Publications by authors named "Russ Hauser"

379 Publications

Endocrine Disrupting Chemicals and Risk of Testicular Cancer A Systematic Review and Meta-analysis.

J Clin Endocrinol Metab 2021 Jul 16. Epub 2021 Jul 16.

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

The incidence of many hormone-dependent diseases, including testicular cancer, have sharply increased in all high-income countries during the 20th century. This is not fully explained by established risk factors. Concurrent, increasing exposure to antiandrogenic environmental endocrine disrupting chemicals (EDCs) in fetal life may partially explain this trend. This systematic review assessed available evidence regarding the association between environmental EDC exposure and risk of testicular cancer (seminomas and non-seminomas). Following PRISMA guidelines, a search of English peer-reviewed literature published prior to December 14 th, 2020, in the databases PubMed and Embase® was performed. Among the 279 identified records, 19 were eligible for quality assessment and 10 for further meta-analysis. The completeness of reporting was high across papers, but over 50% were considered subject to potential risk of bias. Mean age at diagnosis was 31.9 years. None considered effects of EDCs multipollutant mixtures. The meta-analyses showed that maternal exposure to combined EDCs was associated with a higher risk of testicular cancer in male offspring (summary RRs: 2.16, (95% CI:1.78-2.62); 1.93 (95% CI:1.49-2.48); 2.78 (95% CI:2.27-3.41) for all, seminoma, non-seminoma respectively). Similarly, high maternal exposures to grouped organochlorines and organo-halogens were associated with higher risk of seminoma and non-seminoma in the offspring. Summary estimates related to postnatal adult male EDC exposures were inconsistent.Maternal but not postnatal adult male, EDC exposures were consistently associated with a higher risk of testicular cancer, particularly risk of non-seminomas. However, the quality of studies was mixed and considering the fields complexity, more prospective studies of prenatal EDC multipollutant mixture exposures and testicular cancer are needed.
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http://dx.doi.org/10.1210/clinem/dgab523DOI Listing
July 2021

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

Fertil Steril 2021 Jul 5. Epub 2021 Jul 5.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Objective: To explore windows of vulnerability to prenatal urinary phenol concentrations and preterm birth.

Design: Prospective cohort.

Setting: A large fertility center in Boston, Massachusetts.

Patient(s): A total of 386 mothers who sought fertility treatment and gave birth to a singleton between 2005 and 2018.

Intervention(s): None.

Main Outcome Measure(s): Singleton live birth with gestational age <37 completed weeks.

Result(s): Compared with women with non-preterm births, urinary bisphenol A (BPA) concentrations were higher across gestation among women with preterm births, particularly during mid-to-late pregnancy and among those with female infants. Second trimester BPA concentrations were associated with preterm birth (Risk Ratio [RR] 1.24; 95%CI: 0.92, 1.69), which was primarily driven by female (RR 1.40; 95%CI: 1.04, 1.89) and not male (RR 0.85; 95%CI 0.50, 1.46) infants. First trimester paraben concentrations were also associated with preterm birth (RR 1.17; 95%CI: 0.94, 1.46) and similarly the association was only observed for female (RR 1.46; 95% CI: 1.10, 1.94) and not male infants (RR 0.94; 95%CIC: 0.72, 1.23). First trimester urinary bisphenol S concentrations showed a suggested risk of preterm birth (RR 1.25; 95%CI: 0.82, 1.89), although the small case numbers precluded sex-specific examination.

Conclusion(s): We found preliminary evidence of associations between mid-to-late pregnancy BPA and early pregnancy paraben concentrations with preterm birth among those with female infants only. Preterm birth risk may be compound, sex, and window specific. Given the limited sample size of this cohort, results should be confirmed in larger studies, including fertile populations.
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http://dx.doi.org/10.1016/j.fertnstert.2021.03.053DOI Listing
July 2021

Ambient PM gross β-activity and glucose levels during pregnancy.

Environ Health 2021 Jun 14;20(1):70. Epub 2021 Jun 14.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Exposure to ionizing radiation has been associated with insulin resistance and type 2 diabetes. In light of recent work showing an association between ambient particulate matter (PM) gross β-activity and gestational diabetes mellitus (GDM) among pregnant women, we examined pregnancy glucose levels in relation to PM gross β-activity to better understand this pathway.

Methods: Our study included 103 participants receiving prenatal care at Beth Israel Deaconess Medical Center in Boston, MA. PM gross β-activity was obtained from US Environmental Protection Agency's RadNet program monitors, and blood glucose levels were obtained from the non-fasting glucose challenge test performed clinically as the first step of the 2-step GDM screening test. For each exposure window we examined (i.e., moving average same-day, one-week, first-trimester, and second-trimester PM gross β-activity), we fitted generalized additive models and adjusted for clinical characteristics, socio-demographic factors, temporal variables, and PM with an aerodynamic diameter ≤ 2.5 μm (PM). Subgroup analyses by maternal age and by body mass index were also conducted.

Results: An interquartile range increase in average PM gross β-activity during the second trimester of pregnancy was associated with an increase of 17.5 (95% CI: 0.8, 34.3) mg/dL in glucose concentration. Associations were stronger among younger and overweight/obese participants. Our findings also suggest that the highest compared to the lowest quartile of one-week exposure was associated with 17.0 (95% CI: - 4.0, 38.0) mg/dL higher glucose levels. No associations of glucose were observed with PM gross β-activity during same-day and first-trimester exposure windows. PM was not associated with glucose levels during any exposure window in our data.

Conclusions: Exposure to higher levels of ambient PM gross β-activity was associated with higher blood glucose levels in pregnant patients, with implications for how this novel environmental factor could impact pregnancy health.
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http://dx.doi.org/10.1186/s12940-021-00744-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204493PMC
June 2021

RUBIC (ReproUnion Biobank and Infertility Cohort): A binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility-related morbidity.

Andrology 2021 Jun 10. Epub 2021 Jun 10.

Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Infertility affects 15%-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth.

Objectives: Three overall questions will be studied: (1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? (2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And (3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up?

Material And Methods: ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skåne University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of biospecimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem.
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http://dx.doi.org/10.1111/andr.13063DOI Listing
June 2021

Optimization of small RNA extraction and comparative study of NGS library preparation from low count sperm samples.

Syst Biol Reprod Med 2021 Jun 3;67(3):230-243. Epub 2021 Jun 3.

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.

Recent studies demonstrate that sperm epigenome is a vehicle that conveys paternal experiences to offspring phenotype. That evidence triggers interest of both experimental and epidemiological studies of epigenetic markers in sperm. Since samples are often unique in epidemiological studies, a careful and efficient use of the material is a critical requirement. The goal of this study was to provide optimization of methods for the isolation of small RNAs from spermatozoa and library preparation for sequencing. A total 67 fractionated sperm samples from the Russian Children's Study biobank prospectively collected at 18-20 years of age were used to isolate small RNAs with median (IQR) input total sperm count 17.0 (7.4-35.9) million. Twenty-four pairs of libraries were prepared using the NEBNext and NEXTFlex kits, 19 libraries using NEBNext and 6 using NEXTFlex. All libraries were sequenced on NextSeq 500, and the results were evaluated as a function of the number of small non-coding RNA (sncRNA) detected, quality parameters of sequencing libraries, as well as technical features of sample preparation. Although the same amount of miRNA input was used for NEBNext and NEXTFlex libraries, the concentration of DNA in NEBNext libraries was significantly higher in comparison with NEXTFlex libraries. In high input (sperm count >28 million and more than 25 ng miRNA in library) NEXTFlex Small RNA-Seq kit detected more microRNAs. In low input, the NEBNext proved more effective. The tricks and traps to protocol optimization are presented, including an efficient and effector gel-based system for the removal of sequencing library adaptors.
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http://dx.doi.org/10.1080/19396368.2021.1912851DOI Listing
June 2021

Urinary phthalate metabolite concentrations and serum hormone levels in pre- and perimenopausal women from the Midlife Women's Health Study.

Environ Int 2021 May 15;156:106633. Epub 2021 May 15.

Department of Comparative Biosciences, University of Illinois, Urbana, IL 61802, United States; Institute for Genomic Biology, University of Illinois, Urbana, IL 61801, United States. Electronic address:

Background: Phthalate exposure is associated with altered reproductive function, but little is known about associations between phthalate and hormone levels in midlife women.

Methods: This cross-sectional analysis includes 45-54-year-old pre- and perimenopausal women from Baltimore, MD and its surrounding counties enrolled in the Midlife Women's Health Study (n = 718). Serum and urine samples were collected from participants once a week for four consecutive weeks to span the menstrual cycle. Serum samples were assayed for estradiol, testosterone, progesterone, sex hormone binding globulin (SHBG), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH), and geometric means were calculated for each hormone across all four weeks. Urine samples were analyzed for nine phthalate metabolites from pools of one-to-four urine samples. Phthalate metabolite concentrations were specific gravity-adjusted and assessed as individual metabolites or as molar sums of metabolites from common parents (di(2-ethylhexyl) phthalate metabolites, ∑DEHP), exposure sources (plastic, ∑Plastics; personal care products, ∑PCP), biological activity (anti-androgenic, ∑AA), and sum of all metabolites (∑Phthalates). We used linear regression models to assess overall associations of phthalate metabolites with hormones, controlling for important demographic, lifestyle, and health factors. We also explored whether associations differed by menopause status, body mass index (BMI), and race/ethnicity.

Results: Most participants were non-Hispanic white (67%) or black (29%), college-educated (65%), employed (80%), and had somewhat higher mean urinary phthalate metabolite concentrations than other U.S. women. Overall, the following positive associations were observed between phthalate metabolites and hormones: ∑DEHP (%Δ: 4.9; 95%CI: 0.5, 9.6), ∑Plastics (%Δ: 5.1; 95%CI: 0.3, 10.0), and ∑AA (%Δ: 7.8; 95%CI: 2.3, 13.6) with estradiol; MiBP (%Δ: 6.6; 95%CI: 1.5, 12.1) with testosterone; ∑DEHP (%Δ: 8.3; 95%CI: 1.5, 15.6), ∑Plastics (%Δ: 9.8; 95%CI: 2.4, 17.7), MEP (%Δ: 4.6; 95%CI: 0.1, 9.2), ∑PCP (%Δ: 6.0; 95%CI: 0.2, 12.2), ∑Phthalates (%Δ: 9.0; 95%CI: 2.1, 16.5), and ∑AA (%Δ: 12.9; 95%CI: 4.4, 22.1) with progesterone; and MBP (%Δ: 8.5; 95%CI: 1.2, 16.3) and ∑AA (%Δ: 9.0; 95%CI: 1.3, 17.4) with AMH. Associations of phthalate metabolites with hormones differed by menopause status (strongest in premenopausal women for estradiol, progesterone, and FSH), BMI (strongest in obese women for progesterone), and race/ethnicity (strongest in non-Hispanic white women for estradiol and AMH).

Conclusions: We found that phthalate metabolites were positively associated with several hormones in midlife women, and that some demographic and lifestyle characteristics modified these associations. Future longitudinal studies are needed to corroborate these findings in more diverse midlife populations.
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http://dx.doi.org/10.1016/j.envint.2021.106633DOI Listing
May 2021

Peripubertal serum levels of dioxins, furans and PCBs in a cohort of Russian boys: can empirical grouping methods yield meaningful exposure variables?

Chemosphere 2021 Jul 25;275:130027. Epub 2021 Feb 25.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. Electronic address:

Background: Dioxins, furans and polychlorinated biphenyls (PCBs) are endocrine disruptors with half-lives of months to years in humans. Peripubertal exposure to these chemicals may disrupt pubertal timing. Biomarker exposure metrics like the sum of non-dioxin-like PCBs in serum (∑NDL-PCBs) involve chemicals with different hypothetical effects. Empirical exposure metrics represent an alternative that requires no knowledge of biological mechanisms.

Methods: From 2003 to 2005, 516 Russian boys aged 8-9 residing near a plant that historically produced organochlorine pesticides were enrolled in the Russian Children's Study. At enrollment, blood was collected for measurement of organochlorine chemicals by the Centers for Disease Control and Prevention (CDC). Variable cluster analysis was used to empirically group serum levels of 45 dioxins, furans and PCBs into eight cluster scores. These scores were compared to the sum of dioxin-like toxic equivalents (∑TEQs) and ∑NDL-PCBs using Spearman correlation coefficients.

Results: Clustering appeared to reflect number and position of chlorine atoms. Clusters 4, 7 and 1 contained, respectively, tri/tetra-, tetra/penta-, and hexa/hepta-chlorinated PCBs with chlorines at the 4,4' positions. Clusters 2, 8 and 5 contained, respectively, tetra-to hexa-, hexa/hepta-, and hepta/octa-chlorinated PCBs with chlorines at the 2,2' positions. ∑NDL-PCBs were highly correlated with 4,4'-chlorinated clusters 1 and 7 (Spearman's ρ = 0.8) and less so with all other clusters (Spearman's ρ = 0.4-0.5).

Conclusions: In this cohort of Russian boys, baseline serum dioxins, furans and PCBs seemed to cluster by chlorination pattern, possibly reflecting shared persistence, metabolism or source of exposure. The widely used measure ∑NDL-PCB seemed most representative of 4,4'-chlorinated PCBs.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130027DOI Listing
July 2021

Dataset of testicular germ cell tumors (TGCT) risk associated with serum polychlorinated biphenyl (PCB) by age at diagnosis and histologic types.

Data Brief 2021 Jun 27;36:107014. Epub 2021 Mar 27.

School of Public Health, Brown University, Providence, RI 02903, USA.

In a population-based case control study of testicular germ cell tumors (TGCT), we reported a strong positive association between serum levels of Wolff's Group 1 (potentially estrogenic) polychlorinated biphenyl (PCBs) and risk of TGCT, and the observed associations were similar for both seminoma and non-seminoma. While the observed specific associations between TGCT and Wolff's Group 1 PCBs cannot be easily explained by bias or confounding, a question can still be asked, that is, could the relationship between PCBs and TGCT differ by age at diagnosis? PCBs tend to bioaccumulate, with more heavily chlorinated PCB congeners tending to have longer half-lives. Half-lives of PCB congeners were reported ranging from 4.6 years for PCB-28 to 41.0 years for PCB-156. The half-life for the heavy PCB congeners (17.8 years) was found to be approximately twice that for the light PCBs (9.6 years) in early studies. Therefore, the same PCB concentration measured in a 20-year-old vs. a 55-year-old is unlikely to represent the same lifetime PCB exposure or type of PCB exposure. In this analysis, we stratified the data by median age of diagnosis of TGCT and further stratified by histologic type of TGCT (seminoma vs non-seminoma) to explore if the risk of TGCT associated with PCB exposures differs by age.
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http://dx.doi.org/10.1016/j.dib.2021.107014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076715PMC
June 2021

Association between follicular fluid phthalate concentrations and extracellular vesicle microRNAs expression.

Hum Reprod 2021 05;36(6):1590-1599

Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Study Question: Are phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)?

Summary Answer: Phthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs.

What Is Known Already: Phthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF.

Study Design, Size, Duration: Prospective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital.

Participants/materials, Setting, Methods: We 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 Chance: Of 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 Caution: The 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 Findings: Phthalate 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 Interests: This 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 Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab063DOI Listing
May 2021

Assessing Indoor Dust Interference with Human Nuclear Hormone Receptors in Cell-Based Luciferase Reporter Assays.

Environ Health Perspect 2021 Apr 14;129(4):47010. Epub 2021 Apr 14.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Per- and polyfluoroalkyl substances (PFAS), organophosphate esters (OPEs), and polybrominated diphenyl ethers (PBDEs) are hormone-disrupting chemicals that migrate from building materials into air and dust.

Objectives: We aimed to quantify the hormonal activities of 46 dust samples and identify chemicals driving the observed activities.

Methods: We evaluated associations between hormonal activities of extracted dust in five cell-based luciferase reporter assays and dust concentrations of 42 measured PFAS, OPEs, and PBDEs, transformed as either raw or potency-weighted concentrations based on Tox21 high-throughput screening data.

Results: All dust samples were hormonally active, showing antagonistic activity toward peroxisome proliferator-activated receptor () (100%; 46 of 46 samples), thyroid hormone receptor () (89%; 41 samples), and androgen receptor (AR) (87%; 40 samples); agonist activity on estrogen receptor () (96%; 44 samples); and binding competition with thyroxine () on serum transporter transthyretin (TTR) (98%; 45 samples). Effects were observed with as little as of extracted dust. In regression models for each chemical class, interquartile range increases in potency-weighted or unknown-potency chemical concentrations were associated with higher hormonal activities of dust extracts (potency-weighted: , , ; , , ; , , ; , , ; unknown-potency: , , ; , , ), adjusted for chemicals with active, inactive, and unknown Tox21 designations.

Discussion: All indoor dust samples exhibited hormonal activities, which were associated with PFAS, PBDE, and OPE levels. Reporter gene cell-based assays are relatively inexpensive, health-relevant evaluations of toxic loads of chemical mixtures that building occupants are exposed to. https://doi.org/10.1289/EHP8054.
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http://dx.doi.org/10.1289/EHP8054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045486PMC
April 2021

Urinary phthalate metabolite concentrations and hot flashes in women from an urban convenience sample of midlife women.

Environ Res 2021 06 17;197:110891. Epub 2021 Mar 17.

Department of Comparative Biosciences, University of Illinois, Urbana, IL, 61802, USA; Institute for Genomic Biology, University of Illinois, Urbana, IL, 61802, USA. Electronic address:

Context: Phthalate exposure is associated with altered reproductive function, but little is known about associations of phthalate exposure with risk of hot flashes.

Objective: To investigate associations of urinary phthalate metabolite levels with four hot flash outcomes in midlife women.

Design: A cross-sectional study of the first year of a prospective cohort of midlife women, the Midlife Women's Health Study (2006-2015), a convenience sample from an urban setting.

Participants: 728 multi-racial/ethnic pre- and perimenopausal women aged 45-54 years.

Outcome Measures: Women completed questionnaires about hot flash experience and provided 1-4 urine samples over four consecutive weeks that were pooled for analysis. Phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: ƩPhthalates; DEHP: ƩDEHP), exposure sources (plastics: ƩPlastic; personal care products: ƩPCP), and modes of action (anti-androgenic: ƩAA). Covariate-adjusted logistic regression models were used to assess associations of continuous natural log-transformed phthalate metabolite concentrations with hot flash outcomes. Analyses were conducted to explore whether associations differed by menopause status, body mass index (BMI), race/ethnicity, and depressive symptoms.

Results: Overall, 45% of women reported a history of hot flashes. Compared to women who never experienced hot flashes, every two-fold increase in ƩPlastic was associated with 18% (OR: 1.18; 95%CI: 0.98, 1.43) and 38% (OR: 1.38; 95%CI: 1.11, 1.70) higher odds of experiencing hot flashes in the past 30 days and experiencing daily/weekly hot flashes, respectively. Some associations of phthalates with certain hot flash outcomes differed by menopause status, BMI, race/ethnicity, and depressive symptoms.

Conclusions: This study suggests that phthalates are associated with hot flash experience and may impact hot flash risk in women who are susceptible to experiencing hot flashes.
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http://dx.doi.org/10.1016/j.envres.2021.110891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187273PMC
June 2021

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

Environ Int 2021 06 25;151:106440. Epub 2021 Feb 25.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Massachusetts General Hospital Fertility Center, Harvard Medical School, Boston, MA, USA; Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.envint.2021.106440DOI Listing
June 2021

Per- and polyfluoroalkyl substances and calcifications of the coronary and aortic arteries in adults with prediabetes: Results from the diabetes prevention program outcomes study.

Environ Int 2021 06 22;151:106446. Epub 2021 Feb 22.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification.

Methods And Results: This study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14 years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (<10), moderate (11-400) and severe (>400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC > 11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR = 1.26 (95% CI:1.08, 1.47) for moderate CAC and OR = 1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR = 1.67 (95% CI:1.10, 2.54) and OR = 1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes.

Conclusions: Prediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations.
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http://dx.doi.org/10.1016/j.envint.2021.106446DOI Listing
June 2021

Neurotoxicity of Ortho-Phthalates: Recommendations for Critical Policy Reforms to Protect Brain Development in Children.

Am J Public Health 2021 04 18;111(4):687-695. Epub 2021 Feb 18.

Stephanie M. Engel is with the Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill. Heather B. Patisaul is with the Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh. Charlotte Brody is with Healthy Babies Bright Futures, Charlottesville, VA. Russ Hauser is with the Department of Environmental Health at the Harvard T. H. Chan School of Public Health, Boston, MA. Ami R. Zota is with the Department of Environmental and Occupational Health, George Washington University Milken School of Public Health, Washington, DC. Deborah H. Bennet is with the Department of Public Health Sciences, School of Medicine, University of California at Davis. Maureen Swanson is with The Arc of the United States, Washington, DC. Robin M. Whyatt is with the Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY.

Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning, attention, and behavioral disorders in childhood. This growing body of evidence, along with known adverse effects on male reproductive tract development, calls for immediate action.Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simultaneously. We thus recommend that a class approach be used in assessing health impacts as has been done with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from products that lead to exposure of pregnant women, women of reproductive age, infants, and children. Specific attention should be focused on reducing exposures among socially vulnerable populations such as communities of color, who frequently experience higher exposures.Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multipronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is feasible.
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http://dx.doi.org/10.2105/AJPH.2020.306014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958063PMC
April 2021

Associations of Maternal Androgen-Related Conditions With Risk of Autism Spectrum Disorder in Progeny and Mediation by Cardiovascular, Metabolic, and Fertility Factors.

Am J Epidemiol 2021 04;190(4):600-610

Fetal exposure to elevated androgens is thought to contribute to autism spectrum disorder (ASD) risk. However, data rely heavily on in utero androgens measurements, which also reflect fetal secretions. Thus, in utero hyperandrogenemia might indicate adverse autism-related neurogenesis that has already occurred affecting fetal androgen homeostasis, rather than being a cause of the disorder. Associations between maternal androgen-related conditions and ASD could more directly implicate androgens' etiological role. We examined the association between maternal hyperandrogenemia-related conditions, focusing primarily on polycystic ovarian syndrome (PCOS), and progeny ASD, in an Israeli cohort of 437,222 children born in 1999-2013. Odds ratios and 95% confidence intervals were estimated using generalized estimating equations. Multiple mediation analyses using natural effect models were conducted to evaluate combined mediation of the PCOS effect by androgen-related cardiovascular, metabolic, and fertility factors. Results indicated that children of mothers with PCOS had higher ASD odds compared with children of mothers without PCOS (odds ratio = 1.42, 95% confidence interval: 1.24,1.64), and this effect was only partly mediated by the factors considered. Elevated odds were also observed for other hyperandrogenemia-related conditions. Findings provide support for direct involvement of maternal hyperandrogenemia in ASD etiology. Alternatively, findings might reflect shared genetic and/or environmental factors independently affecting maternal androgen homeostasis and fetal neurodevelopment.
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http://dx.doi.org/10.1093/aje/kwaa219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024051PMC
April 2021

Serum polychlorinated biphenyl (PCB) levels and risk of testicular germ cell tumors: A population-based case-control study in Connecticut and Massachusetts.

Environ Pollut 2021 Jan 11;273:116458. Epub 2021 Jan 11.

School of Public Health, Brown University, Providence, RI, USA, 02903. Electronic address:

The incidence rate of testicular germ cell tumors (TGCT) has continuously increased in Western countries over the last several decades. Some epidemiologic studies have reported that the endocrine disrupting polychlorinated biphenyls (PCBs) in serum may be associated with TGCT risk, but the evidence is inconsistent. Our goal was to investigate whether serum levels of PCBs are associated with the increase of TGCT risk. We conducted a population-based case-control study of 308 TGCT cases and 323 controls, all residents of Connecticut and Massachusetts. Serum levels of 56 PCBs congeners were measured using gas chromatography and unconditional logistic regression model was used to evaluate the risk of TGCT associated with total PCBs exposure, groups of PCBs categorized by Wolff's functional groups, and individual PCB congeners. The results showed that there was no association between total serum levels of PCBs and risk of TGCT overall (quartile 4 (Q4) vs. quartile 1 (Q1) odds ratio (OR) and 95% confidence interval (C.I.) = 1.0 (0.6-1.9), ρ trend = 0.9). However, strong positive association was observed between total serum levels of Wolff's Group 1 (potentially estrogenic) PCBs and risk of overall TGCT (Q4 vs. Q1 OR = 2.5, 95% CI = 1.3-4.7, ρ trend <0.05) as well as seminoma and non-seminoma subtypes. Wolff's Group 1 PCB congeners that showed an increased risk of TGCT included: 25, 44, 49, 52, 70, 101, 174, and 201/177. Considering the continuing increase of TGCT, these associations should be replicated in different populations with larger sample size.
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http://dx.doi.org/10.1016/j.envpol.2021.116458DOI Listing
January 2021

Per- and polyfluoroalkyl substances and kidney function: Follow-up results from the Diabetes Prevention Program trial.

Environ Int 2021 03 19;148:106375. Epub 2021 Jan 19.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA. Electronic address:

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in populations worldwide and may hinder kidney function. The objective of the study was to determine longitudinal associations of plasma PFAS concentrations with estimated glomerular filtration rate (eGFR) and evaluate whether a lifestyle intervention modify the associations. We studied 875 participants initially randomized to the lifestyle or placebo arms in the Diabetes Prevention Program (DPP, 1996-2002) trial and Outcomes Study (DPPOS, 2002-2014). We ran generalized linear mixed models accounting a priori covariates to evaluate the associations between baseline PFAS concentrations and repeated measures of eGFR, separately, for six PFAS (PFOS, PFOA, PFHxS, EtFOSAA, MeFOSAA, PFNA); then used quantile-based g-computation to evaluate the effects of the six PFAS chemicals as a mixture. The cohort was 64.9% female; 73.4% 40-64 years-old; 29.4% with hypertension; 50.5% randomized to lifestyle intervention and 49.5% to placebo and had similar plasma PFAS concentrations as the general U.S. population in 1999-2000. Most participants had normal kidney function (eGFR > 90 mL/min/1.73 m) over the approximately 14 years of follow-up. We found that plasma PFAS concentrations during DPP were inversely associated with eGFR during DPPOS follow-up. Each quartile increase in baseline plasma concentration of the 6 PFAS as a mixture was associated with 2.26 mL/min/1.73 m lower eGFR (95% CI: -4.12, -0.39) at DPPOS Year 5, approximately 9 years since DPP randomization and PFAS measurements. The lifestyle intervention did not modify associations, but inverse associations were stronger among participants with hypertension at baseline. Among prediabetic adults, we found inverse associations between baseline plasma PFAS concentrations and measures of eGFR throughout 14 years of follow-up. The lifestyle intervention of diet, exercise and behavioral changes did not modify the associations, but persons with hypertension may have heightened susceptibility.
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http://dx.doi.org/10.1016/j.envint.2020.106375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929640PMC
March 2021

A Prospective Ultrasound Study of Plasma Polychlorinated Biphenyl Concentrations and Incidence of Uterine Leiomyomata.

Epidemiology 2021 03;32(2):259-267

From the Department of Epidemiology, Boston University School of Public Health, Boston, MA.

Background: Uterine leiomyomata, or fibroids, are hormone-dependent neoplasms of the myometrium that can cause severe gynecologic morbidity. In previous studies, incidence of these lesions has been positively associated with exposure to polychlorinated biphenyls (PCBs), a class of persistent endocrine-disrupting chemicals. However, previous studies have been retrospective in design and none has used ultrasound to reduce disease misclassification.

Methods: The Study of Environment, Lifestyle, and Fibroids is a prospective cohort of 1,693 reproductive-aged Black women residing in Detroit, Michigan (enrolled during 2010-2012). At baseline and every 20 months for 5 years, women completed questionnaires, provided blood samples, and underwent transvaginal ultrasound to detect incident fibroids. We analyzed 754 baseline plasma samples for concentrations of 24 PCB congeners using a case-cohort study design. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals for the association between plasma PCB concentrations and ultrasound-detected fibroid incidence over a 5-year period.

Results: We observed little association between PCB congener concentrations and fibroid incidence. The HR for a one-standard deviation increase in log-transformed total PCBs was 0.94 (95% CI = 0.78, 1.1). The PCB congener with the largest effect estimate was PCB 187 (HR for a one-standard deviation increase in log-transformed exposure = 0.88, 95% CI = 0.73, 1.1). Associations did not seem to vary strongly across PCB groupings based on hormonal activity.

Conclusions: In this cohort of reproductive-aged Black women, plasma PCB concentrations typical of the contemporary general population were not appreciably associated with higher risk of fibroids.
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http://dx.doi.org/10.1097/EDE.0000000000001320DOI Listing
March 2021

Incidence of uterine leiomyoma in relation to urinary concentrations of phthalate and phthalate alternative biomarkers: A prospective ultrasound study.

Environ Int 2021 02 21;147:106218. Epub 2020 Dec 21.

Department of Epidemiology, 715 Albany Street, Boston University School of Public Health, Boston, MA, United States.

Background: Numerous studies suggest that some phthalates have adverse reproductive effects. However, literature on the association between phthalates and incidence of uterine leiomyomata (UL) is limited and inconsistent, with no existing prospective studies.

Objectives: We examined the association of urinary concentrations of phthalate and phthalate alternative biomarkers with UL incidence.

Methods: We conducted a case-cohort analysis within a subgroup of 754 participants in the Study of the Environment, Lifestyle, and Fibroids (SELF), a prospective cohort of premenopausal Black women aged 23-35 years who were recruited during 2010-2012. We quantified fourteen phthalates and two phthalate alternative [1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH)] biomarkers in urine collected at baseline, 20 months, and 40 months. Transvaginal ultrasounds identified UL at baseline and every 20 months during 60 months of follow-up. We evaluated the individual biomarkers, molar sum of di(2-ethylhexyl) phthalate [ΣDEHP] and potency-weighted sum of anti-androgenic [WΣAA] biomarkers. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between biomarkers and UL incidence. We then used quantile g-computation to examine joint associations of multiple phthalate biomarkers with UL incidence.

Results: Most individual biomarkers showed weak-to-moderate inverse associations with UL incidence. HRs comparing highest vs. lowest quartiles of mono-isobutyl phthalate (MiBP) and mono-hydroxyisobutyl phthalate (MHiBP) concentrations were 0.63 (95% CI: 0.40, 1.01) and 0.61 (95% CI: 0.38, 0.96), respectively. Inverse associations for specific phthalates were stronger among women with BMI ≥ 30 kg/m. HRs comparing detectable vs. nondetectable concentrations of DINCH biomarkers were 0.92 (95% CI: 0.62, 1.35) for cyclohexane-1,2-dicarboxylic acid mono hydroxyisononyl ester (MHNCH) and 0.68 (95% CI: 0.38, 1.18) for cyclohexane-1,2-dicarboxylic acid mono carboxyisoocytl ester (MCOCH). For the DEHP metabolite of mono(2-ethylhexyl) phthalate (MEHP), we observed weak-to-moderate positive associations. HRs comparing highest vs. lowest quartiles for MEHP and ΣDEHP were 1.29 (95% CI: 0.82, 2.06) and 0.96 (95% CI: 0.61, 1.50), respectively. In the mixtures analysis, the HR for a joint quartile increase in phthalate biomarker concentrations was 0.90 (95% CI: 0.73, 1.08).

Discussion: In this prospective ultrasound study of reproductive-aged Black women, urinary concentrations of phthalate and DINCH biomarkers were not appreciably associated with higher risk of UL, either individually or jointly.
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http://dx.doi.org/10.1016/j.envint.2020.106218DOI Listing
February 2021

Identifying windows of susceptibility to endocrine disrupting chemicals in relation to gestational weight gain among pregnant women attending a fertility clinic.

Environ Res 2021 03 25;194:110638. Epub 2020 Dec 25.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA. Electronic address:

Background: Exposure to endocrine disrupting chemicals (EDC), such as phthalates and phenols, during pregnancy may be associated with excessive gestational weight gain (GWG), an important predictor of future health of the mother and the offspring. There is however a paucity of literature examining this association, and no study has accounted for the complex nature of EDCs exposure as a time-varying mixture of chemicals.

Objective: We examined the association between trimester-specific EDCs mixture and GWG in pregnant women attending a fertility clinic, to identify windows of susceptibility to such exposures, and assess the individual contribution of each chemical over pregnancy.

Methods: We included 243 pregnant women from the Environment and Reproductive Health (EARTH) Study, who provided up to 3 urine samples (one per trimester), and with available data on GWG. Urinary concentrations of 7 phthalate metabolites, bisphenol A, and 2 parabens, corrected for specific gravity, were included in the analysis. The association between trimester-specific EDCs mixture and GWG was evaluated using multiple regression models - categorizing exposures into concentration quartiles- and with Bayesian Kernel Machine Regression (BKMR), while adjusting for potential confounders. Hierarchical BKMR (hBKMR) was used to account for the time-varying nature of chemical concentrations over pregnancy, identifying the most important trimester and most important EDC within each trimester.

Results: During 1st trimester, higher GWG was observed at higher sum of metabolites of di (2-ethylhexyl) phthalate (ΣDEHP) from both multiple regression (e.g. comparing the 4th quartile with the 1st: β = 2.36 kg, 95% CI: 0.47, 5.19) and BKMR. During 2nd and 3rd trimesters, positive associations with mono-n-butyl phthalate and propylparaben, and negative with ΣDEHP and methylparaben were observed. When evaluating exposures as a time-varying mixture with hBKMR, 1st trimester was the most important exposure window when evaluating prenatal urinary EDCs in relation to GWG. Within the 1st trimester, urinary ΣDEHP, mono-isobutyl phthalate and propylparaben had the highest contribution in the positive association between the mixture and GWG.

Conclusion: We observed positive associations between urinary EDCs during pregnancy, especially DEHP metabolites, and GWG. Our results suggest the 1st trimester of pregnancy as the time window of highest susceptibility to the effects of EDCs on GWG, with potential indication for the design of public health interventions, informing prevention strategies for reducing sources of exposure at specific time points.
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http://dx.doi.org/10.1016/j.envres.2020.110638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946748PMC
March 2021

Impact of "healthier" materials interventions on dust concentrations of per- and polyfluoroalkyl substances, polybrominated diphenyl ethers, and organophosphate esters.

Environ Int 2021 05 19;150:106151. Epub 2020 Oct 19.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Per- and polyfluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDEs), and organophosphate esters (OPEs) are found in building materials and associated with thyroid disease, infertility, and impaired development. This study's objectives were to (1) compare levels of PFAS, PBDEs, and OPEs in dust from spaces with conventional versus "healthier" furniture and carpet, and (2) identify other product sources of flame retardants in situ. We measured 15 PFAS, 8 PBDEs, and 19 OPEs in dust from offices, common areas, and classrooms having undergone either no intervention (conventional rooms in older buildings meeting strict fire codes; n = 12), full "healthier" materials interventions (rooms with "healthier" materials in buildings constructed more recently or gut-renovated; n = 7), or partial interventions (other rooms with at least "healthier" foam furniture but more potential building contamination; n = 28). We also scanned all materials for bromine and phosphorus as surrogates of PBDEs and OPEs respectively, using x-ray fluorescence. In multilevel regression models, rooms with full "healthier" materials interventions had 78% lower dust levels of PFAS than rooms with no intervention (p < 0.01). Rooms with full "healthier" interventions also had 65% lower OPE levels in dust than rooms with no intervention (p < 0.01) and 45% lower PBDEs than rooms with only partial interventions (p < 0.10), adjusted for covariates related to insulation, electronics, and furniture. Bromine loadings from electronics in rooms were associated with PBDE concentrations in dust (p < 0.05), and the presence of exposed insulation was associated with OPE dust concentrations (p < 0.001). Full "healthier" materials renovations successfully reduced chemical classes in dust. Future interventions should address electronics, insulation, and building cross-contamination.
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http://dx.doi.org/10.1016/j.envint.2020.106151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940547PMC
May 2021

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

Environ Int 2021 01 15;146:106171. Epub 2020 Oct 15.

Departments of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, United States; Departments of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, United States.

Background: Few epidemiologic studies have evaluated the impact of paternal environmental exposures, particularly as mixtures, on couples' pregnancy outcomes.

Objective: We investigated whether mixtures of paternal urinary bisphenol A (BPA), paraben, and phthalates were associated with pregnancy outcomes among couples attending a fertility center.

Methods: 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.

Results: 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.

Conclusion: Paternal mixtures of urinary concentrations of DEHP metabolites were related to higher infertility treatment failure.
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http://dx.doi.org/10.1016/j.envint.2020.106171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775891PMC
January 2021

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

Fertil Steril 2020 11 6;114(5):1058-1066. Epub 2020 Oct 6.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.fertnstert.2020.05.044DOI Listing
November 2020

Follicular fluid anti-Müllerian hormone (AMH) concentrations and outcomes of in vitro fertilization cycles with fresh embryo transfer among women at a fertility center.

J Assist Reprod Genet 2020 Nov 6;37(11):2757-2766. Epub 2020 Oct 6.

Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Purpose: To enhance the understanding of the clinical significance of anti-Müllerian hormone (AMH) in follicular fluid, we aimed to determine the variability of AMH concentrations in follicular fluid within and across IVF cycles and whether high follicular fluid AMH concentrations are associated with improved clinical IVF outcomes.

Methods: This was a retrospective cohort study of companion follicular fluid and serum samples from 162 women enrolled in the Environment and Reproductive Health (EARTH) Study between 2010 and 2016. AMH concentrations were quantified using a sandwich enzyme-linked immunosorbent assay. Spearman correlation and intra-class correlation (ICC) were calculated to assess variability of follicular fluid AMH, and generalized linear mixed models were used to evaluate the associations of FF AMH with IVF outcomes.

Results: The median (interquartile range, IQR) age of the 162 women was 34.0 years (32.0, 37.0). Follicular fluid AMH concentrations were highly correlated between follicles within each IVF cycle (Spearman r = 0.78 to 0.86) and across cycles for each woman (ICC 0.87 (95% CI 0.81 to 0.92)). Compared with women in the highest tertile of FF AMH (mean AMH = 2.3 ng/ml), women in the lowest tertile (mean AMH = 0.2 ng/ml) had lower serum AMH (T1 = 0.1 ng/ml vs. T3 = 0.6 ng/ml, p < 0.0001). In adjusted models, higher tertiles of follicular fluid AMH concentrations were associated with lower mean endometrial thickness and higher probability of clinical pregnancy.

Conclusions: Follicular fluid AMH concentrations show little variability between pre-ovulatory follicles, and higher pre-ovulatory follicular fluid AMH may predict a higher probability of clinical pregnancy.
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http://dx.doi.org/10.1007/s10815-020-01956-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642031PMC
November 2020

Correlates of urinary concentrations of phthalate and phthalate alternative metabolites among reproductive-aged Black women from Detroit, Michigan.

J Expo Sci Environ Epidemiol 2021 05 26;31(3):461-475. Epub 2020 Sep 26.

Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

Background: Phthalates are endocrine-disrupting chemicals that are widely present in consumer products. In the United States, Black women are more highly exposed to phthalates than other racial/ethnic groups, yet information on predictors of phthalate exposure among Black women is limited.

Objective: We evaluated the association of demographics, lifestyle, reproductive history, and personal care product use with urinary concentrations of phthalate and phthalate alternative metabolites, using cross-sectional data from a study of 754 Black women from Detroit, Michigan (2010-2012).

Methods: Women completed questionnaires and provided urine specimens which were analyzed for 16 phthalate and phthalate alternative metabolites. We used linear regression models to estimate mean percentage differences and 95% confidence intervals (CIs) in concentrations across levels of correlates.

Results: Monoethyl phthalate (MEP) and MBP concentrations were positively associated with personal care product use, particularly nail products. Educational attainment was positively associated with high molecular weight phthalate concentrations but inversely associated with monobenzyl phthalate (MBzP) concentrations. Parity was positively associated with MBzP concentrations and inversely associated with concentrations of MEP and high molecular weight phthalates.

Significance: We found that sociodemographics, reproductive characteristics, and use of certain personal care products were associated with urinary phthalate concentrations among Black women. Our results emphasize the importance of examining exposure determinants among multiply marginalized populations.
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http://dx.doi.org/10.1038/s41370-020-00270-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994206PMC
May 2021

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

Environ Res 2021 01 22;192:110226. Epub 2020 Sep 22.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envres.2020.110226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736216PMC
January 2021

Ambient air pollution and risk of pregnancy loss among women undergoing assisted reproduction.

Environ Res 2020 12 13;191:110201. Epub 2020 Sep 13.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Vincent Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Accumulating evidence suggests that air pollution increases pregnancy loss; however, most previous studies have focused on case identification from medical records, which may underrepresent early pregnancy losses. Our objective was to investigate the association between acute and chronic exposure to ambient air pollution and time to pregnancy loss among women undergoing assisted reproductive technologies (ART) who are closely followed throughout early pregnancy. We included 275 women (345 human chorionic gonadotropin (hCG)-confirmed pregnancies) undergoing ART at a New England academic fertility center. We estimated daily nitrogen dioxide (NO), ozone (O), fine particulate matter <2.5 μm (PM), and black carbon (BC) exposures using validated spatiotemporal models estimated from first positive hCG test until day of failure or live birth. Air pollution exposures were averaged over the past week and the whole pregnancy. Multivariable Cox proportional hazards models were used to estimate the hazards ratio (HR) for pregnancy loss for an interquartile range (IQR) increase in pollutant exposure. We tested for violation of proportional hazards by considering an interaction between time (in days) since positive hCG (<30 days vs. ≥30 days) and air pollution. The incidence of pregnancy loss was 29 per 100 confirmed pregnancies (n = 99). Among pregnancies not resulting in live birth, the median (IQR) time to loss was 21 (11, 30) days following positive hCG. Average past week exposures to NO, O, PM, and BC were not associated with time to pregnancy loss. Exposure throughout pregnancy to NO was not associated with pregnancy loss; however, there was a statistically significant interaction with time (p-for-interaction<0.001). Specifically, an IQR increase in exposure to NO was positively associated with pregnancy loss after 30 days (HR = 1.34, 95% CI: 1.13, 1.58), but not in the first 30 days after positive hCG (HR = 0.83, 95% CI: 0.57, 1.20). Overall pregnancy exposure to O, PM, and BC were not associated with pregnancy loss regardless of timing. Models evaluating joint effects of all pollutants yielded similar findings. In conclusion, acute and chronic exposure to NO, O, PM, and BC were not associated with risk of pregnancy loss; however, higher exposure to NO throughout pregnancy was associated with increased risk of loss 30 days after positive hCG. In this cohort, later pregnancy losses appeared more susceptible to the detrimental effects of air pollution exposure.
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http://dx.doi.org/10.1016/j.envres.2020.110201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658021PMC
December 2020

Peripubertal serum concentrations of organochlorine pesticides and semen parameters in Russian young men.

Environ Int 2020 11 29;144:106085. Epub 2020 Aug 29.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Background: Epidemiologic literature on the relation of organochlorine pesticides (OCPs) with semen quality among adult men has been inconclusive, and no studies have prospectively explored the association between peripubertal serum OCPs and semen parameters in young men.

Objective: To evaluate prospective associations of peripubertal serum concentrations of hexachlorobenzene (HCB), β-hexachlorocylohexane (β-HCH), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) with semen parameters among young Russian men.

Methods: This prospective cohort study included 152 young men who enrolled in the Russian Children's Study (2003-2005) at age 8-9 years and were followed annually until young adulthood. HCB, β-HCH, and p,p'-DDE concentrations were measured at the CDC by mass spectrometry in serum collected at enrollment. Between 18 and 23 years, semen samples (n = 298) were provided for analysis of volume, concentration, and progressive motility; we also calculated total sperm count and total progressive motile count. Linear mixed models were used to examine the longitudinal associations of quartiles of serum HCB, β-HCH and p,p'-DDE with semen parameters, adjusting for total serum lipids, body mass index, smoking, abstinence time and baseline dietary macronutrient intake.

Results: Lipid-adjusted medians (IQR) for serum HCB, βHCH and p,ṕ-DDE, respectively, were 150 ng/g lipid (102-243), 172 ng/g lipid (120-257) and 275 ng/g lipid (190-465). In adjusted models, we observed lower ejaculated volume with higher serum concentrations of HCB and βHCH, along with reduced progressive motility with higher concentrations of βHCH andp,ṕ-DDE. Men in the highest quartile of serum HCB had a mean (95% Confidence Interval, CI) ejaculated volume of 2.25 mL (1.89, 2.60), as compared to those in the lowest quartile with a mean (95% CI) of 2.97 mL (2.46, 3.49) (p = 0.03). Also, men in the highest quartile of serum p,ṕ-DDE had a mean (95% CI) progressive motility of 51.1% (48.6, 53.7), as compared to those in the lowest quartile with a mean (95% CI) of 55.1% (51.7, 58.5) (p = 0.07).

Conclusion: In this longitudinal Russian cohort study, peripubertal serum concentrations of selected OCPs were associated with lower ejaculated volume and progressive motility highlighting the importance of the peripubertal window when evaluating chemical exposures in relation to semen quality.
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November 2020

Machine learning vs. classic statistics for the prediction of IVF outcomes.

J Assist Reprod Genet 2020 Oct 11;37(10):2405-2412. Epub 2020 Aug 11.

Department of Obstetrics and Gynecology, Sheba Medical Center, 52561, Ramat Gan, Israel.

Purpose: To assess whether machine learning methods provide advantage over classic statistical modeling for the prediction of IVF outcomes.

Methods: The study population consisted of 136 women undergoing a fresh IVF cycle from January 2014 to August 2016 at a tertiary, university-affiliated medical center. We tested the ability of two machine learning algorithms, support vector machine (SVM) and artificial neural network (NN), vs. classic statistics (logistic regression) to predict IVF outcomes (number of oocytes retrieved, mature oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births) based on age and BMI, with or without clinical data.

Results: Machine learning algorithms (SVM and NN) based on age, BMI, and clinical features yielded better performances in predicting number of oocytes retrieved, mature oocytes, fertilized oocytes, top-quality embryos, positive beta-hCG, clinical pregnancies, and live births, compared with logistic regression models. While accuracies were 0.69 to 0.9 and 0.45 to 0.77 for NN and SVM, respectively, they were 0.34 to 0.74 using logistic regression models.

Conclusions: Our findings suggest that machine learning algorithms based on age, BMI, and clinical data have an advantage over logistic regression for the prediction of IVF outcomes and therefore can assist fertility specialists' counselling and their patients in adjusting the appropriate treatment strategy.
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http://dx.doi.org/10.1007/s10815-020-01908-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550518PMC
October 2020

Urinary Concentrations of Phthalate Metabolite Mixtures in Relation to Serum Biomarkers of Thyroid Function and Autoimmunity among Women from a Fertility Center.

Environ Health Perspect 2020 06 9;128(6):67007. Epub 2020 Jun 9.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women.

Objective: We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity.

Methods: This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005-2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (, ) and triiodothyronine (, ), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores.

Results: We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of , , , and [absolute difference: ; 95% confidence interval (CI): , ; ; absolute difference: ; 95% CI: , ; ; absolute difference: ; 95% CI: 0.54, ; ; and absolute difference: ; 95% CI: , ; , respectively]. Using BKMR, we observed that mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was the primary contributor to these negative associations. DEHP and non-DEHP factor scores were not associated with serum TSH, TgAb, or TPOAb.

Conclusions: Mixtures of urinary DEHP metabolites were inversely associated with serum biomarkers of thyroid function but not with autoimmunity, which were within normal ranges for healthy adult women. https://doi.org/10.1289/EHP6740.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282564PMC
June 2020
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