Shelley Ehrlich

Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic.

Bisphenol A (BPA) impairs spermatogenesis in animals, but human studies are lacking. We measured urinary BPA concentrations, semen quality, and sperm DNA damage (comet assay) in 190 men recruited through an infertility clinic. BPA was detected in 89% of samples, with a median (interquartile range [IQR]) concentration of 1.3 (0.8-2.5) ng/mL. Urinary BPA concentration was associated with slightly elevated, though not statistically significant, odds for below reference sperm concentration, motility, and morphology. When modeled as continuous dependent variables, an IQR increase in urinary BPA concentration was associated with declines in sperm concentration, motility, and morphology of 23% (95%CI -40%, -0.3%), 7.5% (-17%, +1.5%), and 13% (-26%, -0.1%), respectively, along with a 10% (0.03%, 19%) increase in sperm DNA damage measured as the percentage of DNA in comet tail. In conclusion, urinary BPA may be associated with declined semen quality and increased sperm DNA damage, but confirmatory studies are needed.

Bisphenol A and Reproductive Health: Update of Experimental and Human Evidence, 2007–2013

Background: In 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on reproduction. Objective: In this review, we summarize data obtained since 2007, focusing on a) findings from human and animal studies, b) the effects of BPA on a variety of reproductive end points, and c) mechanisms of BPA action. Methods: We reviewed the literature published from 2007 to 2013 using a PubMed search based on keywords related to BPA and male and female reproduction. Discussion: Because BPA has been reported to affect the onset of meiosis in both animal and in vitro models, interfere with germ cell nest breakdown in animal models, accelerate follicle transition in several animal species, alter steroidogenesis in multiple animal models and women, and reduce oocyte quality in animal models and women undergoing in vitro fertilization (IVF), we consider it an ovarian toxicant. In addition, strong evidence suggests that BPA is a uterine toxicant because it impaired uterine endometrial proliferation, decreased uterine receptivity, and increased implantation failure in animal models. BPA exposure may be associated with adverse birth outcomes, hyperandrogenism, sexual dysfunction, and impaired implantation in humans, but additional studies are required to confirm these associations. Studies also suggest that BPA may be a testicular toxicant in animal models, but the data in humans are equivocal. Finally, insufficient evidence exists regarding effects of BPA on the oviduct, the placenta, and pubertal development. Conclusion: Based on reports that BPA impacts female reproduction and has the potential to affect male reproductive systems in humans and animals, we conclude that BPA is a reproductive toxicant. Citation: Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. 2014. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect 122:775–786; http://dx.doi.org/10.1289/ehp.1307728

Variability of Urinary Phthalate Metabolite and Bisphenol A Concentrations before and during Pregnancy

Background: Gestational phthalate and bisphenol A (BPA) exposure may increase the risk of adverse maternal/child health outcomes, but there are few data on the variability of urinary biomarkers before and during pregnancy. Objective: We characterized the variability of urinary phthalate metabolite and BPA concentrations before and during pregnancy and the ability of a single spot urine sample to classify average gestational exposure. Methods: We collected 1,001 urine samples before and during pregnancy from 137 women who were partners in couples attending a Boston fertility clinic and who had a live birth. Women provided spot urine samples before (n ≥ 2) and during (n ≥ 2) pregnancy. We measured urinary concentrations of monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate, monobenzyl phthalate (MBzP), four metabolites of di-(2-ethylhexyl) phthalate (DEHP), and BPA. After adjusting for specific gravity, we characterized biomarker variability using intraclass correlation coefficients (ICCs) and conducted several surrogate category analyses to determine whether a single spot urine sample could adequately classify average gestational exposure. Results: Absolute concentrations of phthalate metabolites and BPA were similar before and during pregnancy. Variability was higher during pregnancy than before pregnancy for BPA and MBzP, but similar during and before pregnancy for MBP, MEP, and ΣDEHP. During pregnancy, MEP (ICC = 0.50) and MBP (ICC = 0.45) were less variable than BPA (ICC = 0.12), MBzP (ICC = 0.25), and ΣDEHP metabolites (ICC = 0.08). Surrogate analyses suggested that a single spot urine sample may reasonably classify MEP and MBP concentrations during pregnancy, but more than one sample may be necessary for MBzP, DEHP, and BPA. Conclusions: Urinary phthalate metabolites and BPA concentrations were variable before and during pregnancy, but the magnitude of variability was biomarker specific. A single spot urine sample adequately classified MBP and MEP concentrations during pregnancy. The present results may be related to unique features of the women studied, and replication in other pregnancy cohorts is recommended.

Urinary bisphenol A concentrations and ovarian response among women undergoing IVF

Bisphenol A (BPA) is a synthetic chemical used in the manufacture of materials present in many common consumer products. In experimental animals, BPA caused oocyte aneuploidy and reduced production of oestradiol. In a prospective cohort study, we investigated the association between urinary BPA concentrations and ovarian response among women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital (MGH) Fertility Center. The geometric mean of two specific-gravity (SG) adjusted urinary BPA concentrations collected during each IVF cycle was used as the cycle-specific BPA exposure level. BPA concentrations were measured using online solid phase extraction coupled to isotope dilution-high-performance liquid chromatography-tandem mass spectrometry. Peak serum oestradiol was measured using the Elecsys Estradiol II immunoassay kit. Multivariable mixed effect models and Poisson regression models adjusting for correlation between multiple IVF cycles in the same woman were used to evaluate the association between urinary BPA concentrations and ovarian response, adjusting for age, BMI and day 3 follicle stimulating hormone (FSH) levels, a clinical measure of ovarian reserve. Urinary BPA concentrations were measured in 84 women (mean age 35.6 years) undergoing 112 IVF cycles; 23 women (27%) contributed more than one IVF cycle. BPA concentrations ranged from <0.4 to 25.5 microg/L (geometric mean 2.52 +/- SD 3.2); 15% of urine samples had concentrations <0.4 microg/L. Peak serum oestradiol levels correlated with the total number of oocytes retrieved per cycle (r = 0.65, p < 0.001). For each log unit increase in SG-BPA, there was an average decrease of 12% (95% CI: 4, 23%; p = 0.007) in the number of oocytes retrieved and an average decrease of 213 pg/ml (95% CI: -407, -20; p = 0.03) in peak oestradiol. BPA was detected in the urine of the majority of women undergoing IVF, and was inversely associated with number of oocytes retrieved and peak oestradiol levels.

Low dose effects of bisphenol A

In 2007, a group of experts critically analyzed hundreds of publications on bisphenol A (BPA), including the evidence for low dose effects. Here, we have updated these evaluations to determine the strength of the evidence for low dose effects of BPA. Based on the cut-offs for “low doses” established previously (i.e., the lowest observed adverse effect level [LOAEL], or 50 mg/kg/day for mammalian studies), we identified more than 450 low dose studies. Using an integrative approach, we examined five endpoints in depth that had evidence from two or more study types (in vitro, in vivo laboratory animal, and human). Based on all available studies, we are confident that consistent, reproducible, low dose effects have been demonstrated for BPA. We conclude that the doses that reliably produce effects in animals are 1–4 magnitudes of order lower than the current LOAEL of 50 mg/kg/day and many should be considered adverse.

Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF

STUDY QUESTION In women undergoing IVF, are urinary bisphenol A (BPA) concentrations associated with ovarian response and early reproductive outcomes, including oocyte maturation and fertilization, Day 3 embryo quality and blastocyst formation? SUMMARY ANSWER Higher urinary BPA concentrations were found to be associated with decreased ovarian response, number of fertilized oocytes and decreased blastocyst formation. WHAT IS KNOWN ALREADY Experimental animal and in vitro studies have reported associations between BPA exposure and adverse reproductive outcomes. We previously reported an association between urinary BPA and decreased ovarian response [peak serum estradiol (E(2)) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limited human data on reproductive health outcomes, such as fertilization and embryo development. STUDY DESIGN, SIZE AND DURATION Prospective preconception cohort study. One hundred and seventy-four women aged 18-45 years and undergoing 237 IVF cycles were recruited at the Massachusetts General Hospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010. These women were followed until they either had a live birth or discontinued treatment. Cryothaw and donor egg cycles were not included in the analysis. PARTICIPANTS/MATERIALS, SETTING AND METHODS Urinary BPA concentrations were measured by online solid-phase extraction-high-performance liquid chromatography-isotope dilution-tandem mass spectrometry. Mixed effect models, poisson regression and multivariate logistic regression models were used wherever appropriate to evaluate the association between cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation (metaphase II), fertilization, embryo quality and cleavage rate. We accounted for correlation among multiple IVF cycles in the same woman using generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) µg/l. After adjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was a significant linear dose-response association between increased urinary BPA concentrations and decreased number of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreased E(2) levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, when compared with the lowest quartile, respectively; P-value for trend = 0.001). The mean number of oocytes and normally fertilized oocytes decreased by 24 and 27%, respectively, for the highest versus the lowest quartile of urinary BPA (trend test P < 0.001 and 0.002, respectively). Women with urinary BPA above the lowest quartile had decreased blastocyst formation (trend test P-value = 0.08). LIMITATIONS AND REASONS FOR CAUTION Potential limitations include exposure misclassification due to the very short half-life of BPA and its high variability over time; uncertainty about the generalizability of the results to the general population of women conceiving naturally and limited sample. WIDER IMPLICATIONS OF THE FINDINGS The results from this extended study, using IVF as a model to study early reproductive health outcomes in humans, indicate a negative dose-response association between urinary BPA concentrations and serum peak E(2) and oocyte yield, confirming our previous findings. In addition, we found significantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and a suggestive association between BPA urinary concentrations and decreased blastocyst formation, thus indicating that BPA may alter reproductive function in susceptible women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and grant OH008578 from the National Institute for Occupational Safety and Health. None of the authors has actual or potential competing financial interests. DISCLAIMER 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.

Urinary Bisphenol A Concentrations and Implantation Failure among Women Undergoing in Vitro Fertilization

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.

Predictors and variability of urinary paraben concentrations in men and women, including before and during pregnancy.

Background: Parabens are suspected endocrine disruptors and ubiquitous preservatives used in personal care products, pharmaceuticals, and foods. No studies have assessed the variability of parabens in women, including during pregnancy. Objective: We evaluated predictors and variability of urinary paraben concentrations. Methods: We measured urinary concentrations of methyl (MP), propyl (PP), and butyl paraben (BP) among couples from a fertility center. Mixed-effects regression models were fit to examine demographic predictors of paraben concentrations and to calculate intraclass correlation coefficients (ICCs). Results: Between 2005 and 2010, we collected 2,721 spot urine samples from 245 men and 408 women. The median concentrations were 112 µg/L (MP), 24.2 µg/L (PP), and 0.70 µg/L (BP). Urinary MP and PP concentrations were 4.6 and 7.8 times higher in women than men, respectively, and concentrations of both MP and PP were 3.8 times higher in African Americans than Caucasians. MP and PP concentrations we CI re slightly more variable in women (ICC = 0.42, 0.43) than men (ICC = 0.54, 0.51), and were weakly correlated between partners (r = 0.27–0.32). Among 129 pregnant women, urinary paraben concentrations were 25–45% lower during pregnancy than before pregnancy, and MP and PP concentrations were more variable (ICCs of 0.38 and 0.36 compared with 0.46 and 0.44, respectively). Conclusions: Urinary paraben concentrations were more variable in women compared with men, and during pregnancy compared with before pregnancy. However, results for this study population suggest that a single urine sample may reasonably represent an individual’s exposure over several months, and that a single sample collected during pregnancy may reasonably classify gestational exposure.

Handling of Thermal Receipts as a Source of Exposure to Bisphenol A

Human exposure to bisphenol A (BPA) has been associated with adverse health outcomes, including reproductive function in adults1 and neurodevelopment in children exposed perinatally.2 Exposure to BPA is primarily through dietary ingestion, including consumption of canned foods.3 A less-studied source of exposure is thermal receipt paper,4 handled daily by many people at supermarkets, ATM machines, gas stations, and other settings. We hypothesized that handling of thermal receipts significantly increases BPA exposure, but use of gloves during handling minimizes exposure.

Body mass index and short-term weight change in relation to treatment outcomes in women undergoing assisted reproduction

OBJECTIVE To assess the relation between body mass index (BMI) and short-term weight change with assisted reproductive technology (ART) outcomes. DESIGN Prospective cohort study. SETTING Fertility center. PATIENT(S) A total of 170 women undergoing 233 ART cycles. INTERVENTION(S) Baseline BMI and short-term weight change were related to ART outcomes. Regression models accounting for repeated observations were used to adjust data for potential confounders. MAIN OUTCOME MEASURE(S) Peak E2 levels, oocyte yield, MII yield, fertilization rate, embryo quality, postive [beta]-hCH, clinical pregnancy and live birth rates. RESULT(S) Overweight and obesity were associated with lower live birth rates. The adjusted live birth rate (95% confidence interval) was 42% (28%-58%) among women with a BMI between 20 and 22.4 kg/m(2) and 23% (14%-36%) among overweight or obese women. Short-term weight loss was associated with a higher proportion of metaphase II (MII) oocytes retrieved. The adjusted proportion of MII eggs was 91% (87%-94%) for women who lost 3 kg or more and 86% (81%-89%) for women whose weight remained stable. This association was stronger among women who were overweight or obese at baseline. Short-term weight loss was unrelated to positive β-hCG, clinical pregnancy, or live birth rates. CONCLUSION(S) Overweight and obesity were related to lower live birth rates in women undergoing ART. Short-term weight loss was related to higher MII yield, particularly among overweight and obese women, but unrelated to clinical outcomes.