Urinary bisphenol A concentrations and implantation failure among women undergoing in vitro fertilization

Shelley Ehrlich, Paige L Williams, Stacey A Missmer, Jodi A Flaws, Katharine F Berry, Antonia M Calafat, Xiaoyun Ye, John C Petrozza, Diane Wright, Russ Hauser, Shelley Ehrlich, Paige L Williams, Stacey A Missmer, Jodi A Flaws, Katharine F Berry, Antonia M Calafat, Xiaoyun Ye, John C Petrozza, Diane Wright, Russ Hauser

Abstract

Background: Bisphenol A (BPA) is a synthetic chemical widely used in the production of polycarbonate plastic and epoxy resins found in numerous consumer products. In experimental animals, BPA increases embryo implantation failure and reduces litter size.

Objective: We evaluated the association of urinary BPA concentrations with implantation failure among women undergoing in vitro fertilization (IVF).

Methods: We used online solid phase extraction-high performance liquid chromatography-isotope dilution tandem mass spectrometry to measure urinary BPA concentrations in 137 women in a prospective cohort study among women undergoing IVF at the Massachusetts General Hospital Fertility Center in Boston, Massachusetts. We used logistic regression to evaluate the association of cycle-specific urinary BPA concentrations with implantation failure, accounting for correlation among multiple IVF cycles in the same woman using generalized estimating equations. Implantation failure was defined as a negative serum β-human chorionic gonadotropin test (β-hCG < 6 IU/L) 17 days after egg retrieval.

Results: Among 137 women undergoing 180 IVF cycles, urinary BPA concentrations had a geometric mean (SD) of 1.53 (2.22) µg/L. Overall, 42% (n = 75) of the IVF cycles resulted in implantation failure. In adjusted models, there was an increased odds of implantation failure with higher quartiles of urinary BPA concentrations {odds ratio (OR) 1.02 [95% confidence interval (CI): 0.35, 2.95}, 1.60 (95% CI: 0.70, 3.78), and 2.11 (95% CI: 0.84, 5.31) for quartiles 2, 3, and 4, respectively, compared with the lowest quartile (p-trend = 0.06).

Conclusion: There was a positive linear dose-response association between BPA urinary concentrations and implantation failure.

Conflict of interest statement

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Crude and adjusted OR (95% CI) for the associations of quartiles (Q) of urinary BPA concentrations in relation to implantation failure among 137 women undergoing 180 IVF cycles. aAdjusted for age (≥ 37 years vs. < 37 years) and day of embryo transfer (day 5 vs. day 3). bAdjusted for age (≥ 37 years vs. < 37 years), day of embryo transfer (day 5 vs. day 3), and IVF protocol (flare/antagonist vs. luteal).

References

    1. Bae B, Jeong JH, Lee SJ. The quantification and characterization of endocrine disruptor bisphenol-A leaching from epoxy resin. Water Sci Technol. 2002;46(11–12):381–387.
    1. Berger RG, Foster WG, deCatanzaro D. Bisphenol-A exposure during the period of blastocyst implantation alters uterine morphology and perturbs measures of estrogen and progesterone receptor expression in mice. Reprod Toxicol. 2010;30(3):393–400.
    1. Berger RG, Hancock T, deCatanzaro D. Influence of oral and subcutaneous bisphenol-A on intrauterine implantation of fertilized ova in inseminated female mice. Reprod Toxicol. 2007;23(2):138–144.
    1. Berger RG, Shaw J, deCatanzaro D. Impact of acute bisphenol-A exposure upon intrauterine implantation of fertilized ova and urinary levels of progesterone and 17β-estradiol. Reprod Toxicol. 2008;26(2):94–99.
    1. Biedermann S, Tschudin P, Grob K. Transfer of bisphenol A from thermal printer paper to the skin. Anal Bioanal Chem. 2010;398(1):571–576.
    1. Braun JM, Kalkbrenner AE, Calafat AM, Bernert JT, Ye X, Silva MJ, et al. Variability and predictors of urinary bisphenol A concentrations during pregnancy. Environ Health Perspect. 2011;119:131–137.
    1. Brede C, Fjeldal P, Skjevrak I, Herikstad H. Increased migration levels of bisphenol A from polycarbonate baby bottles after dishwashing, boiling and brushing. Food Addit Contam. 2003;20(7):684–689.
    1. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ Health Perspect. 2008;116:39–44.
    1. Carson DD, Bagchi I, Dey SK, et al. Embryo implantation. Dev Biol. 2000;223:217–237.
    1. CDC (Centers for Disease Control and Prevention) Fourth National Report on Human Exposure to Environmental Chemicals—Updated Tables. 2011. Available: [accessed 1 February 2012]
    1. Cooke PS, Buchanan DL, Young P, Setiawan T, Brody J, Korach KS, et al. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci USA. 1997;94(12):6535–6540.
    1. Dodds EC, Lawson W. Synthetic estrogenic agents without the phenanthrene nucleus. Nature. 1936;137:996. [Letter]
    1. Food and Agriculture Organization of the United Nations/World Health Organization. Joint FAO/WHO Expert Meeting to Review Toxicological and Health Aspects of Bisphenol A—Summary Report including Report of Stakeholder Meeting on Bisphenol A. 2010. Available: [accessed 4 June 2011]
    1. Fritz MA, Speroff L. Philadelphia: Lippincott Wilkins and Williams; 2011. Clinical Gynecologic Endocrinology and Infertility. 8th ed.
    1. Fujimoto VY, Kim D, vom Saal FS, Lamb JD, Taylor JA, Bloom MS. Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization. Fertil Steril. 2011;95(5):1816–1819.
    1. Giorgetti C, Terriou P, Auquier P, Hans E, Spach JL, Salzmann J, et al. Embryo score to predict implantation after in-vitro fertilization: based on 957 single embryo transfers. Hum Reprod. 1995;10(9):2427–2431.
    1. Hornung RW, Reed L. Estimation of average concentration in the presence of nondetectable values. Appl Occup Environ Hyg. 1990;5(1):46–51.
    1. Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, et al. Bisphenol A exposure causes meiotic aneuploidy in the female mouse. Curr Biol. 2003;13(7):546–553.
    1. Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Hum Reprod. 2002;17(11):2839–2841.
    1. Joskow R, Barr DB, Barr JR, Calafat AM, Needham LL, Rubin C. Exposure to bisphenol A from bis-glycidyl dimethacrylate-based dental sealants. J Am Dent Assoc. 2006;137(3):353–362.
    1. Lee HJ, Chattopadhyay S, Gong EY, Ahn RS, Lee K. Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor. Toxicol Sci. 2003;75(1):40–46.
    1. Ma WG, Song H, Das SK, Paria BC, Dey SK. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci USA. 2003;100(5):2963–2968.
    1. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Human Reprod Update. 2002;8(4):333–343.
    1. Mahalingaiah S, Meeker JD, Pearson KR, Calafat AM, Ye X, Petrozza J, et al. Temporal variability and predictors of urinary bisphenol A concentrations in men and women. Environ Health Perspect. 2008;116:173–178.
    1. Meeker JD, Ehrlich S, Toth TL, Wright DL, Calafat AM, Trisini AT, et al. Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reprod Toxicol. 2010;30(4):532–539.
    1. Mok-Lin E, Ehrlich S, Williams PL, Petrozza J, Wright DL, Calafat AM, et al. Urinary bisphenol A concentrations and ovarian response among women undergoing IVF. Int J Androl. 2010;33(2):385–393.
    1. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345(19):1400–1408.
    1. Paria BC, Huet-Hudson YM, Dey SK. Blastocyst’s state of activity determines the “window” of implantation in the receptive mouse uterus. Proc Natl Acad Sci USA. 1993;90(21):10159–10162.
    1. Quesada I, Fuentes E, Viso-Leon MC, Soria B, Ripoll C, Nadal A. Low doses of the endocrine disruptor bisphenol-A and the native hormone 17β-estradiol rapidly activate transcription factor CREB. FASEB J. 2002;16(12):1671–1673.
    1. Rehman KS, Bukulmez O, Langley M, Carr BR, Nackley AC, Doody KM, et al. Late stages of embryo progression are a much better predictor of clinical pregnancy than early cleavage in intracytoplasmic sperm injection and in vitro fertilization cycles with blastocyst-stage transfer. Fertil Steril. 2007;87(5):1041–1052.
    1. Sasaki N, Okuda K, Kato T, Kakishima H, Okuma H, Abe K, et al. Salivary bisphenol-A levels detected by ELISA after restoration with composite resin. J Mater Sci Mater Med. 2005;16(4):297–300.
    1. Sugiura-Ogasawara M, Ozaki Y, Sonta S, Makino T, Suzumori K. Exposure to bisphenol A is associated with recurrent miscarriage. Hum Reprod. 2005;20(8):2325–2329.
    1. Takai Y, Tsutsumi O, Ikezuki Y, Hiroi H, Osuga Y, Momoeda M, et al. Estrogen receptor-mediated effects of a xenoestrogen, bisphenol A, on preimplantation mouse embryos. Biochem Biophys Res Commun. 2000;270(3):918–921.
    1. Takai Y, Tsutsumi O, Ikezuki Y, Kamei Y, Osuga Y, Yano T, et al. 2001Preimplantation exposure to bisphenol A advances postnatal development. Reprod Toxicol 151): 71–74.
    1. Tsutsui T, Tamura Y, Yagi E, Hasegawa K, Takahashi M, Maizumi N, et al. Bisphenol-A induces cellular transformation, aneuploidy and DNA adduct formation in cultured Syrian hamster embryo cells. Int J Cancer. 1998;75(2):290–294.
    1. U.S. EPA (U.S. Environmental Protection Agency) Integrated Risk Information—Bisphenol A (CASRN 80–05–7). 1993. Available: [accessed 1 February 2012]
    1. Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol. 2007;24(2):139–177.
    1. Varayoud J, Ramos JG, Bosquiazzo VL, Lower M, Munoz-de-Toro M, Luque EH. Neonatal exposure to bisphenol A alters rat uterine implantation-associated gene expression and reduces the number of implantation sites. Endocrinology. 2011;152(3):1101–1111.
    1. Volkel W, Colnot T, Csanady GA, Filser JG, Dekant W. Metabolism and kinetics of bisphenol A in humans at low doses following oral administration. Chem Res Toxicol. 2002;15(10):1281–1287.
    1. vom Saal FS, Myers JP. Bisphenol A and risk of metabolic disorders. JAMA. 2008;300(11):1353–1355.
    1. Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006;147(6) suppl:S56–S69.
    1. Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319(4):189–194.
    1. Wozniak AL, Bulayeva NN, Watson CS. Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-α–mediated Ca2+ fluxes and prolactin release in GH3/B6 pituitary tumor cells. Environ Health Perspect. 2005;113:431–439.
    1. Xiao S, Honglu D, Smith MA, Song X, Ye X. Preimplantation exposure to bisphenol A (BPA) affects embryo transport, preimplantation embryo development, and uterine receptivity in mice. Reprod Toxicol. 2011;32(4):434–441.
    1. Ye X, Kuklenyik Z, Needham LL, Calafat AM. Automated on-line column-switching HPLC-MS/MS method with peak focusing for the determination of nine environmental phenols in urine. Anal Chem. 2005;77(16):5407–5413.
    1. Ye X, Wong LY, Bishop AM, Calafat AM. Variability of urinary concentrations of bisphenol A in spot samples, first morning voids, and 24-hour collections. Environ Health Perspect. 2011;119:983–988.

Source: PubMed

3
Iratkozz fel