Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Comparison of the Short Term Toxicity of Phthalate Diesters and Monoesters in Sprague-Dawley Male Rats

  • Kwack, Seung-Jun (National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration) ;
  • Han, Eun-Young (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Park, Jae-Seok (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Bae, Jung-Yun (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Ahn, Il-Young (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Lim, Seong-Kwang (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Kim, Dong-Hyun (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Jang, Dong-Eun (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Choi, Lan (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Lim, Hyun-Jung (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Kim, Tae-Hyung (College of Pharmacy, Pusan National University) ;
  • Patra, Nabanita (College of Pharmacy, Pusan National University) ;
  • Park, Kui-Lea (National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration) ;
  • Kim, Hyung-Sik (College of Pharmacy, Pusan National University) ;
  • Lee, Byung-Mu (Division of Toxicology, College of Pharmacy, Sungkyunkwan University)
  • Published : 2010.03.04
Download PDF
⟨ Previous Next ⟩

Abstract

This study was carried out to investigate the short term toxicity of nine phthalate diesters including di-2(ethylhexyl) phthalate (DEHP), di(n-butyl) phthalate (DBP), di-n-octyl phthalate (DnOP), diethyl phthalate (DEP), butylbenzyl phthalate (BBP), dimethyl phthalate (DMP), di-isodecyl phthalate (DIDP), diundecyl phthalate (DUP), and di-isononyl phthalate (DINP) and five phthalate monoesters including mono- (2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBuP), monobenzyl phthalate (MBeP), monoethyl phthalate (MEP), monomethyl phthalate (MMP) and phthalic acid (PA) in Sprague-Dawley male rats. Animals were administered 250 mg/kg/day (monoesters and PA) or 500 mg/kg/day (diesters) of phthalate for two weeks. All animals were examined for body and organ weights, blood hematology, serum biochemistry, and urine analysis. The body weight gain was significantly lower in rats treated with BBP, DBP, DINP, MEHP, MBuP, and PA than that of control. Liver weights were significantly increased in the DEHP, DBP, DnOP, DIDP, and MEHP groups as compared to the control group. Testes weights were significantly decreased only in the DEHP-, DnOP-, and DIDP-treated groups as compared to the control. Significant differences in hematological changes were not observed in any treatment groups. Significant increases in blood glucose levels were observed in the DEHP, MEHP, and MBeP groups. Aspartate aminotransferase (AST) levels were significantly increased in the DBP, DUP, DINP, MBuP, and MBeP groups, whereas alanine aminotransferase (ALT) levels were significantly increased only in the DEHP and MEHP groups. Serum ALP levels were significantly higher in phthalate diester (500 mg/kg/day)-treated rats as compared to control. However, the total cholesterol level was significantly reduced in the DEHP- and DIDP-treated groups, whereas serum triglyceride (TG) levels were higher in the DINP-, MEHP-, and MBuP-treated groups. These results suggest that short term toxicity of phthalate monoesters produces adverse effects as similar to phthalate diesters in Sprague-Dawley rats.

Keywords

References

  1. Albro, P.W. and Moore, B. (1974). Identification of the metabolites of simple phthalate diesters in rat urine. J. Chlomatgr., 134, 209-218.
  2. Autian, J. (1973). Toxicity and health threats of phthalate esters: review of the literature. Environ. Health Perspect., 4, 3-26. https://doi.org/10.2307/3428178
  3. Blount, B.C., Silva, M.J., Caudill, S.P., Needham, L.L., Pirkle, J.L., Sampson, E.J., Lucier, G.W., Jackson, R.J. and Brock, J.W. (2000). Levels of seven urinary phthalate metabolites in a human reference population. Environ. Health Perspect., 108, 979-982. https://doi.org/10.1289/ehp.00108979
  4. Daniel, J.W. and Bratt, H. (1974). The absorption, metabolism and tissue distribution of di(2-ethylhexyl)phthalate in rats. Toxicology, 2, 51-65. https://doi.org/10.1016/0300-483X(74)90042-0
  5. Eigenberg, D.A., Bozigian, H.P., Carter, D.E. and Sipes, I.G. (1986). Distribution, excretion, and metabolism of butylbenzyl phthalate in the rat. J. Toxicol. Environ. Health, 17, 445-456. https://doi.org/10.1080/15287398609530839
  6. Ema, M., Miyawaki, E., Hirose, A. and Kamata, E. (2003). 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., 17, 407-412. https://doi.org/10.1016/S0890-6238(03)00037-6
  7. Fisher, J.S. (2004). Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction, 127, 305-315. https://doi.org/10.1530/rep.1.00025
  8. Gangolli, S.D. (1982). Testicular effects of phthalate esters. Environ. Health Perspect., 45, 77-84. https://doi.org/10.1289/ehp.824577
  9. Gotz, F., Thieme, S. and Dorner, G. (2001). Female infertilityeffect of Perinatal xenoestrogen exposure on reproductive functions in animals and humans. Folia. Histochem. Cytobiol., 39, 40-43.
  10. Gray, L.E., Ostby, J., Furr, J., Price, M., Veeramachaneni, D.N. and Parks, L. (2000). Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol. Sci., 58, 350-365. https://doi.org/10.1093/toxsci/58.2.350
  11. Hurst, C.H. and Waxman, D.J. (2003). Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol. Sci., 74, 297-308 https://doi.org/10.1093/toxsci/kfg145
  12. Kim, H.S., Kim, T.S., Shin, J.H., Moon, H.J., Kang, I.H., Kim, I.Y., Oh, J.Y. and Han, S.Y. (2004). Neonatal exposure to di(nbutyl) phthalate (DBP) alters male reproductive-tract development. J. Toxicol. Environ. Health A, 67, 2045-2060. https://doi.org/10.1080/15287390490514859
  13. Lhuguenot, J.C., Mitchell, A.M., Milner, G., Lock, E.A. and Elcombe, C.R. (1985). The metabolism of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP) in rats: in vivo and in vitro dose and time dependency of metabolism. Toxicol. Appl. Pharmacol., 80, 11-22. https://doi.org/10.1016/0041-008X(85)90096-1
  14. Li, L.H., Jester, W.F., Laslett, A.L. and Orth, J.M. (2000). A single dose of di-(2-ethylhexyl) phthalate in neonatal rats alters gonocytes, reduces sertoli cell proliferation, and decreases cyclin D2 expression. Toxicol. Appl. Pharmacol., 166, 222-229. https://doi.org/10.1006/taap.2000.8972
  15. Maloney, E.K. and Waxman, D.J. (1999). Trans-activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. Toxicol. Appl. Pharmacol., 161, 209-218.1 https://doi.org/10.1006/taap.1999.8809
  16. Nakae, J., Tajima, T., Sugawara, T., Arakane, F., Hanaki, K., Hotsubo, T., Igarashi, N., Igarashi, Y., Ishii, T., Koda, N., Kondo, T., Kohno, H., Nakagawa, Y., Tachibana, K., Takeshima, Y., Tsubouchi, K., Strauss, J.F. 3rd and Fujieda, K. (1997). Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia. Human Mol. Genetics., 6, 571-576. https://doi.org/10.1093/hmg/6.4.571
  17. Nativelle, C., Picard, K., Valentin, I., Lhuguenot, J.C. and Chagnon, M.C. (1999). Metabolism of n-butyl benzyl phthalate in the female wistar rat. Identification of new metabolites. Food Chem. Toxicol., 37, 905-917. https://doi.org/10.1016/S0278-6915(99)00071-X
  18. Okubo, T., Suzuki, T., Yokoyama, Y., Kano, K. and Kano, I. (2003). Estimation of estrogenic and anti-estrogenic activities of some phthalate diesters and monoesters by MCF-7 cell proliferation assay in vitro. Biol. Pharm. Bull., 26, 1219-1224. https://doi.org/10.1248/bpb.26.1219
  19. Park, J.D., Habeebu, S.S. and Klaassen, C.D. (2002). Testicular toxicity of di-(2-ethylhexyl)phthalate in young Sprague-Dawley rats. Toxicology, 171, 105-115. https://doi.org/10.1016/S0300-483X(01)00567-4
  20. Peck, C.C., Odom, D.G., Albro, P.W., Jess, D.A. and Barrett, B.B. (1981). Effect of heat on the conversion of di-2-ethylhexyl phthalate to mono-2-ethylhexyl phthalate in human plasma. Transfusion, 21, 163-166. https://doi.org/10.1046/j.1537-2995.1981.21281178151.x
  21. Pollack, G.M., Shen, D.D. and Dorr, M.B. (1989). Contribution of metabolites to the route- and time-dependent hepatic effects of di-(2-ethylhexyl)phthalate in the rat. J. Pharmacol. Exp. Ther., 248, 176-181.
  22. Rhee, G.S., Kim, S.H., Kim, S.S., Sohn, K.H., Kwack, S.J., Kim, B.H. and Park, K.L. (2002). Comparison of embryotoxicity of ESBO and phthalates esters using an in vitro battery system. Toxicol. In Vitro, 16, 443-448. https://doi.org/10.1016/S0887-2333(02)00026-7
  23. Ryu, J.Y., Whang, J., Park, H., Im, J.Y., Kim, J., Ahn, M.Y., Lee, J., Kim, S.H., Lee, B.M., Yoo, S.D., Kwack, S.J., Oh, J.H., Park, K.L., Han, S.Y. and Kim, H.S. (2007). Di(2-ethylhexyl) phthalate induces apoptosis through peroxisome proliferatorsactivated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats. J. Toxicol. Environ. Health A, 70, 1296-1303. https://doi.org/10.1080/15287390701432160
  24. Shaffer, C.B., Carpenter, C.P. and Smyth, H.F. (1945). Acute and subacute toxicity of DEHP with note upon its metabolism. J. Indust. Hyg. Toxicol., 27, 130-135.
  25. Shono, T. and Suita, S. (2003). Dose-dependent effect of phthalate ester on testicular descent in pre- and post natal rats. Urol. Res., 31, 293-296. https://doi.org/10.1007/s00240-003-0330-5
  26. Sjoberg, P., Lindqvist, N.G. and Ploen, L. (1986). Age-dependent response of the rat testes to di(2-ethylhexyl)phthalate. Environ. Health Perspect., 65, 237-242.
  27. Sonde, V., D'Souza, A., Tarapore, R., Pereira, L., Khare, M.P., Sinkar, P., Krishnan, S. and Rao, C.V. (2000). Simultaneous administration of diethylphthalate and ethyl alcohol and its toxicity in male Sprague Dawley rats. Toxicology, 147, 23-31. https://doi.org/10.1016/S0300-483X(00)00164-5
  28. Stocco, D.M. (2001). Tracking the role of a StAR in the sky of the new millennium. Mol. Endocrinol., 15, 1245-1254. https://doi.org/10.1210/me.15.8.1245
  29. Tanaka, A., Matsumoto, A. and Yamaha, T. (1978). Biochemical studies on phthalic esters. III. Metabolism of dibutyl phthalate (DBP) in animals. Toxicology, 9, 109-123. https://doi.org/10.1016/0300-483X(78)90036-7
  30. Teirlynck, O., Kaufman, J.M., Bogaert, M.G. and Roels, H. (1988). Testicular toxicity induced by single dosing of di- and mono-(2-ethylhexyl)phthalate in the rat. Toxicol. Lett., 40, 85-91. https://doi.org/10.1016/0378-4274(88)90186-5
  31. Thomas, J.A., Darby, T.D., Wallin, R.F., Garvin, P.J. and Martis, L. (1978). A review of the biological effects of di-(2-ethylhexyl) phthalate. Toxicol. Appl. Pharmacol., 45, 1-27. https://doi.org/10.1016/0041-008X(78)90024-8
  32. Tsutsumi, T., Ichihara, T., Kawabe, M., Yoshino, H., Asamoto, M., Suzuki, S. and Shirai, T. (2004). Renal toxicity induced by folic acid is associated with the enhancement of male reproductive toxicity of di(n-butyl)phthalate in rats. Reprod. Toxicol., 18, 35-42. https://doi.org/10.1016/j.reprotox.2003.08.004
  33. Waterman, S.J., Keller, L.H., Trimmer, G.W., Freeman, J.J., Nikiforov, A.I., Harris, S.B., Nicolich, M.J. and McKee, R.H. (2000). Two-generation reproduction study in rats given diisononyl phthalate in the diet. Reprod. Toxicol., 14, 21-36. https://doi.org/10.1016/S0890-6238(99)00067-2
  34. Zacharewski, T. (1998). Identification and assessment of endocrine disruptors: limitations of in vivo and in vitro assays. Environ. Health Perspect., 106, 577-582. https://doi.org/10.2307/3433808

Cited by

  1. Quercetin attenuates di-(2-ethylhexyl) phthalate-induced testicular toxicity in adult rats vol.35, pp.3, 2016, https://doi.org/10.1177/0960327115580602
  2. Association of diethylhexyl phthalate with obesity-related markers and body mass change from birth to 3 months of age vol.70, pp.5, 2016, https://doi.org/10.1136/jech-2015-206315
  3. The influence of phthalates and bisphenol A on the obesity development and glucose metabolism disorders vol.55, pp.3, 2017, https://doi.org/10.1007/s12020-016-1158-4
  4. Percentage fractions of urinary di(2-ethylhexyl) phthalate metabolites: Association with obesity and insulin resistance in Korean girls vol.13, pp.11, 2018, https://doi.org/10.1371/journal.pone.0208081
  5. Morphometric Evaluation of the Seminiferous Tubules and the Antioxidant Protective Effects of Gallic Acid and Quercetin in the Testis and Liver of Butyl Phthalate Treated Rats pp.0974-0422, 2018, https://doi.org/10.1007/s12291-018-0788-0