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Causal mediation analysis aims to characterize an exposure's effect on an outcome and quantify the indirect effect that acts through a given mediator or a group of mediators of interest. With the increasing availability of measurements on a large number of potential mediators, like the epigenome or the microbiome, new statistical methods are needed to simultaneously accommodate high-dimensional mediators while directly target penalization of the natural indirect effect (NIE) for active mediator identification. Here, we develop two novel prior models for identification of active mediators in high-dimensional mediation analysis through penalizing NIEs in a Bayesian paradigm. Both methods specify a joint prior distribution on the exposure-mediator effect and mediator-outcome effect with either (a) a four-component Gaussian mixture prior or (b) a product threshold Gaussian prior. By jointly modelling the two parameters that contribute to the NIE, the proposed methods enable penalization on their product in a targeted way. Resultant inference can take into account the four-component composite structure underlying the NIE. We show through simulations that the proposed methods improve both selection and estimation accuracy compared to other competing methods. We applied our methods for an in-depth analysis of two ongoing epidemiologic studies: the Multi-Ethnic Study of Atherosclerosis (MESA) and the LIFECODES birth cohort. The identified active mediators in both studies reveal important biological pathways for understanding disease mechanisms.

BackgroundOxidative stress from excess reactive oxygen species (ROS) is a hypothesized contributor to preterm birth. Per- and polyfluoroalkyl substances (PFAS) exposure is reported to generate ROS in laboratory settings, and is linked to adverse birth outcomes globally. However, to our knowledge, the relationship between PFAS and oxidative stress has not been examined in the context of human pregnancy.ObjectiveTo investigate the associations between prenatal PFAS exposure and oxidative stress biomarkers among pregnant people.MethodsOur analytic sample included 428 participants enrolled in the Illinois Kids Development Study and Chemicals In Our Bodies prospective birth cohorts between 2014 and 2019. Twelve PFAS were measured in second trimester serum. We focused on seven PFAS that were detected in>65% of participants. Urinary levels of 8-isoprostane-prostaglandin-F2α, prostaglandin-F2α, 2,3-dinor-8-iso-PGF2α, and 2,3-dinor-5,6-dihydro-8-iso-PGF2α were measured in the second and third trimesters as biomarkers of oxidative stress. We fit linear mixed-effects models to estimate individual associations between PFAS and oxidative stress biomarkers. We used quantile g-computation and Bayesian kernel machine regression (BKMR) to assess associations between the PFAS mixture and averaged oxidative stress biomarkers.ResultsLinear mixed-effects models showed that an interquartile range increase in perfluorooctane sulfonic acid (PFOS) was associated with an increase in 8-isoprostane-prostaglandin-F2α (β=0.10, 95% confidence interval=0, 0.20). In both quantile g-computation and BKMR, and across all oxidative stress biomarkers, PFOS contributed the most to the overall mixture effect. The six remaining PFAS were not significantly associated with changes in oxidative stress biomarkers.ConclusionsOur study is the first to investigate the relationship between PFAS exposure and biomarkers of oxidative stress during human pregnancy. We found that PFOS was associated with elevated levels of oxidative stress, which is consistent with prior work in animal models and cell lines. Future research is needed to understand how prenatal PFAS exposure and maternal oxidative stress may affect fetal development.

Exposure to essential and non-essential metals is widespread. Metals exposure is linked to epigenetic, particularly DNA methylation, differences. The strength of evidence with respect to the metal exposure type, timing, and level, as well as the DNA methylation association magnitude, and reproducibility are not clear. Focusing on the most recent 3 years, we reviewed the human epidemiologic evidence (n = 26 studies) and the toxicologic animal model evidence (n = 18 studies) for associations between metals exposure and DNA methylation.In humans, the greatest number of studies focused on lead exposure, followed by studies examining cadmium and arsenic. Approximately half of studies considered metals exposure during the in utero period and measured DNA methylation with the genome-wide Illumina arrays in newborn blood or placenta. Few studies performed formal replication testing or meta-analyses. Toxicology studies of metals and epigenetics had diversity in model systems (mice, rats, drosophila, tilapia, and zebrafish were represented), high heterogeneity of tissues used for DNA methylation measure (liver, testis, ovary, heart, blood, brain, muscle, lung, kidney, whole embryo), and a variety of technologies used for DNA methylation assessment (global, gene specific, genome-wide). The most common metals tested in toxicologic studies were lead and cadmium. Together, the recent studies reviewed provide the strongest evidence for DNA methylation signatures with prenatal metals exposures. There is also mounting epidemiologic evidence supporting lead, arsenic, and cadmium exposures with DNA methylation signatures in adults. The field of metals and DNA methylation is strengthened by the inclusion of both epidemiology and toxicology approaches, and further advancements can be made by coordinating efforts or integrating analyses across studies. Future advances in understanding the molecular basis of sequence specific epigenetic responses to metals exposures, methods for handling exposure mixtures in a genome-wide analytic framework, and pipelines to facilitate collaborative testing will continue to advance the field.

Lipidome-wide metabolites may be useful biomarkers of pregnancy outcomes. We sought to characterize maternal lipidomic signatures associated with preterm birth and neonatal anthropometric parameters. Plasma samples were collected 24–28 weeks gestation, and lipidomic profiling was quantified using high-performance liquid chromatography tandem mass spectrometry. Lipid metabolites were analyzed individually and as whole lipid classes and subgroups based on degree of hydrocarbon chain saturation. Associations were estimated using linear and logistic regression. After false discovery adjustment (q

Diverse toxicological mechanisms may mediate the impact of environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. In this study, we introduce an analytical framework for multivariate mediation analysis to identify mediation pathways (q = 61 mediators) in the relationship between environmental toxicants (p = 38 analytes) and gestational age at delivery. Our analytical framework includes: (1) conducting pairwise mediation for unique exposure-mediator combinations, (2) exposure dimension reduction by estimating environmental risk scores, and (3) multivariate mediator analysis using either Bayesian shrinkage mediation analysis, population value decomposition, or mediation pathway penalization. Dimension reduction demonstrates that a one-unit increase in phthalate risk score is associated with a total effect of 1.07 lower gestational age (in weeks) at delivery (95% confidence interval: 0.48–1.67) and eicosanoids from the cytochrome p450 pathway mediated 26% of this effect (95% confidence interval: 4–63%). Eicosanoid products derived from the cytochrome p450 pathway may be important mediators of phthalate toxicity., Diverse toxicological mechanisms may mediate the impact of environmental toxicants on pregnancy outcomes. In this study the authors introduce an analytical framework for multivariate mediation analysis to identify mediation pathways in the relationship between environmental toxicants and gestational age at delivery.

Exposure to trace metals may impact reproductive health outcomes through perturbations in maternal immune signaling molecules. We conducted a cross-sectional study of 390 pregnant women from the LIFECODES birth cohort and investigated the associations between 17 urinary metals and five immune biomarkers measured in the 3(rd) trimester (median 26 weeks gestation). We used linear regression to estimate pair-wise associations and applied elastic net and Bayesian kernel machine regression to identify important contributing exposures analytes as well as non-linear effects. Maternal urinary manganese, nickel, and barium were positively associated with maternal plasma interleukin-1β (IL-1β). Elastic net and Bayesian kernel machine regression identified manganese as the dominant trace metal in association with IL-1β. An interquartile range difference in manganese (0.6 μg/L) was associated with a 29% increase in IL-1β (95% CI: 12.4 – 48.2). In conclusion, trace metal exposures were associated with biomarkers of immune perturbations, and this warrants further investigation.

Phthalates are used in the manufacturing of consumer products, resulting in ubiquitous human exposure to phthalate mixtures. Previous work has suggested that phthalates display endocrine-disrupting capabilities, and exposure is associated with early delivery.To assess mediating effects of hormone concentrations on associations between phthalate mixtures and preterm birth (PTB).Repeated urinary phthalates and serum hormones were measured among 1011 women in the PROTECT Puerto Rico birth cohort from 2011-2019. We utilized ridge regression to create phthalate environmental risk scores (ERS), which represent weighted summaries of total phthalate exposure. Mediation analyses were conducted on a subset of 705 women. We additionally conducted fetal sex-specific analyses.Free thyroxine (FT4) mediated 9.6% of the association between high molecular weight (HMW) ERS at 18 weeks and reduced gestational age at delivery (95%CI:1.07-29.9). Progesterone at 26 weeks mediated 21.1% and 16.2% of the association between HMW ERS at 18 and 22 weeks, and spontaneous PTB, respectively. Among male fetuses, corticotropin releasing hormone (CRH) at 18 weeks mediated 28.2% of the association between low molecular weight ERS and spontaneous PTB.We provide introductory evidence of hormone disruption on the causal pathway between phthalate exposure and early delivery. We also show differences by fetal sex, but larger sample size is necessary to validate our findings.This study provides introductory evidence that an alteration of hormone concentrations occurs on the causal pathway between gestational phthalate mixture exposure and subsequent PTB. In addition to the novel application of repeated biomarker measurements and mixtures methods in causal mediation analyses, we also explored differences between classes of phthalate compounds and between fetal sexes. We show that differential endocrine pathways may be disrupted with exposures to low versus HMW phthalate compounds, and that pregnancies with a male fetus may be more susceptible to endocrine disruption than those with a female fetus.

We consider Bayesian high-dimensional mediation analysis to identify among a large set of correlated potential mediators the active ones that mediate the effect from an exposure variable to an outcome of interest. Correlations among mediators are commonly observed in modern data analysis; examples include the activated voxels within connected regions in brain image data, regulatory signals driven by gene networks in genome data, and correlated exposure data from the same source. When correlations are present among active mediators, mediation analysis that fails to account for such correlation can be suboptimal and may lead to a loss of power in identifying active mediators. Building upon a recent high-dimensional mediation analysis framework, we propose two Bayesian hierarchical models, one with a Gaussian mixture prior that enables correlated mediator selection and the other with a Potts mixture prior that accounts for the correlation among active mediators in mediation analysis. We develop efficient sampling algorithms for both methods. Various simulations demonstrate that our methods enable effective identification of correlated active mediators, which could be missed by using existing methods that assume prior independence among active mediators. The proposed methods are applied to the LIFECODES birth cohort and the Multi-Ethnic Study of Atherosclerosis (MESA) and identified new active mediators with important biological implications.

BackgroundPhthalates have been reported to alter circulating lipid concentrations in animals, and investigation of these associations in humans will provide greater understanding of potential mechanisms for health outcomes.Objectiveto explore associations between phthalate metabolite biomarkers and lipidomic profiles among pregnant women (n = 99) in the Puerto Rico PROTECT cohort.MethodsWe measured 19 urinary phthalate metabolites during 24-28 weeks of pregnancy. Lipidomic profiles were identified from plasma samples by liquid chromatography-mass spectrometry-based shotgun lipidomics. Relationships between phthalates and lipid profiles were estimated using compound-by-compound comparisons in multiple linear regression and dimension reduction techniques. We derived sums for each lipid class and sub-class (saturated, monounsaturated, polyunsaturated) which were then regressed on phthalates. Associations were adjusted for false discovery.ResultsAfter controlling for multiple comparisons, 33 phthalate-lipid associations were identified (q-valueSignificanceCharacterization of associations between lipidomic markers and phthalates during pregnancy will yield mechanistic insight for maternal and child health outcomes.Impact StatementThis study leverages emerging technology to evaluate lipidome-wide signatures of phthalate exposure during pregnancy. Circulating lipids are critical for biological processes including inflammation, cell-to-cell communication, and metabolism. Therefore, lipid signatures of phthalate exposure provide insight into potential toxicological mechanisms. Characterization of these mechanisms are relevant for informing the etiology of maternal and children’s health outcomes.

Background Preterm birth is defined by the onset of labor at a gestational age shorter than 37 weeks, and it can lead to premature birth and impose a threat to newborns’ health. The Puerto Rico PROTECT cohort is a well-characterized prospective birth cohort that was designed to investigate environmental and social contributors to preterm birth in Puerto Rico, where preterm birth rates have been elevated in recent decades. To elucidate possible relationships between metabolites and preterm birth in this cohort, we conducted a nested case-control study to conduct untargeted metabolomic characterization of maternal plasma of 31 women who experienced preterm birth and 69 controls who underwent full-term labor at 24–28 gestational weeks. Results A total of 333 metabolites were identified and annotated with liquid chromatography/mass spectrometry. Subsequent weighted gene correlation network analysis shows that the fatty acid and carene-enriched module has a significant positive association (P = 8e−04, FDR = 0.006) with preterm birth. After controlling for potential clinical confounders, a total of 38 metabolites demonstrated significant changes uniquely associated with preterm birth, where 17 of them were preterm biomarkers. Among 7 machine-learning classifiers, the application of random forest achieved a highly accurate and specific prediction (AUC = 0.92) for preterm birth in testing data, demonstrating their strong potential as biomarkers for preterm births. The 17 preterm biomarkers are involved in cell signaling, lipid metabolism, and lipid peroxidation functions. Additional modeling using only the 19 spontaneous preterm births (sPTB) and controls identifies 16 sPTB markers, with an AUC of 0.89 in testing data. Half of the sPTB overlap with those markers for preterm births. Further causality analysis infers that suberic acid upregulates several fatty acids to promote preterm birth. Conclusions Altogether, this study demonstrates the involvement of lipids, particularly fatty acids, in the pathogenesis of preterm birth.

This study examined the relationship between prenatal maternal stress (PREMS) and non-nutritive suck (NNS) and tested its robustness across 2 demographically diverse populations.The study involved 2 prospective birth cohorts participating in the national Environmental influences on Child Health Outcomes (ECHO) Program: Illinois Kids Development Study (IKIDS) and ECHO Puerto Rico (ECHO-PROTECT). PREMS was measured during late pregnancy via the 10-item Perceived Stress Scale (PSS-10). NNS was sampled from 1- to 8-week-olds using a custom pacifier for ~5 min.Overall, 237 mother-infant dyads completed this study. Despite several significant differences, including race/ethnicity, income, education, and PREMS levels, significant PREMS-NNS associations were found in the 2 cohorts. In adjusted linear regression models, higher PREMS, measured through PSS-10 total scores, related to fewer but longer NNS bursts per minute.A significant association was observed between PREMS and NNS across two diverse cohorts. This finding is important as it may enable the earlier detection of exposure-related deficits and, as a result, earlier intervention, which potentially can optimize outcomes. More research is needed to understand how NNS affects children's neurofunction and development.In this double-cohort study, we found that higher maternal perceived stress assessed in late pregnancy was significantly associated with fewer but longer sucking bursts in 1- to 8-week-old infants. This is the first study investigating the association between prenatal maternal stress (PREMS) and infant non-nutritive suck (NNS), an early indicator of central nervous system integrity. Non-nutritive suck is a potential marker of increased prenatal stress in diverse populations. Non-nutritive suck can potentially serve as an early indicator of exposure-related neuropsychological deficits allowing for earlier interventions and thus better prognoses.

Early-life lead (Pb) exposure has been linked to adverse neurodevelopmental outcomes. Recent evidence has indicated a critical role of DNA methylation (DNAm) in cognition, and Pb exposure has also been shown to alter DNAm. However, it is unknown whether DNAm is part of the mechanism of Pb neurotoxicity. This longitudinal study investigated the associations between trimester-specific (T1, T2, and T3) maternal blood Pb concentrations, gene-specific DNAm in umbilical cord blood, and infant neurodevelopmental outcomes at 12 and 24 months of age (mental development index, psychomotor development index, and behavioral rating scale of orientation/engagement and emotional regulation) among 85 mother–infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study. In the mediation analysis for this pilot study, P

Endogenous signaling molecules derived from lipids, peptides, and DNA, are important regulators of physiological processes during pregnancy. The effect of their collective impact on preterm birth (delivery

Introduction Preterm birth continues to be a significant public heath concern and is a leading cause of perinatal and infant mortality. Environmental exposures to phenols and parabens are suspected to potentially contribute to the pathology of preterm birth, yet limited human studies have characterized the extent to which these toxicants are associated with birth outcomes. Methods We examined the associations between phenols, parabens, and preterm birth, within pregnant women who were recruited early in gestation into the LIFECODES cohort at Brigham and Women's Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points in pregnancy and analyzed for phenols and parabens. We selected 130 cases of preterm birth (defined as delivery before 37 weeks gestation), and 350 random controls. We categorized preterm birth subtypes based on clinical presentation and identified 75 cases of spontaneous preterm birth (characterized by spontaneous preterm labor and/or preterm premature rupture of membranes), and 37 cases of placental preterm birth (characterized by preeclampsia and/or intrauterine growth restriction). We used multivariate logistic regression with visit specific and geometric averages of phenols and parabens to determine associations with preterm birth. Results We observed moderate variability in urinary phenol and paraben concentrations over pregnancy with intraclass correlation coefficients ranging between 0.45 and 0.68. Regression analyses indicated mostly null associations. We observed inverse associations, notably between 2,5-dichlorophenol and overall preterm birth (adjusted odds ratio [95% confidence interval, CI]: 0.79 [0.67 – 0.94]), and this relationship was consistent by study visit. Conversely, ethyl paraben was associated with increased risk for placental preterm birth (adjusted odds ratio [95% CI]: 1.47 [1.14 – 1.91]). Bisphenol-S detection at visit 4 was associated with overall preterm birth (adjusted odds ratio [95% CI]: 2.05 [1.09, 3.89]). Conclusions While the findings from this study largely indicate null associations, we observed some relationships between select phenols, parabens and preterm birth, which warrants further investigation of these toxicants and birth outcomes.

Background Maternal immune system regulation is critical for maintenance of a healthy pregnancy and fetal development. Exposure to phenols and parabens is widespread, and may be linked to systemic inflammation and alteration of circulating immunological biomarkers. Objective We sought to characterize associations between repeated measures of individual urinary phenols, parabens and plasma inflammatory markers across pregnancy. Methods In the LIFECODES prospective birth cohort, we conducted a nested preterm birth case-control study, including 130 cases and 352 controls. In urine samples collected from each participant at up to four study visits during pregnancy, we measured concentrations of six phenols and four parabens, as well as five plasma inflammatory markers. We used multivariable linear mixed models to analyze repeated measures of exposures on inflammatory markers. We created and applied inverse probability weights to account for the sampling approach. Results We observed bidirectional associations between select phenols and parabens and inflammatory markers. An interquartile range increase in triclosan (55.2 ng/mL) was associated with a 12.5% (95% CI: 3.67, 22.0) increase in C-reactive protein, a 7.95% (95% CI: 1.95, 14.3) increase in interleukin 10, and a 7.93% (95% CI: 3.82, 12,2) increase in tumor necrosis factor-α. Additionally, an interquartile range increase in 2,5-dichlorophenol (11.0 ng/mL) was associated with a 10% increase in C-reactive protein (95% CI: 1.92, 18.7). Conversely, an interquartile range increase in ethyl paraben (10.4 ng/mL) was associated with a 7.7% decrease in interleukin‑1β (95% CI: −14.1, −0.86). Conclusions Our findings can be organized into two thematic frameworks, one where concentrations of urinary phenols and parabens during pregnancy reflected a pro-inflammatory relationship with immunological biomarkers, and the other contrary theme – an anti-inflammatory relationship. These findings have implications for fetal development and reproductive outcomes, and emphasize the need for further research on immunological mechanisms of phenol and paraben action during pregnancy.

Background: Humans are exposed to mixtures of toxicants that can impact several biological pathways. We investigated the associations between multiple classes of toxicants and an extensive panel of biomarkers indicative of lipid metabolism, inflammation, oxidative stress, and angiogenesis. Methods: We conducted a cross-sectional study of 173 participants (median 26 wk gestation) from the LIFECODES birth cohort. We measured exposure analytes of multiple toxicant classes [metals, phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs)] in urine samples. We also measured endogenous biomarkers (eicosanoids, cytokines, angiogenic markers, and oxidative stress markers) in either plasma or urine. We estimated pair-wise associations between exposure analytes and endogenous biomarkers using multiple linear regression after adjusting for covariates. We used adaptive elastic net regression, hierarchical Bayesian kernel machine regression, and sparse-group LASSO regression to evaluate toxicant mixtures associated with individual endogenous biomarkers. Results: After false-discovery adjustment (q

There is an urgent need to measure the impacts of COVID-19 among gay men and other men who have sex with men (MSM). We conducted a cross-sectional survey with a global sample of gay men and other MSM (n = 2732) from April 16, 2020 to May 4, 2020, through a social networking app. We characterized the economic, mental health, HIV prevention and HIV treatment impacts of COVID-19 and the COVID-19 response, and examined whether sub-groups of our study population are disproportionately impacted by COVID-19. Many gay men and other MSM not only reported economic and mental health consequences, but also interruptions to HIV prevention and testing, and HIV care and treatment services. These consequences were significantly greater among people living with HIV, racial/ethnic minorities, immigrants, sex workers, and socio-economically disadvantaged groups. These findings highlight the urgent need to mitigate the negative impacts of COVID-19 among gay men and other MSM.Existe una necesidad urgente para medir los impactos de COVID-19 entre hombres gay y otros hombres que tienen sexo con hombres (HSH). Hemos conducido una encuesta multifuncional con una prueba mundial de hombres gay y otros HSH (n = 2732) desde el 16 de Abril hasta el 4 de Mayo del 2020, a través de una aplicación de red social. Nosotros caracterizamos los impactos económicos, de salud mental, prevención del VIH y tratamiento del VIH e impactos a COVID-19 y la respuesta de COVID-19, y examinamos si subgrupos de nuestra población de estudio fueron impactados desproporcionadamente por COVID-19. Muchos hombres no tan solo reportaron consecuencias económicas y de salud mental, sino también interrupciones de prevención y de pruebas de VIH, y cuidado del VIH y servicios de tratamiento. Encontramos consecuencias más significantes entre personas viviendo con VIH, grupos raciales/etnicos, migrantes, sexo servidores, y groupos socioeconomicamente disfavorecidos. Los resultados subrayan la necesidad crucial de mitigar los impactos multifacéticos de COVID-19 entre los hombres homosexuales y otros HSH, especialmente para aquellos con vulnerabilidades entrelazadas.

BackgroundMetals exposures have important health effects in pregnancy. The maternal epigenome may be responsive to these exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation.MethodsIn the Early Autism Risk Longitudinal Investigation (EARLI) cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) in 215 participants using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured in the same specimens on the Illumina 450K array (201 participants). A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal to elucidate downstream pathways.ResultsIn multiple linear regression, we observed hypermethylation at 11 DNA methylation sites associated with lead (FDR q-value CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead associated sites were enriched (FDR q-value ARID2. Manganese associated sites were enriched for cellular metabolism pathways (FDR q-value0.86).DiscussionSingle DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways. Future studies should replicate our findings to characterize potential toxicological mechanisms of trace metals through the maternal epigenome.

Background: Phthalates are used in manufacturing of a myriad of consumer products, resulting in ubiquitous human exposure to a mixture of phthalate compounds. Previous work has suggested that phthalates display endocrine disrupting capabilities, and exposure is associated with adverse birth outcomes including preterm birth. This work therefore aimed to assess the mediating effects of hormone concentrations on associations between phthalate mixtures and adverse birth outcomes. Methods: Repeated phthalate metabolites (13) were measured in urine at three time points and hormones (9) were measured in serum at two time points, spanning 16-28 weeks gestation, among 1011 women in the PROTECT (Puerto Rico Testsite for Exploring Contamination Threats) birth cohort. We utilized ridge regression to create phthalate environmental risk scores (ERS) at each study visit grouped by phthalates of high versus low molecular weight (HMW, LMW), which represent a weighted sum of exposure to the mixture of metabolites. Causal mediation analyses were conducted on a subset of 705 women for whom complete phthalate and hormone data were available. We additionally conducted exploratory analyses stratified by fetal sex. Findings: Positive associations between HMW phthalate ERS at the first study visit and odds of spontaneous PTB and reduced gestational age at delivery among all pregnancies were modestly mediated by changes in fT4 (8.81% (-0.55, 51.2) and 9.60% (1.07, 29.9) mediated, respectively). Though total effects of the corresponding ERS on the outcome were not significant, we also observed significant mediating effects for the ratio of testosterone to SHBG at visit 1 on the association between LMW phthalate ERS and spontaneous PTB, and for progesterone at visit 3 on the associations between visits 1 and 2 HMW phthalate ERS and spontaneous PTB among all pregnancies. Among only pregnancies with a male fetus, the inverse association between visit 2 LMW phthalate ERS and spontaneous PTB was marginally mediated by visit 3 CRH (10.8% (-2.5, 32.9) mediated). Interpretation: These results provide introductory evidence of hormone disruption on the causal pathway between phthalate exposure and early delivery. We also provide evidence of differences by fetal sex, but a larger sample size is necessary to validate our findings. Funding: National Institutes of Health, National Institute of Environmental Health Sciences Declaration of Interest: None to declare. Ethical Approval: This study was approved by the research and ethics committees of the University of Michigan School of Public Health, University of Puerto Rico, Northeastern University, and participating hospitals and clinics. All study participants provided full informed consent prior to participation.

Background: There are diverse toxicological mechanisms that may mediate the impact of several toxicant classes (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outco...

Diverse toxicological mechanisms may mediate the impact of environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. In this study we introduce an analytical pipeline for high-dimensional mediation analysis to identify mediation pathways (q = 63 mediators) in the relationship between environmental toxicants (p = 38 analytes) and gestational age at delivery. Our analytical pipeline included: (1) conducting pairwise mediation for unique exposure-mediator combinations, (2) subjecting mediators to Bayesian shrinkage mediation analysis and population value decomposition, and (3) exposure dimension reduction by estimating environmental risk scores. Dimension reduction demonstrated that a one unit increase in phthalate risk score was associated with a total effect of 1.09 lower gestational age (in weeks) at delivery (95% confidence interval: 1.78 – 0.36) and eicosanoids from the cytochrome p450 pathway mediated 24.5% of this effect (95% confidence interval: 4%-66%). Eicosanoid products derived from the cytochrome p450 pathway may be important mediators of phthalate toxicity.

Supplemental Digital Content is available in the text., Toxic metals have been associated with lower birth weight while essential metals have been associated with higher birth weight. Evidence for other metals is either inconsistent or limited in terms of number of studies. This study analyzed 17 urinary metals, individually and as a mixture, and their association with measures of fetal growth in the LIFECODES birth cohort. Ultrasound was used to measure the abdominal circumference, head circumference, and femur length and measures were used to calculate estimated fetal weight at ~26 and ~35 weeks. We calculated the z score based on gestational age at scan, and estimated fetal weight (EFW) was combined with birth weight for longitudinal analyses. Metals were measured in samples collected at ~26 weeks. We used linear mixed-effects models to examine associations between metals and repeated measures of each outcome, controlling for covariates. Principal components analysis reduced the biomarkers to predictors that may share some commonality. We found that an interquartile range increase in selenium was inversely associated with femur length z score as well as other growth outcomes. Other essential metals, however, were associated with an increase in growth. Finally, the PCA component comprised of arsenic, mercury, and tin was associated with decreased head circumference z score (−0.14 [95% CI, −0.23, −0.05]).

Background Exposure to some toxic metals, such as lead and cadmium, has been associated with increased oxidative stress. However less is known about other metals and metal mixtures, especially in pregnant women who are a vulnerable population. Methods To study the relationship between exposure to trace metals and oxidative stress, we analyzed a panel of 17 metals and two oxidative stress biomarkers (8-isoprostane and 8-hydroxydeoxyguanosine [8-OHdG]) in urine samples collected at ~26 weeks gestation from pregnant women in Boston (n = 380). We used linear regression models to calculate percent differences and 95% confidence intervals (CI) in oxidative stress markers for an interquartile range (IQR) increase in each urinary metal with adjustment for other metals. In addition, we applied principal components analysis (PCA) and Bayesian kernel machine regression (BKMR), to examine cumulative effects (within correlated groups of exposures as well as overall) and interactions. Results We estimated 109% (95% CI: 47, 198) higher 8-isoprostane and 71% (95% CI: 45, 102) higher 8-OHdG with an IQR increase in urinary selenium (Se). We also estimated higher 8-isoprostane (47%, 95% CI: 20.5, 79.4) and 8-OHdG (15.3%, 95% CI: 5.09, 26.5) in association with urinary copper (Cu). In our PCA, we observed higher 8-isoprostane levels in association with the “essential” PC (highly loaded by Cu, Se, and Zinc). In BKMR analyses, we also estimated higher levels of both oxidative stress biomarkers with increasing Se and Cu as well as increasing levels of both oxidative stress biomarkers in association with cumulative concentrations of urinary trace metals. Conclusion We observed higher 8-isoprostane and 8-OHdG levels in association with urinary trace metals and elements, particularly Se and Cu, in linear models and using mixtures approaches. Additionally, increasing cumulative exposure to urinary trace metals was associated with higher levels of both oxidative stress biomarkers. The beneficial effects of these compounds should be carefully questioned.

One in ten infants born in the United States is born preterm, or prior to 37 weeks gestation. Exposure to elevated levels of metals, such as lead and arsenic, has been linked to higher risk of preterm birth (PTB), but consequences of lower levels of exposure and less studied metals are unclear. We examined the associations between 17 urinary trace metals individually and in mixtures in relation to PTB. The LIFECODES birth cohort enrolled pregnant women at

Background Preterm birth is a significant public health concern and exposure to phthalates has been shown to be associated with an increased odds of preterm birth. Even modest reductions in gestational age at delivery could entail morbid consequences for the neonate and analyzing data with this additional information may be useful. In the present analysis, we consider gestational age at delivery as our outcome of interest and examine associations with multiple phthalates. Methods Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Women’s Hospital in Boston, Massachusetts. Urine samples were collected at up to four time points during gestation for urinary phthalate metabolite measurement, and birth outcomes were recorded at delivery. From this population, we selected all 130 cases of preterm birth (

BACKGROUND: Maternal immune system regulation is critical for maintenance of a healthy pregnancy and fetal development. Exposure to phenols and parabens is widespread, and may be linked to systemic inflammation and alteration of circulating immunological biomarkers. OBJECTIVE: We sought to characterize associations between repeated measures of individual urinary phenols, parabens and plasma inflammatory markers across pregnancy. METHODS: In the LIFECODES prospective birth cohort, we conducted a nested preterm birth case-control study, including 130 cases and 352 controls. In urine samples collected from each participant at up to four study visits during pregnancy, we measured concentrations of six phenols and four parabens, as well as five plasma inflammatory markers. We used multivariable linear mixed models to analyze repeated measures of exposures on inflammatory markers. We created and applied inverse probability weights to account for the sampling approach. RESULTS: We observed bidirectional associations between select phenols and parabens and inflammatory markers. An interquartile range increase in triclosan (55.2 ng/mL) was associated with a 12.5% (95% CI: 3.67, 22.0) increase in C-reactive protein, a 7.95% (95% CI: 1.95, 14.3) increase in interleukin 10, and a 7.93% (95% CI: 3.82, 12,2) increase in tumor necrosis factor-α. Additionally, an interquartile range increase in 2,5-dichlorophenol (11.0 ng/mL) was associated with a 10% increase in C-reactive protein (95% CI: 1.92, 18.7). Conversely, an interquartile range increase in ethyl paraben (10.4 ng/mL) was associated with a 7.7% decrease in interleukin-1β (95% CI: −14.1, −0.86). CONCLUSIONS: Our findings can be organized into two thematic frameworks, one where concentrations of urinary phenols and parabens during pregnancy reflected a pro-inflammatory relationship with immunological biomarkers, and the other contrary theme – an anti-inflammatory relationship. These findings have implications for fetal development and reproductive outcomes, and emphasize the need for further research on immunological mechanisms of phenol and paraben action during pregnancy.

Background Maternal supply of thyroid hormones during pregnancy serves a critical role in fetal development. Although animal and in vitro studies provide evidence for thyroid hormone disruption as a result of bisphenol A (BPA) exposure, there is still a lack of evidence in human studies, particularly in the context of pregnancy. Objectives We aimed to explore the associations between urinary BPA concentrations and plasma thyroid hormone parameters during gestation in pregnant women, and also investigated potential windows of vulnerability during gestation. Methods Our study population included 116 cases of preterm birth and 323 controls from a nested case-control study. We measured BPA in urine and thyroid hormone parameters in plasma samples collected at up to four study visits during pregnancy (median for each visit: 9.64, 17.9, 26.0, and 35.1 weeks gestation). We used linear mixed models for repeated measures analyses, and multivariate linear regression models stratified by study visit to explore potential windows of susceptibility. Results In our repeated measures analysis, BPA and thyrotropin (TSH) were inversely associated. An interquartile range (IQR) increase in BPA was associated with an 8.21% decrease in TSH (95% confidence interval [CI]: − 14.2, − 1.83), and a 4.79% increase in free T4 (95% CI: 0.82, 8.92). BPA and TSH were also inversely associated in our cross-sectional analyses at visits 3 and 4. Conclusions Our results suggest that TSH is inversely associated with urinary BPA in a consistent manner across pregnancy. Disruption of TSH levels during pregnancy can potentially impact child development and interfere with normal birth outcomes.