DOI QR코드

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Di-(2-ethylhexyl) Phthalate (DEHP) and Uterine Histological Characteristics

  • Cheon, Yong-Pil (Division of Developmental Biology and Physiology, Dept. of Biotechnology, Sungshin University)
  • 투고 : 2020.03.03
  • 심사 : 2020.03.12
  • 발행 : 2020.03.31

초록

Phthalates and those metabolites have long history in industry and suspected to have deficient effects in development and reproduction. These are well-known anti-androgenic chemicals and many studies have examined the effects of these compounds on male reproduction as toxins and endocrine disruptors. Uterus is a key organ for proper embryo development, successful reproduction, and health of eutherian mammals including women. To understand the effects of the phthalate, the horizontal approach with a whole group of phthalate is best but the known phthalates are huge and all is not uncovered. Di-(2-ethylhexyl) phthalate (DEHP) is the most common product of plasticizers in polymer products and studied many groups. Although, there is limited studies on the effects of phthalates on the female, a few studies have proved the endocrine disrupting characters of DEHP or phthalate mixture in female. An acute and high dose of DEHP has adverse effects on uterine histological characters. Recently, it has been revealed that a chronical low-dose exposing of DEHP works as endocrine disrupting chemicals (EDC). DEHP can induce various cellular responses including the expression regulation of steroid hormone receptors, transcription factors, and paracrine factors. Interestingly, the response of uterus to DEHP is not monotonous and the exposed female has various phenotypes in fertility. These suggest that the exposing of DEHP may causes of histological modification in uterus and of disease in female such as endometriosis, hyperplasia, and myoma in addition to developmental and reproductive toxicity.

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참고문헌

  1. Agarwal DK, Eustis S, Lamb JC 4th, Reel JR, Kluwe WM (1986) Effects of di (2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats. Environ Health Perspect 65:343-350. https://doi.org/10.1289/ehp.8665343
  2. Ahern TP, Broe A, Lash TL, Cronin-Fenton D, Ulrichsen SP, Christiansen PM, Cole BF, Tamimi RM, Sorensen HT, Damkier P (2019) Phthalate exposure and breast cancer incidence: A Danish nationwide cohort study. J Clin Oncol 37:1800-1809. https://doi.org/10.1200/JCO.18.02202
  3. Ambe K, Sakakibara Y, Sakabe A, Makino H, Ochibe T, Tohkin M (2019) Comparison of the developmental/reproductive toxocity and hepatotoxicity of phthalate esters in rats using an open toxicity data source. J Toxicol Sci 44:245-255. https://doi.org/10.2131/jts.44.245
  4. Austrian Competition & Consumer Commission [ACCC]. Chemical hazards & injuries. Accessed from: https://www.productsafety.gov.au/about-us/chemicals/chemical-hazards-injuries. Accessed at February 1, 2020.
  5. Balalian AA, Whyatt RM, Liu X, Insel BJ, Rauh VA, Herbstman J, Factor-Litvak P (2019) Prenatal and childhood exposure to phthalates and motor skills at age 11 years. Environ Res 171:416-427. https://doi.org/10.1016/j.envres.2019.01.046
  6. Bansal A, Henao-Mejia J, Simmons RA (2018) Immune system: An emerging player in mediating effects of endocrine disruptors on metabolic health. Endocrinology 159:32-45. https://doi.org/10.1210/en.2017-00882
  7. Berger K, Eskenazi B, Balmes J, Kogut K, Holland N, Calafat AM, Harley KG (2019) Prenatal high molecular weight phthalates and bisphenol A, and childhood respiratory and allergic outcomes. Peidatr Allergy Immunol 30:36-46. https://doi.org/10.1111/pai.12992
  8. Biemann R, Navarrete Santos A, Navarrete Santos A, Riemann D, Knelangen J, Bluher M, Koch H, Fisher B (2012) Endocrine disrupting chemicals affect the adipogenic differentiation off mesenchymal stem cells in distinct ontogenetic windows. Biochem Biophys Res Comm 417:747-752. https://doi.org/10.1016/j.bbrc.2011.12.028
  9. Borman ED, Foster WG, deCatanzaro D (2017) Concurrent administration of diethylhexyl phthalate reduces the threshold dose at which bisphenol A disrupts blastocyst implantation and cadherins in mice. Environ Toxicol Pharmacol 49:105-111. https://doi.org/10.1016/j.etap.2016.12.003
  10. Burton GJ, Watson AL, Hempstock JN, Jauniaux E (2002) Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab 87:2954-2959. https://doi.org/10.1210/jc.87.6.2954
  11. Carlson KR (2010) Toxicity review of di-n-octyl phthalate (DnOP). U.S. Consumer Product Safety Commission, Bethesda, MD.
  12. Carpenter KD, Hayashi K, Spencer TE (2003) Ovarian regulation of endometrial gland morphogenesis and activin-follistatin system in the neonatal ovine uterus. Biol Reprod 69:851-860. https://doi.org/10.1095/biolreprod.103.016337
  13. Caserta D, Bordi G, Ciagrdo F, Marci R, Rocca CL, Tait S, Bergamasco B, Stecca L, Mantovani A, Guerranti C, Fanello EL, Perra G, Borghini F, Foardi SE, Moscarini M (2013) The influence of endocrine disruptors in a selected population of infertile women. Gynecol Endocrinol 29:444-447. https://doi.org/10.3109/09513590.2012.758702
  14. Cavanagh JA, Trought K, Mitchell C, Northcott G, Tremblay LA (2018) Assessment of endocrine disruption and oxidative potential of bisphenol-A, triclosan, nonylphenol, diethylhexyl phthalate, galaxolide, and carbamazepine, common contaminants of municipal biosolids. Toxicol In Vitro 48:342-349. https://doi.org/10.1016/j.tiv.2018.02.003
  15. Cha S, Jung K, Lee MY, Hwang YJ, Yang E, Lee SH, Jung HI, Cheon YP (2018) Nonmonotonic effects of chronic low-dose di (2-ethylhexyl) phthalate on gonadal weight and reproduction. Dev Reprod 22:85-94. https://doi.org/10.12717/DR.2018.22.1.085
  16. IHS Markit (2018) Plasticizers (Report). In: Chemical Economics Handbook. IHS Markit, London, UK.
  17. Chen X, Xu S, Tan T, Lee ST, Chen SH, Lee FW, Xu SJ, Ho KC (2014) Toxicity and estrogenic endocrine disrupting activity of phthalates and their mixtures. Int J Environ Res Public Health 11:3156-3168. https://doi.org/10.3390/ijerph110303156
  18. Cheon YP, Li Q, Xu X, DeMayo FJ, Bagchi IC, Bagchi MK (2002) A genomic approach to identify novel progesterone receptor regulated pathways in the uterus during implantation. Mol Endocrinol 16:2853-28571. https://doi.org/10.1210/me.2002-0270
  19. Cho T, Lee H (2018) Current status and tasks of endocrine disruptor management in Korea: Regulation of bisphenol A, phthalate and nonylphenol. J Law Politic Res 18:73-107. https://doi.org/10.17926/kaolp.2018.18.2.73
  20. Cho YJ, Park SB, Han M (2015) Di-(2-ethylhexyl)-phthalate induces oxidative stress in human endometrial stromal cells in vitro. Mol Cell Endocrinol 407:9-17. https://doi.org/10.1016/j.mce.2015.03.003
  21. Chung D, Gao F, Jegga AG, Das SK (2015) Estrogen mediated epithelial proliferation in the uterus is directed by stromal Fgf10 nd Bmp8a. Mol Cell Endocrinol 400:48-60. https://doi.org/10.1016/j.mce.2014.11.002
  22. Cobellis L, Latini G, De Felice C, Razzi S, Paris I, Ruggieri F, Mazzeo P, Petraglia F (2003) High plasma connetrations of di-(2-ethylhexyl)-phthalate in women with endometriosis. Hum Reprod 18:1512-1515. https://doi.org/10.1093/humrep/deg254
  23. Crobeddu B, Ferraris E, Kolasa E, Plante I (2019) Di (2-ethylhexyl) phthalate (DEHP) increases proliferation of epithelial breast cancer cells through progesterone receptor dysregulation. Environ Res 173:165-173. https://doi.org/10.1016/j.envres.2019.03.037
  24. Cunha GR (1976) Epithelial-stromal interactions in development of the urogenital tract. Int Rev Cytol 47:137-194. https://doi.org/10.1016/S0074-7696(08)60088-1
  25. Cunha GR (1989) Development of the urogenital tract. In: Meisami E, Timiras PS (eds), Handbook of Human Growth and Developmental Biology. CRC Press, Boca Raton, FL, pp 247-271.
  26. Dalgaard M, Nellemann C, Lam HR, Sorensen IK, Ladefoged O (2001) The acute effects of mono (2-ethylhexyl) phthalate (MEHP) on testes of prepubertal Wistar rats. Toxicol Lett 122:69-79. https://doi.org/10.1016/S0378-4274(01)00348-4
  27. Damgaard NI, Main KM, Toppari J, Skakkebaek NE (2002) Impact of exposure to endocrine disrupters inutero and in childhood on adult reproduction. Best Pract Res Clin Endocrinol Metab 16:289-309. https://doi.org/10.1053/beem.2002.0205
  28. Danish Environmental Protection Agency [Danish EPA] (2013) Phthalate Strategy. Danish Environmental Protection Agency. Copenhagne, Demark.
  29. David RM, Moore MR, Finney DC, Guest D (2000b) Chronic toxicity of di (2-ethylhexyl) phthalate in mice. Toxicol Sci 58:377-385. https://doi.org/10.1093/toxsci/58.2.377
  30. Deng T, Du Y, Wang Y, Teng X, Hua X, Yuan X, Yao Y, Guo N, Li Y (2020) The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: A prospective single-center study. Ecotoxicol Environ Saf 188:109884. https://doi.org/10.1016/j.ecoenv.2019.109884
  31. Dharma SJ, Nandedkar TD (2001) Apoptosis in endometrium of mouse during estrous cycle. Indian J Exp Biol 39:218-222.
  32. Duty SM, Calafat AM, Silva MJ, Ryan L, Hauser R (2005) Phthalate exposure and reproductive hormones in adult man. Hum Reprod 20:604-610. https://doi.org/10.1093/humrep/deh656
  33. European Chemicals Bureau (2007) European Union Risk Assessment Report: Benzyl Butyl Phthaltate. European Chemicals Bureau, Oslo, Norway.
  34. Ferguson KK, McElrath TF, Ko YA, Mukherjee B, Meeker JD (2014) Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth. Enciron Int 70:118-124.
  35. Fromme H, Lahrz T, Kraft M, Fembacher L, Dietrich S, Sievering S, Burghardt R, Schuster R, Bolte G, Volkel W. 2013. Phthalates in German daycare centers: Occurrence in air and dust and the excretion of their metabolites by children (LUPE3). Environ Int 61:64-72. https://doi.org/10.1016/j.envint.2013.09.006
  36. Fu Y, Dong J, You M, Cong Z, Wei L, Fu H, Wang Y, Che J (2019) Maternal di-(2-ethylhexyl) phthalate exposure inhibits cerebellar granule precursor cell proliferation via down-regulation the Shh signaling pathway in male offspring. Chemosphere 215:313-322. https://doi.org/10.1016/j.chemosphere.2018.10.040
  37. Gillum N, Karabekian Z, Swift LM, Brown RP, Kay MW, Sarvazyan N (2009) Clinically relevant concentrations of di (2-ethylhexyl) phthalate (DEHP) uncouple cardiac syncytium. Toxicol Appl Pharmacol 236:25-38. https://doi.org/10.1016/j.taap.2008.12.027
  38. Gray CA, Bartol FF, Taylor KM, Wiley AA, Ramsey WS, Ott TL, Bazer FW, Spencer TE (2000) Ovine uterine gland knock-out model: Effects of gland ablation on the estrous cycle. Biol Reprod 62:448-456. https://doi.org/10.1095/biolreprod62.2.448
  39. Gray CA, Burghardt RC, Johnson GA, Bazer FW, Spencer TE (2002) Evidence that absence of endometrial gland secretions in uterine gland knockout ewes compromises conceptus survival and elongation. Reproduction 124:289-300. https://doi.org/10.1530/reprod/124.2.289
  40. Guo Y, Wang L, Kannan K (2014) Phthalates and parabens in personal care products from China: Concentrations and human exposure. Arch Environ Contam Toxicol 66:113-119. https://doi.org/10.1007/s00244-013-9937-x
  41. Hannon PR, Brannick KE, Wang W, Flaws JA (2015) Mono (2-ethylhexyl) phthalate accelerates early folliculogenesis and inhibits steroidogenesis in cultured mouse whole ovaries and antral follicles. Biol Reprod 92:120. https://doi.org/10.1095/biolreprod.115.129148
  42. Hannon PR, Peretz J, Flaws JA (2014) Daily exposure to di (2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice. Biol Reprod 90:136. https://doi.org/10.1095/biolreprod.114.119032
  43. Hauser R (2006) The environment and male fertility: Recent research on emerging chemicals and semen quality. Semin Reprod Med 24:156-167. https://doi.org/10.1055/s-2006-944422
  44. Hauser R, Calafat AM (2005) Phthalates and human health. Occup Environ Med 62:806-818. https://doi.org/10.1136/oem.2004.017590
  45. Hauser R, Gaskins AJ, Souter I, Smith KW, Dodge LE, Ehrlich S, Meeker JD, Calafat AM, Williams PL (2016) Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: Results from the EARTH study. Environ Health Perspect 124:831-839. https://doi.org/10.1289/ehp.1509760
  46. HBM4EU (2020) HBM4EU priority substance group: Phthalates & hexamoll dinch. in: Scoping Document (1st round of prioritization). v3.1. HBM4EU, Dessau-Rosslau, Germany.
  47. Hellwig J, Freudenberger H, Jackh R (1997) Differential prenatal toxicity of branched phthalate esters in rats. Food Chem Toxicol 35:501-512. https://doi.org/10.1016/S0278-6915(97)00008-2
  48. Hinton RH, Mitchell FE, Mann A, Chescoe D, Price SC, Nunn A, Grasso P, Bridges JW (1986) Effects of phthalic acid esters on the liver and thyroid. Environ Health Perspect 70:195-210. https://doi.org/10.1289/ehp.8670195
  49. Hirosawa N, Yano K, Suzuki Y, Sakamoto Y (2006) Endocrine disrupting effect of di-(2-ethylhexyl) phthalate on female rats and proteome analyses of their pituitaries. Proteomics 6:958-971. https://doi.org/10.1002/pmic.200401344
  50. Holladay SD, Smialowicz RJ (2000) Development of the murine and human immune system: Differential effects of immunotoxicants depend on time off exposure. Environ Health Perspect 108:463-473.
  51. Houston KD, Copland JA, Broaddus RR, Gottardis MM, Fischer SM, Walker CL (2003) Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferator: Activated receptor gamma ligands in uterine leiomyoma. Cancer Res 63:1221-1227.
  52. Howdeshell KL, Rider CV, Wilson VS, Furr JR, Lambright CR, Gray LE Jr. (2015) Dose addition models based on biologically relevant reductions in fetal testosterone accurately predict postnatal reproductive tract alterations by a phthalate mixture in rats. Toxicol Sic 148:488-502. https://doi.org/10.1093/toxsci/kfv196
  53. Howdeshell KL, Wilson VS, Furr J, Lambright CR, Rider CV, Blystone CR, Hotchkiss AK, Gray LE Jr. 2008. A mixture of five phthalate esters inhibits fetal testicular testosterone production in the Sprague-Dawley rat in a cumulative, dose-additive manner. Toxicol Sci 105:153-165. https://doi.org/10.1093/toxsci/kfn077
  54. Hu GX, Lian QQ, Ge RS, Hardy DO, Li XK. 2009. Phthalate-induced testicular dysgenesis syndrome: Leydig cell influence. Trend Endocrinol Metabol 20:139-145. https://doi.org/10.1016/j.tem.2008.12.001
  55. Hu J, Zhang X, Nothnick WB, Spencer TE. 2004. Matrix metalloproteinases and their tissue inhibitors in the developing neonatal mouse uterus. Biol Reprod 71:1598-1604 https://doi.org/10.1095/biolreprod.104.031559
  56. Huang Q, Zhang H, Chen YJ, Chi YL, Dong S. 2016. The inflammation response to DEHP through $PPAR{\gamma}$ in endometrial cells. Int J Environ Res Public Health 13:318. https://doi.org/10.3390/ijerph13030318
  57. Jensen MS, Anand-Ivell R, Norgaard-Pedersen B, Jonsson BA, Bonde JP, Hougaard DM, Cohen A, Lindh C, Ivell R, Toft G. 2015. Amniotic fluid phthalate levels and male fetal gonad function. Epidemiology 26:91-99. https://doi.org/10.1097/EDE.0000000000000198
  58. Jeong JW, Kwak I, Lee KY, Kim TH, Large MJ, Stewart CL, Kaestner KH, Lydon JP, DeMayo FJ. 2010. Foxa2 is essential for mouse endometrial gland development and fertility. Biol Reprod 83:396-403. https://doi.org/10.1095/biolreprod.109.083154
  59. Jobling S, Reynolds T, White R, Parker MG, Sumpter JP. 1995. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ Health Respect 103:582-587. https://doi.org/10.1289/ehp.95103582
  60. Kalo D, Hadas R, Furmanetal O, Ben-Ari J, Maor Y, Patterson DG, Tomey C, Roth Z. 2015. Carryover effects of acute DEHP exposure on ovarian function and oocyte developmental competence in lactating cows. PLoS ONE 10:e0130896. https://doi.org/10.1371/journal.pone.0130896
  61. Kamendulis L, Isenberg JS, Smith JH, Pugh Jr G, Lington AW, Klauning JE. 2002. Comparative effects of phthalate monoesters on gap junctional intercellular communication and peroxisome proliferation in rodent and primate hepatocytes. J Toxicol Environ Health A 65:569-588. https://doi.org/10.1080/152873902317349736
  62. Kariyazono Y, Taura J, Hattori Y, Ishii Y, Narimatsu S, Fujimura M, Takeda T, Yamada H. 2015. Effect of in utero exposure to endocrine disruptors on fetal steroidogenesis governed by the pituitary-gonad axis: A study in rats using different ways of administration. J Toxicol Sci 40:909-916. https://doi.org/10.2131/jts.40.909
  63. Kim J, Cha S, Lee MY, Hwang YJ, Yang E, Ryou C, Jung HI, Cheon YP. 2018. Chronic low-dose nonylphenol or di-(2-ethylhexyl) phthalate has a different estrogen-like response in mouse uterus. Dev Reprod 22:379-391. https://doi.org/10.12717/DR.2018.22.4.379
  64. Kim JH, Kim SH, Oh YS, Ihm HJ, Chae HD, Kim CH, Kang BM. 2017. In vitro effects of phthalate esters in human myometrial and leiomyoma cells and increased urinary level of phthalate metabolite in women with uterine leiomyoma. Fertil Steril 107:1061-1069. https://doi.org/10.1016/j.fertnstert.2017.01.015
  65. Kim JH, Park HY, Bae S, Lim YH, Hong YC. 2013. Diethylhexyl phthalates is associated with insulin resistance via oxidative stress in the elderly: A panel study. PLoS ONE 8:e71392. https://doi.org/10.1371/journal.pone.0071392
  66. Kim SH, Cho S, Ihm HJ, Oh YS, Heo SH, Chun S, Im H, Chae HD, Kim CH, kang BM. 2015. Possible role of phthalate in the pathogenesis of endomeriosis: In vitro, animal, and human data. J Clin Endocrinol Metab 100:1502-1511.
  67. Kim SH, Chun S, Jang JY, Chae HD, Kim CH, Kang BM. 2011. Increased plasma levels of phthalte esters in women with advanced-stage endometriosis: A prospective case-control study. Fertil Steril 95:357-359. https://doi.org/10.1016/j.fertnstert.2010.07.1059
  68. Klinge CM. 2001. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 29:2905-2919. https://doi.org/10.1093/nar/29.14.2905
  69. Kurita T. 2011. Normal and abnormal epithelial differentiation in the female reproductive tract. Differentiation 82:117-126. https://doi.org/10.1016/j.diff.2011.04.008
  70. Kurita T, Cooke PS, Cunha GR. 2001. Epithelial-stromal tissue interaction in paramesonephric (Mullerian) epithelial differentiation. Dev Biol 240:194-211. https://doi.org/10.1006/dbio.2001.0458
  71. Lee S, Martinez-Arguelles DB, Campioli E, Papadopoulos V (2017) Fetal exposure to low levels of the plasticizer DEHP predisposes the adult male adrenal gland to endocrine disruption. Endocrinology 158:304-318.
  72. Li K, Liszka M, Zhou C, Brehm E, Flaws JA, Nowak RA (2020) Prenatal exposure to a phthalate mixture leads to multigenerational and transgenerational effects on uterine morphology and function in mice. Reprod Toxil 93:178-190. https://doi.org/10.1016/j.reprotox.2020.02.012
  73. Li Q, Kannan A, DeMayo FJ, Lydon JP, Cooke PS, Yamagishi H, Srivastava D, Bagchi MK, Bagchi IC (2011) The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science 331:912-916. https://doi.org/10.1126/science.1197454
  74. Li S, Davis B (2007) Evaluating rodent vaginal and uterine histology in toxicity studies. Birth Defects Res B Dev Reprod Toxicol 80:246-252. https://doi.org/10.1002/bdrb.20120
  75. Liu T, Jia Y, Zhou L, Wang Q, Sun D, Xu J, Wu J, Ghen H, Xu F, Ye L (2016) Effects of di-(2-ethylhexyl) phthalate on the hypothalamus: Uterus in pubertal female rats. Int J Environ Res Public Health 13:1130. https://doi.org/10.3390/ijerph13111130
  76. Liu T, Li N, Zhu J, Yu G, Guo K, Zhou L, Zheng D, Qu X, Huang J, Chen X, Wang S, Ye L (2014) Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-ovarian axis in adult female rats. Reprod Toxicol 46:141-147. https://doi.org/10.1016/j.reprotox.2014.03.006
  77. Lovekamp-Swan T, Dais BJ (2003) Mechanisms of phthalate ester toxicity in the female reproductive system. Environ Health Perspect 111:139-145. https://doi.org/10.1289/ehp.5658
  78. Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11162-11166. https://doi.org/10.1073/pnas.90.23.11162
  79. Lyche JL, Gutleb AC, Bergman A, Eriksen GS, Murk ATJ, Ropstad E, Saunders M, Skaare JU (2009) Reproductive and developmental toxicity of phthalates. J Toxicol Environ Health B Crit Rev 12:225-249. https://doi.org/10.1080/10937400903094091
  80. Ma M, Kondo T, Ban S, Umemura T, Kurahashi N, Takeda M, Kishi R (2006) Exposure of prepubertal female rats to inhaled di (2-ethylhexyl) phthalate affects the onset of puberty and postpubertal reproductive functions. Toxicol Sci 93:164-171. https://doi.org/10.1093/toxsci/kfl036
  81. Ma M, Zhang Y, Pei X, Duan Z (2011) Effects of di-(2-ethylhexyl) phthalate exposure on reproductive development and PPARs in prepubertal female rats. J Hyg Res 40:688-692.
  82. Ma W, Tan J, Matsumoto H, Robert B, Abrahamson DR, Das SK, Dey SK (2001) Adult tissue angiogenesis: Evidence for negative regulation by estrogen in the uterus. Mol Endocrinol 15:1983-1992. https://doi.org/10.1210/mend.15.11.0734
  83. Marcus GJ (1974) Mitosis in the rat uterus during the estrous cycle, early pregnancy, and early pseudopregnancy. Biol Reprod 10:447-452. https://doi.org/10.1095/biolreprod10.4.447
  84. Martinez-Arguelles DB, Culty M, Zirkin BR, Papadopoulos V (2009) In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis. Endocrinology 150:5575-5585 https://doi.org/10.1210/en.2009-0847
  85. Martinez-Arguelles DB, Guichard T, Culty M, Zirkin BR, Papadopoulos V (2011) In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod 85:51-61. https://doi.org/10.1095/biolreprod.110.089920
  86. Maskarinec G, Noh JJ (2004) The effect of migration on cancer incidence among Japenese in Hawaii. Ethn Dis 14:431-439.
  87. Masse J, Watrin T, Laurent A, Deschamps S, Guerrier D, Pellerin I (2009) The developing female genital tract: From genetics to epigenetics. Int J Dev Biol 53:411-424. https://doi.org/10.1387/ijdb.082680jm
  88. Meeker JD, Calafat AM, Hauser R (2007) Di (2-ethylhexyl) phthaltate metabolites may alter thyroid hormone levels in men. Environ Health Perspet 115:1029-1034. https://doi.org/10.1289/ehp.9852
  89. Mericskay M, Kitajewski J, Sassoon D (2004) Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Development 131:2061-2072. https://doi.org/10.1242/dev.01090
  90. Morgan M, Deoraj A, Felty Q, Roy D (2017) Environment estrogen-like endocrine disrupting chemicals and breast cancer. Mol Cell Endocrinol 457:89-102. https://doi.org/10.1016/j.mce.2016.10.003
  91. Nardulli AM, Shapiro DJ (1993) DNA bending by nuclear receptors. Receptor 3:247-255.
  92. NTP Center for the Evaluation of Risks to Human Reproduction (2003) NTP-CERHR monograph on the potential human reproductive and developmental effects of di-n-hexyl phthalate (DNHP). NIH Publication No. 03-4489. National Toxicology Program U.S. Department of Health and Human Services, Research Triangle Park, NC.
  93. Ohta Y, Sato T, Iguchi T (1993) Immunocytochemical localization of progesterone receptor in the reproductive tract of adult female rats. Biol Reprod 48:205-213. https://doi.org/10.1095/biolreprod48.1.205
  94. Okada A, Sato T, Ohta Y, Iguchi T (2005) Sex steroid hormone receptors in the developing female reproductive tract of laboratory rodents. J Toxicol Sci 30:75-89. https://doi.org/10.2131/jts.30.75
  95. Owens M (2015) Phthalates: Health Effects, Detection and Exposure Prevention. Nova Science, New York, NY.
  96. Pak VM, McCauley LA (2007) Risks of phthalate exposure among the general population: Implications for occupational health nurses. AAOHN J 55:12-17. https://doi.org/10.1177/216507990705500102
  97. Park C, Lee J, Kong B, Park J, Song H, Choi K, Guon T, Lee Y (2019) The effects of bisphenol A, benzyl butyl phthalate, and di (2-ethylhexyl) phthalate on estrogen receptor alpha in estrogen receptor-positive cells under hypoxia. Environ Pollut 248:774-781. https://doi.org/10.1016/j.envpol.2019.02.069
  98. Radke EG, Galizia A, Thayer KA, Cooper GS (2019) Phthalate exposure and metabolic effects: A systematic review of the human epidemiological evidence. Environ Int 132:104768. https://doi.org/10.1016/j.envint.2019.04.040
  99. Reddy BS, Rozati R, Reddy BV, Raman NV (2006) Association of phthalate esters with endometriosis in Indian women. BJOG 113:515-520. https://doi.org/10.1111/j.1471-0528.2006.00925.x
  100. Richardson KA, Hannon PR, Johnson-Walker YJ, Myint MS, Flaws JA, Nowak RA (2018) Di (2-ethylhexyl) phthalate (DEHP) alters proliferation and uterine gland numbers in the uteri of adult exposed mice. Reprod Toxicol 77:70-79. https://doi.org/10.1016/j.reprotox.2018.01.006
  101. Rier S, Foster WG (2002) Environmental dioxins and endometriosis. Toxicol Sci 70:161-170. https://doi.org/10.1093/toxsci/70.2.161
  102. Robbins WA (2005) Adverse effects of exposure to phthalates: Communicating risks to workers. AAOHN J 53:59-62. https://doi.org/10.1177/216507990505300203
  103. Rowdhwal SSS, Chen J (2018) Toxic effects of di-2-ethylhexyl phthalate: An overview. Biomed Res Int 2018:1750368.
  104. Rudel RA, Perovich LJ (2009) Endocrine disrupting chemicals in indoor and outdoor air. Atmos Environ 43:170-181. https://doi.org/10.1016/j.atmosenv.2008.09.025
  105. Rusyn I, Corton JC (2012) Mechanistic considerations for human relevance of cancer hazard of di (2-ethylhexyl) phthalate. Mutat Res 750:141-158. https://doi.org/10.1016/j.mrrev.2011.12.004
  106. Schmidt JS, Schaedlich K, Fiandanese N, Pocar P, Fischer B (2012) Effects of di (2-ethylhexyl) phthalate (DEHP) on female fertility and adipogenesis in C3H/N mice. Environ Health Perspect 120:1123-1129. https://doi.org/10.1289/ehp.1104016
  107. Serrano SE, Braun J, Trasande L, Dills R, Sathyanarayana S (2014) Phthalates and diet: A review of the food monitoring and epidemilogy data. Environ Health 13:43. https://doi.org/10.1186/1476-069X-13-43
  108. Sheikh IA, Abu-Elmagd M, Turki RF, Damanhouri GA, Beg MA, Al-Qahtani M (2016) Endocrine disruption: In silico perspectives of interactions of di-(2-ethylhexyl) phthalae and its five major metabolites with progesterone receptor. BMS Struct Biol 16:16. https://doi.org/10.1186/s12900-016-0066-4
  109. 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. https://doi.org/10.1289/ehp.961041296
  110. Silva MJ, Furr J, Samandar E, Preau JL Jr, Gray LE Needham LL, Calafat AM (2011) Urinary and serum metabolites of di-n-pentyl phthalate in rats. Chemosphere 82:431-436. https://doi.org/10.1016/j.chemosphere.2010.09.052
  111. Singh M, Chaudhry P, Asselin E (2011) Bridging endometrial receptivity and implantation: Network of hormones, cytokkines and growth factors. J Endocrinol 210:5-14. https://doi.org/10.1530/JOE-10-0461
  112. Sioen I, Fierens T, Van Holderbeke M, Geers L, Bellemans M, De Maeyer M, Servaes K, Vanermen G, Boon PE, De Henauw S (2012) Phthaltes dietary exposure and food sources for Belgian preschool childern and adults. Environ Int 48:102-108. https://doi.org/10.1016/j.envint.2012.07.004
  113. Snejdrova E, Dittrich M (2012) Pharmaceutically used plasticizers. In: Luqman M (ed), Recent admvances in plasticizers. InTech, Rijeka, Croatia.
  114. Somasundaram DB, Manokaran K, Selvanesan BC, Bhaskaran RS (2016) Impact of di-(2-ethylhexyl) phthalate on the uterus of adult Wister rats. Hum Exp Toxicol 36:565-572. https://doi.org/10.1177/0960327116657601
  115. Spencer TE, Bartol FF, Wiley AA, Coleman DA, Wolfe DF (1993) Neonatal porcine endometrial development involves coordinated changes in DNA synthesis, glycosaminoglycan distribution, and 3H-glucosamine labeling. Biol Reprod 48:729-740. https://doi.org/10.1095/biolreprod48.4.729
  116. Spencer TE, Dunlap KA, Filant J (2012) Comparative developmental biology of the uterus: Insights into mechanisms and developmental disruption. Mol Cell Endocrinol 354:34-53. https://doi.org/10.1016/j.mce.2011.09.035
  117. Street ME, Angelini S, Bernasconi S, Burgio E, Cassio A, Catellani C, Cirillo F, Deodati A, Fabbrizi E, Fanos V, Gargano G, Grossi E, Iughetti L, Lazzeroni P, Mantovani A, Migliore L, Palanza P, Panzica G, papini AM, Parmigiani S, Predieri B, Sartori C, Tridenti G, Amarri S (2018) Current knowledge on endocrine disrupting chemicals (EDCs) from animal biology to humans, from pregnancy to adulthood: Highlights from a national Italian meeting. Int J Mol Sci 19:1647. https://doi.org/10.3390/ijms19061647
  118. Su PH, Chen JY, Lin CY, Chen HY, liao PC, Ying TH, Wang SL (2014) Sex steroid hormone levels and reproductive development of eight-year-old children following in utero and environmental exposure to phthalates. PLOS One 9:e102788. https://doi.org/10.1371/journal.pone.0102788
  119. Tan J, Paria BC, Dey SK, Das SK (1999) Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse. Endocrinology 140:5310-5321. https://doi.org/10.1210/en.140.11.5310
  120. Taylor KM, Chen C, Gray CA, Bazer FW, Spencer TE (2001) Expression of messenger ribonucleic acids for fibroblast growth factors 7 and 10, hepatocyte growth factor, and insulinlike growth factors and their receptors in the neonatal ovine uterus. Biol Reprod 64:1236-1246. https://doi.org/10.1095/biolreprod64.4.1236
  121. Tomic D, Frech MS, Babus JK, Symonds D, Furth PA, Koos RD, Flaws JA (2007) Effects of $ER{\alpha}$ overexpression on female reproduction in mice. Reprod Toxicol 23:317-325. https://doi.org/10.1016/j.reprotox.2006.08.004
  122. Tomonari Y, Kurata Y, David RM, Gans G, Kawasuso T, Katoh M (2006) Effects of di (2-ethylhexyl) phthalates (DEHP) on genital organs from juvenile common marmosets: I. Morphological and biochemical investigation in 65-week toxicity study. J Toxicol Environ Health 69:1651-1672. https://doi.org/10.1080/15287390600630054
  123. Veeramachaneni DN, Klinefelter GR (2014) Phthalate-induced pathology in the foetal testis involves more than decreased testosterone production. Reproduction 147:435-442. https://doi.org/10.1530/REP-13-0441
  124. Ventrice P, Ventrice D, De Sarro G (2013) Phthalates: European regulation, chemistry, pharmacokinetic and related toxicity. Environ Toxicol Pharmacol 36:88-96. https://doi.org/10.1016/j.etap.2013.03.014
  125. Walker CL (2011) Epigenomic reprogramming of the developing reproductive tract and disease susceptibility in adulthood. Birth Defects Res A: Clin Mol Tertol 91:666-671. https://doi.org/10.1002/bdra.20827
  126. Wang H, Eriksson H, Sahlin L (2000) Estrogen receptors alpha and beta in the female reproductive tract of the rat during the estrous cycle. Biol Reprod 63:1331-1340. https://doi.org/10.1095/biolreprod63.5.1331
  127. Wang Y, Zhu H, Kannan K (2019) A review of biomonitoring of phthalate exposures. Toxics 7:21. https://doi.org/10.3390/toxics7020021
  128. Watkins DJ, Sanchez BN, Tellez-Rojo M, Lee JM, Mercado-Garcia A, Blank-Goldenberg C, Peterson KE, Meeker JD (2017) Impact of phthalate and BPA exposure during in utero windwons of susceptibility on reproductive hormones and sexual maturation in peripubertal males. Environ Health 16:69. https://doi.org/10.1186/s12940-017-0278-5
  129. Zamkowska D, Kanwacka A, Jurewicz J, Radwan M (2018) Environmental exposure to nonpersistent endocrine disrupting chemicals and smen quality: An overview of the current epidemiological enidence. Intern J Occupation Med Environ Health 31:377-414.
  130. Zhou C, Gao L, Flaws JA (2017) Exposure to an environmentaly relevant phthalate mixtue causes transgenerational effects on female reproduction in mice. Endocrinology 158:1739-1754. https://doi.org/10.1210/en.2017-00100