Research Urinary Bisphenol A Concentrations and Implantation Failure among Women Undergoing in Vitro Fertilization Shelley Ehrlich,1 Paige L. Williams,2 Stacey A. Missmer,3,4 Jodi A. Flaws,5 Katharine F. Berry,3 Antonia M. Calafat,6 Xiaoyun Ye,6 John C. Petrozza,7 Diane Wright,7 and Russ Hauser 1,4,7 1Department of Environmental Health, and 2Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA; 3Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; 4Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA; 5Comparative Biosciences, University of Illinois at Urbana–Champaign, Urbana, Illinois, USA; 6National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; 7Vincent Memorial Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, Massachusetts, USA c onclusi k ey words 2012] 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. o Bjectiv : 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. r esult : Among 137 women undergoing 180 IVF cycles, urinary BPA concentrations had a geo- metric mean (SD) of 1.53 (2.22) µg/L. Overall, 42% (n = 75) of the IVF cycles resulted in implan- tation 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, respec- tively, compared with the lowest quartile (p-trend = 0.06). : hTere was a positive linear dose–response association between BPA urinary concen - trations and implantation failure. : bisphenol A, embryo implantation, fertility, human, reproduction, women. Environ Health Perspect 120:978–983 (2012). http://dx.doi.org/10.1289/ehp.1104307 [Online 6 April Bisphenol A (BPA) is a ubiquitous chemical widely used in the manufacture of poly­ carbonate plastics found in some water bottles (Brede et al. 2003), the lining of food and bev­ erage cans and water pipes (Bae et al. 2002), and some dental sealants and composites (Joskow et al. 2006; Sasaki et al. 2005). BPA can also be used in the manufacture of ther­ mal receipt paper (Biedermann et al. 2010; vom Saal and Myers 2008). Widespread use of BPAc­ontaining consumer products has led to ubiquitous exposure to BPA in the general population (Vandenberg et al. 2007). In the 2003–2004 National Health and Nutrition Examination Survey (NHANES), BPA was detected in > 90% of urine samples obtained from a representative sample of U.S. residents (Calafat et al. 2008). Detectable concentrations of BPA have also been measured in human follicular fluid (1–2 µg/L) and amniotic fluid (1–9 µg/L) (Ikezuki et al. 2002), suggesting that exposure may occur as early as the peri­ conception period. During the past several decades, infertil­ ity rates have increased, and approximately 10–15% of couples in the United States and 978 other developed countries are infertile (Fritz and Speroff 2011), in part because of delayed childbearing. An important determinant of reduced fertility is failed implantation, which is thought to account for 50–75% of preclinical pregnancy losses in humans (Macklon et al. 2002; Norwitz et al. 2001). Implantation is orchestrated and regulated by a very carefully synchronized interplay of hormonal signals and feedback loops, making it potentially vulnerable to chemicals such as BPA that may disrupt endocrine signaling (Berger et al. 2010; Ma et al. 2003; Varayoud et al. 2011). Although BPA has been known to have estrogenic properties since 1936 (Dodds and Lawson 1936), the biological activity of BPA is rather complex and still not fully under­ stood. More recently in in vitro studies, BPA was found to have measurable activity in mul­ tiple assays involving signaling pathways for estrogen, androgen, and thyroid hormones (Food and Agriculture Organization of the United Nations / World Health Organization 2010; Lee et al. 2003; Quesada et al. 2002; Welshons et al. 2006; Wozniak et al. 2005). These hormonal effects may contribute to a disruption of reproductive function. In addi­ tion, experimental studies in animals suggest that BPA exposure adversely affects female fertility (Berger et al. 2007, 2008, 2010; Takai et al. 2001; Tsutsui et al. 1998). An increased incidence of failed intrauterine implantation was observed in mice after sub­ cutaneous exposure to environmentally rele­ vant low concentrations of BPA (Takai et al. 2001; Tsutsui et al. 1998). Litter size, num­ ber of implantation sites, and the percent­ age of females delivering pups were decreased after single­dose administration of BPA dur ­ ing the critical time window for implantation. Similar effects were observed in mice after ingestion and subcutaneous administration of higher doses of BPA (Berger et al. 2007, 2008, 2010; Xiao et al. 2011). Few human studies have examined the association of BPA with female fertility and pregnancy outcomes, primarily because of the practical challenges involved in studying early pregnancy end points among couples conceiv­ ing naturally (Fujimoto et al. 2011; MokL­in et al. 2010; Sugiura­Ogasawara et al. 2005). Therefore, we investigated the relationship between urinary BPA concentrations and implantation failure among women under­ going in vitro fertilization (IVF). Address correspondence to R. Hauser, Harvard School of Public Health, 665 Huntington Ave., Building I, 14th Floor, Boston, MA 02115, USA. Telephone: (617) 432­ 3326. Fax: (617) 432­ 0219. E­mail: rhauser@hsph.harvard.edu We thank the Harvard research team for their hard work and dedication to the study. We thank X. Zhou, R. Hennings, and L. Jia for technical assis­ tance measuring urinary bisphenol A. Finally, we give special thanks to the patients undergoing in vitro fertilization who participated in the study. This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and OH008578 from the National Institute for Occupational Safety and Health. The findings and conclusions in this report are those of the authors and do not necessarily repre­ sent the views of the Centers for Disease Control and Prevention. The authors declare they have no actual or potential competing financial interests. Received 5 August 2011; accepted 6 April 2012. ovlume 120 | number 7 | July 2012 • Environmental Health Perspectives