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. 1986 Mar;65:255–262. doi: 10.1289/ehp.8665255

Genetic toxicology of phthalate esters: mutagenic and other genotoxic effects.

G R Douglas, A P Hugenholtz, D H Blakey
PMCID: PMC1474701  PMID: 3709450

Abstract

The effects of DEHP on sperm morphology and on peripheral blood micronuclei were studied for 12 weeks following five subacute IP injections of DEHP at 1/6, 1/12, and 1/60 of the LD50 per day. Sperm morphology was examined in both adult mice and rats, while peripheral blood micronuclei were scored in mice up to 4 weeks after treatment. In mice, DEHP at 1/6 LD50 significantly depressed body weight gain for up to 12 weeks after treatment, and reduced epididymal sperm number by 4 weeks. Numbers of morphologically abnormal sperm did not differ from controls in the 12 weeks following treatment. In addition, DEHP did not increase the numbers of peripheral blood micronuclei. Studies in the rat indicated that exposure to doses of 1/6 and 1/12 of the LD50 per day of DEHP resulted in a reduced gain in body weight compared to controls. Testis weight, sperm number, and numbers of morphologically abnormal sperm were unaffected by DEHP following treatment. In separate experiments, DEHP did not induce sister chromatid exchange (SCE) or DNA damage in Chinese hamster ovary (CHO) cells. Although DEHP is known to cause testicular atrophy in rats and to a lesser extent in mice, it did not cause an increase in abnormal sperm in either species. Together with the CHO and micronucleus data, these findings suggest that DEHP has a low probability of causing genetic damage capable of being transmitted through the male germ line.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abe S., Sasaki M. Chromosome aberrations and sister chromatid exchanges in Chinese hamster cells exposed to various chemicals. J Natl Cancer Inst. 1977 Jun;58(6):1635–1641. doi: 10.1093/jnci/58.6.1635. [DOI] [PubMed] [Google Scholar]
  2. Autian J. Antifertility effects and dominant lethal assays for mutagenic effects of DEHP. Environ Health Perspect. 1982 Nov;45:115–118. doi: 10.1289/ehp.8245115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cairnie A. B., Leach K. E. Quantitative studies of cytological damage in mouse testis produced by exposure to heat. Can J Genet Cytol. 1980;22(1):93–102. doi: 10.1139/g80-012. [DOI] [PubMed] [Google Scholar]
  4. Creasy D. M., Foster J. R., Foster P. M. The morphological development of di-N-pentyl phthalate induced testicular atrophy in the rat. J Pathol. 1983 Mar;139(3):309–321. doi: 10.1002/path.1711390307. [DOI] [PubMed] [Google Scholar]
  5. Curto K. A., Thomas J. A. Comparative effects of diethylhexyl phthalate or monoethylhexyl phthalate on male mouse and rat reproductive organs. Toxicol Appl Pharmacol. 1982 Jan;62(1):121–125. doi: 10.1016/0041-008x(82)90108-9. [DOI] [PubMed] [Google Scholar]
  6. Dillingham E. O., Autian J. Teratogenicity, mutagenicity, and cellular toxicity of phthalate esters. Environ Health Perspect. 1973 Jan;3:81–89. doi: 10.1289/ehp.730381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Douglas G. R., Grant C. E., Bell R. D., Salamone M. F., Heddle J. A., Nestmann E. R. Comparative mammalian in vitro and in vivo studies on the mutagenic activity of rhodamine WT. Mutat Res. 1983 Jul;118(1-2):117–125. doi: 10.1016/0165-1218(83)90121-0. [DOI] [PubMed] [Google Scholar]
  8. Foster P. M., Thomas L. V., Cook M. W., Gangolli S. D. Study of the testicular effects and changes in zinc excretion produced by some n-alkyl phthalates in the rat. Toxicol Appl Pharmacol. 1980 Jul;54(3):392–398. doi: 10.1016/0041-008x(80)90165-9. [DOI] [PubMed] [Google Scholar]
  9. Gangolli S. D. Testicular effects of phthalate esters. Environ Health Perspect. 1982 Nov;45:77–84. doi: 10.1289/ehp.824577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gesler R. M. Toxicology of di-2-ethylhexyl phthalate and other phthalic acid ester plasticizers. Environ Health Perspect. 1973 Jan;3:73–79. doi: 10.1289/ehp.730373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gray T. J., Butterworth K. R. Testicular atrophy produced by phthalate esters. Arch Toxicol Suppl. 1980;4:452–455. doi: 10.1007/978-3-642-67729-8_106. [DOI] [PubMed] [Google Scholar]
  12. Hugenholtz A. P., Bruce W. R. Radiation induction of mutations affecting sperm morphology in mice. Mutat Res. 1983 Jan;107(1):177–185. doi: 10.1016/0027-5107(83)90087-8. [DOI] [PubMed] [Google Scholar]
  13. Kirby P. E., Pizzarello R. F., Lawlor T. E., Haworth S. R., Hodgson J. R. Evaluation of di-(2-ethylhexyl)phthalate and its major metabolites in the Ames test and L5178Y mouse lymphoma mutagenicity assay. Environ Mutagen. 1983;5(5):657–663. doi: 10.1002/em.2860050504. [DOI] [PubMed] [Google Scholar]
  14. Kozumbo W. J., Kroll R., Rubin R. J. Assessment of the mutagenicity of phthalate esters. Environ Health Perspect. 1982 Nov;45:103–109. doi: 10.1289/ehp.8245103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lee H., Kalmus G. W. Cytotoxic effect of di(2-ethylhexyl) phthalate on cultured chick embryonic cells. Experientia. 1974 Jul 15;30(7):800–801. doi: 10.1007/BF01924194. [DOI] [PubMed] [Google Scholar]
  16. Oishi S., Hiraga K. Testicular atrophy induced by phthalic acid esters: effect on testosterone and zinc concentrations. Toxicol Appl Pharmacol. 1980 Mar 30;53(1):35–41. doi: 10.1016/0041-008x(80)90378-6. [DOI] [PubMed] [Google Scholar]
  17. Oishi S. Testicular atrophy of rats induced by di-2-ethylhexyl phthalate: effects of vitamin A and zinc concentrations in the testis, liver and serum. Toxicol Lett. 1984 Jan;20(1):75–78. doi: 10.1016/0378-4274(84)90186-3. [DOI] [PubMed] [Google Scholar]
  18. Osterloh J., Letz G., Pond S., Becker C. An assessment of the potential testicular toxicity of 10 pesticides using the mouse-sperm morphology assay. Mutat Res. 1983 Mar;116(3-4):407–415. doi: 10.1016/0165-1218(83)90079-4. [DOI] [PubMed] [Google Scholar]
  19. Phillips B. J., James T. E., Gangolli S. D. Genotoxicity studies of di(2-ethylhexyl)phthalate and its metabolites in CHO cells. Mutat Res. 1982 Oct-Nov;102(3):297–304. doi: 10.1016/0165-1218(82)90139-2. [DOI] [PubMed] [Google Scholar]
  20. Ruddick J. A., Villeneuve D. C., Chu I., Nestmann E., Miles D. An assessment of the teratogenicity in the rat and mutagenicity in Salmonella of mono-2-ethylhexyl phthalate. Bull Environ Contam Toxicol. 1981 Aug;27(2):181–186. doi: 10.1007/BF01611005. [DOI] [PubMed] [Google Scholar]
  21. Sanders H. O., Mayer F. L., Jr, Walsh D. F. Toxicity, residue dynamics, and reproductive effects of phthalate esters in aquatic invertebrates. Environ Res. 1973 Mar;6(1):84–90. doi: 10.1016/0013-9351(73)90020-0. [DOI] [PubMed] [Google Scholar]
  22. Schlegel R., MacGregor J. T. The persistence of micronuclei in peripheral blood erythrocytes: detection of chronic chromosome breakage in mice. Mutat Res. 1982 Jul;104(6):367–369. doi: 10.1016/0165-7992(82)90171-3. [DOI] [PubMed] [Google Scholar]
  23. Seed J. L. Mutagenic activity of phthalate esters in bacterial liquid suspension assays. Environ Health Perspect. 1982 Nov;45:111–114. doi: 10.1289/ehp.8245111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Seth P. K., Srivastava S. P., Agarwal D. K., Chandra S. V. Effect of di-2-ethylhexyl phthalate (DEHP) on rat gonads. Environ Res. 1976 Oct;12(2):131–138. doi: 10.1016/0013-9351(76)90015-3. [DOI] [PubMed] [Google Scholar]
  25. Shiota K., Chou M. J., Nishimura H. Embryotoxic effects of di-2-ethylhexyl phthalate (DEHP) and di-n-buty phthalate (DBP) in mice. Environ Res. 1980 Jun;22(1):245–253. doi: 10.1016/0013-9351(80)90136-x. [DOI] [PubMed] [Google Scholar]
  26. Singh A. R., Lawrence W. H., Autian J. Mutagenic and antifertility sensitivities of mice to di-2-ethylhexyl phthalate (DEHP) and dimethoxyethyl phthalate (DMEP). Toxicol Appl Pharmacol. 1974 Jul;29(1):35–46. doi: 10.1016/0041-008x(74)90159-8. [DOI] [PubMed] [Google Scholar]
  27. Singh A. R., Lawrence W. H., Autian J. Teratogenicity of phthalate esters in rats. J Pharm Sci. 1972 Jan;61(1):51–55. doi: 10.1002/jps.2600610107. [DOI] [PubMed] [Google Scholar]
  28. Stenchever M. A., Allen M. A., Jerominski L., Petersen R. V. Effects of bis(2-ethylhexyl) phthalate on chromosomes of human leukocytes and human fetal lung cells. J Pharm Sci. 1976 Nov;65(11):1648–1651. doi: 10.1002/jps.2600651121. [DOI] [PubMed] [Google Scholar]
  29. Teranishi H., Kasuya M. The effects of phthalate esters on fibroblasts in primary culture. Toxicol Lett. 1980 Jun;6(1):11–15. doi: 10.1016/0378-4274(80)90094-6. [DOI] [PubMed] [Google Scholar]
  30. Tomita I., Nakamura Y., Aoki N., Inui N. Mutagenic/carcinogenic potential of DEHP and MEHP. Environ Health Perspect. 1982 Nov;45:119–125. doi: 10.1289/ehp.8245119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Topham J. C. Do induced sperm-head abnormalities in mice specifically identify mammalian mutagens rather than carcinogens? Mutat Res. 1980 Oct;74(5):379–387. doi: 10.1016/0165-1161(80)90195-8. [DOI] [PubMed] [Google Scholar]
  32. Yagi Y., Nakamura Y., Tomita I., Tsuchikawa K., Shimoi N. Teratogenic potential of di- and mono-(2-ethylhexyl)phthalate in mice. J Environ Pathol Toxicol. 1980 Sep;4(2-3):533–544. [PubMed] [Google Scholar]
  33. Zeiger E., Haworth S., Speck W., Mortelmans K. Phthalate ester testing in the National Toxicology Program's environmental mutagenesis test development program. Environ Health Perspect. 1982 Nov;45:99–101. doi: 10.1289/ehp.824599. [DOI] [PMC free article] [PubMed] [Google Scholar]

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