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The Impact of Di(2-ethylhexyl)phthalate on Cancer Progression

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer, mainly serves as an additive to render polyvinyl chloride (PVC) soft and flexible. PVC plastics have become ubiquitous in our modern society. Yet, the leaching of DEHP from PVC-based consumables ultimately results in the deposition in certain tissues via inadvertent applications. Health risks for human populations exposed to DEHP has been assumed by studies on rodents and other species, including the DEHP-induced developmental dysregulation, reproductive impairments, tumorigenesis, and diseases in a transgenerational manner. In this review, we comprehensively summarize the accumulated literature regarding the multifaceted roles of DEHP in the activation of the nuclear receptors, the alteration of the redox homeostasis, epigenetic modifications and the acquisition of chemoresistance.

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References

  • Abdullah LN, Chow EK (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Abel J, Haarmann-Stemmann T (2010) An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 391:1235–1248

    Article  PubMed  CAS  Google Scholar 

  • Akingbemi BT, Youker RT, Sottas CM et al (2001) Modulation of rat Leydig cell steroidogenic function by di(2-ethylhexyl)phthalate. Biol Reprod 65:1252–1259

    Article  PubMed  CAS  Google Scholar 

  • Akingbemi BT, Ge R, Klinefelter GR et al (2004) Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. Proc Natl Acad Sci USA 101:775–780

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Albro PW, Lavenhar SR (1989) Metabolism of di(2-ethylhexyl)phthalate. Drug Metab Rev 21:13–34

    Article  PubMed  CAS  Google Scholar 

  • Albro PW, Hass JR, Peck CC et al (1982) Applications of isotope differentiation for metabolic studies with di-(2-ethylhexyl) phthalate. J Environ Sci Health B 17:701–714

    Article  PubMed  CAS  Google Scholar 

  • Andrade AJ, Grande SW, Talsness CE et al (2006) A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): effects on androgenic status, developmental landmarks and testicular histology in male offspring rats. Toxicology 225:64–74

    Article  PubMed  CAS  Google Scholar 

  • Angelini A, Centurione L, Sancilio S et al (2011) The effect of the plasticizer diethylhexyl phthalate on transport activity and expression of P-glycoprotein in parental and doxo-resistant human sarcoma cell lines. J Biol Regul Homeost Agents 25:203–211

    PubMed  CAS  Google Scholar 

  • Asai D, Tahara Y, Nakai M et al (2000) Structural essentials of xenoestrogen dialkyl phthalates to bind to the estrogen receptors. Toxicol Lett 118:1–8

    Article  PubMed  CAS  Google Scholar 

  • Barber ED, Astill BD, Moran EJ et al (1987) Peroxisome induction studies on seven phthalate esters. Toxicol Ind Health 3:7–24

    Article  PubMed  CAS  Google Scholar 

  • Barr DB, Silva MJ, Kato K et al (2003) Assessing human exposure to phthalates using monoesters and their oxidized metabolites as biomarkers. Environ Health Perspect 111:1148–1151

    Article  PubMed  PubMed Central  Google Scholar 

  • Bility MT, Thompson JT, McKee RH et al (2004) Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. Toxicol Sci 82:170–182

    Article  PubMed  CAS  Google Scholar 

  • Blom A, Ekman E, Johannisson A et al (1998) Effects of xenoestrogenic environmental pollutants on the proliferation of a human breast cancer cell line (MCF-7). Arch Environ Contam Toxicol 34:306–310

    Article  PubMed  CAS  Google Scholar 

  • Borch J, Dalgaard M, Ladefoged O (2005) Early testicular effects in rats perinatally exposed to DEHP in combination with DEHA—apoptosis assessment and immunohistochemical studies. Reprod Toxicol 19:517–525

    Article  PubMed  CAS  Google Scholar 

  • Borch J, Metzdorff SB, Vinggaard AM et al (2006) Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis. Toxicology 223:144–155

    Article  PubMed  CAS  Google Scholar 

  • Botelho GG, Bufalo AC, Boareto AC et al (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  PubMed  CAS  Google Scholar 

  • Braissant O, Foufelle F, Scotto C et al (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137:354–366

    Article  PubMed  CAS  Google Scholar 

  • Carpenter CP, Weil CS, Smyth HF Jr (1953) Chronic oral toxicity of di-(2-ethylhexyl) phthalate of rats, guinea pigs, and dogs. AMA Arch Ind Hyg Occup Med 8:219–226

    PubMed  CAS  Google Scholar 

  • Cattley RC, Conway JG, Popp JA (1987) Association of persistent peroxisome proliferation and oxidative injury with hepatocarcinogenicity in female F-344 rats fed di(2-ethylhexyl)phthalate for 2 years. Cancer Lett 38:15–22

    Article  PubMed  CAS  Google Scholar 

  • Chen FP, Chien MH (2014) Lower concentrations of phthalates induce proliferation in human breast cancer cells. Climacteric 17:377–384

    Article  PubMed  CAS  Google Scholar 

  • Chen ML, Chen JS, Tang CL et al (2008) The internal exposure of Taiwanese to phthalate–an evidence of intensive use of plastic materials. Environ Int 34:79–85

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Liu YN, Zhou QH et al (2013) Effects of low concentrations of di-(2-ethylhexyl) and mono-(2-ethylhexyl) phthalate on steroidogenesis pathways and apoptosis in the murine leydig tumor cell line MLTC-1. Biomed Environ Sci 26:986–989

    PubMed  CAS  Google Scholar 

  • Chiazze L Jr, Ference LD (1981) Mortality among PVC-fabricating employees. Environ Health Perspect 41:137–143

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi K, Joo H, Campbell JL Jr et al (2012) In vitro metabolism of di(2-ethylhexyl) phthalate (DEHP) by various tissues and cytochrome P450s of human and rat. Toxicol In Vitro 26:315–322

    Article  PubMed  CAS  Google Scholar 

  • Corton JC, Lapinskas PJ, Gonzalez FJ (2000) Central role of PPARalpha in the mechanism of action of hepatocarcinogenic peroxisome proliferators. Mutat Res 448:139–151

    Article  PubMed  CAS  Google Scholar 

  • Dalsenter PR, Santana GM, Grande SW et al (2006) Phthalate affect the reproductive function and sexual behavior of male Wistar rats. Hum Exp Toxicol 25:297–303

    Article  PubMed  CAS  Google Scholar 

  • Dansen TB, Wirtz KW (2001) The peroxisome in oxidative stress. IUBMB Life 51:223–230

    Article  PubMed  CAS  Google Scholar 

  • David RM, Moore MR, Cifone MA et al (1999) Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery. Toxicol Sci 50:195–205

    Article  PubMed  CAS  Google Scholar 

  • David RM, Moore MR, Finney DC et al (2000a) Chronic toxicity of di(2-ethylhexyl)phthalate in mice. Toxicol Sci 58:377–385

    Article  PubMed  CAS  Google Scholar 

  • David RM, Moore MR, Finney DC et al (2000b) Chronic toxicity of di(2-ethylhexyl)phthalate in rats. Toxicol Sci 55:433–443

    Article  PubMed  CAS  Google Scholar 

  • DeKeyser JG, Stagliano MC, Auerbach SS et al (2009) Di(2-ethylhexyl) phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant CAR2. Mol Pharmacol 75:1005–1013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334

    Article  PubMed  CAS  Google Scholar 

  • Doull J, Cattley R, Elcombe C et al (1999) A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA risk assessment guidelines. Regul Toxicol Pharmacol 29:327–357

    Article  PubMed  CAS  Google Scholar 

  • Doyle TJ, Bowman JL, Windell VL et al (2013) Transgenerational effects of di-(2-ethylhexyl) phthalate on testicular germ cell associations and spermatogonial stem cells in mice. Biol Reprod 88:112

    Article  PubMed  PubMed Central  Google Scholar 

  • Dzhekova-Stojkova S, Bogdanska J, Stojkova Z (2001) Peroxisome proliferators: their biological and toxicological effects. Clin Chem Lab Med 39:468–474

    Article  PubMed  CAS  Google Scholar 

  • Eagon PK, Chandar N, Epley MJ et al (1994) Di(2-ethylhexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia. Int J Cancer 58:736–743

    Article  PubMed  CAS  Google Scholar 

  • Eagon PK, Teepe AG, Elm MS et al (1999) Hepatic hyperplasia and cancer in rats: alterations in copper metabolism. Carcinogenesis 20:1091–1096

    Article  PubMed  CAS  Google Scholar 

  • Erkekoglu P, Kocer-Gumusel B (2014) Genotoxicity of phthalates. Toxicol Mech Methods 24:616–626

    Article  PubMed  CAS  Google Scholar 

  • Erkekoglu P, Zeybek ND, Giray BK et al (2014) The effects of di(2-ethylhexyl)phthalate on rat liver in relation to selenium status. Int J Exp Pathol 95:64–77

    Article  PubMed  CAS  Google Scholar 

  • Ernst J, Jann JC, Biemann R et al (2014) Effects of the environmental contaminants DEHP and TCDD on estradiol synthesis and aryl hydrocarbon receptor and peroxisome proliferator-activated receptor signalling in the human granulosa cell line KGN. Mol Hum Reprod 20:919–928

    Article  PubMed  CAS  Google Scholar 

  • Falconer IR, Chapman HF, Moore MR et al (2006) Endocrine-disrupting compounds: a review of their challenge to sustainable and safe water supply and water reuse. Environ Toxicol 21:181–191

    Article  PubMed  CAS  Google Scholar 

  • Fay M, Donohue JM, De Rosa C (1999) ATSDR evaluation of health effects of chemicals. VI. Di(2-ethylhexyl)phthalate. Agency for toxic substances and disease registry. Toxicol Ind Health 15:651–746

    Article  PubMed  CAS  Google Scholar 

  • Feng S, Jacobsen SE, Reik W (2010) Epigenetic reprogramming in plant and animal development. Science 330:622–627

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fojo T, Bates S (2003) Strategies for reversing drug resistance. Oncogene 22:7512–7523

    Article  PubMed  CAS  Google Scholar 

  • Fong JP, Lee FJ, Lu IS et al (2014) Estimating the contribution of inhalation exposure to di-2-ethylhexyl phthalate (DEHP) for PVC production workers, using personal air sampling and urinary metabolite monitoring. Int J Hyg Environ Health 217:102–109

    Article  PubMed  CAS  Google Scholar 

  • Ge RS, Chen GR, Dong Q et al (2007) Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats. J Androl 28:513–520

    Article  PubMed  CAS  Google Scholar 

  • Gillum N, Karabekian Z, Swift LM et al (2009) Clinically relevant concentrations of di (2-ethylhexyl) phthalate (DEHP) uncouple cardiac syncytium. Toxicol Appl Pharmacol 236:25–38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Go RE, Hwang KA, Choi KC (2015) Cytochrome P450 1 family and cancers. J Steroid Biochem Mol Biol 147:24–30

    Article  PubMed  CAS  Google Scholar 

  • Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627

    Article  PubMed  CAS  Google Scholar 

  • Gray TJ, Gangolli SD (1986) Aspects of the testicular toxicity of phthalate esters. Environ Health Perspect 65:229–235

    PubMed  PubMed Central  CAS  Google Scholar 

  • Gray TJ, Beamand JA, Lake BG et al (1982) Peroxisome proliferation in cultured rat hepatocytes produced by clofibrate and phthalate ester metabolites. Toxicol Lett 10:273–279

    Article  PubMed  CAS  Google Scholar 

  • Gray TJ, Lake BG, Beamand JA et al (1983) Peroxisomal effects of phthalate esters in primary cultures of rat hepatocytes. Toxicology 28:167–179

    Article  PubMed  CAS  Google Scholar 

  • Gray LE Jr, Ostby J, Furr J et al (2000) Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci 58:350–365

    Article  PubMed  CAS  Google Scholar 

  • Hagmar L, Akesson B, Nielsen J et al (1990) Mortality and cancer morbidity in workers exposed to low levels of vinyl chloride monomer at a polyvinyl chloride processing plant. Am J Ind Med 17:553–565

    Article  PubMed  CAS  Google Scholar 

  • Hajkova P, Ancelin K, Waldmann T et al (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452:877–881

    Article  PubMed  CAS  Google Scholar 

  • Halden RU (2010) Plastics and health risks. Annu Rev Public Health 31:179–194

    Article  PubMed  Google Scholar 

  • Hardell L, Ohlson CG, Fredrikson M (1997) Occupational exposure to polyvinyl chloride as a risk factor for testicular cancer evaluated in a case-control study. Int J Cancer 73:828–830

    Article  PubMed  CAS  Google Scholar 

  • Harris RS, Hodge HC, Maynard EA et al (1956) Chronic oral toxicity of 2-ethylhexyl phthalate in rats and dogs. AMA Arch Ind Health 13:259–264

    PubMed  CAS  Google Scholar 

  • Harris CA, Henttu P, Parker MG et al (1997) The estrogenic activity of phthalate esters in vitro. Environ Health Perspect 105:802–811

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hayashi F, Tamura H, Yamada J et al (1994) Characteristics of the hepatocarcinogenesis caused by dehydroepiandrosterone, a peroxisome proliferator, in male F-344 rats. Carcinogenesis 15:2215–2219

    Article  PubMed  CAS  Google Scholar 

  • Hines CJ, Hopf NB, Deddens JA et al (2011) Estimated daily intake of phthalates in occupationally exposed groups. J Expo Sci Environ Epidemiol 21:133–141

    Article  PubMed  CAS  Google Scholar 

  • Hokanson R, Hanneman W, Hennessey M et al (2006) DEHP, bis(2)-ethylhexyl phthalate, alters gene expression in human cells: possible correlation with initiation of fetal developmental abnormalities. Hum Exp Toxicol 25:687–695

    Article  PubMed  CAS  Google Scholar 

  • Holohan C, Van Schaeybroeck S, Longley DB et al (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726

    Article  PubMed  CAS  Google Scholar 

  • Hong EJ, Ji YK, Choi KC et al (2005) Conflict of estrogenic activity by various phthalates between in vitro and in vivo models related to the expression of Calbindin-D9k. J Reprod Dev 51:253–263

    Article  PubMed  CAS  Google Scholar 

  • Howdeshell KL, Furr J, Lambright CR et al (2007) Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. Toxicol Sci 99:190–202

    Article  PubMed  CAS  Google Scholar 

  • Huang PC, Tsai CH, Liang WY et al (2015) Age and gender differences in urinary levels of eleven phthalate metabolites in general taiwanese population after a DEHP episode. PLoS One 10:e0133782

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hurst CH, Waxman DJ (2003) Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol Sci 74:297–308

    Article  PubMed  CAS  Google Scholar 

  • Hwang DY, Cho JS, Oh JH et al (2005) An in vivo bioassay for detecting antiandrogens using humanized transgenic mice coexpressing the tetracycline-controlled transactivator and human CYP1B1 gene. Int J Toxicol 24:157–164

    Article  PubMed  CAS  Google Scholar 

  • Ito Y, Yamanoshita O, Asaeda N et al (2007) Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor alpha-independent pathway. J Occup Health 49:172–182

    Article  PubMed  CAS  Google Scholar 

  • Ito Y, Nakamura T, Yanagiba Y et al (2012) Plasticizers may activate human hepatic peroxisome proliferator-activated receptor alpha less than that of a mouse but may activate constitutive androstane receptor in liver. PPAR Res 2012:201284

  • Johnson DR, Klaassen CD (2002) Regulation of rat multidrug resistance protein 2 by classes of prototypical microsomal enzyme inducers that activate distinct transcription pathways. Toxicol Sci 67:182–189

    Article  PubMed  CAS  Google Scholar 

  • Johnson EF, Hsu MH, Savas U et al (2002) Regulation of P450 4A expression by peroxisome proliferator activated receptors. Toxicology 181–182:203–206

    Article  PubMed  Google Scholar 

  • Kambia K, Dine T, Gressier B et al (2003) Induction of propranolol metabolism in isolated rats hepatocytes treated by di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP). Eur J Drug Metab Pharmacokinet 28:217–222

    Article  PubMed  CAS  Google Scholar 

  • Kang ER, Iqbal K, Tran DA et al (2011) Effects of endocrine disruptors on imprinted gene expression in the mouse embryo. Epigenetics 6:937–950

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim IY, Han SY, Moon A (2004) Phthalates inhibit tamoxifen-induced apoptosis in MCF-7 human breast cancer cells. J Toxicol Environ Health A 67:2025–2035

    Article  PubMed  CAS  Google Scholar 

  • Kim NY, Kim TH, Lee E et al (2010) Functional role of phospholipase D (PLD) in di(2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague-Dawley rats. J Toxicol Environ Health A 73:1560–1569

    Article  PubMed  CAS  Google Scholar 

  • Kirshner JR, He S, Balasubramanyam V et al (2008) Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther 7:2319–2327

    Article  PubMed  CAS  Google Scholar 

  • Kluwe WM, Haseman JK, Douglas JF et al (1982) The carcinogenicity of dietary di(2-ethylhexyl) phthalate (DEHP) in Fischer 344 rats and B6C3F1 mice. J Toxicol Environ Health 10:797–815

    Article  PubMed  CAS  Google Scholar 

  • Knapp P, Jarzabek K, Blachnio A et al (2006) The role of peroxisome proliferator-activated receptors (PPAR) in carcinogenesis. Ginekol Pol 77:643–651

    PubMed  Google Scholar 

  • Koch HM, Drexler H, Angerer J (2003a) An estimation of the daily intake of di(2-ethylhexyl)phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ Health 206:77–83

    Article  PubMed  CAS  Google Scholar 

  • Koch HM, Rossbach B, Drexler H et al (2003b) Internal exposure of the general population to DEHP and other phthalates–determination of secondary and primary phthalate monoester metabolites in urine. Environ Res 93:177–185

    Article  PubMed  CAS  Google Scholar 

  • Kono T, Obata Y, Wu Q et al (2004) Birth of parthenogenetic mice that can develop to adulthood. Nature 428:860–864

    Article  PubMed  CAS  Google Scholar 

  • Kruger T, Long M, Bonefeld-Jorgensen EC (2008) Plastic components affect the activation of the aryl hydrocarbon and the androgen receptor. Toxicology 246:112–123

    Article  PubMed  CAS  Google Scholar 

  • Lake BG, Gray TJ, Lewis DF et al (1987) Structure-activity relationships for induction of peroxisomal enzyme activities by phthalate monoesters in primary rat hepatocyte cultures. Toxicol Ind Health 3:165–183

    Article  PubMed  CAS  Google Scholar 

  • Lapinskas PJ, Brown S, Leesnitzer LM et al (2005) Role of PPARalpha in mediating the effects of phthalates and metabolites in the liver. Toxicology 207:149–163

    Article  PubMed  CAS  Google Scholar 

  • LaRocca J, Binder AM, McElrath TF et al (2014) The impact of first trimester phthalate and phenol exposure on IGF2/H19 genomic imprinting and birth outcomes. Environ Res 133:396–406

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Law MY, Moody DE (1991) In vitro inhibition of mouse and rat glutathione S-transferases by di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid and clofibric acid. Toxicol In Vitro 5:207–210

    Article  PubMed  CAS  Google Scholar 

  • Lee FI, Harry DS (1974) Angiosarcoma of the liver in a vinyl-chloride worker. Lancet 1:1316–1318

    Article  PubMed  CAS  Google Scholar 

  • Lee HK, Kim TS, Kim CY et al (2012) Evaluation of in vitro screening system for estrogenicity: comparison of stably transfected human estrogen receptor-alpha transcriptional activation (OECD TG455) assay and estrogen receptor (ER) binding assay. J Toxicol Sci 37:431–437

    Article  PubMed  CAS  Google Scholar 

  • Lemberger T, Braissant O, Juge-Aubry C et al (1996) PPAR tissue distribution and interactions with other hormone-signaling pathways. Ann N Y Acad Sci 804:231–251

    Article  PubMed  CAS  Google Scholar 

  • Lhuguenot JC, Mitchell AM, Milner G et al (1985) The metabolism of di(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP) in rats: in vivo and in vitro dose and time dependency of metabolism. Toxicol Appl Pharmacol 80:11–22

    Article  PubMed  CAS  Google Scholar 

  • Li L, Zhang T, Qin XS et al (2014) Exposure to diethylhexyl phthalate (DEHP) results in a heritable modification of imprint genes DNA methylation in mouse oocytes. Mol Biol Rep 41:1227–1235

    Article  PubMed  CAS  Google Scholar 

  • Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205:275–292

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Carrillo L, Hernández-Ramírez RU, Calafat AM et al (2010) Exposure to phthalates and breast cancer risk in northern Mexico. Environ Health Perspect 118:539–544

    Article  PubMed  CAS  Google Scholar 

  • Magda D, Miller RA (2006) Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin Cancer Biol 16:466–476

    Article  PubMed  CAS  Google Scholar 

  • Maloney EK, Waxman DJ (1999) trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. Toxicol Appl Pharmacol 161:209–218

    Article  PubMed  CAS  Google Scholar 

  • Manikkam M, Tracey R, Guerrero-Bosagna C et al (2013) Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One 8:e55387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mann AH, Price SC, Mitchell FE et al (1985) Comparison of the short-term effects of di(2-ethylhexyl) phthalate, di(n-hexyl) phthalate, and di(n-octyl) phthalate in rats. Toxicol Appl Pharmacol 77:116–132

    Article  PubMed  CAS  Google Scholar 

  • Melis JP, Kuiper RV, Zwart E et al (2013) Slow accumulation of mutations in Xpc−/− mice upon induction of oxidative stress. DNA Repair 12:1081–1086

    Article  PubMed  CAS  Google Scholar 

  • Melnick RL (2001) Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of di(2-ethylhexyl)phthalate (DEHP)? Environ Health Perspect 109:437–442

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Michael M, Doherty MM (2005) Tumoral drug metabolism: overview and its implications for cancer therapy. J Clin Oncol 23:205–229

    Article  PubMed  CAS  Google Scholar 

  • Mitchell AM, Lhuguenot JC, Bridges JW et al (1985a) Identification of the proximate peroxisome proliferator(s) derived from di(2-ethylhexyl) phthalate. Toxicol Appl Pharmacol 80:23–32

    Article  PubMed  CAS  Google Scholar 

  • Mitchell FE, Price SC, Hinton RH et al (1985b) Time and dose-response study of the effects on rats of the plasticizer di(2-ethylhexyl) phthalate. Toxicol Appl Pharmacol 81(3 Pt):371–392

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto M, Sasakawa S (1987) Effects of plasticizers and plastic bags on granulocyte function during storage. Vox Sang 53:19–22

    Article  PubMed  CAS  Google Scholar 

  • Monson RR, Peters JM, Johnson MN (1974) Proportional mortality among vinyl-chloride workers. Lancet 2:397–398

    Article  PubMed  CAS  Google Scholar 

  • Moody DE, Reddy JK, Lake BG et al (1991) Peroxisome proliferation and nongenotoxic carcinogenesis: commentary on a symposium. Fundam Appl Toxicol 16:233–248

    Article  PubMed  CAS  Google Scholar 

  • Morison IM, Ramsay JP, Spencer HG (2005) A census of mammalian imprinting. Trends Genet 21:457–465

    Article  PubMed  CAS  Google Scholar 

  • Murray GI, Taylor MC, McFadyen MC et al (1997) Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res 57:3026–3031

    PubMed  CAS  Google Scholar 

  • National Toxicology P (1982) Carcinogenesis bioassay of Di(2-ethylhexyl)phthalate (CAS No. 117-81-7) in F344 rats and B6C3F1 mice (feed studies). Natl Toxicol Program Tech Rep Ser 217:1–127

    Google Scholar 

  • Ohashi A, Kotera H, Hori H et al (2005) Evaluation of endocrine disrupting activity of plasticizers in polyvinyl chloride tubes by estrogen receptor alpha binding assay. J Artif Organs 8:252–256

    Article  PubMed  CAS  Google Scholar 

  • Okubo T, Suzuki T, Yokoyama Y et al (2003) Estimation of estrogenic and anti-estrogenic activities of some phthalate diesters and monoesters by MCF-7 cell proliferation assay in vitro. Biol Pharm Bull 26:1219–1224

    Article  PubMed  CAS  Google Scholar 

  • Omiecinski CJ, Remmel RP, Hosagrahara VP (1999) Concise review of the cytochrome P450s and their roles in toxicology. Toxicol Sci 48:151–156

    Article  PubMed  CAS  Google Scholar 

  • Osumi T, Hashimoto T (1978) Enhancement of fatty acyl-CoA oxidizing activity in rat liver peroxisomes by di-(2-ethylhexyl)phthalate. J Biochem 83:1361–1365

    Article  PubMed  CAS  Google Scholar 

  • Palmer CN, Hsu MH, Griffin KJ et al (1998) Peroxisome proliferator activated receptor-alpha expression in human liver. Mol Pharmacol 53:14–22

    Article  PubMed  CAS  Google Scholar 

  • Palut D (1997) Proliferation of peroxisomes and the hepatocarcinogenic process. Rocz Panstwowego Zakl Hig 48:1–11

    CAS  Google Scholar 

  • Parks LG, Ostby JS, Lambright CR et al (2000) The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 58:339–349

    Article  PubMed  CAS  Google Scholar 

  • Posnack NG, Idrees R, Ding H et al (2015) Exposure to phthalates affects calcium handling and intercellular connectivity of human stem cell-derived cardiomyocytes. PLoS One 10:e0121927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pradeep S, Benjamin S (2012) Mycelial fungi completely remediate di(2-ethylhexyl)phthalate, the hazardous plasticizer in PVC blood storage bag. J Hazard Mater 235–236:69–77

    Article  PubMed  CAS  Google Scholar 

  • Rajesh P, Balasubramanian K (2014) Phthalate exposure in utero causes epigenetic changes and impairs insulin signalling. J Endocrinol 223:47–66

    Article  PubMed  CAS  Google Scholar 

  • Rao MS, Reddy JK (1987) Peroxisome proliferation and hepatocarcinogenesis. Carcinogenesis 8:631–636

    Article  PubMed  CAS  Google Scholar 

  • Reddy JK, Hashimoto T (2001) Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 21:193–230

    Article  PubMed  CAS  Google Scholar 

  • Sarath Josh MK, Pradeep S, Vijayalekshmi Amma KS et al (2014) Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor alpha, beta, gamma subtypes: an in silico approach. J Appl Toxicol 34:754–765

    Article  PubMed  CAS  Google Scholar 

  • Sasaki H, Matsui Y (2008) Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 9:129–140

    Article  PubMed  CAS  Google Scholar 

  • Schmid P, Schlatter C (1985) Excretion and metabolism of di(2-ethylhexyl)phthalate in man. Xenobiotica 15:251–256

    Article  PubMed  CAS  Google Scholar 

  • Schoonjans K, Staels B, Auwerx J (1996) The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1302:93–109

    Article  PubMed  CAS  Google Scholar 

  • Selenskas S, Teta MJ, Vitale JN (1995) Pancreatic cancer among workers processing synthetic resins. Am J Ind Med 28:385–398

    Article  PubMed  CAS  Google Scholar 

  • Shelby MD (2006) NTP-CERHR monograph on the potential human reproductive and developmental effects of di (2-ethylhexyl) phthalate (DEHP). Ntp Cerhr Mon (18):v (vii–7, II–iii–xiii passim)

    Google Scholar 

  • Simard J, Ricketts ML, Gingras S et al (2005) Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. Endocr Rev 26:525–582

    Article  PubMed  CAS  Google Scholar 

  • Sims JN, Graham B, Pacurari M et al (2014) Di-ethylhexylphthalate (DEHP) modulates cell invasion, migration and anchorage independent growth through targeting S100P in LN-229 glioblastoma cells. Int J Environ Res Public Health 11:5006–5019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Soule HD, Vazguez J, Long A et al (1973) A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51:1409–1416

    Article  PubMed  CAS  Google Scholar 

  • Stroheker T, Cabaton N, Nourdin G et al (2005) Evaluation of anti-androgenic activity of di-(2-ethylhexyl)phthalate. Toxicology 208:115–121

    Article  PubMed  CAS  Google Scholar 

  • Svechnikov K, Landreh L, Weisser J et al (2010) Origin, development and regulation of human Leydig cells. Horm Res Paediatr 73:93–101

    Article  PubMed  CAS  Google Scholar 

  • Tabershaw IR, Gaffey WR (1974) Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 16:509–518

    Article  PubMed  CAS  Google Scholar 

  • Takeshita A, Inagaki K, Igarashi-Migitaka J et al (2006) The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. J Endocrinol 190:897–902

    Article  PubMed  CAS  Google Scholar 

  • Tammen SA, Friso S, Choi SW (2013) Epigenetics: the link between nature and nurture. Mol Aspects Med 34:753–764

    Article  PubMed  CAS  Google Scholar 

  • Tamura H, Iida T, Watanabe T et al (1990) Long-term effects of hypolipidemic peroxisome proliferator administration on hepatic hydrogen peroxide metabolism in rats. Carcinogenesis 11:445–450

    Article  PubMed  CAS  Google Scholar 

  • Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591

    Article  PubMed  CAS  Google Scholar 

  • Tugwood JD, Aldridge TC, Lambe KG et al (1996) Peroxisome proliferator-activated receptors: structures and function. Ann N Y Acad Sci 804:252–265

    Article  PubMed  CAS  Google Scholar 

  • Tuma RS (2008) Reactive oxygen species may have antitumor activity in metastatic melanoma. J Natl Cancer Inst 100:11–12

    Article  PubMed  Google Scholar 

  • van Ommen B, Bogaards JJ, Peters WH et al (1990) Quantification of human hepatic glutathione S-transferases. Biochem J 269:609–613

    Article  PubMed  PubMed Central  Google Scholar 

  • Vasquez-Vivar J, Martasek P, Hogg N et al (1997) Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry 36:11293–11297

    Article  PubMed  CAS  Google Scholar 

  • Vo TT, Jung EM, Dang VH et al (2009) Differential effects of flutamide and di-(2-ethylhexyl) phthalate on male reproductive organs in a rat model. J Reprod Dev 55:400–411

    Article  PubMed  CAS  Google Scholar 

  • Voskoboinik I, Drew R, Ahokas JT (1996) Differential effect of peroxisome proliferators on rat glutathione S-transferase isoenzymes. Toxicol Lett 87:147–155

    Article  PubMed  CAS  Google Scholar 

  • Voskoboinik I, Ooi SG, Drew R et al (1997) Peroxisome proliferators increase the formation of BPDE-DNA adducts in isolated rat hepatocytes. Toxicology 122:81–91

    Article  PubMed  CAS  Google Scholar 

  • Voss C, Zerban H, Bannasch P et al (2005) Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague-Dawley rats. Toxicology 206:359–371

    Article  PubMed  CAS  Google Scholar 

  • Wang B, Zhou SF (2009) Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem 16:4066–4218

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Fujii H, Knipp GT (2002) Expression of PPAR and RXR isoforms in the developing rat and human term placentas. Placenta 23:661–671

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Li Y, Ahmad A et al (2011) Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol 8:27–33

    Article  PubMed  CAS  Google Scholar 

  • Wang YC, Chen HS, Long CY et al (2012) Possible mechanism of phthalates-induced tumorigenesis. Kaohsiung J Med Sci 28(7 suppl):S22–S27

    Article  PubMed  CAS  Google Scholar 

  • Ward JM, Peters JM, Perella CM et al (1998) Receptor and nonreceptor-mediated organ-specific toxicity of di(2-ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor alpha-null mice. Toxicol Pathol 26:240–246

    Article  PubMed  CAS  Google Scholar 

  • Wilson VS, Howdeshell KL, Lambright CS et al (2007) Differential expression of the phthalate syndrome in male Sprague-Dawley and Wistar rats after in utero DEHP exposure. Toxicol Lett 170:177–184

    Article  PubMed  CAS  Google Scholar 

  • Wu MT, Wu CF, Wu JR et al (2012) The public health threat of phthalate-tainted foodstuffs in Taiwan: the policies the government implemented and the lessons we learned. Environ Int 44:75–79

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki H, Shimada T (1999) Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by human cytochrome P450 enzymes. Xenobiotica 29:231–241

    Article  PubMed  CAS  Google Scholar 

  • Yen TH, Lin-Tan DT, Lin JL (2011) Food safety involving ingestion of foods and beverages prepared with phthalate-plasticizer-containing clouding agents. J Formos Med Assoc 110:671–684

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Ge R, Hardy MP (2008) Androgen-forming stem Leydig cells: identification, function and therapeutic potential. Dis Markers 24:277–286

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang S, Ma J, Fu Z et al (2016) Promotion of breast cancer cells MDA-MB-231 invasion by di(2-ethylhexyl)phthalate through matrix metalloproteinase-2/-9 overexpression. Environ Sci Pollut Res Int 23:9742–9749

    Article  PubMed  CAS  Google Scholar 

  • Zhu H, Zheng J, Xiao X et al (2010) Environmental endocrine disruptors promote invasion and metastasis of SK-N-SH human neuroblastoma cells. Oncol Rep 23:129–139

    Article  PubMed  Google Scholar 

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Acknowledgements

The study was financially supported by Grant nos. NSC102-2632-B-037-001-MY3, MOST105-2311-B-037-001 and MOST106-2320-B-037-012 from the National Science Council, Taiwan, Ministry of Science and Technology, Taiwan; KMU-TP103A17, KMU-TP104A3 and KMU-TP105A07 by the grant Aim for the Top Universities Grant; Grant nos. NSYSU-KMU105-P017 and NSYSU-KMU106-P019 from the NSYSU-KMU Joint Research Project, Kaohsiung Medical University, Taiwan.

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Authors and Affiliations

  1. Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Chon-Kit Chou

  2. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Chon-Kit Chou, Ya-Ting Yang, Ho-Chun Yang, Shih-Shin Liang & Chien-Chih Chiu

  3. Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Shih-Shin Liang, Tsu-Nai Wang, Eing-Mei Tsai & Chien-Chih Chiu

  4. Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Tsu-Nai Wang

  5. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Po-Lin Kuo

  6. Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, 402, Taiwan

    Hui-Min David Wang

  7. Headquarters of Research Centers, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Eing-Mei Tsai

  8. Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan

    Eing-Mei Tsai

  9. Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan

    Chien-Chih Chiu

  10. Department of Medical Research, Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Chien-Chih Chiu

  11. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Chien-Chih Chiu

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  1. Chon-Kit Chou
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Correspondence to Eing-Mei Tsai or Chien-Chih Chiu.

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Chou, CK., Yang, YT., Yang, HC. et al. The Impact of Di(2-ethylhexyl)phthalate on Cancer Progression. Arch. Immunol. Ther. Exp. 66, 183–197 (2018). https://doi.org/10.1007/s00005-017-0494-2

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