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Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid.

ABSTRACT: BACKGROUND:Phenols and phthalates are potential endocrine disrupting chemicals (EDCs) that are associated with adverse health outcomes. These EDCs dysregulate a number of biomolecules and pathways, including microRNAs. MicroRNAs can be carried in transport systems called extracellular vesicles (EVs) that are present in most biofluids. EVs in the follicular fluid, which fills the ovarian follicle and influences oocyte developmental competency, carry microRNAs (EV-miRNAs) that have been associated with In Vitro Fertilization (IVF) outcomes. However, it remains unclear whether EDCs affect EV-miRNAs in follicular fluid. OBJECTIVES:This study sought to determine whether urinary concentrations of phenols and phthalates biomarkers are associated with EV-miRNAs expression in follicular fluid collected from women undergoing IVF treatment. METHODS:This cross-sectional study included 130 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital. Participants provided urine samples during ovarian stimulation and on the day of oocyte retrieval. We assessed urinary concentrations of five phenols, eight phthalate metabolites, and one phthalate alternative metabolite. EV-miRNAs were isolated from follicular fluid and their expression profiles were measured using the TaqMan Open Array® Human microRNA panel. We fitted multivariable linear regression models and principal component analysis to examine associations between individual and molar sums of exposure biomarkers and EV-miRNAs. RESULTS:Of 754 miRNAs tested, we detected 133 EV-miRNAs in the microRNA array which expressed in at least 50% of the follicular fluid samples. After adjusting for multiple testing, we identified eight EV-miRNAs associated with individual phenols and phthalate metabolites, as well as molar ?DEHP that met a q?

SUBMITTER: Martinez RM

PROVIDER: S-EPMC6343661 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid.

Martinez Rosie M RM Hauser Russ R Liang Liming L Mansur Abdallah A Adir Michal M Dioni Laura L Racowsky Catherine C Bollati Valentina V Baccarelli Andrea A AA Machtinger Ronit R

Environment international 20181124

<h4>Background</h4>Phenols and phthalates are potential endocrine disrupting chemicals (EDCs) that are associated with adverse health outcomes. These EDCs dysregulate a number of biomolecules and pathways, including microRNAs. MicroRNAs can be carried in transport systems called extracellular vesicles (EVs) that are present in most biofluids. EVs in the follicular fluid, which fills the ovarian follicle and influences oocyte developmental competency, carry microRNAs (EV-miRNAs) that have been as ...[more]

PMID: 30481674

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Project description:Study questionAre phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)?Summary answerPhthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs.What is known alreadyPhthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF.Study design, size, durationProspective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital.Participants/materials, setting, methodsWe assessed FF concentrations of 12 phthalate metabolites. EV-miRNAs were isolated from aliquots of the same FF, and their expression profiles were measured using a human miRNA panel. Associations between EV-miRNAs that were present in >50% of the samples and phthalate metabolites that were measured in >74% of the FF samples were tested. Genes regulated by EV-miRNAs that were found to be significantly (false discovery rate q-value < 0.1) correlated with FF-phthalates were analyzed for pathways linked with female fertility using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources and Kyoto Encyclopedia of Genes and Genomes (KEGG).Main results and the role of chanceOf 12 phthalate metabolites, 11 were measured in at least one FF sample. Mono (6-COOH-2-methylheptyl) phthalate (MCOMHP), mono-2-ethyl-5-carboxypentyl phthalate (mECPP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono (7-COOH-2-methyloctyl) phthalate (MCOMOP) were detected in more than 74% of the samples. Of 754 EV-miRNAs tested, 39 were significantly associated either with MEP, MBzP, MCOMOP, MCOMHP and/or with mECPP, after adjusting for multiple testing (P < 0.05). KEGG-based pathway enrichment analysis of the genes regulated by these miRNAs showed that these EV-miRNAs may be involved in pathways related to ovary or oocyte development, maturation and fertilization.Limitations, reasons for cautionThe use of miRNA panel array limits the number of potential relevant miRNAs. Moreover, several of the phthalate metabolites examined may be biased due to internal (enzymatic activity) or external (contamination in medical interventions) causes.Wider implications of the findingsPhthalate metabolites may alter follicular EV-miRNAs profile and thus impair pathways that are involved with oocyte development, maturation and fertilization. Our results contribute to understanding of possible mechanism(s) in which endocrine disruptor chemicals interfere with female fertility.Study funding/competing interestsThis work was supported by the National Institutes of Environmental Health Sciences [Grant R21-ES024236]; and Environmental Health Fund, Israel [Grant 1301], no competing interests.Trial registration numberN/A.

Project description:BACKGROUND:Phthalates and phenols are suspected endocrine disrupting chemicals that may adversely impact fetal outcomes following in utero exposure. Understanding predictors of exposure to phthalates and phenols during the prenatal period is important. METHODS:We measured urinary concentrations of 15 phthalate metabolites and 11 phenols in 446 pregnant women enrolled in the Healthy Start pre-birth cohort. Creatinine-adjusted geometric means (GM) for each urinary biomarker were compared across categories of potential sociodemographic and dietary predictors. To assess the independent relationship between each significant food group predictor and biomarker we used multivariable models, adjusted for sociodemographic predictors. RESULTS:The phthalate metabolites with the highest concentrations were monoethyl phthalate (GM: 41.1µg/g creatinine) and monocarboxyisooctyl phthalate (GM: 20.5µg/g creatinine). Benzophenone-3 (GM: 124.6µg/g creatinine) and methyl paraben (GM: 119.9µg/g creatinine) were the phenols with the highest concentrations. Concentrations of the metabolites of di-n-butyl phthalate and di(2-ethylhexyl) phthalate were significantly higher in younger, unmarried or unemployed mothers, those who were overweight or obese, those with lower educational attainment, or those of minority race/ethnicity (p-values < 0.05). Metabolites of di-n-butyl phthalate concentrations were 18% lower in those who consumed milk ? 7 times per week (95% CI: 30-4%). Benzophenone-3 and triclosan concentrations were significantly higher in older, married, or employed mothers, those with normal body mass index, higher educational attainment, higher household income, or who were non-Hispanic white (p-values < 0.05). Benzophenone-3 concentrations were 62% higher in those who consumed seafood ? 5 times per month (95% CI: 16-127%). CONCLUSIONS:We observed differences in urinary concentrations of phthalates and phenol biomarkers by sociodemographic predictors in an ethnically diverse cohort of pregnant women. These results and future analyses from this prospective cohort will help inform targeted interventions to reduce exposure to these potential endocrine disrupting chemicals during pregnancy.

Project description:BACKGROUND:Phthalates and bisphenol A (BPA) are environmental contaminants that may affect early embryonic development. OBJECTIVE:To assess the association between phthalate metabolites and BPA with early pregnancy endpoints in a cohort of women followed from before conception. METHODS:We quantified 11 phthalate metabolites and BPA in 137 conception cycles from naturally conceived clinical pregnancies. Phthalate metabolites and BPA concentrations were measured in a pooled sample of three daily morning urine specimens. Daily urinary hormone measurements had previously been used to define ovulation, implantation, and corpus luteum rescue. We assessed associations between conception cycle exposures (phthalate biomarkers and BPA) and 1) time from ovulation to implantation; 2) type of corpus luteum rescue (timing and pattern of rise in progesterone: early, late, or no rise); and 3) rate of initial rise in hCG. RESULTS:Mono(3-carboxypropyl) phthalate (MCPP) and mono-isobutyl phthalate (MiBP) were associated with earlier implantation (6-8 days vs. 9 days (the most commonly observed); per natural log-unit, OR (95% CI) =?2.8 (1.2, 6.7) and OR (CI) =?2.1 (1.2, 3.7), respectively). Monoethyl phthalate (MEP) was associated with later implantation (10-12 days vs. 9 days); OR (CI) =?1.5 (1.0, 2.1). Compared with implantation on day 9, BPA was significantly associated with both earlier and later implantation (OR=2.2 for both). Women with concentrations above the median of monobenzyl phthalate (MBzP) (p?=?0.04) or above the median of the molar sum of four di(2-ethylhexyl) phthalate metabolites (?DEHP) (p?=?0.08) had a slower initial rise in hCG. Increasing MCPP was associated with an increased odds of a late rise rescue (OR (CI) =?2.9 (1.0, 8.5); late rise vs. early rise), while increasing MEP was associated with a no rise rescue (OR (CI) =?1.6 (0.9, 2.8); no rise vs. early rise). CONCLUSIONS:The reported associations varied in their direction of effect, some potentially protective, others adverse. This may reflect the complexity with which these potential endocrine disrupting chemicals can be acting, but chance findings are also possible. Given that women continue to be exposed to these compounds (or their precursors), continued research on the effects they may have on pregnancy is warranted.

Project description:BackgroundPreeclampsia represents a major cause of maternal mortality and morbidity worldwide. Although it is known that the placenta plays a central role in development of preeclampsia, investigation into the contribution of environmental toxicants to the risk of preeclampsia has been sparse.ObjectivesIn the present study we examined the relationship between longitudinally measured urinary BPA and phthalate metabolite concentrations during gestation and preeclampsia.MethodsA nested case-control study of preterm birth was performed in 2011 from women enrolled in a prospective birth cohort study at Brigham and Women's Hospital in Boston. There were 50 cases of preeclampsia as part of this study. Urine samples were analyzed for concentrations of BPA and nine phthalate metabolites several times during pregnancy. Adjusted Cox proportional hazard models were used to calculate hazard ratios of preeclampsia in association with an interquartile range increase in BPA and phthalate concentrations and were weighted to reflect results generalizable to the base population.ResultsAdjusted hazard ratios indicated that an interquartile range increase of urinary concentrations of BPA (1.53; 95% CI: 1.04, 2.25) and MEP (monoethyl phthalate) (1.72; 95% CI: 1.28, 2.30) at 10 weeks gestation was associated with onset of preeclampsia, whereas significantly elevated hazard ratios were found across gestation for all DEHP [di(2-ethylhexyl) phthalate] metabolites. These relationships differed based on infant sex.ConclusionsUrinary concentrations of BPA and several phthalate metabolites were significantly associated with increased risk of preeclampsia. If validated, these results indicate an environmental contribution of endocrine-disrupting chemicals to preeclampsia and suggest a modifiable means to reduce the mortality and morbidity associated with this condition.CitationCantonwine DE, Meeker JD, Ferguson KK, Mukherjee B, Hauser R, McElrath TF. 2016. Urinary concentrations of bisphenol A and phthalate metabolites measured during pregnancy and risk of preeclampsia. Environ Health Perspect 124:1651-1655;?http://dx.doi.org/10.1289/EHP188.

Dataset Information

Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid.

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Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid.

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