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Exposure to diethylhexyl phthalate (DEHP) results in a heritable modification of imprint genes DNA methylation in mouse oocytes

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Abstract

Diethylhexyl phthalate (DEHP) is an estrogen-like compound widely used as a plasticizer in commercial products and is present in medical devices, and common household items. It is considered an endocrine disruptor since studies on experimental animals clearly show that exposure to DEHP can alter epigenetics of germ cells. This study was designed to assess the effects of DEHP on DNA methylation of imprinting genes in germ cells from fetal and adult mouse. Pregnant mice were treated with DEHP at doses of 0 and 40 μg DEHP/kg body weight/day from 0.5 to 18.5 day post coitum. The data revealed DEHP exposure significantly reduced the percentage of methylated CpG sites in Igf2r and Peg3 differentially methylated regions (DMRs) in primordial germ cells from female and male fetal mouse, particularly, in the oocytes of 21 dpp mice (F1), which were produced by the pregnant micetreated with DEHP. More surprisingly, the modification of the DNA methylation of imprinted genes in F1 mouse oocytes was heritable to F2 offspring which exhibit lower percentages of methylated CpG sites in imprinted genes DMRs. In conclusion, DEHP exposure can affect the DNA methylation of imprinting genes not only in fetal mouse germ cells and growing oocytes, but also in offspring’s oocytes.

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References

  1. Singh S, Li SS (2012) Epigenetic effects of environmental chemicals bisphenol a and phthalates. Int J Mol Sci 13(8):10143–10153

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Zhang T, Li L, Qin XS, Zhou Y, Zhang XF, Wang LQ, De Felici M, Chen H, Qin GQ, Shen W (2013b). Di-(2-ethylhexyl) phthalate and bisphenol A exposure impairs mouse primordial follicle assembly in vitro. Environ Mol Mutagen

  3. Zhang XF, Zhang LJ, Li L, Feng YN, Chen B, Ma JM, Huynh E, Shi QH, De Felici M, Shen W (2013) Diethylhexyl phthalate exposure impairs follicular development and affects oocyte maturation in the mouse. Environ Mol Mutagen 54(5):354–361

    Article  CAS  PubMed  Google Scholar 

  4. Zhang XF, Zhang T, Wang L, Zhang HY, Chen YD, Qin XS, Feng YM, Feng YN, Shen W, Li L (2013) Effects of diethylhexyl phthalate (DEHP) given neonatally on spermatogenesis of mice. Mol Biol Rep 40:6509–6517

    Article  CAS  PubMed  Google Scholar 

  5. Ambruosi B, Uranio MF, Sardanelli AM, Pocar P, Martino NA, Paternoster MS, Amati F, Dell’Aquila ME (2009) In vitro acute exposure to DEHP affects oocyte meiotic maturation, energy and oxidative stress parameters in a large animal model. PLoS One 6(11):e27452

    Article  Google Scholar 

  6. Braun JM, Smith KW, Williams PL, Calafat AM, Berry K, Ehrlich S, Hauser R (2012) Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy. Environ Health Perspect 120(5):739–745

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Carnevali O, Tosti L, Speciale C, Peng C, Zhu Y, Maradonna F (2010) DEHP impairs zebrafish reproduction by affecting critical factors in oogenesis. PLoS One 5(4):e10201

    Article  PubMed Central  PubMed  Google Scholar 

  8. Dalman A, Eimani H, Sepehri H, Ashtiani SK, Valojerdi MR, Eftekhari-Yazdi P, Shahverdi A (2008) Effect of mono-(2-ethylhexyl) phthalate (MEHP) on resumption of meiosis, in vitro maturation and embryo development of immature mouse oocytes. BioFactors 33(2):149–155

    Article  CAS  PubMed  Google Scholar 

  9. Lovekamp TN, Davis BJ (2001) Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicol Appl Pharmacol 172(3):217–224

    Article  CAS  PubMed  Google Scholar 

  10. Zhang GL, Zhang XF, Feng YM, Li L, Sun XF, Sun ZY, Shen W (2013) Exposure to bisphenol A results in a decline in mouse spermatogenesis. Reprod Fertil Dev 25(6):847–859

    Article  CAS  PubMed  Google Scholar 

  11. Song ZH, Min LJ, Pan QJ, Shi QH, Shen W (2009) Maternal imprinting during mouse oocyte growth in vivo and in vitro. Biochem Biophys Res Commun 387:800–805

    Article  CAS  PubMed  Google Scholar 

  12. Chao HH, Zhang XF, Chen B, Pan B, Zhang LJ, Li L, Sun XF, Shi QH, Shen W (2012) Bisphenol A exposure modifies methylation of imprinted genes in mouse oocytes via the estrogen receptor signaling pathway. Histochem Cell Biol 137(2):249–259

    Article  CAS  PubMed  Google Scholar 

  13. Eichenlaub-Ritter U, Vogt E, Cukurcam S, Sun F, Pacchierotti F, Parry J (2008) Exposure of mouse oocytes to bisphenol A causes meiotic arrest but not aneuploidy. Mutat Res 651(1–2):82–92

    Article  CAS  PubMed  Google Scholar 

  14. Hunt PA, Lawson C, Gieske M, Murdoch B, Smith H, Marre A, Hassold T, VandeVoort CA (2012) Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey. Proc Natl Acad Sci USA 109(43):17525–17530

    Article  CAS  PubMed  Google Scholar 

  15. Anderson OS, Nahar MS, Faulk C, Jones TR, Liao C, Kannan K, Weinhouse C, Rozek LS, Dolinoy DC (2012) Epigenetic responses following maternal dietary exposure to physiologically relevant levels of bisphenol A. Environ Mol Mutagen 53(5):334–342

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Susiarjo M, Sasson I, Mesaros C, Bartolomei MS (2013) Bisphenol A exposure disrupts genomic imprinting in the mouse. PLoS Genet 9(4):e1003401

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Zhang HQ, Zhang XF, Zhang LJ, Chao HH, Pan B, Feng YM, Li L, Sun XF, Shen W (2012) Fetal exposure to bisphenol A affects the primordial follicle formation by inhibiting the meiotic progression of oocytes. Mol Biol Rep 39(5):5651–5657

    Article  CAS  PubMed  Google Scholar 

  18. Zhang XF, Zhang LJ, Feng YN, Chen B, Feng YM, Liang GJ, Li L, Shen W (2012) Bisphenol A exposure modifies DNA methylation of imprint genes in mouse fetal germ cells. Mol Biol Rep 39(9):8621–8628

    Article  CAS  PubMed  Google Scholar 

  19. Pesce M, De Felici M (1995) Purification of mouse primordial germ cells by MiniMACS magnetic separation system. Dev Biol 170:722–725

    Article  CAS  PubMed  Google Scholar 

  20. Bromer JG, Zhou Y, Taylor MB, Doherty L, Taylor HS (2010) Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J 24(7):2273–2280

    Article  CAS  PubMed  Google Scholar 

  21. Kundakovic M, Gudsnuk K, Franks B, Madrid J, Miller RL, Perera FP, Champagne FA (2013) Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure. Proc Natl Acad Sci USA 110(24):9956–9961

    Article  CAS  PubMed  Google Scholar 

  22. Kundakovic M, Champagne FA (2011) Epigenetic perspective on the developmental effects of bisphenol A. Brain Behav Immun 25:1084–1093

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Dolinoy DC, Huang D, Jirtle RL (2007) Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA 104(32):13056–13061

    Article  CAS  PubMed  Google Scholar 

  24. Yaoi T, Itoh K, Nakamura K, Ogi H, Fujiwara Y, Fushiki S (2008) Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A. Biochem Biophys Res Commun 376:563–567

    Article  CAS  PubMed  Google Scholar 

  25. Pathak S, D’Souza R, Ankolkar M, Gaonkar R, Balasinor NH (2010) Potential role of estrogen in regulation of the insulin-like growth factor2-H19 locus in the rat testis. Mol Cell Endocrinol 15:110–117

    Article  Google Scholar 

  26. Pathak S, Kedia-Mokashi N, Saxena M, D’Souza R, Maitra A, Parte P, Gill-Sharma M, Balasinor N (2009) Effect of tamoxifen treatment on global and insulin-like growth factor 2–H19 locus-specific DNA methylation in rat spermatozoa and its association with embryo loss. Fertil Steril 91:2253–2263

    Article  CAS  PubMed  Google Scholar 

  27. Doshi T, D’souza C, Vanage G (2013) Aberrant DNA methylation at Igf2-H19 imprinting control region in spermatozoa upon neonatal exposure to bisphenol A and its association with post implantation loss. Mol Biol Rep 40(8):4747–4757

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work is supported by National Basic Research Program of China (973 Program, 2012CB944401), National Nature Science Foundation (31201120 and 31001010) and Program for New Century Excellent Talents in University (NCET-12-1026), Foundation of Distinguished Young Scholars (JQ201109), and Nature Science Foundation of Hubei Province (2011CDB230).

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The authors fully declare any financial or other potential conflict of interest.

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Authors and Affiliations

  1. Laboratory of Germ Cell Biology, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, 266109, China

    Lan Li, Teng Zhang, Xun-Si Qin, Wei Ge, Zhu-Mei Hou & Wei Shen

  2. Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China

    Lan Li & Hong Chen

  3. Center for Reproductive Biology, Weifang People’s Hospital, Weifang, 261041, China

    Hua-Gang Ma & Li-Lan Sun

  4. College of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan, 430023, China

    Ping Chen & Xi-Feng Zhang

  5. Inno Tech Nutrition Solutions, 715 Marion Street, Winnipeg, MB, R2J 0K6, Canada

    Guo-Qing Qin

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  1. Lan Li
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  2. Teng Zhang
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  3. Xun-Si Qin
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  4. Wei Ge
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  10. Guo-Qing Qin
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  11. Wei Shen
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Correspondence to Xi-Feng Zhang.

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Li, L., Zhang, T., Qin, XS. et al. Exposure to diethylhexyl phthalate (DEHP) results in a heritable modification of imprint genes DNA methylation in mouse oocytes. Mol Biol Rep 41, 1227–1235 (2014). https://doi.org/10.1007/s11033-013-2967-7

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  • DOI: https://doi.org/10.1007/s11033-013-2967-7

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