Paternal mixtures of urinary concentrations of phthalate metabolites, bisphenol A and parabens in relation to pregnancy outcomes among couples attending a fertility center.

Few epidemiologic studies have evaluated the impact of paternal environmental exposures, particularly as mixtures, on couples' pregnancy outcomes. We investigated whether mixtures of paternal urinary bisphenol A (BPA), paraben, and phthalates were associated with pregnancy outcomes among couples attending a fertility center. We included 210 couples undergoing 300 in vitro fertilization (IVF) between 2004 and 2017 in this prospective analysis. We quantified paternal urinary biomarker concentrations in one sample per cycle using isotope-dilution tandem mass spectrometry. We used principal component analysis (PCA) to identify correlations of biomarker concentrations and multivariable Cox proportional hazards models for discrete survival time to estimate the hazard ratios (HRs) and 95% CIs for the associations between PCA-derived factor scores and probability of failing to achieve a live birth. Interactions were also included in the models to examine strength of associations over three vulnerable periods [embryo transfer to implantation, implantation to clinical pregnancy, and clinical pregnancy to live birth]. Models were adjusted for paternal and maternal ages and body mass indexes, urinary dilution (specific gravity) and year of collection, infertility diagnosis, and other PCA factor scores. Sensitivity analyses with further adjustment for maternal PCA factor scores were performed. We identified three factors, representing di-2-ethylhexyl phthalate (DEHP) metabolites, BPA and non-DEHP metabolites, and parabens, accounting for 56%, 15% and 10%, respectively, of the total variance explained. An interquartile range (25th and 75th percentiles) increase in the DEHP-related factor score was associated with elevated probability of failing prior to live birth (HR = 1.41, 95% CI: 1.08, 1.81) and the association was stronger between implantation and clinical pregnancy as well as between clinical pregnancy and live birth compared to before implantation. The overall HRs of failure for the BPA/non-DEHP-related and paraben-related factor scores were HR = 1.24 (95% CI: 0.97, 1.59) and HR = 0.99 (95% CI: 0.80, 1.24). We found similar HRs when additionally adjusting for maternal PCA factor scores. Paternal mixtures of urinary concentrations of DEHP metabolites were related to higher infertility treatment failure.

Mínguez-Alarcón L ，Bellavia A ，Gaskins AJ ，Chavarro JE ，Ford JB ，Souter I ，Calafat AM ，Hauser R ，Williams PL ，EARTH Study Team ... -  《-》

Urinary concentrations of bisphenol A, parabens and phthalate metabolite mixtures in relation to reproductive success among women undergoing in vitro fertilization.

We have previously investigated whether urinary concentrations of bisphenol A (BPA), parabens, and phthalate metabolites were individually associated with reproductive outcomes among women undergoing in vitro fertilization (IVF) treatment. However, humans are typically exposed to many man-made chemicals simultaneously. Thus, investigating one chemical at a time may not represent the effect of mixtures. To investigate whether urinary concentrations of BPA, parabens, and phthalate metabolite mixtures are associated with reproductive outcomes among women undergoing IVF. This prospective cohort study included 420 women contributing 648 IVF cycles who provided up to two urine samples per cycle prior to oocyte retrieval (N = 1145) between 2006 and 2017 at the Massachusetts General Hospital Fertility Center, and had available urine biomarker data. Urinary concentrations of BPA, parabens, and phthalate metabolites were quantified using isotope-dilution tandem mass spectrometry. Intermediate and clinical end-points of IVF treatments were abstracted from electronic medical records. Principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) were used to identify main patterns of BPA, parabens, and phthalate metabolites concentrations. We used generalized linear mixed models to evaluate the association between PCA-derived factor scores, in quartiles, and IVF outcomes, using random intercepts to account for multiple IVF cycles and adjusting for known confounders. Because of temporal trends in exposure, we conducted a sensitivity analysis restricted to women who underwent IVF cycles in the earlier years of study (2006-2012). Urinary concentrations of BPA, parabens, and most phthalate metabolites were significantly lower during the second half of the study period (2013-2017) than during the first half (2006-2012). None of the three factors derived from the PCA [di(2-ethylhexyl) phthalate (DEHP), non-DEHP, and paraben] was associated with IVF outcomes in the main analyses. Similarly, BKRM analyses did not identify any associations of individual urinary concentrations of BPA, paraben and phthalate metabolites with IVF outcomes while accounting for correlation between exposures. However, in sensitivity analyses restricted to women who underwent IVF cycles from 2006 to 2012, where concentrations of most phthalates and phenols were higher, there were decreases in implantation, clinical pregnancy, and live birth across quartiles of the DEHP factor. Specifically, women in the highest quartile of the DEHP factor had, on average, lower probabilities of implantation (-22% p, trend = 0.08), clinical pregnancy (-24% p, trend = 0.14), and live birth (-38% p, trend = 0.06) compared to women in the lowest quartile. Among this group of women, BKMR results did not identify any single contributor driving the decreased probabilities of live birth within the DEHP factor. We confirmed that women undergoing IVF are concurrently exposed to multiple endocrine disrupting chemicals (EDCs). While we found no overall significant associations, we observed diminished pregnancy success with specific clusters of chemicals among women who underwent IVF cycles in earlier years of study, when urinary concentrations of these EDCs were higher.

Mínguez-Alarcón L ，Messerlian C ，Bellavia A ，Gaskins AJ ，Chiu YH ，Ford JB ，Azevedo AR ，Petrozza JC ，Calafat AM ，Hauser R ，Williams PL ，Earth Study Team ... -  《-》

Parental preconception exposure to phenol and phthalate mixtures and the risk of preterm birth.

Parental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown. We included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples' joint mixtures in relation to preterm birth. PCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples' total mixture concentrations. In this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome.

Zhang Y ，Mustieles V ，Williams PL ，Wylie BJ ，Souter I ，Calafat AM ，Demokritou M ，Lee A ，Vagios S ，Hauser R ，Messerlian C ... -  《-》

Paternal Urinary Concentrations of Parabens and Other Phenols in Relation to Reproductive Outcomes among Couples from a Fertility Clinic.

Dodge LE ，Williams PL ，Williams MA ，Missmer SA ，Toth TL ，Calafat AM ，Hauser R ... -  《-》

Association of preconception mixtures of phenol and phthalate metabolites with birthweight among subfertile couples.

Although parental preconception exposure to some phenols and phthalates have been associated with reduced birthweight, few studies have examined these chemicals as complex mixtures. We included 384 mothers and 211 fathers (203 couples) who gave birth to 384 singletons from a prospective cohort of couples seeking fertility evaluation. Urinary concentrations of bisphenol A (BPA), parabens, and 11 phthalate metabolites including those of di(2-ethylhexyl) phthalate (DEHP) were examined. Birthweight was abstracted from delivery records. We used principal component analysis and Bayesian Kernel Machine Regression (BKMR) to examine maternal and paternal preconception mixtures in relation to singleton birthweight. We also fit couple-based BKMR with hierarchical variable selection to assess couples' joint mixtures in relation to birthweight. PC scores of maternal and paternal preconception low molecular weight phthalates factor, and paternal preconception DEHP-BPA factor were associated with reduced birthweight. In BKMR models, we found that maternal preconception monoethyl phthalate and BPA concentrations, and paternal preconception mono-n-butyl phthalate concentrations were inversely associated with birthweight when the remaining mixture components were held at their median concentrations. In couple-based BKMR models, paternal preconception biomarkers contributed more to couples' joint effect on birthweight compared with maternal preconception biomarkers. A decreasing trend of birthweight was observed across quantiles of maternal, paternal, and couples' total preconception mixture concentrations, respectively. Results from this preconception cohort of subfertile couples suggest a complex interplay between paternal and maternal preconception exposure to mixtures of nonpersistent chemicals, with both parental windows of exposure jointly contributing to reduced birthweight.

Zhang Y ，Mustieles V ，Williams PL ，Souter I ，Calafat AM ，Demokritou M ，Lee A ，Vagios S ，Hauser R ，Messerlian C ... -  《-》