Abstract
Di(2-ethylhexyl) phthalate (DEHP) is a widely used synthetic polymer in the industry. DEHP may induce reproductive and developmental toxicity, obesity, carcinogenesis and cause abnormal endocrine function in both human and wildlife. The aim of this study was to investigate trace element and mineral levels in relation of kidney and liver damage in DEHP-administered rats. Therefore, prepubertal male rats were dosed with 0, 100, 200, and 400 mg/kg/day of DEHP. At the end of the experiment, trace element and mineral levels, glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR) and glutathione S-transferase (GST) enzyme activities were evaluated in the serum, liver, and kidney samples of rats. Furthermore, serum clinical biochemistry parameters, organ/body weight ratios and histological changes were investigated to evaluate impact of DEHP more detailed. Our data indicated that sodium (Na), calcium (Ca), potassium (K), lithium (Li), rubidium (Rb) and cesium (Cs) levels significantly decreased, however iron (Fe) and selenium (Se) concentrations significantly increased in DEHP-administered groups compared to the control in the serum samples. On the other hand, upon DEHP administration, selenium concentration, G6PD and GR activities were significantly elevated, however 6-PGD activity significantly decreased compared to the control group in the kidney samples. Decreased G6PD activity was the only significant change between anti-oxidant enzyme activities in the liver samples. Upon DEHP administration, aberrant serum biochemical parameters have arisen and abnormal histological changes were observed in the kidney and liver tissue. In conclusion, DEHP may induce liver and kidney damage, also result abnormalities in the trace element and mineral levels.
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Vos JG, Dybing E, Greim HA, Ladefoged O, Lambré C, Tarazona JV, Brandt I, Vethaak AD (2000) Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation. Crit Rev Toxicol 30:71–133. https://doi.org/10.1080/10408440091159176
Sonnenschein C, Soto AM (1998) An updated review of environmental estrogen and androgen mimics and antagonists. J Steroid Biochem Mol Biol 65:143–150
Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, Gore AC (2009) Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocr Rev 30:293–342. https://doi.org/10.1210/er.2009-0002
Halden RU (2010) Plastics and health risks. Annu Rev Public Health 31:179–194. https://doi.org/10.1146/annurev.publhealth.012809.103714
Rettenmeier AW, Mettang T (1997) PVC-plasticizer DEHP—aspects of metabolism and toxicity. Nieren-Und Hochdruckkrankheiten 26:S2–S6
National Toxicology Program (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
Albro PW (1986) Absorption, metabolism, and excretion of di(2-ethylhexyl) phthalate by rats and mice. Environ Health Perspect 65:293–298
Martinez-Arguelles DB, Campioli E, Lienhart C, Fan J, Culty M, Zirkin BR, Papadopoulos V (2014) In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate induces long-term changes in gene expression in the adult male adrenal gland. Endocrinology 155:1667–1678. https://doi.org/10.1210/en.2013-1921
Carlisle J, Henkel S, Li LH, Painter P, Qiao D (2009) Toxicological profile for di-(2ethylhexyl)phthalate (DEHP). California Environmental Protection Agency, 1–52. California
Muscogiuri G, Colao A (2017) Phtalates: new cardiovascular health disruptors? Arch Toxicol 91:1513–1517
Rhodes C, Orton TC, Pratt IS, Batten PL, Bratt H, Jackson SJ, Elcombe CR (1986) Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets: extrapolation of effects in rodents to man. Environ Health Perspect 65:299–307
Reddy JK, Moody DE, Azarnoff DL, Rao MS (1976) Di-(2-ethylhexyl)phthalate: an industrial plasticizer induces hypolipidemia and enhances hepatic catalase and carnitine acetyltransferase activities in rat and mice. Life Sci 18:941–945. https://doi.org/10.1016/0024-3205(76)90412-4
Tanaka A, Adachi T, Takahashi T, Yamaha T (1975) Biochemical studies on phthalic esters I. Elimination, distribution and metabolism of di-(2-ethylhexyl)phthalate in rats. Toxicology 4:253–264
Erkekoglu P, Kocer-Gumusel B (2014) Genotoxicity of phthalates. Toxicol Mech Methods 24:616–626. https://doi.org/10.3109/15376516.2014.960987
Ulusu NN (2015) Glucose-6-phosphate dehydrogenase deficiency and Alzheimer’s disease: partners in crime? The hypothesis. Med Hypotheses 85:219–223
Fan LIQ, Coley J, Miller RT, Cattley RC, Corton JC (2003) Opposing mechanisms of NADPH-cytochrome P450 oxidoreductase regulation by peroxisome proliferators. Biochem Pharmacol 65(6):949–959. https://doi.org/10.1016/S0006-2952(03)00004-2
Harding MM (2004) The architecture of metal coordination groups in proteins. Acta Crystallogr D Biol Crystallogr 60:849–859
Erkekoglu P, Arnaud J, Rachidi W, Kocer-Gumusel B, Favier A, Hincal F (2015)) The effects of di(2-ethylhexyl) phthalate and/or selenium on trace element levels in different organs of rats. J Trace Elements Med Biol: Organ Soc Minerals and Trace Elements 29:296–302. https://doi.org/10.1016/j.jtemb.2014.08.002
Betke K, Brewer GJ, Kirkman HN, Luzzato L, Motulsky AG, Ramot B, Siniscalco M (1967) Standardized method for G-6PD assay of haemolysates. WHO Tech Rep Ser 366:30–32
Pearse B, Rosemeyer M (1975) 6-phosphogluconate dehydrogenase from human erythrocytes. Methods Enzymol 41:220–226
Staal GEJ, Visser J, Weeger C (1969) Purification and properties of glutathione reductase of human erythrocytes. Biochim Biophys Acta 185:39–48
Habig W, Pabst M, Jakoby W (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139
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
Giknis MLA, Clifford CB (2008) Clinical laboratory parameters for Crl:WI (Han). Charles River Laboratories Preclinical Services, Montreal, p 14
Ty Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7(2):27–31. https://doi.org/10.4103/0976-0105.177703
Lamb JC, Chapin RE, Teague J, Lawton AD, Reel JR (1987) Reproductive effects of four phthalic acid esters in the mouse. Toxicol Appl Pharmacol 88(2):255–269
David RM, Moore MR, Finney DC, Guest D (2001) Reversibility of the chronic effects of di(2-ethylhexyl)phthalate. Toxicol Pathol 29:430–439
Fraga CG (2005) Relevance, essentiality and toxicity of trace elements in human health. Mol Asp Med 26:235–244. https://doi.org/10.1016/j.mam.2005.07.013
Xu J, Zhou L, Wang S, Zhu J, Liu T, Jia Y, Sun D, Chen H, Wang Q, Xu F, Zhang Y, Liu H, Zhang T, Ye L (2018) Di-(2-ethylhexyl)-phthalate induces glucose metabolic disorder in adolescent rats. Environ Sci Pollut Res 25(4):3596–3607. https://doi.org/10.1007/s11356-017-0738-z
Rusyn I, Peters JM, Cunningham ML (2006) Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol 36(5):459–479. https://doi.org/10.1080/10408440600779065
Bremner I, Mills CF (1981) Absorption, transport and tissue storage of essential trace elements. Philos Trans R Soc Lond Ser B Biol Sci 294:75–89
Can B, Ulusu NN, Kilinç K, Acan NL, Saran Y, Turan B (2005) Selenium treatment protects diabetes-induced biochemical and ultrastructural alterations in liver tissue. Biol Trace Elem Res 105:135–150
Rayman MP (2000) The importance of selenium to human health. Lancet 356:233–241. https://doi.org/10.1016/S0140-6736(00)02490-9
Stranges S, Sieri S, Vinceti M, Grioni S, Guallar E, Laclaustra M, Muti P, Berrino F, Krogh V (2010) A prospective study of dietary selenium intake and risk of type 2 diabetes. BMC Public Health 10:1–8. https://doi.org/10.1186/1471-2458-10-564
Lu CW, Chang HH, Yang KC, Kuo CS, Lee LT, Huang KC (2016) High serum selenium levels are associated with increased risk for diabetes mellitus independent of central obesity and insulin resistance. BMJ Open Diabetes Res Care 4(1):1–7 e000253. https://doi.org/10.1136/bmjdrc-2016-000253 eCollection 2016
Rayman MP (2012) Selenium and human health. Lancet 379:1256–1268. https://doi.org/10.1016/S0140-6736(11)61452-9
Office of Environmental Health Hazard Assessment (OEHHA) (2001) No significant risk level (NSRL) for the proposition 65 carcinogen di(2-ethylexyl) phthalate. Calif Environ Protect Agency 1–21
Swan SH (2008) Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res 108:177–184. https://doi.org/10.1016/j.envres.2008.08.007
Suliburska J, Bogdański P, Szulińska M (2013) Iron excess disturbs metabolic status and relative gonad mass in rats on high fat, fructose, and salt diets. Biol Trace Elem Res 151(2):263–268
Salata R, Klein I (1987) Effects of lithium on the endocrine system: a review. J Lab Clin Med 110:130–136
Foster R, Lobo MV, Rasmussen H, Marusic ET (1981) Calcium: its role in the mechanism of action of angiotensin II and potassium in aldosterone production. Endocrinology 109:2196–2201. https://doi.org/10.1210/endo-109-6-2196
Arai K, Chrousos GP (2016) Aldosterone deficiency and resistance. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279079/
Bach I, Gati T, Sacely C, Sos J, Udvardy A (1967) Effect of rubidium on aldosterone and corticosterone production in rats. Endocrinology 81:913–914. https://doi.org/10.1210/endo-81-4-913
Kasperek K, Lombeck I, Kiem J, Iyengar GV, Wang YX, Feinendegen LE, Bremer HJ (1982) Platelet selenium in children with normal and low selenium intake. Biol Trace Elem Res 4:29–34
Rossier BC, Baker ME, Studer RA (2015) Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. Physiol Rev 95:297–340. https://doi.org/10.1152/physrev.00011.2014
Dhanya CR, Indu AR, Deepadevi KV, Kurup PA (2003) Inhibition of membrane Na(+)-K+ Atpase of the brain, liver and RBC in rats administered di(2-ethyl hexyl) phthalate (DEHP) a plasticizer used in polyvinyl chloride (PVC) blood storage bags. Indian J Exp Biol 41(8):814–820
Kiyama R, Wada-Kiyama Y (2015) Estrogenic endocrine disruptors: molecular mechanisms of action. Environ Int 83:11–40. https://doi.org/10.1016/j.envint.2015.05.012
Jiang P, Du W, Wu M (2014) Regulation of the pentose phosphate pathway in cancer. Protein Cell 5(8):592–602
Tandogan B, Kuruüzüm-Uz A, Sengezer C, Güvenalp Z, Demirezer LÖ, Ulusu NN (2011) In vitro effects of rosmarinic acid on glutathione reductase and glucose 6-phosphate dehydrogenase. Pharm Biol 49(6):587–594. https://doi.org/10.3109/13880209.2010.533187
Tandogan B, Ulusu NN (2010) A comparative study with colchicine on glutathione reductase. Protein J 29(5):380–385
Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE (2014) Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 94(2):329–354. https://doi.org/10.1152/physrev.00040.2012
Bateman ME, Strong AL, McLachlan JA, Burow ME, Bunnell BA (2017) The effects of endocrine disruptors on adipogenesis and osteogenesis in mesenchymal stem cells: a review. Front Endocrinol 7:1–12. https://doi.org/10.3389/fendo.2016.00171
Lüersen K, Stegehake D, Daniel J, Drescher M, Ajonina I, Ajonina C, Hertel P, Woltersdorf C, Liebau E (2013) The glutathione reductase GSR-1 determines stress tolerance and longevity in Caenorhabditis elegans. PLoS One 8(4):e60731. https://doi.org/10.1371/journal.pone.0060731
Ha M, Wei L, Guan X, Li L, Liu C (2016) p53-dependent apoptosis contributes to di-(2-ethylhexyl) phthalate-induced hepatotoxicity. Environ Pollut 208:416–425. https://doi.org/10.1016/j.envpol.2015.10.009
Wang W, Craig ZR, Basavarajappa MS, Hafner KS, Flaws JA (2012) Mono-(2-ethylhexyl) phthalate induces oxidative stress and inhibits growth of mouse ovarian antral follicles. Biol Reprod 87:152. https://doi.org/10.1095/biolreprod.112.102467
Erkekoglu P, Zeybek ND, Giray B, Asan E, Arnaud J, Hincal F (2011) Reproductive toxicity of di(2-ethylhexyl)phthalate in selenium-supplemented and selenium-deficient rats. Drug Chem Toxicol 34:379–389. https://doi.org/10.3109/01480545.2010.547499
Kijima K, Toyosawa K, Yasuba M, Matsuoka N, Adachi T, Komiyama M, Mori C (2004) Gene expression analysis of the rat testis after treatment with di(2-ethylhexyl) phthalate using cDNA microarray and real-time RT-PCR. Toxicol Appl Pharmacol 200:103–110. https://doi.org/10.1016/j.taap.2004.03.015
Ge RS, Chen GR, Dong Q, Akingbemi B, Sottas CM, Santos M, Sealfon SC, Bernard DJ, Hardy MP (2007) Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats. J Androl 28:513–520. https://doi.org/10.2164/jandrol.106.001909
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This research was supported by Scientific Research Projects Coordination Unit of Hacettepe University (Project number is 1183). Also, the authors gratefully acknowledge the use of the services and facilities of the Koc University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. Findings, opinions or points of view expressed in this article do not necessarily represent the official position or policies of the Ministry of Development.
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Aydemir, D., Karabulut, G., Şimşek, G. et al. Impact of the Di(2-Ethylhexyl) Phthalate Administration on Trace Element and Mineral Levels in Relation of Kidney and Liver Damage in Rats. Biol Trace Elem Res 186, 474–488 (2018). https://doi.org/10.1007/s12011-018-1331-0
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DOI: https://doi.org/10.1007/s12011-018-1331-0