Reproductive outcomes associated with flame retardants among couples seeking fertility treatment: A paternal perspective.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) have been phased out of production for nearly a decade yet are still frequently detected in serum of U.S. adults. PBDE concentrations have been associated with adverse reproductive outcomes and laboratory studies suggest hydroxylated-BDEs (OH-BDEs) may act as endocrine disruptors. We set out to assess the joint effects of paternal and maternal serum PBDE concentrations on in vitro fertilization (IVF) outcomes and the association between paternal serum OH-BDE concentrations and IVF outcomes. METHODS: This analysis included 189 couples (contributing 285 IVF cycles) recruited between 2006 and 2016 from a longitudinal cohort based at Massachusetts General Hospital Fertility Center who completed at least one IVF cycle and had an available blood sample at study entry. Congeners (47, 99, 100, 153, and 154) and OH-BDEs (3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49) were quantified in serum. Log-transformed PBDEs and OH-BDEs were modeled in quartiles for associations with IVF outcomes using multivariable generalized mixed models and cluster weighted generalized estimating equations. RESULTS: Lipid-adjusted concentrations of PBDEs and OH-BDEs were higher in females than in male partners. There were no clear patterns of increases in risk of adverse IVF outcomes associated with PBDEs and OH-BDEs. However, some decreases in associations with IVF outcomes were observed in isolated quartiles. CONCLUSIONS: Our assessment of couple level exposure is unique and highlights the importance of including male and female exposures in the assessment of the influence of environmental toxicants on pregnancy outcomes.

Exploring reproductive associations of serum polybrominated diphenyl ether and hydroxylated brominated diphenyl ether concentrations among women undergoing in vitro fertilization.

STUDY QUESTION: Are serum concentrations of polybrominated diphenyl ethers (PBDEs) and hydroxylated brominated diphenyl ethers (OH-BDEs) associated with IVF endpoints? SUMMARY ANSWER: Positive associations were observed for BDE153 and several OH-BDEs with IVF endpoints. WHAT IS KNOWN ALREADY: PBDEs have been voluntarily phased out of production in the USA and EU due to their persistence and toxicity to humans and ecosystems. PBDEs have been associated with implantation failure among women undergoing IVF, yet some animal studies suggest greater toxicity from their metabolites, OH-BDEs. STUDY DESIGN, SIZE, DURATION: We evaluated a subset of 215 women (contributing 330 IVF cycles) enrolled between 2005 and 2016 in a longitudinal cohort based at Massachusetts General Hospital Fertility Center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The following PBDEs were quantified: 47, 99, 100, 153 and 154 and the following OH-BDEs: 3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49. Clinical endpoints of IVF treatments were abstracted from electronic medical records. Associations of log-transformed PBDEs and OH-BDEs with IVF outcomes were assessed using multivariable generalized mixed models and cluster weighted generalized estimating equation models adjusted for lipids, age, BMI, race, year of sample collection, IVF protocol and FSH levels. Outcomes were adjusted to represent a percent change in outcome with an increase equal to the magnitude of the difference between the 75th and 25th percentiles for each specific compound (interquartile range (IQR) increase). MAIN RESULTS AND THE ROLE OF CHANCE: Detection frequencies were highest for congeners 47 and 153 (82% ≥ method detection limit (MDL)) and metabolites 3 and 5-OH-BDE47 and 4-OH-BDE49 (92% > MDL). PBDE and OH-BDE geometric mean concentrations declined by up to 80% between participants recruited in 2005 and those recruited in 2016. An IQR increase of BDE153 was associated with an increase in the probability of implantation (relative risk (RR) = 1.26, 95% CI: 1.16, 1.36), clinical pregnancy (RR = 1.32, 95% CI: 1.19, 1.46) and live birth (RR = 1.34; 95% CI: 1.15, 1.54). An IQR increase in 3 and 5-OH-BDE47 was associated with increased probabilities of implantation (RR = 1.52; 95% CI: 1.11, 2.09), clinical pregnancy (RR = 1.66; 95% CI: 1.17, 2.36), and live birth (RR = 1.61; 95% CI: 1.07, 2.40). When models were stratified by race (White (86%)/Other race (14%)), associations remained positive for White women, yet inverse associations were observed for Other race women. An IQR increase in BDE47 was associated with a 46% decreased probability of clinical pregnancy (95% CI: 0.31, 0.95) for Other race women. LIMITATIONS, REASONS FOR CAUTION: Despite the long half-lives of PBDEs and OH-BDEs, exposure misclassification is possible for women who underwent multiple treatment cycles over several months or years. It is also possible another medium, such as follicular fluid would be optimal to characterize exposure. We also tested associations for multiple congeners and metabolites with multiple outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Detections of serum concentrations of PBDEs and OH-BDEs were highest in the early years of the study and suggests that the phase-out of these compounds has contributed to a decrease in exposure. The negative associations found for PBDEs and IVF outcomes among other race women suggests the potential for racial disparity. Potential racial disparities in PBDE exposure and exploration of alternative flame retardants with reproductive health outcomes should be the focus of future investigations. STUDY FUNDING/COMPETING INTEREST(S): Funding for this research was supported by the National Institutes of Environmental Health Sciences (NIEHS) [R01 ES009718, ES022955, ES000002 and 009718T32ES007069]. The authors have no conflicts of interest.

The association of urinary organophosphate ester metabolites and self-reported personal care and household product use among pregnant women in Puerto Rico.

BACKGROUND: Organophosphate esters (OPEs) are widely detected among U.S. pregnant women. OPEs, some of which are present in nail polish, have been associated with adverse reproductive health outcomes. More research is needed to investigate associations with OPEs and personal care products (PCP) use. METHODS: Pregnant women (18-40 years) were recruited from two hospitals and five prenatal clinics in Northern Puerto Rico (n = 148 women) between 2011 and 2015. Concentrations of bis(2-chloroethyl) phosphate (BCEtP), bis(1-chloro-2-propyl) phosphate (BCPP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-n-butyl phosphate (DNBP), di-benzyl phosphate (DBzP), di-cresyl phosphate (DCP), DPHP, and 2,3,4,5-tetrabromobenzoic acid (TBBA) were measured twice during pregnancy. Participants completed questionnaires on PCP and household products (HP) use. Associations among products and metabolite concentrations (n = 296 observations) were assessed using linear mixed models. RESULTS: BCEtP, BCPP, BDCPP and DPHP were detected frequently (≥77%). Correlations among metabolites (0.16 ≤ r ≤ 0.35) and Intraclass correlation coefficients (ICCs) (0.03 ≤ ICC≤0.34) were weak-to-moderate. Suntan lotion was associated with a 110% increase in BDCPP. DPHP increased with perfume (51%) and nail polish (49%) use. BCPP increased 46% with pesticide use in home. CONCLUSION: Biomarkers of OPEs were often detected among pregnant women. Associations with PCP and HP use suggest OPEs may be used in such products, specifically in perfume and nail polish. Further investigation into these products is warranted.

Associations between IVF outcomes and essential trace elements measured in follicular fluid and urine: a pilot study.

PURPOSE: A hypothesis-generating pilot study exploring associations between essential trace elements measured in follicular fluid (FF) and urine and in vitro fertilization (IVF) endpoints. METHODS: We recruited 58 women undergoing IVF between 2007 and 2008, and measured cobalt, chromium, copper, manganese, molybdenum, and zinc in FF (n = 46) and urine (n = 45) by inductively coupled plasma mass spectrometry (ICP-MS). We used multivariable regression models to assess the impact of FF and urine trace elements on IVF outcomes, adjusted for age, body mass index, race, and cigarette smoking. RESULTS: Trace elements were mostly present at lower concentrations in FF than in urine. The average number of oocytes retrieved was positively associated with higher urine cobalt, chromium, copper, and molybdenum concentrations. FF chromium and manganese were negatively associated with the proportion of mature oocytes, yet urine manganese had a positive association. FF zinc was inversely associated with average oocyte fertilization. Urine trace elements were significant positive predictors for the total number of embryos generated. FF copper predicted lower embryo fragmentation while urine copper was associated with higher embryo cell number and urine manganese with higher embryo fragmentation. No associations were detected for implantation, pregnancy, or live birth. CONCLUSIONS: Our results suggest the importance of trace elements in both FF and urine for intermediate, although not necessarily clinical, IVF endpoints. The results differed using FF or urine biomarkers of exposure, which may have implications for the design of clinical and epidemiologic investigations. These initial findings will form the basis of a more definitive future study.

Association of personal exposure to power-frequency magnetic fields with pregnancy outcomes among women seeking fertility treatment in a longitudinal cohort study.

OBJECTIVE: To assess for the first time the potential relationships of personal exposure to magnetic fields (MF) with pregnancy outcomes among a cohort of women from a fertility clinic, addressing, through study design, some of the primary limitations of previous studies on this topic. DESIGN: Longitudinal preconception prospective cohort. SETTING: Fertility center. PATIENT(S): Our analysis included 119 women recruited from 2012 to 2018, who underwent in vitro fertilization (IVF) (n = 163 cycles) and/or intrauterine insemination (IUI) (n = 123 cycles). INTERVENTION(S): Women wore personal exposure monitors continuously for up to three consecutive 24-hour time periods separated by several weeks. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, live birth, and pregnancy loss. RESULT(S): The median and maximum of the overall daily mean (daily peak) MF exposure levels were 1.10 mG (2.14 mG) and 15.54 mG (58.73 mG), respectively. MF exposure metrics were highest among women who changed environments four or more times per day. Overall, no statistically significant associations between MF exposure metrics and fertility treatment or pregnancy outcomes were observed in crude or adjusted models. Effect estimates, both positive and negative, varied by outcome and the exposure metric, including the way in which exposure was modeled. CONCLUSION(S): Personal MF exposures were not associated with fertility treatment outcomes or pregnancy outcomes. Despite its limited size, strengths of the study include a longitudinal repeated-measures design, the collection of personal MF exposure data across multiple days, and carefully documented outcome and covariate information among a potentially susceptible study population.

The association of urinary phosphorous-containing flame retardant metabolites and self-reported personal care and household product use among couples seeking fertility treatment.

BACKGROUND: Phosphorous-containing flame-retardants (PFRs) are widely detected. They are used both as a flame retardant as well as plasticizer. METHODS: A subset of 230 women and 229 men were recruited from Massachusetts General Hospital fertility clinic between 2005 and 2015. At each visit, participants completed a questionnaire of personal care product (PCP) and household product (HP) use. Metabolites [bis(1,3-dichloro-2-propyl) phosphate, diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate and bis(1-chloro-2-propyl) phosphate] were measured in urine (1-5 samples; n = 638 women, n = 335 men). Associations were assessed using generalized mixed models, adjusted for SG, age, BMI, smoking, education, and season. RESULTS: In women, moisturizer (60%), nail polish remover (77%), and nail polish (134%) use were associated (p < 0.05) with an increase in DPHP concentrations, while ip-PPP concentrations increased 21-27% with conditioner, cosmetics, deodorant, and hair product use. Mouthwash and vinyl glove use were associated with a respective 31% and 92% increase in DPHP among men. CONCLUSIONS: Our exploratory analysis suggests PFRs may be used as a plasticizer in consumer products, and nail polish use contributes to internal DPHP exposure. Further research is needed to understand how PFRs are used in these products and how it relates to exposure.

An exploratory analysis of urinary organophosphate ester metabolites and oxidative stress among pregnant women in Puerto Rico.

BACKGROUND: Organophosphate esters (OPEs) are used as flame retardants and plasticizers. Oxidative stress, the imbalance of reactive oxygen species and antioxidants, measured prenatally has been associated with adverse birth outcomes including preeclampsia and preterm birth. We are the first study to investigate the relationship between OPEs and oxidative stress among pregnant women. METHODS: Pregnant women 18-40 yrs. were recruited in Northern Puerto Rico (n = 47) between 2011 and 2015. OPE concentrations of: bis(2-chloroethyl) phosphate (BCEtP), bis(1-chloro-2-propyl) phosphate (BCPP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), dibutyl phosphate (DNBP), and diphenyl phosphate (DPHP) and biomarkers for oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane were measured in urine up to three times during pregnancy. Associations between oxidative stress biomarkers and OPEs were assessed using linear mixed models adjusted for specific gravity, age, BMI, and income. RESULTS: Metabolites BCEtP, BDCPP, and DPHP were frequently detected (>97%). OPE metabolite concentrations remained stable over time (Intraclass correlation coefficients (ICCs): 0.51-0.60). Metabolites BCEtP, BCPP, and DPHP were associated with an increase in 8-isoprostane and OHdG. An interquartile range (IQR) increase in BDCPP was associated with a 21% increase in 8-isoprostane (p < 0.01), while and IQR increase in DPHP and BCPP was associated with a 12% increase (p = 0.04, p = 0.08, respectively). IQR increases in BDCPP and DPHP were also associated with an 18 and 19% increase in OHdG, respectively (p < 0.01). CONCLUSION: OPE metabolites were frequently detected and our results suggest that exposure to OPEs is associated with higher levels of oxidative stress. Further investigation into these relationships and birth outcomes is warranted.

First trimester maternal exposures to endocrine disrupting chemicals and metals and fetal size in the Michigan Mother-Infant Pairs study.

Exposures to endocrine disrupting chemicals and metals are near ubiquitous worldwide, and their potential impact on children is a major public health concern. This pilot study was designed to characterize exposures to phthalates, phenols and metals among pregnant women in the first trimester, and to examine associations with fetal biometrics and birth weight. A total of 41 chemicals and elements were analyzed in urine from 56 mothers with full-term newborns from the Michigan Mother-Infant Pairs study. Bivariate analyses identified predictors of exposure biomarkers. Associations between birth weight, Fenton z-scores and second trimester fetal biometrics with toxicants were examined via multivariable linear regression. An average of 30 toxicants were detected in maternal urine. Fast food consumption was associated with several phthalate metabolites, phenols and metals, and canned food consumption with bisphenol F (P <0.05). Mono (3-carboxypropyl) phthalate was significantly associated with higher birth weight and Fenton z-score while the opposite was observed for bisphenol S. Estimated femur length from ultrasonography was significantly inversely associated with arsenic, barium and lead. While limited by sample size, this study is one of the first to evaluate birth outcomes with respect to emerging endocrine disrupting chemicals and to examine associations between toxicants and fetal biometrics. Exposure assessment was provided by the National Institute of Environmental Health Sciences' Children's Health Exposure Analysis Resource (NIEHS CHEAR), a resource available to children's studies with the goal of combining data across cohorts in an effort to characterize the impact of toxicants on child health from birth and beyond.

The association between urinary concentrations of phosphorous-containing flame retardant metabolites and semen parameters among men from a fertility clinic.

BACKGROUND: The use of PFRs has steadily increased as brominated compounds have been or are being phased out. Human exposure is widespread and animal studies have shown adverse impacts on male reproduction, but human data are lacking. OBJECTIVE: To study the associations between urinary concentrations of phosphorous-containing flame retardant (PFR) metabolites and semen parameters. METHODS: A subset of 220 men from an existing longitudinal cohort of couples were recruited from Massachusetts General Hospital fertility clinic between 2005 and 2015. Semen parameters included sperm count, concentration, motility, and morphology; some men had samples measured from multiple clinic visits (up to five visits; n = 269 semen samples). Metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1-chloro-2-propyl) phosphate (BCIPP)] were measured in urine samples (between one and five urine samples per participant; n = 355 urine samples). Semen parameters were evaluated continuously and dichotomized for models. Metabolites were assessed for associations with semen parameters as continuous and categorized into quartiles using multivariable generalized mixed models, adjusted for specific gravity, age, BMI, smoking, and abstinence period. RESULTS: Metabolites BDCIPP, DPHP, and ip-PPP were detected in a high proportion of urine samples (85%, 86%, and 65% respectively). Concentrations varied by season of collection, particularly for BDCIPP where samples collected in the summer were approximately 2-fold higher than concentrations of other seasons (p < 0.0001). The odds of having a sperm count less than 39 mil/ejaculate decreased by 20% for increasing BDCIPP concentrations (p = 0.04). When regressing semen parameters on PFR metabolite quartiles, some negative associations were observed for individual quartiles among sample volume and morphology, but overall associations were weak and inconsistent. CONCLUSION: Detection rates were high for BDCIPP, DPHP, and ip-PPP. We did not observe consistent associations between PFR metabolites and semen parameters. Due to the high prevalence of exposure, further investigation of other potential health effects should be conducted.