Skip to main content

Advertisement

Log in

Bisphenol A Concentrates Preferentially in Human Uterine Leiomyoma and Induces Proliferation in Rat Myometrium

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Objectives

To measure tissue levels of bisphenol A (BPA) in uterine leiomyoma (ULM), adjacent myometrium (Myo-F), and normal myometrium (Myo-N). Also, we tested the effect of BPA treatment on rat myometrium.

Methods

Uterine leiomyomas and Myo-F tissues were isolated from hysterectomy specimens done to treat symptomatic ULMs (N = 30). Normal myometrium is isolated from hysterectomies done on ULM-free uteri for other benign indications (N = 25). Bisphenol A was measured in 1 g of tissue using solid-phase extraction and high-performance liquid chromatography, with fluorescence detectors. Experimentally, adult female rats were fed BPA orally at a dose of 50 mg/kg/d for 90 days. Animals were killed, and their myometrial thickness and proliferating cell nuclear antigen (PCNA) immunostaining were evaluated.

Results

Tissue concentration of BPA in each of ULM (12.3 ± 2.8 µg/g) and Myo-F (10.1 ± 0.2 µg/g) was significantly higher than that of Myo-N (0.58 ± 0.2 µg/g). There was no statistically significant difference in BPA level between ULM and Myo-F within submucous or interstitial/subserous fibroid groups. Compared to control rats, BPA-treated animals showed significantly higher myometrial thickness (168.67 ± 5.7 µm and 281.6 ± 20.32 µm, respectively, P = .003) and increased myometrial PCNA immunoscores (1.5 ± 0.37 and 10.38 ± 0.67, respectively, P ≤ .001).

Conclusion

Bisphenol A concentrates in human ULM tissue and its adjacent Myo-F compared to Myo-N. No significant difference is detected in BPA content of ULM tissue of different subtypes. Bisphenol A increases thickness and induces cellular proliferation in rat myometrium. Taken together, our results support a role of BPA in ULM development/growth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Bulun S. Uterine fibroids. N Engl J Med. 2013; 369(14):1344–1355.

    Article  CAS  PubMed  Google Scholar 

  2. Cramer SF, Patel A. The frequency of uterine leiomyoma. Am J Clin Pathol. 1990; 94(4):435–438.

    Article  CAS  PubMed  Google Scholar 

  3. Othman ER, Al-Hendy A. Molecular genetics and racial disparities in uterine leiomyomas. Best Pract Res Clin Obstet Gynaecol. 2008; 22(4):589–601.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Segars JH, Parrott EC, Nagel JD, et al. Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research:comprehensive review, conference summary and future recommendations. Hum Reprod Update. 2014; 20(3):309–333.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Islam MS, Protic O, Stortoni P, et al. Complex networks of multiple factors in the pathogenesis of uterine leiomyoma. Fertil Steril. 2013; 100(1):178–193.

    Article  CAS  PubMed  Google Scholar 

  6. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007; 87(4):725–736.

    Article  PubMed  Google Scholar 

  7. Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated annual costs of uterine leiomyomas in the United States. Am J Obstet Gynecol. 2012; 206(3):e211.–e9.

    Article  PubMed  Google Scholar 

  8. Marshall LM, Spiegelman D, Barbieri RL, et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol. 1997; 90(6):967–873.

    Article  CAS  PubMed  Google Scholar 

  9. Marshall LM, Spiegelman D, Goldman MB, et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril. 1998; 70(3):432–439.

    Article  CAS  PubMed  Google Scholar 

  10. Lethaby A, VoUenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001; 2:CD000547.

    Google Scholar 

  11. Pohl O, Osterloh I, Gotteland J. Ulipristal acetate—safety and pharmacokinetics following multiple doses of 10–50 mg per day. J Clin Pharm Ther. 2013; 38(4):314–320.

    Article  CAS  PubMed  Google Scholar 

  12. Horak P, Mara M, Dundr P, et al. Effect of a selective progesterone receptor modulator on induction of apoptosis in uterine fibroids in vivo. Int J Endocrinol. 2012; 2012:436174.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Donnez J, Hudecek R, Donnez O, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril. 2015; 103(2):519–27.

    Article  CAS  PubMed  Google Scholar 

  14. Howe SR, Gottardis MM, Everitt JI, Goldsworthy TL, Wolf DC, Walker C. Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines. Am J Pathol. 1995; 146:1568–1579.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Han MS, Byun JC, Park JE, Kim JY, Chung JY, Kim JM. Bisphenol-A concentrations from leiomyoma patients by LC/ MS. Toxicol Res. 2011; 27(1):49–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brotons JA, Olea-Serrano MF, Villalobos M, Pedraza V, Olea N. Xenoestrogens released from lacquer coatings in food cans. Environ Health Perspect. 1995; 103(6):608–612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Caserta D, Mantovani A, Marci R, et al. Environment and women’s reproductive health. Human Reprod Update. 2011; 17:418–33.

    Article  CAS  Google Scholar 

  18. Wetherill YB, Akingbemi BT, Kanno J, et al. In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007; 24(2):178–88.

    Article  CAS  PubMed  Google Scholar 

  19. Caserta D, Di Segni N, Mallozzi M, et al. Bisphenol A and the female reproductive tract:an overview of recent laboratory evidence and epidemiological studies. Reprod Biol Endocrinol. 2014; 12:37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Nagel SC, Hagelbarger JL, McDonnell DP. Development of an ER action indicator mouse for the study of estrogens, selective ER modulators (SERMs), and xenobiotics. Endocrinol. 2001; 142(11):4721–4728.

    Article  CAS  Google Scholar 

  21. Trabert D, De Roos AJ, Schwartz SM, et al. Non-dioxin-like poly-chlorinated biphenyls and risk of endometriosis. Environ Health Perspect. 2010; 118(9):1280–1285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Louis GMB. Persistent lipophilic environmental chemicals and endometriosis:the ENDO study. Environ Health Perspect. 2012; 120(6):811–816.

    Article  PubMed Central  CAS  Google Scholar 

  23. Kandaraki E, Chatzigeorgiou A, Livadas S, et al. Endocrine dis-ruptors and polycystic ovary syndrome (PCOS):elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011; 96(3):E480–E484.

    Article  CAS  Google Scholar 

  24. Rutkowska A, Rachon D. Bisphenol A (BPA) and its potential role in the pathogenesis of the polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2014; 30(4):260–265.

    Article  CAS  PubMed  Google Scholar 

  25. Xiao Q, Li Y, Ouyang H, Xu P, Wu D. High-performance liquid chromatographic analysis of bisphenol A and 4-nonylphenol in serum, liver and testis tissues after oral administration to rats and its application to toxicokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2006; 830(2):322–329.

    Article  CAS  PubMed  Google Scholar 

  26. Schönfelder G, Friedrich K, Paul M, Chahoud I. Developmental effects of prenatal exposure to bisphenol a on the uterus of rat offspring. Neoplasia. 2004; 6(5):584–594.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Jefferson WN, Padilla-Banks E, Newbold RR. Disruption of the female reproductive system by the phytoestrogen genistein. Reprod Toxicol. 2007; 23(3):308–316.

    Article  CAS  PubMed  Google Scholar 

  28. Pollack AZ, Buck Louis GM, Chen Z, et al. Bisphenol A, benzophenone-type ultraviolet filters, and phthalates in relation to uterine leiomyoma. Environ Res. 2015; 137:101–107.

    Article  CAS  PubMed  Google Scholar 

  29. Shen Y, Xu Q, Ren M, Feng X, Cai Y, Gao Y. Measurement of phenolic environmental estrogens in women with uterine leiomyoma. PLoS One. 2013; 8(11):79838.

    Article  CAS  Google Scholar 

  30. Zhou F, Zhang L, Liu A, et al. Measurement of phenolic environmental estrogens in human urine samples by HPLC-MS/MS and primary discussion the possible linkage with uterine leiomyoma. J Chromatogr B Analyt Technol Biomed Life Sci. 2013; 938:80–85.

    Article  CAS  PubMed  Google Scholar 

  31. Weuve J, Hauser R, Calafat AM, Missmer SA, Wise LA. Association of exposure to phthalates with endometriosis and uterine leiomyomata:findings from NHANES, 1999–2004. Environ Health Perspect. 2010; 118(6):825–832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yu L, Moore AB, Castro L, et al. Estrogen regulates MAPK-related genes through genomic and nongenomic interactions between IGF-1-I receptor tyrosine kinase and estrogen receptor-alpha signaling pathways in human uterine leiomyoma cells. J Signal Transduct. 2012; 2012:204236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ishikawa H, Ishi K, Sema VA, Kakazu R, Bulun SE, Kurita T. Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology. 2010; 151(6):2433–2442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Richter C, Bimbaum L, FaraboUini F, et al. in vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007; 24(2):199–224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Monje L, Varayoud J, Munoz-de-toro M, Luque EH, Ramos JG. Exposure of neonatal female rats to bisphenol A disrupt hypothalamic LHRH pre-mRNA processing and estrogen receptor alpha expression in nuclei controlling estrous cycli-city. Reprod Toxicol. 2010; 30(4):625–634.

    Article  CAS  PubMed  Google Scholar 

  36. Lee SG, Kim JY, Chung JY, et al. Bisphenol A exposure during adulthood causes augmentation of follicular atresia and luteal regression by decreasing 17P-estradiol synthesis via downregula-tion of aromatase in rat ovary. Environ Health Perspect. 2013; 121(6):663–669.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kandaraki E, Chatzigeorgiou A, Livadas S, et al. Endocrine dis-ruptors and polycystic ovary syndrome (PCOS):elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab. 2011; 96(3):480–484.

    Article  CAS  Google Scholar 

  38. Shen Y, Ren ML, Feng X, Cai YL, Gao YX, Xu Q. An evidence in vitro for the influence of bisphenol A on uterine leiomyoma. Eur J Obstet Gynecol Reprod Biol. 2014; 178:80–83.

    Article  CAS  PubMed  Google Scholar 

  39. Fernández M, Bourguignon N, Lux-Lantos V, Libertun C. Neonatal exposure to bisphenol a and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats. Environ Health Perspect. 2010; 118(9):1217–1222.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Newbold RR, Jefferson WN, Padilla-Banks E. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol. 2007; 24(2):253–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Grain DA, Janssen SJ, Edwards TM, Heindel J, Ho SM, Hunt P. Female reproductive disorders:the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril. 2008; 90(4):911–840.

    Article  CAS  Google Scholar 

  42. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endocrine-disrupting chemicals:an Endocrine Society scientific statement. Endocr Rev. 2009; 30(4):293–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Greathouse KL, Bredfeldt T, Everitt JI, et al. Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res. 2012; 10(4):546–57 doi:https://doi.org/10.1158/1541-7786.MCR-11-0605.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Essam R. Othman MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Othman, E.R., Al-Adly, D.M.M., Elgamal, D.A. et al. Bisphenol A Concentrates Preferentially in Human Uterine Leiomyoma and Induces Proliferation in Rat Myometrium. Reprod. Sci. 23, 508–514 (2016). https://doi.org/10.1177/1933719115608001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719115608001

Keywords

Navigation