Abstract
3-Chloropropane-1,2-diol (3-MCPD) and its fatty acid esters are formed during thermal treatment of fat-containing foodstuff in the presence of salt. Toxicological studies indicate a carcinogenic potential of 3-MCPD, pointing to the kidney as the main target organ. It is assumed that the toxicological property of 3-MCPD esters is constituted by the release of 3-MCPD during digestion. In a repeated-dose 28-day oral toxicity study using Wistar rats, animals were treated with equimolar doses of either 3-MCPD (10 mg/kg body weight) or 3-MCPD dipalmitate (53 mg/kg body weight). A lower dose of 3-MCPD dipalmitate (13.3 mg/kg body weight) was also applied. No histopathologically visible toxicity was observed in the study. To address molecular mechanisms leading to toxicity of 3-MCPD and its esters, kidney samples were analyzed by a comparative, two-dimensional gel electrophoresis/mass spectrometry proteomic approach. After either 3-MCPD or 3-MCPD dipalmitate treatment, alterations in proteins related to various metabolic pathways, including carbohydrate, amino acid, and fatty acid metabolism, were detected. These findings confirm and complement previous data on the inhibition of glucose metabolism by 3-MCPD. Altogether, broad overlap of 3-MCPD- and 3-MCPD dipalmitate-induced proteomic changes was observed. Further analyses revealed that the observed induction of glutathione S-transferase pi 1 (Gstp1) occurred at the transcriptional level and was not related to nuclear factor (erythroid-derived 2)-like 2 activation. Overall, the results indicate common mechanisms of toxicity for 3-MCPD and its dipalmitate ester. Furthermore, data suggest Gstp1 as a sensitive marker for early 3-MCPD-induced effects in rat kidney.
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References
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
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
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
Barocelli E, Corradi A, Mutti A, Petronini PG (2011) Scientific report submitted to EFSA: “comparison between 3-MCPD and its palmitic esters in a 90-day toxicological study”. In: European Food Safety Authority. http://www.efsa.europa.eu/de/supporting/pub/187e.htm
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
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
Buhrke T, Frenzel F, Kuhlmann J, Lampen A (2014) 2-Chloro-1,3-propanediol (2-MCPD) and its fatty acid esters: cytotoxicity, metabolism, and transport by human intestinal Caco-2 cells. Arch Toxicol. doi:10.1007/s00204-014-1395-3
Chiusolo A, Defazio R, Casartelli A et al (2008) Regucalcin down-regulation in rat kidney tissue after treatment with nephrotoxicants. Toxicol Lett 182(1–3):84–90. doi:10.1016/j.toxlet.2008.08.014
Cho WS, Han BS, Nam KT et al (2008) 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
Cornely R, Rentero C, Enrich C, Grewal T, Gaus K (2011) Annexin A6 is an organizer of membrane microdomains to regulate receptor localization and signalling. IUBMB Life 63(11):1009–1017. doi:10.1002/iub.540
Crabo B, Appelgren LE (1972) Distribution of (14 C) -chlorohydrin in mice and rats. J Reprod Fertil 30(1):161–163
Devarajan P (2005) Cellular and molecular derangements in acute tubular necrosis. Curr Opin Pediatr 17(2):193–199
Devarajan P (2006) Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol : JASN 17(6):1503–1520. doi:10.1681/ASN.2006010017
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
Gorg A, Obermaier C, Boguth G et al (2000) The current state of two-dimensional electrophoresis with immobilized pH gradients. Electrophoresis 21(6):1037–1053. doi:10.1002/(SICI)1522-2683(20000401)21:6<1037:AID-ELPS1037>3.0.CO;2-V
Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12(12):931–947. doi:10.1038/nrd4002
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):328–329
Harvey CJ, Thimmulappa RK, Singh A et al (2009) Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radic Biol Med 46(4):443–453. doi:10.1016/j.freeradbiomed.2008.10.040
Henderson CJ, McLaren AW, Wolf CR (2014) In vivo regulation of human glutathione transferase GSTP by chemopreventive agents. Cancer Res 74(16):4378–4387. doi:10.1158/0008-5472.CAN-14-0792
Henrique R, Jeronimo C (2004) Molecular detection of prostate cancer: a role for GSTP1 hypermethylation. Eur Urol 46(5):660–669; discussion 669 doi: 10.1016/j.eururo.2004.06.014
Hwang M, Yoon E, Kim J, Jang DD, Yoo TM (2009) Toxicity value for 3-monochloropropane-1,2-diol using a benchmark dose methodology. Regul Toxicol Pharmacol : RTP 53(2):102–106. doi:10.1016/j.yrtph.2008.12.005
JECFA (2002) 3-chloro-1,2-propanediol. WHO Food Addit Ser 48:401–432
Jones AR, Fakhouri G (1979) Epoxides as obligatory intermediates in the metabolism of alpha-halohydrins. Xenobiotica 9(10):595–599
Jones AR, Porter LM (1995) Inhibition of glycolysis in boar spermatozoa by alpha-chlorohydrin phosphate appears to be mediated by phosphatase activity. Reprod Fertil Dev 7(5):1089–1094
Jones AR, Gadiel P, Murcott C (1979) The renal toxicity of the rodenticide alpha-chlorohydrin in the rat. Die Naturwissenschaften 66(8):425
Jones AR, Gadiel P, Stevenson D (1981) The fate of oxalic acid in the Wistar rat. Xenobiotica 11(6):385–390
Kim HJ, Vaziri ND (2010) Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Ren Physiol 298(3):F662–F671. doi:10.1152/ajprenal.00421.2009
Li W, Kong AN (2009) Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 48(2):91–104. doi:10.1002/mc.20465
Li J, Wang S, Wang M, Shi W, Du X, Sun C (2013) The toxicity of 3-chloropropane-1,2-dipalmitate in Wistar rats and a metabonomics analysis of rat urine by ultra-performance liquid chromatography-mass spectrometry. Chem Biol Interact 206(2):337–345. doi:10.1016/j.cbi.2013.10.004
Liu M, Grigoryev DN, Crow MT et al (2009) Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int 76(3):277–285. doi:10.1038/ki.2009.157
Liu M, Gao BY, Qin F et al (2012) Acute oral toxicity of 3-MCPD mono- and di-palmitic esters in Swiss mice and their cytotoxicity in NRK-52E rat kidney cells. Food Chem Toxicol 50(10):3785–3791. doi:10.1016/j.fct.2012.07.038
Luckert C, Ehlers A, Buhrke T, Seidel A, Lampen A, Hessel S (2013) Polycyclic aromatic hydrocarbons stimulate human CYP3A4 promoter activity via PXR. Toxicol Lett 222(2):180–188. doi:10.1016/j.toxlet.2013.06.243
Luebeck EG, Buchmann A, Stinchcombe S, Moolgavkar SH, Schwarz M (2000) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver: a quantitative analysis of experimental data using a stochastic model. Toxicol Appl Pharmacol 167(1):63–73. doi:10.1006/taap.2000.8980
Lynch BS, Bryant DW, Hook GJ, Nestmann ER, Munro IC (1998) Carcinogenicity of monochloro-1,2-propanediol (a-chlorohydrin, 3-MCPD). Int J Toxicol 17:47–76
Mattes WB, Daniels KK, Summan M, Xu ZA, Mendrick DL (2006) Tissue and species distribution of the glutathione pathway transcriptome. Xenobiotica 36(10–11):1081–1121. doi:10.1080/00498250600861793
Mohri H, Suter DA, Brown-Woodman PD, White IG, Ridley DD (1975) Identification of the biochemical lesion produced by alpha-chlorohydrin in spermatozoa. Nature 255(5503):75–77
Monastyrskaya K, Babiychuk EB, Hostettler A, Wood P, Grewal T, Draeger A (2009) Plasma membrane-associated annexin A6 reduces Ca2+ entry by stabilizing the cortical actin cytoskeleton. J Biol Chem 284(25):17227–17242. doi:10.1074/jbc.M109.004457
Nurko S, Sogabe K, Davis JA et al (1996) Contribution of actin cytoskeletal alterations to ATP depletion and calcium-induced proximal tubule cell injury. Am J Physiol 270(1 Pt 2):F39–F52
Oberemm A, Ahr HJ, Bannasch P et al (2009) Toxicogenomic analysis of N-nitrosomorpholine induced changes in rat liver: comparison of genomic and proteomic responses and anchoring to histopathological parameters. Toxicol Appl Pharmacol 241(2):230–245. doi:10.1016/j.taap.2009.08.020
Onami S, Cho YM, Toyoda T et al (2014a) 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
Onami S, Cho YM, Toyoda T et al (2014b) A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats. Arch Toxicol 88(4):871–880. doi:10.1007/s00204-013-1190-6
Rabilloud T (2000) Detecting proteins separated by 2-D gel electrophoresis. Anal Chem 72(1):48A–55A
Robjohns S, Marshall R, Fellows M, Kowalczyk G (2003) In vivo genotoxicity studies with 3-monochloropropan-1,2-diol. Mutagenesis 18(5):401–404
Satoh K, Itoh K, Yamamoto M et al (2002) Nrf2 transactivator-independent GSTP1-1 expression in “GSTP1-1 positive” single cells inducible in female mouse liver by DEN: a preneoplastic character of possible initiated cells. Carcinogenesis 23(3):457–462
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, Chem Anal Control Expo Risk Assess 25(4):391–400. doi:10.1080/02652030701385241
Sharma A, Wongkham C, Prasongwattana V et al (2014) Proteomic analysis of kidney in rats chronically exposed to monosodium glutamate. PLoS ONE 9(12):e116233. doi:10.1371/journal.pone.0116233
Skamarauskas J, Carter W, Fowler M et al (2007) The selective neurotoxicity produced by 3-chloropropanediol in the rat is not a result of energy deprivation. Toxicology 232(3):268–276. doi:10.1016/j.tox.2007.01.013
Steiner SR, Milton E, Philbert MA (2013) A comparative study of protein carbonylation and mitochondrial dysfunction using the neurotoxicants 1,3-dinitrobenzene, 3-nitropropionic acid, and 3-chloropropanediol. Neurotoxicology 37:74–84. doi:10.1016/j.neuro.2013.04.004
Sun CY, Zang YC, San YX, Sun W, Zhang L (2010) Proteomic analysis of clear cell renal cell carcinoma. Identification of potential tumor markers. Saudi Med J 31(5):525–532
Svejkovska B, Novotny O, Divinova V, Reblova Z, Dolezal M, Velisek J (2004) Esters of 3-chloropropane-1,2-diol in foodstuffs. Czech J Food Sci 22(5):190–196
Tew KD, Manevich Y, Grek C, Xiong Y, Uys J, Townsend DM (2011) The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer. Free Radic Biol Med 51(2):299–313. doi:10.1016/j.freeradbiomed.2011.04.013
Vaas S, Kreft L, Schwarz M, Braeuning A (2014) Cooperation of structurally different aryl hydrocarbon receptor agonists and beta-catenin in the regulation of CYP1A expression. Toxicology 325C:31–41. doi:10.1016/j.tox.2014.08.010
Weisshaar R (2011) Fatty acid esters of 3-MCPD: overview of occurrence and exposure estimates. Eur J Lipid Sci Technol 113:304–308
Yamaguchi M (2012) Regucalcin, cell signalling-related protein: its multifunctional role in kidney cell regulation. OA Biotechnol 1(1):2
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
Acknowledgments
Expert technical assistance by L. Brandenburger, C. Meckert, C. Rozycki, J. Potkura and E. Zabinsky is greatly acknowledged. We thank Dr. J.D. Hayes (Dundee, UK) for the gift of the Gstp1 antibody. This work was supported by the Federal Institute for Risk Assessment, Grants Nos. 1322-452 and 1322-523.
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Sawada, S., Oberemm, A., Buhrke, T. et al. Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate-induced toxicity in rat kidney. Arch Toxicol 90, 1437–1448 (2016). https://doi.org/10.1007/s00204-015-1576-8
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DOI: https://doi.org/10.1007/s00204-015-1576-8