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Effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on reproductive system of mouse pups

  • Reproductive Toxicology
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Abstract

The aim of this study was to analyze the effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on the reproductive system of mouse pups. The two synthetic isomers used in this study showed higher (3E22NP) or lower (44NP) estrogen receptor (ER) binding activity on in vitro yeast assay than a commercial NP (NPmix). Female mice were implanted with a tube filled with one of three NPs and estradiol-17β (E2) before mating. The tube was kept in the mice throughout pregnancy and lactation period, until their pups had weaned at 28 days of age (PND 28). The data indicated that in males, NPs decreased body weight in some dose groups on PND28 and increased weights of testes and epididymides. However, the rate of seminiferous tubules having elongate spermatids (steps10–16) decreased significantly in NPs and E2 treated groups, except for the 44NP groups. In female mice, NPs and E2 increased weights of ovaries, uterus and vagina in the pups in some dose groups on PND 28. However, there were no differences in the day of vaginal opening and numbers of corpus lutea. The present study demonstrates that the effects of these two isomers of NP on the pup reproduction at PND 28 are not quite different, despite them showing different levels of ER binding activity using in vitro yeast assay.

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References

  • Bhatt BD, Prasad JV, Kalpana G, Ali S (1992) Separation and characterization of isomers of p-nonylphenols by capillary GC/GC-MS/GC-FTIR techniques. J Chromatogr Sci 30:203–210

    CAS  Google Scholar 

  • Chapin RE, Delaney J, Wang Y, Lanning L, Davis B, Collins B, Mintz N, Wolfe G (1999) The effects of 4-nonylphenol in rats: a multigeneration reproduction study. Toxicol Sci 52:80–91

    Article  PubMed  CAS  Google Scholar 

  • Coldham NG, Dave M, Sivapathasundaram S, McDonnell DP, Connor C, Sauer MJ (1997) Evaluation of a recombinant yeast cell estrogen screening assay. Environ Health Perspect 105:734–742

    Article  PubMed  CAS  Google Scholar 

  • Cunny HC, Mayes BA, Rosica KA, Trutter JA, Van Miller JP (1997) Subchronic toxicity (90-day) study with para-nonylphenol in rats. Regul Toxicol Pharmacol 26:172–178

    Article  PubMed  CAS  Google Scholar 

  • de Jager C, Bornman MS, Oosthuizen JMC II (1999) The effect of p-nonylphenol on fertility potential of male rats after gestational, lactational and direct exposure. Andrologia 31:107–113

    Article  PubMed  Google Scholar 

  • El-Dakdoky MH, Helal MAM (2007) Reproductive toxicity of male mice after exposure to nonylphenol. Bull Environ Contam Toxicol 79:188–191

    Article  PubMed  CAS  Google Scholar 

  • Gong Y, Han XD (2006) Nonylphenol-induced oxidative stress and cytotoxicity in testicular Sertoli cells. Reprod Toxicol 22:623–630

    Article  PubMed  CAS  Google Scholar 

  • Han XD, Tu ZG, Gong Y, Shen SN, Wang XY, Kang LN, Hou YY, Chen JX (2004) The toxic effects of nonylphenol on the reproductive system of male rats. Reprod Toxicol 19:215–221

    Article  PubMed  CAS  Google Scholar 

  • Hong EJ, Choi KC, Jeung EB (2004a) Induction of calbindin-D9k messenger RNA and protein by maternal exposure to alkylphenols during late pregnancy in maternal and neonatal uteri of rats. Biol Reprod 71:669–675

    Article  PubMed  CAS  Google Scholar 

  • Hong EJ, Choi KC, Jung YW, Leung PCK, Jeung EB (2004b) Transfer of maternally injected endocrine disruptors through breast milk during lactation induces neonatal calbindin-D9k in the rat model. Reprod Toxicol 18:661–668

    Article  PubMed  CAS  Google Scholar 

  • Hughes PJ, Mclellan H, Lowes DA, Khan SZ, Bilmen JG, Tovey SC, Godfrey RE, Michell RH, Kirk CJ, Michelangeli F (2000) Estrogenic alkylphenols induce cell death by inhibiting testis endoplasmic reticulum Ca 2+ pumps. Biochem Biophys Res Commun 277:568–574

    Article  PubMed  CAS  Google Scholar 

  • Judy BM, Nagel SC, Thayer KA, vom Saal FS, Welshons WV (1999) Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice. Toxicol Ind Health 15:12–25

    Article  PubMed  Google Scholar 

  • Kai O, Hiramatsu Y, Sonoda Y, Sensui N, Imai K (1997) Plasma progesterone concentrations during pregnancy and lactation in Mongolian gerbils (Meriones unguiculatus). Exp Anim 46:157–159

    Article  PubMed  CAS  Google Scholar 

  • Kang KS, Kim HS, Ryu DY, Che JH, Lee YS (2000) Immature uterotrophic assay is more sensitive than ovariectomized uterotrophic assay for the detection of estrogenicity of p-nonylphenol in Sprague-Dawley rats. Toxicol Lett 118:109–115

    Article  PubMed  CAS  Google Scholar 

  • Katase T, Okuda K, Kim YS, Eun H, Takada H, Uchiyama T, Saito H, Makino M, Fujimoto Y (2008) Estrogen equivalent concentration of 13 branched para-nonylphenols in three technical mixtures by isomer-specific determination using their synthetic standards in SIM mode with GC-MS and two new diasteromeric isomers. Chemosphere 70:1961–1972

    Article  PubMed  CAS  Google Scholar 

  • Kim HS, Shin JH, Moon HJ, Kang IH, Kim TS, Kim IY, Seok JH, Pyo MY, Han SY (2002) Comparative estrogenic effects of p-nonylphenol by 3-day uterotrophic assay and female pubertal onset assay. Reprod Toxicol 16:259–268

    Article  PubMed  CAS  Google Scholar 

  • Kim YS, Katase T, Sekine S, Inoue T, Makino M, Uchiyama Y, Fujimoto Y, Yamashita N (2004) Variation in estrogenic activity among fractions of a commercial nonylphenol by high performance liquid chromatography. Chemosphere 54:1127–1134

    Article  PubMed  CAS  Google Scholar 

  • Kim HS, Kang TS, IH KangIH, Kim TS, Moon HJ, Kim IY, Ki H, Park KL, Lee BM, Yoo SD, Han SY (2005) Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats. J Toxicol Environ Health Part A 68:2249–2262

    Article  PubMed  CAS  Google Scholar 

  • Kim YS, Katase T, Makino M, Uchiyama Y, Fujimoto Y, Inoue T, Yamashita N (2005) Separation, structural elucidation and estrogenic activity studies of the structural isomers of 4-nonylphenol by GC-PFC coupled with MS and NMR. Aust J Ecotoxicol 11:137–148

    CAS  Google Scholar 

  • Kimura N, Kimura T, Suzuki M, Totsukawa K (2006) Effect of gestational exposure to nonylphenol on the development and fertility of mouse offspring. J Reprod Develop 52:789–795

    Article  CAS  Google Scholar 

  • Kyselova V, Peknicova J, Buckiova D, Boubelik M (2003) Effects of p-nonylphenol and resveratrol on body and organ weight and in vivo fertility of outbred CD-1 mice. Reprod Biol Endocrinol 1:30

    Article  PubMed  Google Scholar 

  • Lalah JO, Schramm KW, Severin GF, Lenoir D, Henkelmann B, Behechti A, Guenther K, Kettrup A (2003) In vivo metabolism and organ distribution of a branched 14C-nonylphenol isomer inpond snails, Lymnaea stagnalis L. Aquatic Toxicol 62:305–319

    Article  CAS  Google Scholar 

  • Lalah JO, Severin GF, Schramm KW, Lenoir D, Behechti A, Guenther K, Kettrup A (2007) Effects of a branched p-nonylphenol isomer (4-(3′, 6′-dimethyl-3′-heptyl)-phenol) on embryogenesis in Lymnae stagnalis L. Arch Environ Contam Toxicol 52:104–112

    Article  PubMed  CAS  Google Scholar 

  • Laurenzana EM, Balasubramanian G, Weis C, Blaydes B, Newbold RR, Delclos KB (2002) Effect of nonylphenol on serum testosterone levels and testicular steroidogenic enzyme activity in neonatal, pubertal, and adult rats. Chem Biol Interact 139:23–41

    Article  PubMed  CAS  Google Scholar 

  • Laws SC, Carey SA, Ferrell JM, Bodman GJ, Cooper RL (2000) Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats. Toxicol Sci 54:154–167

    Article  PubMed  CAS  Google Scholar 

  • Lee PC, Lee W (1996) In vivo estrogenic action of nonylphenol in immature male rats. Bull Environ Contam Toxicol 57:341–348

    Article  PubMed  CAS  Google Scholar 

  • Markey CM, Wadia PR, Rubin BS, Sonnenschein C, Soto AM (2005) Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract. Biol Reprod 72:1344–1351

    Article  PubMed  CAS  Google Scholar 

  • McClusky LM, de Jager C, Bornman MS (2007) Stage-related increase in the proportion of apoptotic germ cells and altered frequencies of stages in the spermatogenic cycle following gestational, lactational, and direct exposure of male rats to p-nonylphenol. Toxicol Sci 95:249–256

    Article  PubMed  Google Scholar 

  • Moon HJ, Han SY, Shin JH, Kang IH, Kim TS, Hong JH, Kim SH, Fenton SE (2007) Gestational exposure to nonylphenol causes precocious mammary gland development in female rat offspring. J Reprod Develop 53:333–344

    Article  CAS  Google Scholar 

  • Munoz de Toro M, Markey CM, Wadia PR, Luque EH, Rubin BS, Sonnenschein C, Soto AM (2005) Perinatal exposure to bisphenol-A alters peripubertal mammary gland development in mice. Endocrinology 146:4138–4147

    Article  PubMed  CAS  Google Scholar 

  • Nagao T, Saito Y, Usumi K, Nakagomi M, Yoshimura S, Ono H (2000) Disruption of the reproductive system and reproductive performance by administration of nonylphenol to newborn rats. Human Exp Toxicol 19:284–296

    Article  CAS  Google Scholar 

  • Nagao T, Wada K, Marumo H, Yoshimura S, Ono H (2001) Reproductive effects of nonylphenol in rats after gavage administration: a two-generation study. Reprod Toxicol 15:293–315

    Article  PubMed  CAS  Google Scholar 

  • Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV (1997) Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect 105:70–76

    Article  PubMed  CAS  Google Scholar 

  • Newbold RR, Jefferson WN, Padilla-Banks E, Walker VR, Pena DS (2001) Cell response endpoints enhance sensitivity of the immature mouse uterotropic assay. Reprod Toxicol 15:245–252

    Article  PubMed  CAS  Google Scholar 

  • Odum J, Ashby J (2000) Neonatal exposure of male rats to nonylphenol has no effect on the reproductive tract. Toxicol Sci 56:400–404

    Article  PubMed  CAS  Google Scholar 

  • Odum J, Lefevre PA, Tittensor S, Paton D, Routledge EJ, Bereford NA, Sumpter JP, Ashby J (1997) The rodent uterotrophic assay: critical protocol features, studies with nonyl phenols, and comparison with a yeast estrogenicity assay. Reg Toxicol Pharmacol 25:176–188

    Article  CAS  Google Scholar 

  • Odum J, Pyrah ITG, Soames AR, Foster JR, van Miller JP, Joiner RL, Ashby J (1999) Effects of p-nonylphenol (NP) and diethylstilboestrol (DES) on the Alderley Park (Alpk) rat: comparison of mammary gland and uterus sensitivity following oral gavage or implanted mini-pumps. J Appl Toxicol 19:367–378

    Article  PubMed  CAS  Google Scholar 

  • Okada A, Kai O (2008) Effect of estradiol-17βand bisphenol A administered chronically to mice throughout pregnancy and lactation on the male pups’ reproductive system. Asian J Androl 10:271–276

    Article  PubMed  CAS  Google Scholar 

  • Okada A, Niwa Y, Katase T, Kai O (2005) Controlled release of estradiol-17β and bisphenol A from a silicone tube for long-term administration in mice. Anim Sci J 76:535–539

    Article  CAS  Google Scholar 

  • Okada A, Niwa Y, Katase T, Kai O (2009) Release of 4-nonylphenol from a silicone tube implanted in mice. Exp. Anim 58 (in press)

  • Routledge EJ, Sumpter JP (1996) Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environ Toxicol Chem 15:241–248

    Article  CAS  Google Scholar 

  • Russell LD, Ettlin RA, Sinha Hikim AP, Clegg ED (1990) The classification and timing of spermatogenesis. In: Histological and histopathological evaluation of the testis. Cache River Press, Clearwater, Fl, pp 41–58

  • Saito H, Uchiyama T, Makino M, Katase T, Fujimoto Y, Hashizume D (2007) Optical resolution and absolute configuration of branched 4-nonylphenol isomers and their estrogenic activities. J Health Sci 53:177–184

    Article  CAS  Google Scholar 

  • Shelby MD, Newbold RR, Tully DB, Chae K, Davis VL (1996) Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays. Environ Health Perspect 104:1296–1300

    Article  PubMed  CAS  Google Scholar 

  • Shioji H, Tsunoi S, Kobayashi Y, Shigemori T, Ike M, Fujita M, Miyaji Y, Tanaka M (2006) Estrogenic activity of branched 4-nonylphenol isomers examined by yeast two-hybrid assay. J Health Sci 52:132–141

    Article  CAS  Google Scholar 

  • Soto AM, Justicia H, Wray JW, Sonnenschein C (1991) p-Nonyl-phenol: an estrogenic xenobiotic released from “modified” polystyrene. Environ Health Perspect 92:167–173

    Article  PubMed  CAS  Google Scholar 

  • Takagi H, Shibutani M, Masutomi N, Uneyama C, Takahashi N, Mitsumori K, Hirose M (2004) Lack of maternal dietary exposure effects of bisphenol A and nonylphenol during the critical period for brain sexual differentiation on the reproductive/endocrine systems in later life. Arch Toxicol 78:97–105

    Article  PubMed  CAS  Google Scholar 

  • Takahashi O, Oishi S (2000) Disposition of orally administered 2, 2-bis (4-hydroxyphenyl) propane (bisphenol A) in pregnant rats and the placental transfer to fetuses. Environ Health Perspect 108:931–935

    Article  PubMed  CAS  Google Scholar 

  • Tyl RW, Myers CB, Marr MC, Castillo NP, Seely JC, Sloan CS, Veselica MM, Joiner RL, van Miller JP, Simon GS (2006) Three-generation evaluation of dietary para-nonylphenol in CD (Sprague Dawley) rats. Toxicol Sci 92:295–310

    Article  PubMed  CAS  Google Scholar 

  • Uchiyama T, Makino M, Saito H, Kim YS, Katase T, Fujimoto Y (2005) Syntheses and estrogenic activity of 4-nonylphenols. DIOXIN 2005 and ISPAC-25, August 21-26, Toronto (CANADA), pp 2441–2444

  • Van den Belt K, Berckmans P, Vangenechten C, Verheyen R, Witters H (2004) Comparative study on the in vitro/ in vivo estrogenic potencies of 17β-estradiol, estrone, 17α-ethynylestradiol and nonylphenol. Aquatic Toxicol 66:183–195

    Article  CAS  Google Scholar 

  • vom Saal FS, Welshons WV (2006) Large effects from small exposures II. The importance of positive controls in low-dose research on bisphenol A. Environ Res 100:50–76

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Han X, Hou Y, Yao G, Wang Y (2003) Effect of nonylphenol on apoptosis of Sertoli cells in vitro. Bull Environ Contam Toxicol 70:898–904

    Article  PubMed  CAS  Google Scholar 

  • Wheeler TF, Heim JR, Latorre MR, Janes AB (1997) Mass spectral characterization of p-nonylphenol isomers using high-resolution capillary GC-MS. J Chromat Sci 35:19–30

    CAS  Google Scholar 

  • White R, Jobling S, Hoare SA, Sumpter JP, Parker MG (1994) Environmentally persistent alkylphenolic compounds are estrogenic. Endocrinology 135:175–182

    Article  PubMed  CAS  Google Scholar 

  • Woo GH, Shibutani M, Ichiki T, Hamamura M, Lee KY, Inoue K, Hirose M (2007) A repeated 28-day oral dose toxicity study of nonylphenol in rats, based on the ‘enhanced OECD test guideline 407’ for screening of endocrine-disrupting chemicals. Arch Toxicol 81:77–88

    Article  PubMed  CAS  Google Scholar 

  • Yon JM, Kwak DH, Cho YK, Lee SR, Jin Y, Baek IJ, Lee JE, Nahm SS, Choo YK, Lee BJ, Yun YW, Nam SY (2007) Expression pattern of sulfated glycoprotein-2 (SGS-2) mRNA in rat testes exposed to endocrine disruptors. J Reprod Develop 53:1007–1013

    Article  CAS  Google Scholar 

  • Yoo SD, Shin BS, Lee BM, Lee KC, Han SY, Kim HS, Kwack SJ, Park KL (2001) Bioavailability and mammary excretion of bisphenol A in Sprague-Dawley rats. J Toxicol Environ Health 64:417–426

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported in part by a Grant-in aid for the Effective Promotion of Joint Research with Industry, Academia, and Government, the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Science, Sports and Culture in Japan.

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Correspondence to Osamu Kai.

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Sato, T., Saito, H., Uchiyama, T. et al. Effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on reproductive system of mouse pups. Arch Toxicol 83, 1097–1108 (2009). https://doi.org/10.1007/s00204-009-0464-5

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  • DOI: https://doi.org/10.1007/s00204-009-0464-5

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