Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Environmental Health and Preventive Medicine
Published in: Environmental Health and Preventive Medicine 1/2019

Open Access 01-12-2019 | Review article

Di(2-ethylhexyl) phthalate-induced toxicity and peroxisome proliferator-activated receptor alpha: a review

Authors: Yuki Ito, Michihiro Kamijima, Tamie Nakajima

Published in: Environmental Health and Preventive Medicine | Issue 1/2019

Login to get access

Abstract

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.
Literature
1.
2.
3.
Roslev P, Madsen PL, Thyme JB, Henriksen K. Degradation of phthalate and di-(2-Ethylhexyl)phthalate by indigenous and inoculated microorganisms in sludge-amended soil. Appl Environ Microbiol. 1998;64:4711–9.PubMedPubMedCentral
4.
Albro PW. Absorption, metabolism, and excretion of di(2-ethylhexyl) phthalate by rats and mice. Environ Health Perspect. 1986;65:293–8.PubMedPubMedCentral
5.
Albro PW, Corbett JT, Schroeder JL, Jordan S, Matthews HB. Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP. Environ Health Perspect. 1982;45:19–25.PubMedPubMedCentralCrossRef
6.
Albro PW, Lavenhar SR. Metabolism of di(2-ethylhexyl)phthalate. Drug Metab Rev. 1989;21(1):13–34.PubMedCrossRef
7.
Ito Y, Yokota H, Wang R, Yamanoshita O, Ichihara G, Wang H, et al. Species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs of mice, rats, and marmosets. Arch Toxicol. 2005;79:147–54.PubMedCrossRef
8.
Ito Y, Tomizawa M, Suzuki H, Okamura A, Ohtani K, Nunome M, et al. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats. Toxicol Appl Pharmacol. 2014;279:331–7.PubMedCrossRef
9.
Ito Y, Yamanoshita O, Kurata Y, Kamijima M, Aoyama T, Nakajima T. Induction of peroxisome proliferator-activated receptor alpha (PPARalpha)-related enzymes by di(2-ethylhexyl) phthalate (DEHP) treatment in mice and rats, but not marmosets. Arch Toxicol. 2007;81(3):219–26.PubMedCrossRef
10.
Ito Y, Nakamura T, Yanagiba Y, Ramdhan DH, Yamagishi N, Naito H, et al. 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; 2012: 201284.
11.
Hayashi Y, Ito Y, Yanagiba Y, Kamijima M, Naito H, Nakajima T. Differences in metabolite burden of di(2-ethylhexyl)phthalate in pregnant and postpartum dams and their offspring in relation to drug-metabolizing enzymes in mice. Arch Toxicol. 2012;86(4):563–9.PubMedCrossRef
12.
Ito Y, Kamijima M, Hasegawa C, Tagawa M, Kawai T, Miyake M, et al. Species and inter-individual differences in metabolic capacity of di(2-ethylhexyl)phthalate (DEHP) between human and mouse livers. Environ Health Prev Med. 2014;19(2):117–25.PubMedCrossRef
13.
Kersten S, Stienstra R. The role and regulation of the peroxisome proliferator activated receptor alpha in human liver. Biochimie. 2017;136:75–84.PubMedCrossRef
14.
Nakamura T, Ito Y, Yanagiba Y, Ramdhan DH, Kono Y, Naito H, et al. Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor alpha, but not human PPARalpha. Toxicology. 2009;265(1-2):27–33.PubMedPubMedCentralCrossRef
15.
Yang Q, Nagano T, Shah Y, Cheung C, Ito S, Gonzalez FJ. The PPAR alpha-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR alpha. Toxicol Sci. 2008;101(1):132–9.PubMedCrossRef
16.
Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000;405(6785):421–4.PubMedCrossRef
17.
Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347(6294):645–50.PubMedCrossRef
18.
Mandard S, Muller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci. 2004;61(4):393–416.PubMedCrossRef
19.
Maloney EK, Waxman DJ. trans-Activation of PPARα and PPARγ by structurally diverse environmental chemicals. Toxicol Appl Pharmacol. 1999;161(2):209–18.PubMedCrossRef
20.
Kluwe WM, Haseman JK, Douglas JF, Huff JE. The carcinogenicity of dietary di(2-ethylhexyl) phthalate (DEHP) in Fischer 344 rats and B6C3F1 mice. J Toxicol Environ Health. 1982;10(4-5):797–815.PubMedCrossRef
21.
Melnick RL, Morrissey RE, Tomaszewski KE. Studies by the National Toxicology Program on di(2-ethylhexyl)phthalate. Toxicol Ind Health. 1987;3(2):99–118.PubMedCrossRef
22.
23.
24.
25.
26.
Japan Society for Occupational Health. Occupational exposure limits. Jpn J Ind Health. 1992;34:363–84.
27.
Doull J, Cattley R, Elcombe C, Lake BG, Swenberg J, Wilkinson C, et al. A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk Assessment Guidelines. Regul Toxicol Pharmacol. 1999;29(3):327–57.PubMedCrossRef
28.
29.
30.
Hasmall SC, James NH, Macdonald N, Soames AR, Roberts RA. Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression. Arch Toxicol. 2000;74(2):85–91.PubMedCrossRef
31.
Pugh G Jr, Isenberg JS, Kamendulis LM, Ackley DC, Clare LJ, Brown R, et al. Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys. Toxicol Sci. 2000;56(1):181–8.PubMedCrossRef
32.
Ito Y, Yamanoshita O, Asaeda N, Tagawa Y, Lee CH, Aoyama T, et al. Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor alpha-independent pathway. J Occup Health. 2007;49(3):172–82.PubMedCrossRef
33.
Takashima K, Ito Y, Gonzalez FJ, Nakajima T. Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Ppar alpha-null mice. J Occup Health. 2008;50(2):169–80.PubMedCrossRef
34.
Voss C, Zerban H, Bannasch P, Berger MR. Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague-Dawley rats. Toxicology. 2005;206(3):359–71.PubMedCrossRef
35.
David RM, Moore MR, Finney DC, Guest D. Chronic toxicity of di(2-ethylhexyl)phthalate in rats. Toxicol Sci. 2000;55(2):433–43.PubMedCrossRef
36.
Melnick RL. Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of di(2-ethylhexyl)phthalate (DEHP)? Environ Health Perspect. 2001;109(5):437–42.PubMedPubMedCentralCrossRef
37.
Melnick RL. The IARC evaluation of di(2-ethylhexyl)phthalate (DEHP): a flawed decision based on an untested hypothesis. Int J Occup Environ Health. 2002;8(3):284–6.PubMedCrossRef
38.
Melnick RL. Suppression of crucial information in the IARC evaluation of DEHP. Int J Occup Environ Health. 2003;9(1):84–5 discussion 89.PubMedCrossRef
39.
Melnick RL, Brody C, DiGangi J, Huff J. The IARC evaluation of DEHP excludes key papers demonstrating carcinogenic effects. Int J Occup Environ Health. 2003;9(4):400–2.PubMed
40.
41.
Guyton KZ, Chiu WA, Bateson TF, Jinot J, Scott CS, Brown RC, et al. A reexamination of the PPAR-alpha activation mode of action as a basis for assessing human cancer risks of environmental contaminants. Environ Health Perspect. 2009;117(11):1664–72.PubMedPubMedCentralCrossRef
42.
Ward EM, Schulte PA, Straif K, Hopf NB, Caldwell JC, Carreon T, et al. Research recommendations for selected IARC-classified agents. Environ Health Perspect. 2010;118(10):1355–62.PubMedPubMedCentralCrossRef
43.
Rusyn I, Peters JM, Cunningham ML. Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol. 2006;36(5):459–79.PubMedPubMedCentralCrossRef
44.
45.
Corton JC, Peters JM, Klaunig JE. The PPARalpha-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions. Arch Toxicol. 2018;92(1):83–119.PubMedCrossRef
46.
Ren H, Aleksunes LM, Wood C, Vallanat B, George MH, Klaassen CD, et al. Characterization of peroxisome proliferator-activated receptor alpha--independent effects of PPARalpha activators in the rodent liver: di-(2-ethylhexyl) phthalate also activates the constitutive-activated receptor. Toxicol Sci. 2010;113(1):45–59.PubMedCrossRef
47.
48.
Thomas JA, Thomas MJ. Biological effects of di-(2-ethylhexyl) phthalate and other phthalic acid esters. Crit Rev Toxicol. 1984;13(4):283–317.PubMedCrossRef
49.
JCt L, Chapin RE, Teague J, Lawton AD, Reel JR. Reproductive effects of four phthalic acid esters in the mouse. Toxicol Appl Pharmacol. 1987;88(2):255–69.CrossRef
50.
Tyl RW, Price CJ, Marr MC, Kimmel CA. Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice. Fundam Appl Toxicol. 1988;10(3):395–412.PubMedCrossRef
51.
Laskey JW, Berman E. Steroidogenic assessment using ovary culture in cycling rats: effects of bis(2-diethylhexyl)phthalate on ovarian steroid production. Reprod Toxicol. 1993;7(1):25–33.PubMedCrossRef
52.
Eagon PK, Chandar N, Epley MJ, Elm MS, Brady EP, Rao KN. Di(2-ethylhexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia. Int J Cancer. 1994;58(5):736–43.PubMedCrossRef
53.
Davis BJ, Maronpot RR, Heindel JJ. Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats. Toxicol Appl Pharmacol. 1994;128(2):216–23.PubMedCrossRef
54.
Gray LE Jr, Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci. 2000;58(2):350–65.PubMedCrossRef
55.
European Communities. Commission Directive 2001/59/EC of 6 August 2001 adapting to technical progress for the 28th time Council Directive 67/548/EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. Off J Eur Communities. 2001; L 225: 1-333.
56.
Japan Society for Occupational Health. Occupational exposure limit (in Japanese). Sangyo Eiseigaku Zasshi. 2015;57:270–4.
57.
Akingbemi BT, Ge R, Klinefelter GR, Zirkin BR, Hardy MP. Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. Proc Natl Acad Sci U S A. 2004;101(3):775–80.PubMedPubMedCentralCrossRef
58.
Kay VR, Bloom MS, Foster WG. Reproductive and developmental effects of phthalate diesters in males. Crit Rev Toxicol. 2014;44(6):467–98.PubMedCrossRef
59.
Araki A, Mitsui T, Miyashita C, Nakajima T, Naito H, Ito S, et al. Association between maternal exposure to di(2-ethylhexyl) phthalate and reproductive hormone levels in fetal blood: the Hokkaido Study on Environment and Children’s Health. PLoS One. 2014;9(10):e109039.PubMedPubMedCentralCrossRef
60.
Araki A, Mitsui T, Goudarzi H, Nakajima T, Miyashita C, Itoh S, et al. Prenatal di(2-ethylhexyl) phthalate exposure and disruption of adrenal androgens and glucocorticoids levels in cord blood: the Hokkaido Study. Sci Total Environ. 2017;581-582:297–304.PubMedCrossRef
61.
Lin S, Ku HY, Su PH, Chen JW, Huang PC, Angerer J, et al. Phthalate exposure in pregnant women and their children in central Taiwan. Chemosphere. 2011;82(7):947–55.PubMedCrossRef
62.
Wen HJ, Sie L, Su PH, Chuang CJ, Chen HY, Sun CW, et al. Prenatal and childhood exposure to phthalate diesters and sex steroid hormones in 2-, 5-, 8-, and 11-year-old children: a pilot study of the Taiwan Maternal and Infant Cohort Study. J Epidemiol. 2017;27(11):516–23.PubMedPubMedCentralCrossRef
63.
Yolton K, Xu Y, Strauss D, Altaye M, Calafat AM, Khoury J. Prenatal exposure to bisphenol A and phthalates and infant neurobehavior. Neurotoxicol Teratol. 2011;33(5):558–66.PubMedPubMedCentralCrossRef
64.
Nakajima T, Hayashi Y, Ito Y. Prenatal exposure to di(2-ethylhexyl) phthalate and subsequent infant and child health effects. Food Safety. 2015;3(3):70–83.CrossRef
65.
Kim Y, Ha EH, Kim EJ, Park H, Ha M, Kim JH, et al. Prenatal exposure to phthalates and infant development at 6 months: prospective Mothers and Children’s Environmental Health (MOCEH) study. Environ Health Perspect. 2011;119(10):1495–500.PubMedPubMedCentralCrossRef
66.
Hayashi Y, Ito Y, Nakajima T. Effects of exposure to di(2-ethylhexyl)phthalate during fetal period on next generation. Nihon Eiseigaku Zasshi. 2014;69(2):86–91.PubMedCrossRef
67.
Hayashi Y, Ito Y, Nakajima T. Relationship of maternal malnutrition caused by di(2-ethylhexyl) phthalate exposure with lifestyle disease in offspring. Nihon Eiseigaku Zasshi. 2012;67(1):22–5.PubMedCrossRef
68.
Jia X, Harada Y, Tagawa M, Naito H, Hayashi Y, Yetti H, et al. Prenatal maternal blood triglyceride and fatty acid levels in relation to exposure to di(2-ethylhexyl)phthalate: a cross-sectional study. Environ Health Prev Med. 2015;20(3):168–78.PubMedCrossRef
69.
Nakashima R, Hayashi Y, Md K, Jia X, Wang D, Naito H, et al. Exposure to DEHP decreased four fatty acid levels in plasma of prepartum mice. Toxicology. 2013;309:52–60.PubMedPubMedCentralCrossRef
70.
Hayashi Y, Ito Y, Yamagishi N, Yanagiba Y, Tamada H, Wang D, et al. Hepatic peroxisome proliferator-activated receptor alpha may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice. Toxicology. 2011;289(1):1–10.PubMedCrossRef
71.
Hayashi Y, Ito Y, Naito H, Tamada H, Yamagishi N, Kondo T, et al. In utero exposure to di(2-ethylhexyl)phthalate suppresses blood glucose and leptin levels in the offspring of wild-type mice. Toxicology. 2019;415:49–55.PubMedPubMedCentralCrossRef
72.
Minatoya M, Araki A, Miyashita C, Ait Bamai Y, Itoh S, Yamamoto J, et al. Association between prenatal bisphenol A and phthalate exposures and fetal metabolic related biomarkers: The Hokkaido Study on Environment and Children’s Health. Environ Res. 2018;161:505–11.PubMedCrossRef
73.
Wang Y, Chen B, Lin T, Wu S, Wei G. Protective effects of vitamin E against reproductive toxicity induced by di(2-ethylhexyl) phthalate via PPAR-dependent mechanisms. Toxicol Mech Methods. 2017;27(7):551–9.PubMedCrossRef
74.
Peters JM, Taubeneck MW, Keen CL, Gonzalez FJ. Di(2-ethylhexyl) phthalate induces a functional zinc deficiency during pregnancy and teratogenesis that is independent of peroxisome proliferator-activated receptor-alpha. Teratology. 1997;56(5):311–6.PubMedCrossRef
75.
Ward JM, Peters JM, Perella CM, Gonzalez FJ. Receptor and nonreceptor-mediated organ-specific toxicity of di(2-ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor alpha-null mice. Toxicol Pathol. 1998;26(2):240–6.PubMedCrossRef
76.
Food Safety Commission of J. Bis(2-ethylhexyl)phthalate (DEHP). executive summary. Food Safety. 2014;2(1):1–4.CrossRef
77.
European Communities. Commission Directive 2007/19/EC of 30 March 2007 amending Directive 2002/72/EC. Official Journal of the European Union. 2007; L97: 50-69.
78.
79.
80.
European Communities. Entry 51 of Annex XVII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council. 2006.
81.
82.
83.
National Toxicology Program Center for the evaluation of risks to human reproduction, NTP-CERHR monograph on the potential human reproductive and developmental effects of di(2-ethylhexyl)phthalate (DEHP). 2006.
84.
Bernard L, Decaudin B, Lecoeur M, Richard D, Bourdeaux D, Cueff R, et al. Analytical methods for the determination of DEHP plasticizer alternatives present in medical devices: a review. Talanta. 2014;129:39–54.PubMedCrossRef
85.
Ito Y, Grant report #200939055A in Japanese, in Health and Labor Sciences Research Grants 2009.
86.
Hughes BJ, Cox K, Bhat V. Derivation of an oral reference dose (RfD) for di 2-ethylhexyl cyclohexan-1,4-dicarboxylate (DEHCH), an alternative to phthalate plasticizers. Regul Toxicol Pharmacol. 2018;92:128–37.PubMedCrossRef
87.
Minakami H, Grant report #200736012B in Japanese, in Health and Labor Sciences Research Grants 2008.
88.
Konishi S, Cho K, Okajima S, Minakami H, Yamada T, Shiono N. Effects of phthalate exposure on neonates Japan Society of Perinatal and Neonatal Medicine proceedings in Japanese. 2007; 43(2): 410.
89.
Kamijo Y, Hora K, Nakajima T, Kono K, Takahashi K, Ito Y, et al. Peroxisome proliferator-activated receptor alpha protects against glomerulonephritis induced by long-term exposure to the plasticizer di-(2-ethylhexyl)phthalate. J Am Soc Nephrol. 2007;18(1):176–88.PubMedCrossRef
90.
Strassburg CP, Strassburg A, Kneip S, Barut A, Tukey RH, Rodeck B, et al. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut. 2002;50(2):259–65.PubMedPubMedCentralCrossRef
91.
Erythropel HC, Maric M, Nicell JA, Leask RL, Yargeau V. Leaching of the plasticizer di(2-ethylhexyl)phthalate (DEHP) from plastic containers and the question of human exposure. Appl Microbiol Biotechnol. 2014;98(24):9967–81.PubMedCrossRef
92.
Tsai HJ, Chen BH, Wu CF, Wang SL, Huang PC, Tsai YC, et al. Intake of phthalate-tainted foods and microalbuminuria in children: the 2011 Taiwan food scandal. Environ Int. 2016;89-90:129–37.PubMedCrossRef
93.
Huang HB, Kuo PH, Su PH, Sun CW, Chen WJ, Wang SL. Prenatal and childhood exposure to phthalate diesters and neurobehavioral development in a 15-year follow-up birth cohort study. Environ Res. 2019;172:569–77.PubMedCrossRef
94.
Galgani F, Hanke G, Maes T, Global distribution, composition and abundance of marine litter, in Marine Anthropogenic Litter. 2015. p. 29-56.
95.
96.
Fries E, Dekiff JH, Willmeyer J, Nuelle MT, Ebert M, Remy D. Identification of polymer types and additives in marine microplastic particles using pyrolysis-GC/MS and scanning electron microscopy. Environ Sci Process Impacts. 2013;15(10):1949–56.PubMedCrossRef
97.
Bakir A, O’Connor IA, Rowland SJ, Hendriks AJ, Thompson RC. Relative importance of microplastics as a pathway for the transfer of hydrophobic organic chemicals to marine life. Environ Pollut. 2016;219:56–65.PubMedCrossRef
Metadata
Title
Di(2-ethylhexyl) phthalate-induced toxicity and peroxisome proliferator-activated receptor alpha: a review
Authors
Yuki Ito
Michihiro Kamijima
Tamie Nakajima
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Environmental Health and Preventive Medicine / Issue 1/2019
Print ISSN: 1342-078X
Electronic ISSN: 1347-4715
DOI
https://doi.org/10.1186/s12199-019-0802-z

Other articles of this Issue 1/2019

Environmental Health and Preventive Medicine 1/2019 Go to the issue

Research article

Association between human T cell leukemia virus type-1 (HTLV-1) infection and advanced periodontitis in relation to atherosclerosis among elderly Japanese: a cross-sectional study

Research article

A comparative study of the physiological and psychological effects of forest bathing (Shinrin-yoku) on working age people with and without depressive tendencies

Research article

Prevalence and associated factors of scabies among schoolchildren in Dabat district, northwest Ethiopia, 2018

Research article

Prevalence and risk factors of pre-sick building syndrome: characteristics of indoor environmental and individual factors

Research article

Association between incidence of fatal intracerebral hemorrhagic stroke and fine particulate air pollution

Research article

Factors associated with risky driving behaviors for road traffic crashes among professional car drivers in Bahirdar city, northwest Ethiopia, 2016: a cross-sectional study