Prenatal urinary concentrations of phenols and risk of preterm birth: exploring windows of vulnerability.

OBJECTIVE: To explore windows of vulnerability to prenatal urinary phenol concentrations and preterm birth. DESIGN: Prospective cohort. SETTING: A large fertility center in Boston, Massachusetts. PATIENT(S): A total of 386 mothers who sought fertility treatment and gave birth to a singleton between 2005 and 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Singleton live birth with gestational age <37 completed weeks. RESULT(S): Compared with women with non-preterm births, urinary bisphenol A (BPA) concentrations were higher across gestation among women with preterm births, particularly during mid-to-late pregnancy and among those with female infants. Second trimester BPA concentrations were associated with preterm birth (Risk Ratio [RR] 1.24; 95%CI: 0.92, 1.69), which was primarily driven by female (RR 1.40; 95%CI: 1.04, 1.89) and not male (RR 0.85; 95%CI 0.50, 1.46) infants. First trimester paraben concentrations were also associated with preterm birth (RR 1.17; 95%CI: 0.94, 1.46) and similarly the association was only observed for female (RR 1.46; 95% CI: 1.10, 1.94) and not male infants (RR 0.94; 95%CIC: 0.72, 1.23). First trimester urinary bisphenol S concentrations showed a suggested risk of preterm birth (RR 1.25; 95%CI: 0.82, 1.89), although the small case numbers precluded sex-specific examination. CONCLUSION(S): We found preliminary evidence of associations between mid-to-late pregnancy BPA and early pregnancy paraben concentrations with preterm birth among those with female infants only. Preterm birth risk may be compound, sex, and window specific. Given the limited sample size of this cohort, results should be confirmed in larger studies, including fertile populations.

Sources of exposure to urinary phthalates among couples undergoing infertility treatment.

Phthalates have been implicated as reproductive toxicants in animal models and in human populations. This study examined associations between potential exposure sources and urinary phthalate metabolite concentrations among women (n = 56) and their male partners (n = 43) undergoing in vitro fertilization (IVF). On the day of oocyte retrieval, participants provided urine samples and completed questionnaires detailing use of personal care products (PCPs), and consumption of medications, foods, and beverages in the preceding 24 h. Urine was analyzed for MEP, MBP, MPP, MHxP, MEHP, MEHHP, MECPP, MiNP, MiDP, MCHP, and MBzP, via liquid chromatography-tandem mass spectrometry. We employed principal component analysis (PCA) to summarize exposure sources and regression models to estimate associations between exposure patterns and urinary phthalate metabolites, adjusted for confounding variables. Among women, application of more body washes and eye creams, and consumption of more supplements, was associated with greater urinary MECPP [relative difference = 1.36 (95% CI: 1.28, 1.45)] and the molar sum of DEHP metabolites, including MEHP, MEHHP, and MECPP [∑DEHP; 1.26 (95% CI: 1.17, 1.34)]. Among men, consumption of more supplements and allergy medications was associated with greater urinary MECPP, MEHHP, and ∑DEHP [relative difference = 1.13 (95% CI: 1.02, 1.23)] concentrations. Identifying differences in sources of phthalate exposure may help clinicians to intervene to reduce exposure as part of a comprehensive strategy to help improve IVF outcomes.

Home ovulation test use and stress during subfertility evaluation: Subarm of a randomized controlled trial.

OBJECTIVES: A prospective, randomized controlled trial in women seeking to conceive examined the impact of using ovulation tests on self-reported levels of stress, psychological well-being, and quality of life in women with unexplained infertility. METHOD: The test group used a home ovulation test to detect the day of ovulation, whereas the control group were provided with a predicted day of ovulation based on the average length of menstrual cycle reported during study recruitment. Volunteers collected their first morning urine samples to evaluate biochemical levels of stress (urinary cortisol and estrone-3-glucouronide) and completed questionnaires over two complete menstrual cycles. RESULTS: Overall, the use of digital ovulation tests by sub-fertile women under medical care had negligible negative effects and no detectable positive benefit on psychological well-being, according to multiple measurements of stress by questionnaire and biochemical markers. No significant differences were found between groups for all stress measures at the various study time points, except in relation to "couple concordance" where the test group scored much higher than the control group (mean difference at end of study was 21.25 (95% confidence interval: 9.25, 33.25; P = 0.0015)). The maximum difference in log cortisol: creatinine ratio between the test and control groups was -0.28 (95% confidence interval: -0.69, 0.13). CONCLUSIONS: These results do not support propositions that using digital ovulation tests can cause stress in women trying to conceive.

Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study.

STUDY QUESTION: Are preconception phthalate and phthalate replacements associated with sperm differentially methylated regions (DMRs) among men undergoing IVF? SUMMARY ANSWER: Ten phthalate metabolites were associated with 131 sperm DMRs that were enriched in genes related to growth and development, cell movement and cytoskeleton structure. WHAT IS KNOWN ALREADY: Several phthalate compounds and their metabolites are known endocrine disrupting compounds and are pervasive environmental contaminants. Rodent studies report that prenatal phthalate exposures induce sperm DMRs, but the influence of preconception phthalate exposure on sperm DNA methylation in humans is unknown. STUDY DESIGN, SIZE, DURATION: An exploratory cross-sectional study with 48 male participants from the Sperm Environmental Epigenetics and Development Study (SEEDS). PARTICIPANTS/MATERIALS, SETTING, METHODS: The first 48 couples provided a spot urine sample on the same day as semen sample procurement. Sperm DNA methylation was assessed with the HumanMethylation 450 K array. Seventeen urinary phthalate and 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH) metabolite concentrations were measured from spot urine samples. The A-clust algorithm was employed to identify co-regulated regions. DMRs associated with urinary metabolite concentrations were identified via linear models, corrected for false discovery rate (FDR). MAIN RESULTS AND ROLE OF CHANCE: Adjusting for age, BMI, and current smoking, 131 DMRs were associated with at least one urinary metabolite. Most sperm DMRs were associated with anti-androgenic metabolites, including mono(2-ethylhexyl) phthalate (MEHP, n = 83), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, n = 16), mono-n-butyl phthalate (MBP, n = 22) and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl (MCOCH, n = 7). The DMRs were enriched in lincRNAs as well as in regions near coding regions. Functional analyses of DMRs revealed enrichment of genes related to growth and development as well as cellular function and maintenance. Finally, 13% of sperm DMRs were inversely associated with high quality blastocyst-stage embryos after IVF. LIMITATIONS, REASONS FOR CAUTION: Our modest sample size only included 48 males and additional larger studies are necessary to confirm our observed results. Non-differential misclassification of exposure is also a concern given the single spot urine collection. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to report that preconception urinary phthalate metabolite concentrations are associated with sperm DNA methylation in humans. These results suggest that paternal adult environmental conditions may influence epigenetic reprogramming during spermatogenesis, and in turn, influence early-life development. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests.

Paternal and maternal urinary phthalate metabolite concentrations and birth weight of singletons conceived by subfertile couples.

BACKGROUND: Prenatal phthalate exposure has been inconsistently associated with fetal growth and infant birth weight. However, the effect of exposure during the paternal and maternal preconception period remains understudied. OBJECTIVES: To investigate associations of paternal and maternal preconception and maternal prenatal urinary phthalate metabolite concentrations with birth weight. METHODS: The study comprised 364 singletons born to 364 mothers and 195 fathers (195 couples) from the EARTH Study, a prospective cohort of couples from Boston, MA. Births were categorized by mode of conception: in-vitro fertilization based (IVF) (n=208) or non-IVF based (n=156, intrauterine insemination or non-medically assisted/natural conception). We measured urinary concentrations of eleven phthalate metabolites in maternal (n=1425) and paternal (n=489) preconception and maternal prenatal (n=781) samples. Birth weight was abstracted from delivery records. Covariate-adjusted associations between loge-phthalate metabolite concentrations and birth weight were evaluated separately by mode of conception using multivariable linear regression. RESULTS: Each loge-unit increase in paternal urinary concentration of the sum of di(2-ethylhexyl) phthalate (ΣDEHP) metabolites was associated with a 90 gram (95% CI: -165, -15) decrease in birth weight among IVF singletons, but not among non-IVF singletons (18g; 95% CI: -76, 113). Additional adjustment for maternal prenatal ΣDEHP concentrations modestly strengthened findings among IVF singletons. While few associations were found with maternal preconception phthalate metabolites, we observed an inverse relationship between several maternal prenatal urinary phthalate metabolite concentrations and birth weight among IVF singletons in covariate-adjusted models. However, with further adjustment for specific paternal phthalate metabolite concentrations, these associations were attenuated and no longer significant. CONCLUSIONS: Paternal preconception urinary concentration of ΣDEHP metabolites was associated with a decrease in birth weight among IVF-conceived singletons. These results, if replicated, highlight the importance of preconception health, especially among subfertile couples.

Trimester-Specific Urinary Bisphenol A Concentrations and Blood Glucose Levels Among Pregnant Women From a Fertility Clinic.

Context: Women with a history of infertility are at increased risk of impaired glucose tolerance during pregnancy. Studies suggest higher urinary bisphenol A (BPA) concentrations are associated with diabetes in nonpregnant populations, but the association between BPA and glucose levels among pregnant women is unclear. Objective: To assess trimester-specific urinary BPA concentrations in relation to blood glucose levels among subfertile women. Design: Environment and Reproductive Health Study, an ongoing prospective cohort study. Setting: A fertility center in a teaching hospital. Patients: A total of 245 women contributed at least one urine sample during first and/or second trimesters, delivered a singleton or twin pregnancy, and had available blood glucose data (2005 to 2015). Main Outcome Measure: Blood glucose levels after a nonfasting 50-g glucose challenge test at 24 to 28 weeks of gestation. Results: The specific gravity-adjusted geometric mean urinary BPA concentrations during first and second trimesters were 1.39 and 1.27 µg/L, respectively. Second-trimester BPA concentrations were positively associated with blood glucose (P, trend = 0.01). Specifically, the adjusted mean glucose levels (95% confidence interval) for women in the highest quartile of second-trimester BPA concentrations was 119 (112, 126) mg/dL compared with 106 (100, 112) mg/dL for women in the lowest quartile. No associations were observed between first-trimester BPA concentrations and glucose levels. Conclusions: BPA exposure during the second trimester may have adverse effect on blood glucose levels among subfertile women. As the findings represent the first report suggesting a potential etiologically relevant window for BPA and glucose in humans, further studies are needed.

Urinary paraben concentrations and in vitro fertilization outcomes among women from a fertility clinic.

OBJECTIVE: To explore the relationship between urinary paraben concentrations and IVF outcomes among women attending an academic fertility center. DESIGN: Prospective cohort study. SETTING: Fertility clinic in a hospital setting. PATIENT(S): A total of 245 women contributing 356 IVF cycles. INTERVENTION(S): None. Quantification of urinary concentrations of parabens by isotope-dilution tandem mass spectrometry, and assessment of clinical endpoints of IVF treatments abstracted from electronic medical records at the academic fertility center. MAIN OUTCOME MEASURE(S): Total and mature oocyte counts, proportion of high-quality embryos, fertilization rates, and rates of implantation, clinical pregnancy, and live births. RESULT(S): The geometric means of the urinary concentrations of methylparaben, propylparaben, and butylparaben in our study population were 133, 24, and 1.5 µg/L, respectively. In models adjusted for age, body mass index, race/ethnicity, smoking status, and primary infertility diagnosis, urinary methylparaben, propylparaben, and butylparaben concentrations were not associated with IVF outcomes, specifically total and mature oocyte counts, proportion of high embryo quality, and fertilization rates. Moreover, no significant associations were found between urinary paraben concentrations and rates of implantation, clinical pregnancy, and live births. CONCLUSION(S): Urinary paraben concentrations were not associated with IVF outcomes among women undergoing infertility treatments.

Associations between paternal urinary phthalate metabolite concentrations and reproductive outcomes among couples seeking fertility treatment.

INTRODUCTION: Limited evidence suggests that male exposure to ubiquitous environmental phthalates may result in poor reproductive outcomes among female partners. METHODS: This analysis included male-female couples undergoing in vitro fertilization (IVF) and/or intrauterine insemination (IUI). We evaluated associations between the geometric mean of paternal specific gravity-adjusted urinary phthalate concentrations prior to the female partners' cycle and fertilization, embryo quality, implantation, and live birth using generalized linear mixed models. RESULTS: Two-hundred eighteen couples underwent 211 IVF and 195 IUI cycles. Trends were observed between paternal urinary mono-3-carboxypropyl phthalate (MCPP; P=0.01) and mono(carboxyoctyl) phthalate (MCOP; P=0.01) and decreased odds of implantation. MCPP and MCOP were also associated with decreased odds of live birth following IVF (P=0.01 and P=0.04, respectively), and monobutyl phthalate above the first quartile was significantly associated with decreased odds of live birth following IUI (P=0.04). However, most urinary phthalate metabolites were not associated with these reproductive outcomes. CONCLUSION: Selected phthalates were associated with decreased odds of implantation and live birth.

Endocrine disrupting chemicals in urine of Japanese male partners of subfertile couples: a pilot study on exposure and semen quality.

The concentrations of chemicals with suspected endocrine disrupting effect were measured in urine samples collected from 42 Japanese male partners of couples who had infertility consultation at a gynecology clinic in Tokyo. The urinary analytes included metabolites of 5 phthalate diesters, pyrethroid insecticide (3-phenoxybenzoic acid, 3-PBA) and soy isoflavones (daidzein and equol), and cadmium. The semen parameters (semen volume, concentration and motility) of the male subjects were examined at the clinic as a diagnostic screening. Multiple regression analysis using one of the semen parameters examined as dependent variable and urinary biomarkers with age, body mass index, abstinent period, alcohol drinking, smoking and consumption frequency of selected foods as independent variables. For sperm concentration, urinary mono-n-butyl phthalate was selected as a significant independent variable with positive beta, while urinary daidzein was with negative beta. Consumption frequency of coffee (negative) and fruits (positive) were also significant. For sperm motility, urinary 3-PBA was selected as significant with negative beta as well as detectability of equol and frequency of coffee consumption with negative beta while smoking was with positive beta. This pilot study suggested the pyrethroid exposure level and dietary habit (coffee and soy products) as a significant contributor to poorer semen quality.

Urinary phthalate monoesters concentration in couples with infertility problems.

The widespread use of phthalates results in human exposure: phthalates are rapidly metabolized to their respective monoesters and other oxidative products, which are glucuronidated and excreted through the urine and feces. Several in vivo studies showed that some phthalates, in particular diethyl-hexyl phthalate (DEHP), diethyl phthalate (DEP), di(n-butyl)phthalate (DnBP) and n-butylbenzylphthalate (BBzP), are able to interact with the human endocrine system, interfering with the reproduction ability. In this study, 56 couples were recruited from a centre of assisted reproduction. Spot urine samples were collected and five urinary metabolites of the above phthalates were determined using an HPLC/MS/MS analytical method with isotopic dilution. The results were compared with those of 56 couples of parents of one or more children and the statistical analysis revealed a significant difference between the two groups in terms of urinary concentrations of phthalates metabolites. A further step will be the correlation of these results with information on the life styles and working conditions collected through a specifically designed questionnaire.