313. doi: 10.1002/ejlt.201000311 CrossRefGoogle Scholar
  50. Seefelder W, Varga N, Studer A, Williamson G, Scanlan FP, Stadler RH (2008) Esters of 3-chloro-1,2-propanediol (3-MCPD) in vegetable oils: significance in the formation of 3-MCPD. Food Addit Contam Part A 25(4):391–400. doi: 10.1080/02652030701385241 CrossRefGoogle Scholar
  51. Wilson MA (2011) The role of cysteine oxidation in DJ-1 function and dysfunction. Antioxid Redox Signal 15(1):111–122. doi: 10.1089/ars.2010.3481 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K (1988) Salmonella mutagenicity tests: IV. Results from the testing of 300 chemicals. Environ Mol Mutagen 11(Suppl 12):1–157CrossRefPubMedGoogle Scholar
  53. Zelinkova Z, Svejkovska B, Velisek J, Dolezal M (2006) Fatty acid esters of 3-chloropropane-1,2-diol in edible oils. Food Addit Contam 23(12):1290–1298. doi: 10.1080/02652030600887628 CrossRefPubMedGoogle Scholar
  54. Zondler L, Miller-Fleming L, Repici M et al (2014) DJ-1 interactions with a-synuclein attenuate aggregation and cellular toxicity in models of Parkinson’s disease. Cell Death Dis 5:e1350. doi: 10.1038/cddis.2014.307 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Thorsten Buhrke
    • 1
  • Linn Voss
    • 1
  • Anja Briese
    • 1
  • Heike Stephanowitz
    • 2
  • Eberhard Krause
    • 2
  • Albert Braeuning
    • 1
  • Alfonso Lampen
    • 1
  1. 1.Department of Food SafetyGerman Federal Institute for Risk AssessmentBerlinGermany
  2. 2.Mass Spectrometry GroupLeibniz-Institut für Molekulare PharmakologieBerlinGermany

Personalised recommendations