RESEARCH PAPER
Two generation reproductive and developmental toxicity following subchronic exposure of pubescent male mice to di(2-ethylhexyl)phthalate
| 1 | 1 Department of Radiation Protection and Radiobiology, National Institute of Public Health - National Institute of Hygiene, Warsaw, Poland |
| 2 | 2 Department of Environmental Toxicology, National Institute of Public Health - National Institute of Hygiene, Warsaw, Poland |
Ann Agric Environ Med. 2012;19(1):31–37
KEYWORDS
ABSTRACT
Di-(2-ethylhexyl)phthalate (DEHP) is widely present in the human environment.
The study aimed at the investigation of potential genotoxic effects induced by subchronic exposure to DEHP in germ cells of male mice in the first period of puberty, and to check if the transmission of mutation to the next generation via the sperm is possible. 8-weeks exposure to 2,000 mg/kg and 8,000 mg/kg of DEHP diminished sperm count and quality, leading to a reduced percentage of pregnant females mated to exposed males. A slight increase in the frequency of prenatal deaths and dominant lethal mutations, as well as a significantly increased percentage of abnormal skeletons among the F1 offspring of males exposed to 8,000 mg/kg of DEHP, were observed. Exposure of the fathers did not cause a delay in the postnatal development of the offspring, except for fur development in the group of 8,000 mg/kg of DEHP. Gametes of male offspring of exposed fathers showed reduced motility. The results may suggest that diminished spermaozoa quality induced by DEHP may be coincidental with mutations leading to intrauterine deaths and skeletal abnormalities in the offspring.
ACKNOWLEDGEMENTS
This study was funded by the Polish Ministry of Science
and Higher Education, 2004-2007, Project No. 2PO5D2926.
REFERENCES (67)
1.
Iovdijova A, Bencko V. Potential risk of exposure to selected xenobiotic residues and their fate in the food chain. Part 1: Classification of xenobiotics. Ann Agric Environ Med. 2010; 17: 183-192.
2.
Van Wezel AP, van Vlaardingen P, Posthumus R, Crommentuijn GH, Sijm DTHM. Environmental risk limits for two phthalates with special emphasis on endocrine disruptive properties. Ecotoxicol Environ Saf. 2000; 46: 305-321.
3.
ATSDR. Toxicological profile for di(2-ethylhexyl)phthalate. Agency for Toxic Substances and Disease Registry, United States Public Health Service, Atlanta (GA) 1989.
4.
Tanaka T. Reproductive and neurobehavioral toxicity study of bis(2-ethylhexyl) phthalate (DEHP) administered to mice in the diet. Food Chem Toxicol. 2002; 40: 1499-1506.
5.
Environmental Protection Agency. Technical Factsheet on: Di(2-ethyl)Phthalate (DEHP). Office of Ground Water and Drinking Water, Washington DC 1998.
6.
CIRC (Cosmetic Ingredient Review Committee): Final report on the safety assessment of butyl benzyl phthalate. J Am Coll Toxicol. 1992; 11: 1-23.
7.
Albro PW. The biochemical toxicology of di(2-ethylhexyl) and related phthalates: Testicular atrophy and hepatocarcinogenesis. Rev Biochem Toxicol. 1987; 8: 73-119.
8.
Thomas JA, Darby TD, Wallin RF, Gavin PJ, Martis L. A review of the biological effects of di(2-ethylhexyl)phthalate. Toxicol Appl Pharmacol. 1978; 45: 1-27.
9.
Faouzi A, Dine T, Gressier B, Kambia K, Lucky M, Pagniez D, Brunet C, Cazin M, Belabed A, Cazin JC. Exposure of hemodialysis patients to di(2-ethylhexyl)phthalate. Int J Pharmacol. 1999; 180: 113-121.
10.
Hillman LS, Goodwin LS, Sherman WR. Identification and measurement of plasticizer in neonatal tissues after umbilical carters and blood products. New England J Med. 1975; 292: 381-85.
11.
Manojkumar V, Deepadevi KV, Arun P, Nair KG, Lakshmi LR, Kurup PAS. Changes in the concentration of erythrocyte membrane during storage of blood in di(2-ethylhexyl)phthalate (DEHP) plasticized poly vinyl chloride (PVC) blood storage bags. Ind J Med Res. 1999; 109: 157-163.
12.
Sjőberg P, Lindquist NG, Montin G, Ploen L. Effects of repeated intravenous infusions of the plasticizer di(2-ethylhexyl)phthalate in young male rats. Arch Toxicol. 1985; 58: 78-83.
13.
Parks LG, Ostby JS, Lambright CR, Abbott BD, Klinefelter GR, Barlow NJ, Gray LE Jr. The plasticizer diethylhexyl phthalate induced malformations be decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci. 2000; 58: 339-349.
14.
Sharpe RM. Hormones and testis development and possible adverse effects of environmental chemicals. Toxicol Lett. 2001; 120: 221-232.
15.
Shultz VD, Philips S, Sar M, Foster PM, Gaido KW. Altered gene profiles and fetal rats testes after in utero exposure to di(n-buthyl)phthalate. Toxicol Sci. 2001; 64: 235-242.
16.
Wong JS, Gill SS. Gene expression changes induced in mouse liver by di(2- ethylhexyl)phthalate. Toxicol Appl Pharmacol. 2002; 185: 180-96.
17.
DFG, Deutsche Forschungsgemeinschaft. Di(2-ethylhexyl)phthalate (DEHP). In: Greim H (Ed.): Gesundheitsschadliche Arbeitsstoffe-Toxikologischarbeitsmedizinische Begrundungen von MAK-Werten. 35. Erganzungslieferung, Wiley-VCH 2002.
18.
Kavlock R, Boekelheide K, Chapin R, Cunningham M, Faustman E, Foster P, Golub M, Henderson R, Hinberg I, Little R, Seed J, Shea K, Tabacova S, Tyl R, Wiliams P, Zacharewski T. NTP Center for Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reprod Toxicol. 2002; 16: 529-653.
19.
Arcadi FA, Costa C, Imperatore C, Marchese A, Rapisardi A, Salemi M, Trimarchi GR, Costa. G. Oral toxicity of bis(2-ethylhexyl)phthalate during pregnancy and sucking in the Long-Evans rat. Food Chem Toxicol. 1998; 35: 963-970.
20.
ATSDR. Toxicological profile for di(2-ethylhexyl)phthalate (DEHP). Agency for Toxic Substances and Disease Registry, United States Public Health Service, Atlanta (GA) 2002.
21.
Gray LE Jr, Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L. Prenatal 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: 350-65.
22.
Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer di(2-ethylhexyl)phthalate. Environ Health Perspect. 2001; 109: 229-237.
23.
Ashby J, Clapp MJL. The rodent dominant lethal assay: a proposed format for data presentation that alerts to pseudodominant lethal effects. Mutat Res. 1995; 330: 209- 218.
24.
IARC (1982) Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol. 29: Some Industrial Chemicals and Dyestuffs. Summary of Data Reported and Evaluation, 269-293, IARC, Lyon 1982.
25.
Harrison A, Moore PC. Reduction in sperm count and increase in abnormal sperm in the mouse following X-radiation or injection of 22 Na. Health Phys. 1980; 39: 219-224.
26.
Searle AG, Beechey CV. Sperm count, egg-fertilization and dominant lethality after X-irradiation of mice. Mutat Res. 1974; 22: 69-74.
27.
Working PK, Bus JS, Hamm TE Jr. Reproductive effects of inhaled methyl chloride in the male Fisher 344 rat. II. Spermatogonial toxicity and sperm quality. Toxicol Appl Pharmacol. 1985; 77: 144-57.
28.
Wyrobek AJ, Bruce WR. Chemical induction of sperm abnormalities in mice. Proceed Nat Acad Sci USA. 1975; 72: 4425-4429.
29.
Singh NP, Mc Coy M, Tice RR, Schneider EL. A simple technique for quantization of low level of DNA damage in individual cells. Exp Cell Res. 1988; 175: 184-191.
30.
Anderson D, Yu TW, Phillips BJ, Schmezer P. The effects of various antioxidants and other modifying agents on oxygen-radical-generated damage in human lymphocytes in Comet assay. Mutat Res. 1994; 307: 261-71.
31.
Końca K, Lankoff A, Banasik A, Lisowska H, Kuszewski T, Góźdź S, Koza Z, Wójcik A. A cross-platform public domain PC image-analysis program for comet assay. Mutat Res. 2003; 534: 15-20.
32.
Knudsen I, Hansen EV, Meyer OA, Poulsen E. A proposed method for the simultaneous detection of germ cell mutations leading to foetal death (dominant lethality) and of malformations (male teratogenicity). Mutat Res. 1977; 48: 267-270.
33.
Anderson D, Edwards AJ, Brinkworth, MH. Male-mediated F1 effects in mice exposed to 1,3-butadiene. In: Sorsa M, Peltonen K, Vainio H, Hemminki K (Eds.). Butadiene and Styrene: assessment of Health Hazards, 171-181. IARC Scientific Publications No. 127, Lyon 1993.
34.
Kirk KM, Lyon MF. Induction of congenital malformations in the offspring of male mice treated with X-rays at pre-meiotic and post-meiotic stages. Mutat Res. 1984; 125: 75-85.
35.
Hossain M, Devi PU, Bisht KS. Effect of prenatal gamma irradiation during the late fetal period on the postnatal development on the mouse. Teratology. 1999; 59: 133-38.
36.
Lottrup G, Andersson A-M, Leffers H, Martensen GK, Toppari J, Skakkebaek NE, Main, KM. Possible impact of phthalates on infant reproductive health. Int J Androl. 2006; 29: 172-180.
37.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, Mao CS, Redman JB, Termand CL, Sullivan S, Tregue JL. Study of future families. Research Team. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005; 113: 1056-61.
38.
ECB. Search Appendix to Directive 67/48/EEC on classification and labeling of dangerous substances, 2004. Last updated 30/04/2004b.http//ecb.jrc.it/classif... (accessed: 11.2004).
39.
Hellwig J, Freudenberger J, Jackh R. Differential prenatal toxicity of branched phthalate esters in rats. Food Chem Toxicol. 1997; 35: 501-12.
40.
Shirota M, Saito Y, Imai K, Horihucki S, Yoshimura S, Sato M, Nagao T, Ono H, Katoh M. Influence of di(2-ethylhexyl)phthalate on fetal testicular development by oral administration to pregnant rats. J Toxicol Sci. 2005; 30: 175-94.
41.
Gray LE, Barlow NJ, Howdeshell KL, Ostby JS, Furr JR, Gray CL. Transgenerational effects of di(2-ethylhexyl)phthalate in the male CRL:CD(SD) rat: added value of assessing multiple offspring per litter. Toxicol Sci. 2009; 110: 411-25.
42.
IARC (2000) Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol. 77: Some Industrial Chemicals Summary of Data Reported and Evaluation, 41-148, IARC, Lyon, 2000.
43.
Yagi Y, Nakamura Y, Tomita I, Tsuchikawa K, Shimoi N. Teratogenic potential of di- and mono-(2-ethyl)phthalate in mice. J Environ Pathol Toxicol. 1980; 4: 533-544.
44.
Shiota K, Mima S. Assessment of the teratogenicity of di(2-ethylhexyl)phthalate and mono(2-ethylhexyl)phthalate in mice. Arch Toxicol. 1985; 56: 263-266.
45.
Dostal LA, Jenkins WL, Schwetz BA. Hepatic peroxisome proliferation and hypolipidemic effects of di(2-ethylhexyl)phthalate in neonatal and adult rats. Toxicol Appl Pharmacol. 1987; 87: 81-90.
46.
Kwack SJ, Kim KB, Kim HS, Lee BM. Comparative toxicological evaluation of phthalate diesters and metabolites in Sprague-Dawley male rats for risk assessment. J Toxicol Environ Health A. 2009; 72: 1446-54.
47.
Parmar D, Srivastava SP, Seth PK. Effect of di(2-ethylhexyl)phthalate (DEHP) on spermatogenesis in adult rats. Toxicology. 1986; 42: 47-55.
48.
Siddiqui A, Srivastava SP. Effect of di(2-ethylhexyl)phthalate administration on rat sperm count and on sperm metabolic enzymes. Bull Environ Contam Toxicol. 1992; 48: 115-19.
49.
Agarwal DK, Eustis S, Lamb JC, Reel JR, Kluwe WM. Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats. Environ Health Perspect. 1986; 65: 343-50.
50.
Dobrzyńska MM, Czajka U, Tyrkiel EJ. Male-mediated F1 effects in mice exposed to di(2-ethylhexyl)phthalate (DEHP). In: Anderson D, Brinkworth MH (Eds.). Male-mediated developmental toxicity. RSC Publishing 2007.
51.
Katz DF, Diel L, Overstreet JW. Differences in the movement of morphologically normal and abnormal human seminal spermatozoa. Biol Reprod. 1982; 26: 566-70.
52.
Hales BF, Cyr DG. Study designs for the assessment of male-mediated developmental toxicity. In: Robaire B, Hales BF (Eds.). Advances in male mediated developmental toxicology. 271-77. Kluwer Academic/Plenum Publishers, New York 2003.
53.
Bateman AJ. The dominant lethal asssay in the mouse. In: Kilbey B, Legator M, Nicholl W, Ramel C (Eds.). Handbook of Mutagenicity test procedures, 325-35. Elsevier, Amsterdam 1977.
54.
Dostal LA, Chapin RE, Stefanski SA, Harris MW, Schwetz BA. Testicular toxicity and reduced Sertoli cell numbers in neonatal rats by di(2-ethylhexyl)phthalate and the recovery of fertility as adults. Toxicol Appl Pharmacol. 1988; 95: 104-21.
55.
Lamb JC 4 th , Chapin RE, Teaque J, Lawton AD, Reel JR. Reproductive effects of four phthalic acid esters in the mouse. Toxicol Appl Pharmacol. 1987; 88: 255-69.
56.
Faber WD, Deyo JA, Stump DG, Ruble K. Two-generation reproduction study of di-2-ethylhexyl terephthalate in Crl:CD rats. Birth Defects Res Part B Dev Reprod Toxicol. 2007; 80: 69-81.
57.
Ema M, Miyawaki NE, Hirose A, Kamata E. Decreased anogenital distance and increased incidence of undescended testes in fetuses of rats given monobenzyl phthalate, a major metabolite of butyl benzyl phthalate. Reprod Toxicol. 2003; 17: 407-12.
58.
Noriega NC, Howdeshell KL, Furr J, Lambright CR, Wilson VS, Gray LE Jr. Pubertal administration of DEHP delays puberty, suppresses testosterone production, and inhibits reproductive tract development in male Sprague-Dawley and Long-Evants rats. Toxicol Sci. 2009; 111: 163-78.
59.
Song XF, Deng YJ, Zhang DY, Liu X, Wu SD, Wei GH. Effects of di(2-ethylhexyl)phthalate on the testis and testicular gubernaculums of fetal KM mice (Abstr). Zhonghua Nan Ke Xue. 2009; 15: 195-99.
60.
Andrade AJ, Grande SW, Talsness CE, Gericke C, Grote K, Golembiewski A, Sterner-Kock A, Chahoud I. A dose response study following in utero and lactational exposure to di(2-ethylhexyl)phthalate (DEHP): reproductive effects on adult male offspring rats. Toxicology. 2006; 228: 85-97.
61.
Dalsenter PR, Santana GM, Grande SW, Andrado AJ, Araujo SL. Phthalate affects the reproductive function and sexual behavior of male Wistar rats. Hum Exp Toxicol. 2006; 25: 297-303.
62.
Vo TTB, Jung EM, Dang VH, Jung R, Baek J, Choi KC Jeung EB. Differential effects of flutamide and di(2-ethylhexyl) phthalate on male reproductive organs in rat model. J Reprod Develop. 2009; 55: 400-11.
63.
Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during the past 50 years. BMJ. 1992; 305: 609-612.
64.
Horak S, Kamińska J, Olejek A. The fertilization of donor semen between 1982 and 2004 in the industrial area of Upper Silesia (Poland). Ann Agric Environ Med. 2008; 15: 113-118.
65.
Swan SH, Elkin EP, Fenster L. The question of declining sperm density revisited: An analysis of 101 studies published 1934-1996. Environ Health Perspect. 2000; 108: 961-966.
66.
Gray TJ, Butterworth KR. Testicular atrophy produced by phthalate esters. Arch Toxicol. 1980; Suppl 4: 432-455.
67.
Gray TJ, Beamand JA. Effect of some phthalates esters and other testicular toxins on primary cultures of testicular cells. Food Chem Toxicol. 1984; 22: 123-31.
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