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1.
Environ Res ; 252(Pt 4): 119149, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38754604

RESUMO

BACKGROUND: Phthalates are ubiquitous endocrine disruptors. Past studies have shown an association between higher preconception urinary concentrations of phthalate metabolites and lower fertility in women; however, the biological mechanisms remain unclear. Our exploratory study aimed to understand the metabolites and pathways associated with maternal preconception phthalate exposure and examine if any may underline the association between phthalate exposure and live birth using untargeted metabolomics. METHODS: Participants (n = 183) were part of the Environment and Reproductive Health (EARTH) study, a prospective cohort that followed women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital Fertility Center (2005-2016). On the same day, women provided a serum sample during controlled ovarian stimulation, which was analyzed for metabolomics using liquid chromatography coupled with high-resolution mass spectrometry and two chromatography columns, and a urine sample, which was analyzed for 11 phthalate metabolites using targeted approaches. We used multivariable generalized linear models to identified metabolic features associated with urinary phthalate metabolite concentrations and live birth, followed by enriched pathway analysis. We then used a meet-in-the-middle approach to identify overlapping pathways and features. RESULTS: Metabolic pathway enrichment analysis revealed 43 pathways in the C18 negative and 32 pathways in the HILIC positive columns that were significantly associated (p < 0.05) with at least one of the 11 urinary phthalate metabolites or molar sum of di-2-ethylhexyl phthalate metabolites. Lipid, amino acid, and carbohydrate metabolism were the most common pathways associated with phthalate exposure. Five pathways, tryptophan metabolism, tyrosine metabolism, biopterin metabolism, carnitine shuttle, and vitamin B6 metabolism, were also identified as being associated with at least one phthalate metabolite and live birth following IVF. CONCLUSION: Our study provides further insight into the metabolites and metabolomics pathways, including amino acid, lipid, and vitamin metabolism that may underlie the observed associations between phthalate exposures and lower fertility in women.

2.
Fertil Steril ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38697237

RESUMO

OBJECTIVE: To evaluate the association between urinary benzophenone-3 concentrations and measures of ovarian reserve (OR) among women in the Environment and Reproductive Health (EARTH) Study seeking fertility treatment at Massachusetts General Hospital in Boston, Massachusetts. DESIGN: Prospective cohort study. METHODS: Women from the EARTH cohort contributed spot urine samples before assessment of OR outcomes. Antral follicle count (AFC) and day-3 follicle stimulating hormone (FSH) levels were evaluated as part of standard infertility workups during unstimulated menstrual cycles. Quasi-Poisson and linear regression models were used to evaluate the association of specific gravity (SG)-adjusted urinary benzophenone-3 concentrations with AFC and FSH, respectively, with adjustment for age and physical activity. In secondary analyses, models were stratified by age. Sensitivity analyses assessed for confounding by season by restricting to women with exposure and outcome measured in the same season and stratifying by summer vs. non-summer months and for confounding by sunscreen use by restricting to women who filled out product questionnaires and adjusting for and stratifying by average sunscreen use score. RESULTS: The study included 142 women (mean age ± SD, 36.1 ± 4.6; range, 22-45 years) enrolled between 2009 and 2017 with both urinary benzophenone-3 and AFC and 57 women with benzophenone-3 and FSH measurements. Most women were white (78%) and highly educated (49% with a graduate degree). Women contributed a mean of 2.7 urine samples (range, 1-10) with 37% contributing 2 or more samples. Benzophenone-3 was detected in 98% of samples. Geometric mean (GM) SG-corrected urinary benzophenone-3 concentration was 85.9 µ g/L (geometric standard deviation 6.2). There were no associations of benzophenone-3 with AFC and day-3 FSH in the full cohort. In stratified models, a 1-unit increase in log GM benzophenone-3 was associated with AFC 0.91 (95% CI, 0.86, 0.97) times lower among women ≤35 years old and was associated with FSH 0.73 (95% CI, 0.12, 1.34) IU/L higher among women >35 years old. Effect estimates from models stratified by season and sunscreen use were null. CONCLUSION: In main models, urinary benzophenone-3 was not associated with OR. However, younger may be vulnerable to potential effects of benzophenone-3 on AFC. Further research is warranted.

3.
Int J Hyg Environ Health ; 257: 114334, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38350281

RESUMO

BACKGROUND: Eating behaviors are controlled by the neuroendocrine system. Whether endocrine disrupting chemicals have the potential to affect eating behaviors has not been widely studied in humans. We investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate biomarker and bisphenol-A (BPA) concentrations were associated with children's eating behaviors. METHODS: We used data from mother-father-child triads in the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6-13 years whose parent(s) previously enrolled in a fertility clinic-based prospective preconception study. We quantified urinary concentrations of 11 phthalate metabolites and BPA in parents' urine samples collected preconceptionally and during pregnancy. Parents rated children's eating behavior using the Child Eating Behavior Questionnaire (CEBQ). Using multivariable linear regression, accounting for correlation among twins, we estimated covariate-adjusted associations of urinary phthalate biomarkers and BPA concentrations with CEBQ subscale scores. RESULTS: This analysis included 195 children (30 sets of twins), 160 mothers and 97 fathers; children were predominantly non-Hispanic white (84%) and 53% were male. Paternal and maternal preconception monobenzyl phthalate (MBzP) concentrations and maternal preconception mono-n-butyl phthalate (MnBP) were positively associated with emotional overeating, food responsiveness, and desire to drink scores in children (ß's= 0.11 [95% CI: 0.01, 0.20]-0.21 [95% CI: 0.10, 0.31] per loge unit increase in phthalate biomarker concentration). Paternal preconception BPA concentrations were inversely associated with scores on food approaching scales. Maternal pregnancy MnBP, mono-isobutyl phthalate (MiBP) and MBzP concentrations were associated with increased emotional undereating scores. Maternal pregnancy monocarboxy-isononyl phthalate concentrations were related to decreased food avoiding subscale scores. CONCLUSIONS: In this cohort, higher maternal and paternal preconception urinary concentrations of some phthalate biomarkers were associated with increased food approaching behavior scores and decreased food avoiding behavior scores, which could lead to increased adiposity in children.


Assuntos
Compostos Benzidrílicos , Poluentes Ambientais , Fenóis , Ácidos Ftálicos , Feminino , Gravidez , Humanos , Masculino , Criança , Estudos Prospectivos , Exposição Materna , Ácidos Ftálicos/urina , Exposição Ambiental , Biomarcadores/urina , Comportamento Alimentar , Poluentes Ambientais/urina
4.
Sci Rep ; 14(1): 5009, 2024 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424222

RESUMO

Smoking exposure during adulthood can disrupt oocyte development in women, contributing to infertility and possibly adverse birth outcomes. Some of these effects may be reflected in epigenome profiles in granulosa cells (GCs) in human follicular fluid. We compared the epigenetic modifications throughout the genome in GCs from women who were former (N = 15) versus never smokers (N = 44) undergoing assisted reproductive technologies (ART). This study included 59 women undergoing ART. Smoking history including time since quitting was determined by questionnaire. GCs were collected during oocyte retrieval and DNA methylation (DNAm) levels were profiled using the Infinium MethylationEPIC BeadChip. We performed an epigenome-wide association study with robust linear models, regressing DNAm level at individual loci on smoking status, adjusting for age, ovarian stimulation protocol, and three surrogate variables. We performed differentially methylated regions (DMRs) analysis and over-representation analysis of the identified CpGs and corresponding gene set. 81 CpGs were differentially methylated among former smokers compared to never smokers (FDR < 0.05). We identified 2 significant DMRs (KCNQ1 and RHBDD2). The former smoking-associated genes were enriched in oxytocin signaling, adrenergic signaling in cardiomyocytes, platelet activation, axon guidance, and chemokine signaling pathway. These epigenetic variations have been associated with inflammatory responses, reproductive outcomes, cancer development, neurodevelopmental disorder, and cardiometabolic health. Secondarily, we examined the relationships between time since quitting and DNAm at significant CpGs. We observed three CpGs in negative associations with the length of quitting smoking (p < 0.05), which were cg04254052 (KCNIP1), cg22875371 (OGDHL), and cg27289628 (LOC148145), while one in positive association, which was cg13487862 (PLXNB1). As a pilot study, we demonstrated epigenetic modifications associated with former smoking in GCs. The study is informative to potential biological pathways underlying the documented association between smoking and female infertility and biomarker discovery for smoking-associated reproductive outcomes.


Assuntos
Epigênese Genética , Estudo de Associação Genômica Ampla , Humanos , Feminino , Adulto , Projetos Piloto , Fumar/efeitos adversos , Fumar/genética , Metilação de DNA , Reprodução , Proteínas de Membrana/genética
5.
Front Glob Womens Health ; 5: 1293255, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38379838

RESUMO

Background: The epidemiologic literature on women's perceived stress in relation to perinatal outcomes has been inconclusive and does not consider the preconception window of exposure. Objective: To evaluate whether women's preconception perceived stress is related to live birth, gestational age, and birthweight in a cohort receiving fertility treatment. Methods: This observational study included women seeking fertility care at the Massachusetts General Hospital (2004-2019). During preconception, women provided information on their psychological stress using the short version of the validated Perceived Stress Scale 4 (PSS-4). We used regression models to evaluate the associations of stress with live birth (N = 768 attempting to conceive) and perinatal outcomes (N = 413 live births) while adjusting for confounders. Stratified analyses by mode of conception [natural, intrauterine insemination (IUI), and IVF (in vitro fertilization)] and selected socioeconomic factors (race, education, and income) were also conducted. Results: Higher psychological stress was negatively associated with the overall probability of live birth (adjusted RR = 0.95, 95% CI: 0.92, 0.98), particularly among women conceiving using IVF. However, we found no association between women's psychological stress and gestational age and birth weight in the overall analyses and also stratified by mode of conception. Similarly, we observed no differences in women's psychological stress with any of the measured outcomes by socioeconomic factors. Discussion: These results highlight the importance of considering the preconception window and mode of conception when evaluating the relationship between women's preconception stress and live birth.

6.
Environ Int ; 183: 108337, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38088019

RESUMO

BACKGROUND: Epidemiologic studies on health effects of parental preconception exposures are limited despite emerging evidence from toxicological studies suggesting that such exposures, including to environmental chemicals, may affect offspring health. OBJECTIVE: We investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate metabolite and bisphenol A (BPA) concentrations were associated with child behavior. METHODS: We analyzed data from the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6-11 years whose parent(s) previously enrolled in the prospective preconception Environment and Reproductive Health (EARTH) study. Using linear mixed models, we estimated covariate-adjusted associations of 11 urinary phthalate metabolite and BPA concentrations collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 (BASC-3) T-scores (higher scores indicate more problem behaviors). RESULTS: This analysis included 134 mothers, 87 fathers and 157 children (24 sets of twins); parents were predominantly non-Hispanic white (mothers and fathers86%). Higher maternal preconception or pregnancy monobenzyl phthalate (MBzP) concentrations were related to higher mean externalizing problems T-scores in their children (ß = 1.3 per 1-loge unit increase; 95 % CI: -0.2, 2.4 and ß = 2.1, 95 % CI: 0.7, 3.6, respectively). Higher maternal preconception monocarboxyoctyl phthalate (MCOP) was suggested to be related to lower mean externalizing problems T-scores (ß = -0.9; 95 % CI: -1.8, 0.0). Higher paternal preconception MCOP was suggestively associated with lower internalizing problems (ß = -0.9; 95 %CI:-1.9, 0.1) and lower Behavioral Symptoms Index (BSI) T-scores (ß = -1.3; 95 % CI: -2.1, -0.4). CONCLUSION: In this cohort, higher maternal preconception and pregnancy MBzP were associated with worse parent-reported child behavior, while higher maternal and paternal preconception MCOP concentrations were related to lower BASC-3 scores.


Assuntos
Compostos Benzidrílicos , Poluentes Ambientais , Fenóis , Ácidos Ftálicos , Masculino , Criança , Feminino , Gravidez , Humanos , Estudos Prospectivos , Exposição Materna , Ácidos Ftálicos/urina , Pai , Comportamento Infantil , Poluentes Ambientais/urina
7.
Andrology ; 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38153162

RESUMO

BACKGROUND: Epidemiologic studies of the effects of parental preconception paraben exposures on child behavior are limited despite emerging evidence suggesting that such exposures may affect offspring neurodevelopment. OBJECTIVE: We investigated whether maternal and paternal preconception and maternal pregnancy urinary concentrations of parabens were associated with child behavior. METHODS: We analyzed data from the Preconception Environmental exposure And Childhood health Effects Study, an ongoing prospective cohort of children aged 6-13 years and their parents. We estimated covariate-adjusted associations of loge -transformed urinary methyl, propyl, and butyl paraben concentrations (individually using linear regression models and as a mixture using quantile g-computation) collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 and Behavior Rating Inventory of Executive Function T-scores (higher scores indicate more problem behaviors). RESULTS: This analysis included 140 mothers, 81 fathers, and 171 children (25 sets of twins); parents were predominantly non-Hispanic white (88% for both mothers and fathers). In single paraben models, higher paternal preconception urinary propyl and methyl paraben concentrations were associated with higher Internalizing Problem T-scores (propyl paraben ß $\beta \;$ = 1.7; 95% confidence interval: 0.6, 2.8, methyl paraben ß $\beta \;$ = 2.2; 95% confidence interval: 0.5, 3.9) and higher Behavioral Symptom Index T-scores (propyl paraben ß $\beta \;$ = 1.4; 95% confidence interval: 0.3, 2.5, methyl paraben ß $\beta \;$ = 1.6; 95% confidence interval: -0.1, 3.3). Each quantile increase in the paternal mixture of three parabens was associated with a 3.4 (95% confidence interval: 0.67, 6.1) and 2.5 (95% confidence interval: 0.01, 5.0) increased internalizing problem and Behavioral Symptom Index T-scores respectively. Higher paternal preconception ( ß $\beta \;$ = 1.0; 95% confidence interval: 0.04, 1.9) and maternal preconception ( ß $\beta \;$ = 1.1 95% confidence interval: -0.1, 2.2) concentrations of propyl paraben were associated with higher Behavior Rating Inventory of Executive Function Metacognition Index T-scores in children, but the paraben mixtures was not. CONCLUSION: In this cohort, paternal preconception urinary concentrations of propyl and methyl paraben were associated with worse parent-reported child behaviors.

8.
Hum Reprod ; 38(11): 2196-2207, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37740688

RESUMO

STUDY QUESTION: What metabolic pathways and metabolites in the serum and follicular fluid are associated with peak estradiol levels and the number of mature oocytes? SUMMARY ANSWER: In the serum metabolome, mostly fatty acid and amino acid pathways were associated with estradiol levels and mature oocytes while in the follicular fluid metabolome, mostly lipid, vitamin, and hormone pathways were associated with peak estradiol levels and mature oocytes. WHAT IS KNOWN ALREADY: Metabolomics has identified several metabolic pathways and metabolites associated with infertility but limited data are available for ovarian stimulation outcomes. STUDY DESIGN, SIZE, DURATION: A prospective cohort study of women undergoing IVF from 2009 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 125 women undergoing a fresh IVF cycle at a fertility clinic in the Northeast United States who provided a serum and follicular fluid sample. Untargeted metabolomics profiling was conducted using liquid chromatography with high-resolution mass spectrometry in two chromatography columns (C18 and hydrophilic interaction chromatography (HILIC)). The main ovarian stimulation outcomes were peak serum estradiol levels and number of mature oocytes. We utilized adjusted generalized linear regression models to identify significant metabolic features. Models were adjusted for age,BMI, initial infertility diagnosis, and ovarian stimulation protocol. We then conducted pathway analysis using mummichog and metabolite annotation using level-1 evidence. MAIN RESULTS AND ROLE OF CHANCE: In the serum metabolome, 480 and 850 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively. Additionally, 437 and 538 features were associated with mature oocytes in the C18 and HILIC columns, respectively. In the follicular fluid metabolome, 752 and 929 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively, Additionally, 993 and 986 features were associated with mature oocytes in the C18 and HILIC columns, respectively. The most common pathways associated with peak estradiol included fatty acids (serum and follicular fluid), hormone (follicular fluid), and lipid pathways (follicular fluid). The most common pathways associated with the number of mature oocytes retrieved included amino acids (serum), fatty acids (serum and follicular fluid), hormone (follicular fluid), and vitamin pathways(follicular fluid). The vitamin D3 pathway had the strongest association with both ovarian stimulation outcomes in the follicularfluid. Four and nine metabolites were identified using level-1 evidence (validated identification) in the serum and follicular fluid metabolomes, respectively. LIMITATIONS, REASONS FOR CAUTION: Our sample was majority White and highly educated and may not be generalizable to thewider population. Additionally, residual confounding is possible and the flushing medium used in the follicular fluid could have diluted our results. WIDER IMPLICATIONS OF THE FINDINGS: The pathways and metabolites identified by our study provide novel insights into the biologicalmechanisms in the serum and follicular fluid that may underlie follicular and oocyte development, which could potentially be used to improve ovarian stimulation outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the following grants from the National Institute of Environmental Health Sciences (P30-ES019776, R01-ES009718, R01-ES022955, P30-ES000002, R00-ES026648, and T32-ES012870), and National Institute of Diabetes and Digestive and Kidney Diseases (P30DK046200). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Líquido Folicular , Infertilidade , Feminino , Humanos , Líquido Folicular/metabolismo , Estudos Prospectivos , Infertilidade/metabolismo , Indução da Ovulação/métodos , Estradiol , Metaboloma , Ácidos Graxos , Vitaminas/metabolismo , Lipídeos , Oócitos/metabolismo , Fertilização in vitro
9.
Sci Total Environ ; 898: 165536, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37453702

RESUMO

Although prior studies have found associations of the ovarian reserve with urinary concentrations of some individual phenols and phthalate metabolites, little is known about the potential associations of these chemicals as a mixture with the ovarian reserve. We investigated whether mixtures of four urinary phenols (bisphenol A, butylparaben, methylparaben, propylparaben) and eight metabolites of five phthalate diesters including di(2-ethylhexyl) phthalate were associated with markers of the ovarian reserve among 271 women attending a fertility center who enrolled in the Environment and Reproductive Health study (2004-2017). The analysis was restricted to one outcome per study participant using the earliest outcome after the last exposure assessment. Ovarian reserve markers included lower antral follicle count (AFC) defined as AFC < 7, circulating serum levels of day 3 follicle stimulating hormone (FSH) assessed by immunoassays, and diminished ovarian reserve (DOR) defined as either AFC < 7, FSH > 10 UI/L or primary infertility diagnosis of DOR. We applied Bayesian Kernel Machine Regression (BKMR) and quantile g-computation to estimate the joint associations and assess the interactions between chemical exposure biomarkers on the markers of the ovarian reserve while adjusting for confounders. Among all 271 women, 738 urine samples were collected. In quantile g-computation models, a quartile increase in the exposure biomarkers mixture was not significantly associated with lower AFC (OR = 1.10, 95 % CI = 0.52, 2.30), day 3 FSH levels (Beta = 0.30, 95 % CI = -0.32, 0.93) or DOR (OR = 1.02, 95 % CI = 0.52, 2.05). Similarly, BKMR did not show any evidence of associations between the mixture and any of the studied outcomes, or interactions between chemicals. Despite the lack of associations, these results need to be explored among women in other study cohorts.


Assuntos
Dietilexilftalato , Infertilidade Feminina , Reserva Ovariana , Humanos , Feminino , Clínicas de Fertilização , Teorema de Bayes , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/urina , Hormônio Foliculoestimulante , Biomarcadores
10.
Sci Total Environ ; 898: 165353, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37437643

RESUMO

Endocrine disrupting chemicals (EDCs) can adversely affect human health and are ubiquitously found in everyday products. We examined temporal trends in urinary concentrations of EDCs and their replacements. Urinary concentrations of 11 environmental phenols, 15 phthalate metabolites, phthalate replacements such as two di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) metabolites, and triclocarban were quantified using isotope-dilution tandem mass spectrometry. This ecological study included 996 male and 819 female patients who were predominantly White/Caucasian (83 %) with an average age of 35 years and a BMI of 25.5 kg/m2 seeking fertility treatment in Boston, MA, USA. Patients provided a total of 6483 urine samples (median = 2, range = 1-30 samples per patient) between 2000 and 2017. Over the study period, we observed significant decreases (% per year) in urinary concentrations of traditional phenols, parabens, and phthalates such as bisphenol A (ß: -6.3, 95 % CI: -7.2, -5.4), benzophenone-3 (ß: -6.5, 95 % CI: -1.1, -18.9), parabens ((ß range:-5.4 to -14.2), triclosan (ß: -18.8, 95 % CI: -24, -13.6), dichlorophenols (2.4-dichlorophenol ß: -6.6, 95 % CI: -8.8, -4.3); 2,5-dichlorophenol ß: -13.6, 95 % CI: -17, -10.3), di(2-ethylhexyl) phthalate metabolites (ß range: -11.9 to -22.0), and other phthalate metabolites including mono-ethyl, mono-n-butyl, and mono-methyl phthalate (ß range: -0.3 to -11.5). In contrast, we found significant increases in urinary concentrations of environmental phenol replacements including bisphenol S (ß: 3.9, 95 % CI: 2.7, 7.6) and bisphenol F (ß: 6, 95 % CI: 1.8, 10.3), DINCH metabolites (cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester [MHiNCH] ß: 20, 95 % CI: 17.8, 22.2; monocarboxyisooctyl phthalate [MCOCH] ß: 16.2, 95 % CI: 14, 18.4), and newer phthalate replacements such as mono-3-carboxypropyl phthalate, monobenzyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate and di-isobutyl phthalate metabolites (ß range = 5.3 to 45.1), over time. Urinary MHBP concentrations remained stable over the study period. While the majority of biomarkers measured declined over time, concentrations of several increased, particularly replacement chemicals that are studied.


Assuntos
Dietilexilftalato , Poluentes Ambientais , Ácidos Ftálicos , Humanos , Masculino , Feminino , Adulto , Parabenos/análise , Boston , Ácidos Ftálicos/urina , Fenóis/análise , Poluentes Ambientais/análise , Exposição Ambiental/análise
11.
Toxics ; 11(6)2023 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37368621

RESUMO

The associations between urinary phenol concentrations and markers of thyroid function and autoimmunity among potentially susceptible subgroups, such as subfertile women, have been understudied, especially when considering chemical mixtures. We evaluated cross-sectional associations of urinary phenol concentrations, individually and as a mixture, with serum markers of thyroid function and autoimmunity. We included 339 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2009-2015). We quantified four phenols in urine using isotope dilution high-performance liquid chromatography-tandem mass spectrometry, and biomarkers of thyroid function (thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4), and triiodothyronine (fT3, TT3)), and autoimmunity (thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies (Ab)) in serum using electrochemoluminescence assays. We fit linear and additive models to investigate the association between urinary phenols-both individually and as a mixture-and serum thyroid function and autoimmunity, adjusted for confounders. As a sensitivity analysis, we also applied Bayesian Kernel Machine Regression (BKMR) to investigate non-linear and non-additive interactions. Urinary bisphenol A was associated with thyroid function, in particular, fT3 (mean difference for a 1 log unit increase in concentration: -0.088; 95% CI [-0.151, -0.025]) and TT3 (-0.066; 95% CI [-0.112, -0.020]). Urinary methylparaben and triclosan were also associated with several thyroid hormones. The overall mixture was negatively associated with serum fT3 concentrations (mean difference comparing all four mixture components at their 75th vs. 25th percentiles: -0.19, 95% CI [-0.35, -0.03]). We found no evidence of non-linearity or interactions. These results add to the current literature on phenol exposures and thyroid function in women, suggesting that some phenols may alter the thyroid system.

12.
Clin Epigenetics ; 15(1): 84, 2023 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-37179367

RESUMO

BACKGROUND: Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005-2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO2) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO2 or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate < 0.1. RESULTS: There were no associations between NO2 or supplemental folic acid intake and epigenetic age acceleration of GC. NO2 and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO2 exposure was associated with 1.7% higher DNAm. There was no association between NO2 and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO2-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies. CONCLUSIONS: We found no associations between NO2, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.


Assuntos
Poluição do Ar , Metilação de DNA , Humanos , Feminino , Poluição do Ar/efeitos adversos , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Envelhecimento/genética , Ácido Fólico/efeitos adversos
13.
Reprod Biomed Online ; 46(6): 956-964, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37085427

RESUMO

RESEARCH QUESTION: Is self-reported psychological stress associated with markers of ovarian reserve among subfertile women? DESIGN: Observational study of women (n = 520) seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health study between 2005 and 2019. Women completed the short version of the validated PSS4, which assesses psychological stress. Ovarian reserve markers included AFC and circulating serum levels of day-3 FSH, with AMH assessed in a subset of participants (n = 185). RESULTS: Higher total PSS4 scores were negatively associated with AFC and serum AMH levels. Analyses adjusted for age, BMI, race, smoking, education, physical activity and type of infertility diagnosis. Women in the second and third tertiles of stress had lower AFC (13.3, 95% CI 12.7 to 13.8; and 13.5, 95% CI 13.0 to 14.1) compared with women in the lowest tertile of psychological stress score (14.3, 95% CI 13.8 to 14.9, both P < 0.05). Women in the second and third tertiles of total PSS4 scores also had lower mean serum AMH compared with women in the lowest tertile (2.99, 95% CI 2.24 to 3.74), and (2.99 95% CI 2.22 to 3.76) versus (3.94 95% CI 3.23 to 4.64). These associations varied by several socioeconomic factors, and were observed among women who were younger, belonging to minority races, with a college degree or with annual household income less than $100,000. CONCLUSIONS: Higher perceived stress was negatively associated with AFC and serum AMH levels. These associations varied by several socioeconomic factors.


Assuntos
Infertilidade Feminina , Reserva Ovariana , Feminino , Humanos , Folículo Ovariano , Infertilidade Feminina/diagnóstico , Hormônio Antimülleriano
14.
Hum Reprod ; 38(4): 529-536, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36772979

RESUMO

STUDY QUESTION: Are occupational factors associated with markers of testicular function among men attending a fertility center? SUMMARY ANSWER: Men working non-daytime/rotating shifts and those with physically demanding jobs have higher sperm concentration and total sperm count as well as higher estradiol and total testosterone concentrations. WHAT IS KNOWN ALREADY: Semen quality has declined during recent decades and has been negatively correlated with higher risks of common chronic diseases and mortality, highlighting its public health importance beyond fertility and reproduction. While most of the previous epidemiology literature on male fertility has focused on environmental exposures, dietary factors, and other related variables, little attention has been paid to occupational factors. STUDY DESIGN, SIZE, DURATION: This observational study included 377 men who were male partners in couples seeking infertility treatment at a fertility center, who enrolled in the Environment and Reproductive Health (EARTH) study between 2005 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Self-reported information on lifting/moving heavy objects, typical shift, and physical level of exertion at work was collected from a take-home questionnaire. Semen samples were analyzed following World Health Organization guidelines. Enzyme immunoassays were used to assess reproductive hormone concentrations. Linear regression models were used to evaluate the association between occupational factors and measures of testicular function, while adjusting for covariates such as age, BMI, education, race, smoking, and abstinence time, and accounting for multiple semen samples (mean = 2, min-max = 1-9) in analyses for semen parameters. MAIN RESULTS AND THE ROLE OF CHANCE: Men had a median (interquartile range) age of 36 (33, 39) years and were predominantly Caucasian (87%). Of the men who completed the survey, 12% reported often lifting or moving heavy objects at work, 6% reported heavy physical exertion at work, and 9% reported evening or rotating shifts. Men who reported often lifting or moving heavy objects at work had 46% higher sperm concentrations (P = 0.01) and 44% higher total counts (P = 0.01) compared with men who reported never lifting or moving heavy objects at work. Similar results were found for men working in rotating shifts compared to those in day shifts, as well as for men involved in heavy levels of physical exertion compared to those with light levels at work. We also found that men involved in heavy/moderate levels of physical exertion at work had higher circulating testosterone concentrations compared to those with lighter exertion (adjusted means of 515 and 427 ng/dl, respectively, P = 0.08), and men who often moved/lifted heavy objects at work had higher estradiol concentrations, compared to those who never did (adjusted means of 36.8 and 27.1 pg/ml, respectively, P = 0.07). Men working evening/rotating shifts had 24% higher testosterone (P = 0.04) and 45% higher estradiol concentrations (P = 0.01), compared to men working day shifts. No associations were observed for ejaculated volume, total motility, morphologically normal sperm, or serum FSH and LH concentrations. LIMITATIONS, REASONS FOR CAUTION: Due to our study design which recruited men from couples seeking fertility treatment, it may not be possible to generalize our findings to men from the general population. Also, as is the case of all studies based on self-reported questionnaires, measurement error and misclassification of the exposure are potential concerns. WIDER IMPLICATIONS OF THE FINDINGS: Physically demanding jobs and rotating or evening shift occupations may be associated with higher testicular function in men measured as higher sperm concentrations and counts as well as higher serum testosterone and estradiol levels. Confirmation of these findings in other non-fertility clinic study populations is warranted. STUDY FUNDING/COMPETING INTEREST(S): NIH grants R01ES022955, R01ES009718, R01ES033651, and R01ES000002 from the National Institute of Environmental Health Sciences (NIEHS) and Legacy, Inc. R.A.G. works part time for Legacy, Inc., which provided funds to perform this analysis. There are no other conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Análise do Sêmen , Sêmen , Humanos , Masculino , Feminino , Motilidade dos Espermatozoides , Hormônio Foliculoestimulante , Contagem de Espermatozoides , Testosterona , Estradiol
15.
J Endocr Soc ; 8(1): bvad152, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38178907

RESUMO

Context: The association between women's stress and pregnancy glucose levels remain unclear, specifically when considering the preconception period as a sensitive window of exposure. Objective: We investigated whether preconception perceived stress was associated with glucose levels during pregnancy among women attending a fertility center (2004-2019). Methods: Before conception, women completed a psychological stress survey using the short version of the validated Perceived Stress Scale 4 (PSS-4), and blood glucose was measured using a 50-gram glucose load test during late pregnancy as a part of screening for gestational diabetes. Linear and log-binomial regression models were used to assess associations of total PSS-4 scores with mean glucose levels and abnormal glucose levels ( ≥ 140 mg/dL), adjusting for age, body mass index, race, smoking, education, physical activity, primary infertility diagnosis, number of babies, and mode of conception. Results: Psychological stress was positively associated with mean abnormal glucose levels. The adjusted marginal means (95% CI) of mean glucose levels for women in the first, second, and third tertiles of psychological stress were 115 (110, 119), 119 (115, 123), and 124 (119, 128), and mg/dL, respectively (P for trend = .007). Also, women in the second and third tertiles of psychological stress had 4% and 13% higher probabilities of having abnormal glucose compared with women in the first tertile of psychological stress (P trend = .01). Conclusion: These results highlight the importance of considering preconception when evaluating the relationship between women's stress and pregnancy glucose levels.

16.
J Assist Reprod Genet ; 39(12): 2719-2728, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36322231

RESUMO

PURPOSE: To investigate whether history of comorbidities is associated with markers of ovarian reserve among subfertile women. METHODS: This observational study includes 645 women seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health (EARTH) study (2005-2019). Women completed a comprehensive questionnaire including medical diagnosis of comorbidities. Ovarian reserve markers including antral follicle count (AFC), assessed by transvaginal ultrasound, and circulating serum levels of day 3 FSH and AMH, are assessed by immunoassays. We fit linear regression models to evaluate the association between history of comorbidities and markers of ovarian reserve while adjusting for confounders. RESULTS: Self-reported history of hypertension, cancer, and neurological disorders was negatively associated with AFC in unadjusted models and in adjusted models for age, smoking, physical activity, comorbidity count, and BMI. Adjusted mean AFC (95% CI) was lower among women with history of hypertension, compared to women with no self-reported history of hypertension (11.5 vs 15.6, p value 0.0001). In contrast, day 3 FSH levels were positively related to history of eating disorders in both unadjusted and adjusted models (10.8 vs. 7.43 IU/L, p value ≤ 0.0001). Self-reported history of other comorbidities was unrelated to AFC, day 3 FSH, and AMH levels. CONCLUSIONS: History of hypertension, cancer, and neurological disorders was negatively associated with AFC, and eating disorders were positively related to day 3 FSH levels. The prevention of common comorbidities among women in reproductive age may help increase women's fertility given the declining birth rates and increasing use of assisted reproductive technologies in the past years.


Assuntos
Hipertensão , Infertilidade , Reserva Ovariana , Feminino , Humanos , Folículo Ovariano , Hormônio Foliculoestimulante , Comorbidade , Hormônio Antimülleriano
17.
Toxics ; 10(6)2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35736901

RESUMO

We examined whether urinary concentrations of phthalate and phthalate replacement metabolites were associated with lipid biomarker levels among pregnant women. This cross-sectional study included 175 women who enrolled in the Environment and Reproductive Health (EARTH) Study (2005-2017). We used linear regression models to assess the relationship between urinary phthalates and lipid biomarkers [triglycerides, total cholesterol, high density lipoprotein (HDL), non-HDL, and low-density lipoprotein (LDL) cholesterol] levels while adjusting for confounders. Pregnant women in the highest quartile of urinary mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) had, overall, 14% [31 (95% CI = 6.56) mg/dL], 21% [33 (95% CI = 9.57) mg/dL] and 25% [30 (95% CI = 8.53) mg/dL] higher serum total, non-HDL and LDL cholesterol, respectively, compared to women in the lowest quartile of MECPP. Similar positive associations were found for urinary concentrations of other metabolites of di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. Pregnant women with urinary mono-n-butyl phthalate (MBP) in the highest quartile had higher triglycerides and non-HDL cholesterol compared to women with MBP in the lowest quartile. Women with detectable concentrations of two phthalate replacement metabolites had lower HDL cholesterol compared to women with non-detectable concentrations. Gestational urinary concentrations of certain phthalate and phthalate replacement metabolites were associated with lipid levels among these women.

18.
Fertil Steril ; 118(1): 148-157, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35725116

RESUMO

OBJECTIVE: To evaluate the associations of caffeinated, alcoholic, and sweetened beverage intakes with antral follicle count (AFC), a well-accepted biomarker of ovarian reserve. DESIGN: Observational prospective cohort study. SETTING: Fertility center at an academic hospital. PATIENTS: This study includes 567 women seeking fertility care at the Massachusetts General Hospital who participated in the Environment and Reproductive Health Study. INTERVENTION: None. Women self-reported consumption of caffeinated (coffee, tea, soda), alcoholic (wine, beer, liquor), sugar-sweetened, and artificially sweetened beverages using a validated food-frequency questionnaire. MAIN OUTCOME MEASURE: Antral follicle count was assessed using a transvaginal ultrasound performed on the 3rd day of an unstimulated menstrual cycle or on the 3rd day of a progesterone withdrawal bleed. RESULTS: Median (interquartile range) age and AFC were 35.0 (32.0-38.0) years and 13.0 (9.0-18.0), respectively. Median (range) intake of caffeinated, alcoholic, sugar-sweetened, and artificially sweetened beverages in servings/day were 1.08 (0-7.08), 0.35 (0-3.84), 0.04 (0-4.80), and 0.04 (0-7.50), respectively. All examined beverages were unrelated to AFC. The multivariable adjusted mean AFC (95% confidence interval) for women in the top and bottom quartiles of intake were 13.8 (13.0-14.7) and 13.8 (12.9-14.7) for caffeinated beverages; 13.8 (13.0-14.7) and 13.8 (13.0-14.6) for alcoholic beverages; 13.5 (12.6-14.4) and 13.3 (12.4-14.2) for sugar-sweetened beverages; and 13.2 (12.4-14.1) and 13.4 (12.6-14.3) for artificially sweetened beverages. CONCLUSION: Low-to-moderate intakes of caffeinated, alcoholic, sugar-sweetened, and artificially sweetened beverages were unrelated to ovarian reserve, as measured by AFC, in a cohort of women seeking fertility care.


Assuntos
Reserva Ovariana , Bebidas/efeitos adversos , Feminino , Humanos , Estudos Prospectivos , Açúcares , Edulcorantes
19.
Am J Obstet Gynecol ; 227(2): 246.e1-246.e11, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35364062

RESUMO

BACKGROUND: Long-chain omega-3 fatty acids and their food sources have garnered interest as a potential nutrient with wide-range health benefits, including fertility. OBJECTIVE: This study aimed to investigate the association of women's and men's intake of omega-3 fatty acids and omega-3 rich-foods with semen quality and outcomes of infertility treatment with assisted reproductive technologies. STUDY DESIGN: Couples presenting to the Massachusetts General Hospital were invited to enroll in a prospective cohort study (2007-2020). Male and female diets were assessed using a validated 131-item food frequency questionnaire. The primary outcomes were implantation, clinical pregnancy, and live birth probabilities. The secondary outcomes included total and clinical pregnancy loss and conventional semen parameters, for males only. We estimated the relationship between intakes of omega-3 fatty acids, nuts, and fish and the probability (95% confidence interval) of study outcomes using generalized linear mixed models to account for repeated treatment cycles per participant while simultaneously adjusting for age, body mass index, smoking status, education, dietary patterns, total energy intake, and male partner diet. RESULTS: A total of 229 couples and 410 assisted reproductive technology cycles were analyzed for primary and secondary outcomes. Of note, 343 men contributing 896 semen samples were included in analyses for semen quality measures. Women's docosahexaenoic acid + eicosapentaenoic acid intake was positively associated with live birth. The multivariable-adjusted probabilities of live birth for women in the bottom and top quartiles of eicosapentaenoic acid + docosahexaenoic acid intake were 0.36 (95% confidence interval, 0.26-0.48) and 0.54 (95% confidence interval, 0.42-0.66) (P trend=.02). Eicosapentaenoic acid + docosahexaenoic acid intake was inversely related to the risk of pregnancy loss, which was 0.53 among women in the lowest quartile of eicosapentaenoic acid + docosahexaenoic acid intake and 0.05 among women in the highest quartile (P trend=.01). Men's intake of total omega-3 fatty acids was positively related to sperm count, concentration, and motility, but unrelated to any assisted reproductive technology outcomes. Similar associations were observed when evaluating the intake of primary food sources of these fatty acids. CONCLUSION: Women's consumption of omega-3 fatty acids and omega-3-rich foods may improve the probability of conception by decreasing the risk of pregnancy loss. In addition, men's intake of omega-3 fatty acids may influence semen quality.


Assuntos
Ácidos Graxos Ômega-3 , Análise do Sêmen , Animais , Dieta , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Feminino , Humanos , Masculino , Gravidez , Taxa de Gravidez , Estudos Prospectivos , Técnicas de Reprodução Assistida , Sêmen
20.
Sci Total Environ ; 833: 155191, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35421480

RESUMO

The epidemiologic literature on associations between urinary phenol concentrations and lipid profiles during pregnancy is limited. We examined whether urinary concentrations of phenol and phenol replacement biomarkers were associated with serum lipid levels among pregnant women. This cross-sectional study included 175 women attending the Massachusetts General Hospital Fertility Center who enrolled in the Environment and Reproductive Health (EARTH) Study between 2005 and 2017 and had data available on urinary phenol biomarkers and serum lipids during pregnancy. We used linear regression models to assess the relationship between groups of urinary phenol and phenol replacement biomarkers and serum lipid levels [total cholesterol, high density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL) cholesterol, and triglycerides], while adjusting for age at sample collection, pre-pregnancy BMI, education, race, infertility diagnosis, cycle type, number of fetuses, trimester and specific gravity. In adjusted models, pregnant women with urinary propylparaben concentrations in the highest tertile had 10% [22 (95% CI = 5, 40) mg/dL], 12% [19 (95% CI = 2, 36) mg/dL] and 16% [19 (95% CI = 3, 35) mg/dL] higher mean total, non-HDL and LDL cholesterol, respectively, compared to women with concentrations in the lowest tertile. Similar elevations were observed for urinary bisphenol A concentrations. Urinary bisphenol S, benzophenone-3, triclosan, methylparaben, ethylparaben, and butylparaben were unrelated to serum lipids. Among pregnant women, urinary concentrations of bisphenol A and propylparaben were associated with higher serum levels of total, non-HDL and LDL cholesterol.


Assuntos
Compostos Benzidrílicos , Colesterol , Parabenos , Fenóis , Gravidez , Triglicerídeos , Biomarcadores/sangue , Biomarcadores/urina , Colesterol/sangue , Estudos Transversais , Feminino , Humanos , Fenóis/urina , Gravidez/sangue , Gravidez/urina , Saúde Reprodutiva , Triglicerídeos/sangue
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