Online first
Current issue
Archive
Special Issues
About the Journal
Publication Ethics
1/2012 vol. 19
Stats
CC BY-NC 3.0 Poland
Get citation
RESEARCH PAPER
Two generation reproductive and developmental toxicity following subchronic exposure of pubescent male mice to di(2-ethylhexyl)phthalate
Małgorzata M. Dobrzyńska 1
,
 
Ewa J. Tyrkiel 2
,
 
Edyta Derezińska 1
,
 
Krzysztof A. Pachocki 1
,
 
Jan K. Ludwicki 2
 
 
 
More details
Hide details
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
 
Article (PDF)
References (67)
 
KEYWORDS
DEHP
spermatozoa
male-mediated effects
progeny
mice
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
3.
ATSDR. Toxicological profile for di(2-ethylhexyl)phthalate. Agency for Toxic Substances and Disease Registry, United States Public Health Service, Atlanta (GA) 1989.
Google Scholar
 
 
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.
Google Scholar
 
 
5.
Environmental Protection Agency. Technical Factsheet on: Di(2-ethyl)Phthalate (DEHP). Office of Ground Water and Drinking Water, Washington DC 1998.
Google Scholar
 
 
6.
CIRC (Cosmetic Ingredient Review Committee): Final report on the safety assessment of butyl benzyl phthalate. J Am Coll Toxicol. 1992; 11: 1-23.
Google Scholar
 
 
7.
Albro PW. The biochemical toxicology of di(2-ethylhexyl) and related phthalates: Testicular atrophy and hepatocarcinogenesis. Rev Biochem Toxicol. 1987; 8: 73-119.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
14.
Sharpe RM. Hormones and testis development and possible adverse effects of environmental chemicals. Toxicol Lett. 2001; 120: 221-232.
Google Scholar
 
 
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.
Google Scholar
 
 
16.
Wong JS, Gill SS. Gene expression changes induced in mouse liver by di(2- ethylhexyl)phthalate. Toxicol Appl Pharmacol. 2002; 185: 180-96.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
26.
Searle AG, Beechey CV. Sperm count, egg-fertilization and dominant lethality after X-irradiation of mice. Mutat Res. 1974; 22: 69-74.
Google Scholar
 
 
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.
Google Scholar
 
 
28.
Wyrobek AJ, Bruce WR. Chemical induction of sperm abnormalities in mice. Proceed Nat Acad Sci USA. 1975; 72: 4425-4429.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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/classification-labeling (accessed: 11.2004).
Google Scholar
 
 
39.
Hellwig J, Freudenberger J, Jackh R. Differential prenatal toxicity of branched phthalate esters in rats. Food Chem Toxicol. 1997; 35: 501-12.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
47.
Parmar D, Srivastava SP, Seth PK. Effect of di(2-ethylhexyl)phthalate (DEHP) on spermatogenesis in adult rats. Toxicology. 1986; 42: 47-55.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
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.
Google Scholar
 
 
66.
Gray TJ, Butterworth KR. Testicular atrophy produced by phthalate esters. Arch Toxicol. 1980; Suppl 4: 432-455.
Google Scholar
 
 
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.
Google Scholar
 
 
Share
Send by email
RELATED ARTICLE
The effect of the antioxidant N-acetylcysteine on cholinesterase activity in the brain and blood during Pirimiphos methyl poisoning in the course of treatment with atropine alone, and with atropine and obidoxime
Neurotoxic effects of combined exposure to caffeine and pyrethroids in mice
The development of cigarette smoke induced chronic pancreatitis in mice is associated with increased expression of K-Ras and NF-κB
Toxin producing micromycetes on fruit, berries, and vegetables.
Increased urinary excretion of thioethers as a marker for detecting exposure to herbicide containing 2,4-dichlorophenoxyacetic acid dimethylamine - experimental study on mice.
Indexes
 
Keywords index
Topics index
Authors index
eISSN:1898-2263
ISSN:1232-1966
Journals System - logo
Improvement of editorial platform - task financed under the agreement No. 618/P-DUN/2019 by the Minister of Science and Higher Education allocated to the activities of disseminating science.

Improvement of visual identification of the journal - task financed under the agreement No. 618/P-DUN/2019 by the Minister of Science and Higher Education allocated to the activities of disseminating science.

Generation of the DOI (Digital Object Identifier) - task financed under the agreement No. 618/P-DUN/2019 by the Minister of Science and Higher
© 2006-2025 Journal hosting platform by Bentus
Scroll to top