Associations of maternal blood metal concentrations with plasma eicosanoids among pregnant women in Puerto Rico.

BACKGROUND/AIM: Heavy metals are known to induce oxidative stress and inflammation, and the association between metal exposure and adverse birth outcomes is well established. However, there lacks research on biomarker profiles linking metal exposures and adverse birth outcomes. Eicosanoids are lipid molecules that regulate inflammation in the body, and there is growing evidence that suggests associations between plasma eicosanoids and pregnancy outcomes. Eicosanoids may aid our understanding of etiologic birth pathways. Here, we assessed associations between maternal blood metal concentrations with eicosanoid profiles among 654 pregnant women in the Puerto Rico PROTECT birth cohort. METHODS: We measured concentrations of 11 metals in whole blood collected at median 18 and 26 weeks of pregnancy, and eicosanoid profiles measured in plasma collected at median 26 weeks. Multivariable linear models were used to regress eicosanoids on metals concentrations. Effect modification by infant sex was explored using interaction terms. RESULTS: A total of 55 eicosanoids were profiled. Notably, 12-oxoeicosatetraenoic acid (12-oxoETE) and 15-oxoeicosatetraenoic acid (15-oxoETE), both of which exert inflammatory activities, had the greatest number of significant associations with metal concentrations. These eicosanoids were associated with increased concentrations of Cu, Mn, and Zn, and decreased concentrations of Cd, Co, Ni, and Pb, with the strongest effect sizes observed for 12-oxoETE and Pb (ß:-33.5,95 %CI:-42.9,-22.6) and 15-oxoETE and Sn (ß:43.2,95 %CI:11.4,84.1). Also, we observed differences in metals-eicosanoid associations by infant sex. Particularly, Cs and Mn had the most infant sex-specific significant associations with eicosanoids, which were primarily driven by female fetuses. All significant sex-specific associations with Cs were inverse among females, while significant sex-specific associations with Mn among females were positive within the cyclooxygenase group but inverse among the lipoxygenase group. CONCLUSION: Certain metals were significantly associated with eicosanoids that are responsible for regulating inflammatory responses. Eicosanoid-metal associations may suggest a role for eicosanoids in mediating metal-induced adverse birth outcomes.

Adverse birth outcomes are associated with circulating matrix metalloproteinases among pregnant women in Puerto Rico.

Matrix metalloproteinases (MMPs) are major extracellular matrix (ECM) remodeling proteinases and regulate uterine remodeling, which is a critical process for healthy pregnancies. The goal of this study was to investigate associations between maternal blood MMPs during pregnancy and birth outcomes among 898 pregnant women in the Puerto Rico PROTECT birth cohort. MMPs (MMP1, MMP2, and MMP9) were quantified using a customized Luminex assay in blood samples collected at two gestational study visits (around 18 and 26 weeks gestation). Linear and logistic regression models were used to regress continuous and binary birth outcomes, respectively, on MMPs at each study visit separately. Sensitivity analyses were conducted to test for effect modification by fetal sex on associations between MMPs and birth outcomes. We observed significant associations between MMP2 at visit 1 and newborn length that were in the opposite direction from the associations between MMP9 at visit 3 and newborn length. MMPs were associated with increased odds of preeclampsia and gestational diabetes mellitus, though case numbers were low. We also observed significant inverse associations with gestational age for MMP9 and MMP2 at visit 1 and visit 3, respectively, and these associations were observed only in mothers carrying male fetuses. Further, MMP2 was associated with heavier female fetuses, whereas MMP9 was associated with lighter female fetuses. We observed significant associations between birth outcomes and MMPs, and the majority of these associations differed by fetal sex. This study highlighted significant MMPs-birth outcomes associations that may provide a basis to explore the impact of MMPs on endometrium health and physiology.

Maternal blood metal concentrations are associated with C-reactive protein and cell adhesion molecules among pregnant women in Puerto Rico.

Studies have revealed a link between aberrant levels of maternal C-reactive protein (CRP) and cell adhesion molecules (CAMs) with adverse birth outcomes. Some epidemiologic studies have indicated that long-term metal exposures can modulate the levels of CRP and CAMs, but the associations between prenatal metal exposures and the levels of CRP and CAMs have yet to be studied more extensively. In this study, we assessed associations between maternal blood metal levels and CRP/CAMs among 617 pregnant women in the Puerto Rico PROTECT birth cohort. Methods: Blood samples were collected from participants at 16-20 (visit 1) and 24-28 (visit 3) weeks gestation. We measured concentrations of 11 metals using inductively coupled plasma mass spectrometry (ICP-MS). From the blood samples, CRP and CAMs intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) were also quantified using a customized Luminex assay. Linear-mixed effects models (LMEs) were used to regress CRP and CAMs on metals and included random intercepts for study participants to account for correlated repeated outcome measures. Fetal sex and visit effects were estimated using interaction terms between metal exposure variables and fetal sex, as well as visit indicators, respectively. Results: We observed significant positive associations between nickel and CRP (Δ: 7.04, 95% CI = 0.75, 13.73) and between lead and VCAM (Δ: 4.57, 95% CI = 1.36, 7.89). The positive associations were mainly driven by mothers carrying male fetuses. We also observed various visit-specific associations. The significant associations between metals and CRP were predominantly driven by visit 3; however, the significant associations between metals and VCAM were mainly driven by visit 1. Conclusion: Certain maternal blood metal levels were significantly associated with CRP and CAMs and most of these associations were differentially driven by fetal sex, as well as by timing in pregnancy. Future studies should further explore metal-CRP/CAMs associations for a better understanding of the underlying mechanism of metal-induced adverse birth outcomes.

The importance of community during rapid development: The influence of social networks on acute gastrointestinal illness in rural Ecuador.

Social networks are often measured as conduits of infection. Our prior cross-sectional analyses found that denser social ties among individuals reduces transmission of acute gastrointestinal illness (AGI) in coastal Ecuador; social networks can describe both risk and protection. We extend findings to examine how social connectedness influences AGI longitudinally in Ecuador from 2007 to 2013, a time of rapid development, using a two-stage Bayesian hierarchical model to estimate multiple network effects. A larger community network of people to discuss important matters with was consistently protective against AGI over time, and a network defined by people passing time together became a stronger measure of risk, due to increasing population density and travel. These networks were interdependent: the joint effect of having a small passing time network and large important matters network reduced the odds of AGI over time (2007: OR 1.16 (95% CI: 0.94, 1.44), 2013: OR 0.56 (95% CI: 0.45, 0.71)); and synergistic: the people an individual passed time with became the people they discussed important matters with. Focus groups emphasized that with greater remoteness came greater community cohesion resulting in safer WASH practices. Social networks can enhance and reduce health differently as social infrastructure evolves, highlighting the importance of community-level factors in a period of rapid development.

Biomarkers of Exposure to Phthalate Mixtures and Adverse Birth Outcomes in a Puerto Rico Birth Cohort.

BACKGROUND: Humans are exposed to complex mixtures of phthalate chemicals from a range of consumer products. Previous studies have reported significant associations between individual phthalate metabolites and pregnancy outcomes, but mixtures research is limited. OBJECTIVES: We used the Puerto Rico Testsite for Exploring Contamination Threats longitudinal pregnancy cohort to investigate associations between phthalate metabolite mixtures and pregnancy outcomes. METHODS: Women (n=462 carrying females, n=540 carrying males) provided up to three urine samples throughout gestation (median 18, 22, and 26 wk), which were analyzed for 13 phthalate metabolites. Pregnancy outcomes including preterm birth (PTB), spontaneous PTB, small and large for gestational age (SGA, LGA), birth weight z-score, and gestational age at delivery were abstracted from medical records. Environmental risk scores (ERS) were calculated as a weighted linear combination of the phthalates from ridge regression and adaptive elastic net, which are variable selection methods to handle correlated predictors. Birth outcomes were regressed on continuous ERS. We assessed gestational average and visit-specific ERS and stratified all analyses by fetal sex. Finally, we used Bayesian kernel machine regression (BKMR) to explore nonlinear associations and interactions between metabolites. RESULTS: Differences in metabolite weights from ridge and elastic net were apparent between birth outcomes and between fetal sexes. An interquartile range increase in gestational average phthalate ERS was associated with increased odds of PTB [male odds ratio (OR)=1.56; 95% confidence interval (CI): 1.08, 2.27; female OR=1.91; 95% CI: 1.23, 2.98], spontaneous PTB (male OR=2.32; 95% CI: 1.46, 3.68; female OR=2.00; 95% CI: 1.04, 3.82), and reduced gestational age at birth (male ß=-0.39 wk, 95% CI: -0.62, -0.15; female ß=-0.29 wk, 95% CI: -0.52, -0.05). Analyses by study visit suggested that exposure at ∼22 wk (range 20-24 wk) was driving those associations. Bivariate plots from BKMR analysis revealed some nonlinear associations and metabolite interactions that were different between fetal sexes. DISCUSSION: These results suggest that exposure to phthalate mixtures was associated with increased risk of early delivery and highlight the need to study mixtures by fetal sex. We also identified various metabolites displaying nonlinear relationships with measures of birth weight. https://doi.org/10.1289/EHP8990.

Maternal blood metal concentrations are associated with matrix metalloproteinases (MMPs) among pregnant women in Puerto Rico.

BACKGROUND/AIM: Matrix metalloproteinases (MMPs) are important regulators of uterine remodeling, a critical process for healthy pregnancies, and studies have revealed a link between an imbalance in MMPs and adverse birth outcomes. Toxicological studies have indicated that exposure to heavy metals can alter the levels of inflammatory cytokines, including MMPs. Despite growing evidence, the clear association between heavy metal exposure and MMPs has yet to be explored extensively in human populations. To have a better understanding of the association, in this study, we assessed associations between maternal blood metal levels with MMPs among 617 pregnant women in the Puerto Rico PROTECT birth cohort. METHODS: We measured blood concentrations for 11 metals in the first and/or second trimester of pregnancy using ICP-MS. MMPs (MMP1, MMP2, and MMP9) were quantified using a customized Luminex assay. Linear mixed effects models (LMEs) were used to regress MMPs on metals and included random intercepts for study participants to account for correlated repeated outcome measures. Fetal sex effects were estimated using interaction terms between metal exposure variables and fetal sex indicators. RESULTS: We observed significant associations between cesium, manganese, and zinc with all the MMPs that were measured. We also observed differences in metal-MMPs associations by fetal sex. Cobalt was positively associated with MMP1 only in women with male fetuses, and cesium was negatively associated with MMP1 only in women with female fetuses. MMP2 had significant associations with maternal blood metal concentrations only in women with female fetuses. CONCLUSION: Certain metals were significantly associated with MMPs that are responsible for uterine remodeling and healthy pregnancies. Most of these associations differed by fetal sex. This study highlighted significant metal-MMPs associations that may inform research on new avenues for understanding heavy metal-induced adverse birth outcomes and the development of diagnostic tools.

Maternal urinary phthalate metabolites are associated with lipidomic signatures among pregnant women in Puerto Rico.

BACKGROUND: Phthalates 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. OBJECTIVE: To explore associations between phthalate metabolite biomarkers and lipidomic profiles among pregnant women (n = 99) in the Puerto Rico PROTECT cohort. METHODS: We 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 phthalate metabolites 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, mono-unsaturated, polyunsaturated) which were then regressed on phthalate metabolites. Associations were adjusted for false discovery. RESULTS: After controlling for multiple comparisons, 33 phthalate-lipid associations were identified (False discovery rate adjusted p value < 0.05), and diacylglycerol 40:7 and plasmenyl-phosphatidylcholine 35:1 were the most strongly associated with multiple phthalate metabolites. Metabolites of di-2-ethylhexyl phthalate, bis(2-ethylhexyl) phthalate, dibutyl phthalates, and diisobutyl phthalate were associated with increased ceramides, lysophosphatidylcholines, lysophosphatidylethanolamines, and triacylglycerols, particularly those containing saturated and mono-unsaturated fatty acid chains. SIGNIFICANCE: Characterization of associations between lipidomic markers and phthalate metabolites during pregnancy will yield mechanistic insight for maternal and child health outcomes. IMPACT: This study leverages emerging technology to evaluate lipidome-wide signatures of phthalate exposure during pregnancy. The greatest lipid signatures of phthalate exposure were observed for diacylglycerol 40:7 and plasmenyl-phosphatidylcholine 35:1. Polymerized glycerides are important for energy production and regulated through hormone signaling, while plasmenyl-phosphatidylcholines have been implicated in membrane dynamics and important for cell-to-cell signaling. Characterization of these mechanisms are relevant for informing the etiology of maternal and children's health outcomes.

Gestational Hormone Concentrations Are Associated With Timing of Delivery in a Fetal Sex-Dependent Manner.

Background: Early delivery remains a significant public health problem that has long-lasting impacts on mother and child. Understanding biological mechanisms underlying timing of labor, including endocrine disruption, can inform prevention efforts. Methods: Gestational hormones were measured among 976 women in PROTECT, a longitudinal birth cohort in Puerto Rico. We evaluated associations between hormone concentrations at 18 and 26 weeks gestation and gestational age at birth, while assessing effect modification by fetal sex. Exploratory analyses assessed binary outcomes of overall preterm birth (PTB, <37 weeks gestation) and the spontaneous PTB subtype, defined as preterm premature rupture of membranes, spontaneous preterm labor, or both. Multivariable logistic and linear regressions were fit using visit-specific hormone concentrations, and fetal sex-specific effects were estimated using interaction terms. Main outcome models were adjusted for maternal age, education, marital status, alcohol consumption, environmental tobacco smoke exposure, and pre-pregnancy body mass index (BMI). Exploratory models adjusted for maternal age and education. Results: We observed reduced gestational age at birth with higher circulating CRH (ß: -2.73 days, 95% CI: -4.97, -0.42), progesterone (ß: -4.90 days, 95% CI: -7.07, -2.73), and fT4 concentrations (ß: -2.73 days, 95% CI: -4.76, -0.70) at 18 weeks specifically among male fetuses. Greater odds of overall and spontaneous PTB were observed among males with higher CRH, estriol, progesterone, total triiodothyronine (T3), and free thyroxine (fT4) concentrations. Greater odds of PTB among females was observed with higher testosterone concentrations. Conclusions: Various associations between hormones and timing of delivery were modified by fetal sex and timing of hormone measurement. Future studies are needed to understand differential mechanisms involved with timing of labor between fetal sexes.

Performance of urine, blood, and integrated metal biomarkers in relation to birth outcomes in a mixture setting.

BACKGROUND: Studies on the health effects of metal mixtures typically utilize biomarkers measured in a single biological medium, such as blood or urine. However, the ability to evaluate mixture effects are limited by the uncertainty whether a unified medium can fully capture exposure for each metal. Therefore, it is important to compare and assess metal mixtures measured in different media in epidemiology studies. OBJECTIVES: The aim of this study was to examine the mixture predictive performance of urine and blood metal biomarkers and integrated multi-media biomarkers in association with birth outcomes. METHODS: In our analysis of 847 women from the Puerto Rico PROTECT Cohort, we measured 10 essential and non-essential metals in repeated and paired samples of urine and blood during pregnancy. For each metal, we integrated exposure estimates from paired urine and blood biomarkers into multi-media biomarkers (MMBs), using intraclass-correlation coefficient (ICC) and weighted quantile sum (WQS) approaches. Using Ridge regressions, four separate Environmental risk scores (ERSs) for metals in urine, blood, MMBICC, and MMBWQS were computed as a weighted sum of the 10 metal concentrations. We then examined associations between urine, blood, and multi-media biomarker ERSs and birth outcomes using linear and logistic regressions, adjusting for maternal age, maternal education, pre-pregnancy body mass index (BMI), and second-hand smoke exposure. The performance of each ERS was evaluated with continuous and tertile estimates and 95% confidence intervals of the odds ratio of preterm birth using area under the curve (AUC). RESULTS: Pb was the most important contributor of blood ERS as well as the two integrated multi-media biomarker ERSs. Individuals with high ERS (3rd tertile) showed increased odds of preterm birth compared to individuals with low ERS (1st tertile), with 2.8-fold (95% CI, 1.49 to 5.40) for urine (specific gravity corrected); 3.2- fold (95% CI, 1.68 to 6.25) for blood; 3.9-fold (95% CI, 1.72 to 8.66) for multi-media biomarkers composed using ICC; and 5.2-fold (95% CI, 2.34 to 11.42) for multi-media biomarkers composed using WQS. The four ERSs had comparable predictive performances (AUC ranging from 0.64 to 0.68) when urine is examined with specific gravity corrected concentrations. CONCLUSIONS: Within a practical metal panel, measuring metals in either urine or blood may be an equally good approach to evaluate the metals as a mixture. Applications in practical study design require validation of these methods with other cohorts, larger panels of metals and within the context of other adverse health effects of interest.

Individual and joint effects of phthalate metabolites on biomarkers of oxidative stress among pregnant women in Puerto Rico.

Exposures to phthalate compounds have been linked to adverse birth outcomes, potentially through oxidative stress mechanisms. We explored associations between mixtures of biomarkers of phthalate and phthalate replacement metabolites and oxidative stress using lipid peroxidation biomarker 8-iso-prostaglandin-F2α (8-iso-PGF2α). As 8-iso-PGF2α can be generated via both chemical (nonenzymatic) and enzymatic lipid peroxidation pathways, we calculated the ratio of 8-iso-PGF2α/prostaglandin F2α in an attempt to distinguish the potential contributions of the two pathways. Urinary biomarker measurements were taken from 775 pregnant women in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) longitudinal birth cohort at up to three time points during gestation (16-20, 20-24, and 24-28 weeks gestation). Adaptive elastic net with pairwise linear interaction terms (adENET-I) was used to determine individual phthalate metabolites and phthalate interactions that were predictive of lipid oxidative stress biomarkers, and to subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual at each study visit. Repeated ERS were then used in linear mixed effects models to test for associations between biomarkers of phthalate mixtures and biomarkers of oxidative stress. We also used Bayesian kernel machine regression (BKMR) to explore nonlinearity and interactions between phthalate metabolites within the mixture. An increase from the first to fourth quartile of phthalate ERS derived from adENET-I was associated with a 96.7% increase (95% CI: 74.0, 122) in the hypothesized chemical fraction of 8-iso-PGF2α and a 268% increase (95% CI: 139, 465) in the hypothesized enzymatic fraction of 8-iso-PGF2α. BKMR analyses also suggested strong linear associations between the phthalate mixture and biomarkers of lipid oxidative stress. Various phthalates displayed nonlinear relationships with both chemical and enzymatic fractions of 8-iso-PGF2α, and we observed some evidence of interactions between metabolites in the mixture. In conclusion, exposure to phthalate mixtures was strongly associated with linear increases in biomarkers of lipid oxidative stress, and differences observed between hypothesized chemical and enzymatic lipid peroxidation outcomes highlight the need to critically assess pathways of 8-iso-PGF2α generation in relation to environmental exposures.

Psychosocial status modifies the effect of maternal blood metal and metalloid concentrations on birth outcomes.

BACKGROUND: Metal exposure and psychosocial stress in pregnancy have each been associated with adverse birth outcomes, including preterm birth and low birth weight, but no study has examined the potential interaction between them. OBJECTIVES: We examined the modifying effect of psychosocial stress on the association between metals and birth outcomes among pregnant women in Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study. METHODS: In our analysis of 682 women from the PROTECT study, we measured 16 essential and non-essential metals in blood samples at two time points. We administered questionnaires to collect information on depression, perceived stress, social support, and life experience during pregnancy. Using K-means clustering, we categorized pregnant women into one of two groups: "good" and "poor" psychosocial status. We then evaluated whether the effect of blood metals (geometric average) on adverse birth outcomes (gestational age, preterm birth [overall and spontaneous], birth weight z-score, small for gestation [SGA], large for gestation [LGA]) vary between two clusters of women, adjusting for maternal age, maternal education, pre-pregnancy body mass index (BMI), and second-hand smoke exposure. RESULTS: Blood manganese (Mn) was associated with an increased odds ratio (OR) of overall preterm birth (OR/interquartile range [IQR] = 2.76, 95% confidence interval [CI] = 1.25, 6.12) and spontaneous preterm birth (OR/IQR: 3.68, 95% CI: 1.20, 6.57) only among women with "poor" psychosocial status. The association between copper (Cu) and SGA was also statistically significant only among women having "poor" psychosocial status (OR/IQR: 2.81, 95% CI: 1.20, 6.57). We also observed associations between nickel (Ni) and preterm birth and SGA that were modified by psychosocial status during pregnancy. CONCLUSIONS: Presence of "poor" psychosocial status intensified the adverse associations between Mn and preterm birth, Cu and SGA, and protective effects of Ni on preterm. This provides evidence that prenatal psychosocial stress may modify vulnerability to metal exposure.

Maternal Metals/Metalloid Blood Levels Are Associated With Lipidomic Profiles Among Pregnant Women in Puerto Rico.

Background/Aim: The association between heavy metal exposure and adverse birth outcomes is well-established. However, there is a paucity of research identifying biomarker profiles that may improve the early detection of heavy metal-induced adverse birth outcomes. Because lipids are abundant in our body and associated with important signaling pathways, we assessed associations between maternal metals/metalloid blood levels with lipidomic profiles among 83 pregnant women in the Puerto Rico PROTECT birth cohort. Methods: We measured 10 metals/metalloid blood levels during 24-28 weeks of pregnancy. Prenatal plasma lipidomic profiles were identified by liquid chromatography-mass spectrometry-based shotgun lipidomics. We derived sums for each lipid class and sums for each lipid sub-class (saturated, monounsaturated, polyunsaturated), which were then regressed on metals/metalloid. False discovery rate (FDR) adjusted p-values (q-values) were used to account for multiple comparisons. Results: A total of 587 unique lipids from 19 lipid classes were profiled. When controlling for multiple comparisons, we observed that maternal exposure to manganese and zinc were negatively associated with plasmenyl-phosphatidylethanolamine (PLPE), particularly those containing polyunsaturated fatty acid (PUFA) chains. In contrast to manganese and zinc, arsenic and mercury were positively associated with PLPE and plasmenyl-phosphatidylcholine (PLPC). Conclusion: Certain metals were significantly associated with lipids that are responsible for the biophysical properties of the cell membrane and antioxidant defense in lipid peroxidation. This study highlighted lipid-metal associations and we anticipate that this study will open up new avenues for developing diagnostic tools.

Maternal blood metal and metalloid concentrations in association with birth outcomes in Northern Puerto Rico.

BACKGROUND: In previous studies, exposures to heavy metals such as Pb and Cd have been associated with adverse birth outcomes; however, knowledge on effects at low levels of exposure and of other elements remain limited. METHOD: We examined individual and mixture effects of metals and metalloids on birth outcomes among 812 pregnant women in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort. We measured 16 essential and non-essential metal(loid)s in maternal blood collected at 16-20 and 24-28 weeks gestation. We used linear and logistic regression to independently examine associations between geometric mean (GM) concentrations of each metal across visits and gestational age, birthweight z-scores, preterm birth, small for gestational age (SGA), and large for gestational age (LGA). We evaluated effect modification with infant sex*metal interaction terms. To identify critical windows of susceptibility, birth outcomes were regressed on visit-specific metal concentrations. Furthermore, average metal concentrations were divided into tertiles to examine the potential for non-linear relationships. We used elastic net (ENET) regularization to construct Environmental Risk Score (ERS) as a metal risk score and Bayesian Kernel Machine Regression (BKMR) to identify individual metals most critical to each outcome, accounting for correlated exposures. RESULTS: In adjusted models, an interquartile range (IQR) increase in GM lead (Pb) was associated with 1.63 higher odds of preterm birth (95%CI = 1.17, 2.28) and 2 days shorter gestational age (95% CI = -3.1, -0.5). Manganese (Mn) and zinc (Zn) were also associated with higher odds of preterm birth and shorter gestational age; the associations were strongest among the highest tertile for Mn and among females for Zn. Mercury (Hg) was associated with higher risk of preterm birth at the later window of pregnancy. Ni measured later in pregnancy was associated with lower odds of SGA. ENET and BKMR models selected similar metals as "important" predictors of birth outcomes. The association between ERS and preterm birth was assessed and the third tertile of ERS was significantly associated with an elevated odds ratio of 2.13 (95% CI = 1.12, 5.49) for preterm birth compared to the first tertile. CONCLUSION: As the PROTECT cohort has lower Pb concentrations (GM = 0.33 µg/dL) compared to the mainland US, our findings suggest that low-level prenatal lead exposure, as well as elevated Mn and Zn exposure, may adversely affect birth outcomes. Improved understanding on environmental factors contributing to preterm birth, together with sustainable technologies to remove contamination, will have a direct impact in Puerto Rico and elsewhere.

Predictors of urinary and blood Metal(loid) concentrations among pregnant women in Northern Puerto Rico.

Given the potential adverse health effects related to toxic trace metal exposure and insufficient or excessive levels of essential trace metals in pregnant women and their fetuses, the present study characterizes biomarkers of metal and metalloid exposure at repeated time points during pregnancy among women in Puerto Rico. We recruited 1040 pregnant women from prenatal clinics and collected urine, blood, and questionnaire data on demographics, product use, food consumption, and water usage at up to three visits. All samples were analyzed for 16 metal(loid)s: arsenic (As), barium (Ba), beryllium (Be), cadmium (Cd), cobalt (Co), chromium (Cr), cesium (Cs), copper (Cu), mercury (Hg), manganese (Mn), nickel (Ni), lead (Pb), titanium (Ti), uranium (U), vanadium (V), and zinc (Zn). Urine samples were additionally analyzed for molybdenum (Mo), platinum (Pt), antimony (Sb), tin (Sn), and tungsten (W). Mean concentrations of most metal(loid)s were higher among participants compared to the general US female population. We found weak to moderate correlations for inter-matrix comparisons, and moderate to strong correlations between several metal(loid)s measured within each biological matrix. Blood concentrations of Cu, Zn, Mn, Hg, and Pb were shown to reflect reliable biomarkers of exposure. For other metals, repeated samples are recommended for exposure assessment in epidemiology studies. Predictors of metal(loid) biomarkers included fish and rice consumption (urinary As), fish and canned food (blood Hg), drinking public water (blood Pb), smoking (blood Cd), and iron/folic acid supplement use (urinary Cs, Mo, and Sb). Characterization of metal(loid) biomarker variation over time and between matrices, and identification of important exposure sources, may inform future epidemiology studies and exposure reduction strategies.

Interactions between chemicals and non-chemical stressors: The modifying effect of life events on the association between triclocarban, phenols and parabens with gestational length in a Puerto Rican cohort.

BACKGROUND: Phenols and parabens are common additives to consumer products. There is evidence of adverse birth outcomes in association with prenatal exposure to these chemicals, in addition to psychosocial factors. We previously reported an increase in gestational length with bisphenol-A, methylparaben and propylparaben, and a decrease in gestational length with triclocarban. OBJECTIVES: We examined the modifying effect of psychosocial stress on the association between chemicals and gestational length in up to 752 women among a pregnancy cohort study. METHODS: Urinary biomarkers were measured at up to three time points in pregnancy. Multiple linear regression models were conducted to investigate the association between gestational length and the interaction between average exposure biomarkers and LES. Multiple linear regression models regressing the exposure biomarkers in relation to gestational length were also stratified by LES, Negative LES, and Positive LES, based on the subjective ratings of events. Results were transformed into the change in gestational length for an inter-quartile-range difference in the exposure. RESULTS: Of the four psychosocial stress measures, only the life events score (LES) was a significant modifier. Associations between triclocarban, bisphenol-S, methyl- and propylparaben in relation to gestational length were stronger among women with negative Total LES scores. Among women with negative Total LES scores, bisphenol-S and triclocarban were associated with a 3-5 day decrease in gestational length [(-3.15; 95% CI: -6.06, -0.24); (-4.68; 95% CI: -8.47, -0.89)], whereas methylparaben and propylparaben were associated with a 2-3 day increase in gestational length [(2.21; 95% CI: 0.02, 4.40); (2.92; 95% CI: 0.58, 5.26)]. Significant interactions were driven by negative life events, but the association with triclocarban was driven by few positive life events. CONCLUSIONS: Associations between exposure biomarkers and gestational length were stronger in the presence of negative life events. This provides evidence that stress makes the body more vulnerable to chemical exposure.

A repeated measures study of phenol, paraben and Triclocarban urinary biomarkers and circulating maternal hormones during gestation in the Puerto Rico PROTECT cohort.

INTRODUCTION: Prenatal exposure to some phenols and parabens has been associated with adverse birth outcomes. Hormones may play an intermediate role between phenols and adverse outcomes. We examined the associations of phenol and paraben exposures with maternal reproductive and thyroid hormones in 602 pregnant women in Puerto Rico. Urinary triclocarban, phenol and paraben biomarkers, and serum hormones (estriol, progesterone, testosterone, sex-hormone-binding globulin (SHBG), corticotropin-releasing hormone (CRH), total triiodothyronine (T3), total thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH)) were measured at two visits during pregnancy. METHODS: Linear mixed models with a random intercept were constructed to examine the associations between hormones and urinary biomarkers. Results were additionally stratified by study visit. Results were transformed to hormone percent changes for an inter-quartile-range difference in exposure biomarker concentrations (%Δ). RESULTS: Bisphenol-S was associated with a decrease in CRH [(%Δ -11.35; 95% CI: -18.71, - 3.33), and bisphenol-F was associated with an increase in FT4 (%Δ: 2.76; 95% CI: 0.29, 5.22). Butyl-, methyl- and propylparaben were associated with decreases in SHBG [(%Δ: -5.27; 95% CI: -9.4, - 1.14); (%Δ: -3.53; 95% CI: -7.37, 0.31); (%Δ: -3.74; 95% CI: -7.76, 0.27)]. Triclocarban was positively associated with T3 (%Δ: 4.08; 95% CI: 1.18, 6.98) and T3/T4 ratio (%Δ: 4.67; 95% CI: -1.37, 6.65), and suggestively negatively associated with TSH (%Δ: -10.12; 95% CI: -19.47, 0.32). There was evidence of susceptible windows of vulnerability for some associations. At 24-28 weeks gestation, there was a positive association between 2,4-dichlorophenol and CRH (%Δ: 9.66; 95% CI: 0.67, 19.45) and between triclosan and estriol (%Δ: 13.17; 95% CI: 2.34, 25.2); and a negative association between triclocarban and SHBG (%Δ: -9.71; 95% CI:-19.1, - 0.27) and between bisphenol A and testosterone (%Δ: -17.37; 95% CI: -26.7, - 6.87). CONCLUSION: Phenols and parabens are associated with hormone levels during pregnancy. Further studies are required to substantiate these findings.

The associations between prenatal exposure to triclocarban, phenols and parabens with gestational age and birth weight in northern Puerto Rico.

BACKGROUND: Prenatal exposure to certain xenobiotics has been associated with adverse birth outcomes. We examined the associations of triclocarban, phenols and parabens in a cohort of 922 pregnant women in Puerto Rico, the Puerto Rico Testsite for Exploring Contamination Threats Program (PROTECT). METHODS: Urinary triclocarban, phenols and parabens were measured at three time points in pregnancy (visit 1: 16-20 weeks, visit 2: 20-24 weeks, visit 3: 24-28 weeks gestation). Multiple linear regression (MLR) models were conducted to regress gestational age and birthweight z-scores against each woman's log average concentrations of exposure biomarkers. Logistic regression models were conducted to calculate odds of preterm birth, small or large for gestational age (SGA and LGA) in association with each of the exposure biomarkers. An interaction term between the average urinary biomarker concentration and infant sex was included in models to identify effect modification. The results were additionally stratified by study visit to look for windows of vulnerability. Results were transformed into the change in the birth outcome for an inter-quartile-range difference in biomarker concentration (Δ). RESULTS: Average benzophenone-3, methyl- and propyl-paraben concentrations were associated with an increase in gestational age [(Δ 1.90 days; 95% CI: 0.54, 3.26); (Δ 1.63; 95% CI: 0.37, 2.89); (Δ 2.06; 95% CI: 0.63, 3.48), respectively]. Triclocarban was associated with a suggestive 2-day decrease in gestational age (Δ - 1.96; 95% CI: -4.11, 0.19). Bisphenol A measured at visit 1 was associated with a suggestive increase in gestational age (Δ 1.37; 95% CI: -0.05, 2.79). Triclosan was positively associated with gestational age among males, and negatively associated with gestational age among females. Methyl-, butyl- and propyl-paraben were associated with significant 0.50-0.66 decreased odds of SGA. BPS was associated with an increase in the odds of SGA at visit 3, and a suggestive increase in the odds of LGA at visit 1. CONCLUSION: Benzophenone-3, methyl-paraben and propyl-paraben were associated with an increase in gestational age. Concentrations of triclocarban, which were much higher than reported in other populations, were associated with a suggestive decrease in gestational age. The direction of the association between triclosan and gestational age differed by infant sex. Parabens were associated with a decrease in SGA, and BPS was associated with both SGA and LGA depending on the study visit. Further studies are required to substantiate these findings.

Classification and Clustering Methods for Multiple Environmental Factors in Gene-Environment Interaction: Application to the Multi-Ethnic Study of Atherosclerosis.

There has been an increased interest in identifying gene-environment interaction (G × E) in the context of multiple environmental exposures. Most G × E studies analyze one exposure at a time, but we are exposed to multiple exposures in reality. Efficient analysis strategies for complex G × E with multiple environmental factors in a single model are still lacking. Using the data from the Multiethnic Study of Atherosclerosis, we illustrate a two-step approach for modeling G × E with multiple environmental factors. First, we utilize common clustering and classification strategies (e.g., k-means, latent class analysis, classification and regression trees, Bayesian clustering using Dirichlet Process) to define subgroups corresponding to distinct environmental exposure profiles. Second, we illustrate the use of an additive main effects and multiplicative interaction model, instead of the conventional saturated interaction model using product terms of factors, to study G × E with the data-driven exposure subgroups defined in the first step. We demonstrate useful analytical approaches to translate multiple environmental exposures into one summary class. These tools not only allow researchers to consider several environmental exposures in G × E analysis but also provide some insight into how genes modify the effect of a comprehensive exposure profile instead of examining effect modification for each exposure in isolation.

Latent variable models for gene-environment interactions in longitudinal studies with multiple correlated exposures.

Many existing cohort studies designed to investigate health effects of environmental exposures also collect data on genetic markers. The Early Life Exposures in Mexico to Environmental Toxicants project, for instance, has been genotyping single nucleotide polymorphisms on candidate genes involved in mental and nutrient metabolism and also in potentially shared metabolic pathways with the environmental exposures. Given the longitudinal nature of these cohort studies, rich exposure and outcome data are available to address novel questions regarding gene-environment interaction (G × E). Latent variable (LV) models have been effectively used for dimension reduction, helping with multiple testing and multicollinearity issues in the presence of correlated multivariate exposures and outcomes. In this paper, we first propose a modeling strategy, based on LV models, to examine the association between repeated outcome measures (e.g., child weight) and a set of correlated exposure biomarkers (e.g., prenatal lead exposure). We then construct novel tests for G × E effects within the LV framework to examine effect modification of outcome-exposure association by genetic factors (e.g., the hemochromatosis gene). We consider two scenarios: one allowing dependence of the LV models on genes and the other assuming independence between the LV models and genes. We combine the two sets of estimates by shrinkage estimation to trade off bias and efficiency in a data-adaptive way. Using simulations, we evaluate the properties of the shrinkage estimates, and in particular, we demonstrate the need for this data-adaptive shrinkage given repeated outcome measures, exposure measures possibly repeated and time-varying gene-environment association.

A space-time point process model for analyzing and predicting case patterns of diarrheal disease in northwestern Ecuador.

We consider modeling case-patterns under a complex spatial and longitudinal sampling design as conducted via a serial case-control study of diarrheal disease in northwestern Ecuador. We build a two-stage space-time model to understand the role of spatially and temporally referenced covariates that reflect social and natural environments in the sampled region, after accounting for unmeasured residual heterogeneities. All diarrheal case events are collected from 21 sampled communities in Esmeraldes province in Ecuador, during seven sampling cycles from 2003 to 2008. The region of interest comprises 158 communities along a river basin. Prediction of case counts at unsampled communities at a future time is of interest along with estimation of risk-related parameters. We propose a computationally feasible two-stage Bayesian approach to estimate the risk-related parameters and conduct predictive inference. We first apply the log Gaussian Cox process (LGCP), commonly used to model spatial clustering of point patterns, to accommodate temporal variation within the sampled communities. Prediction of the number of cases at unsampled communities at a future time is obtained by a disease mapping model conditional on the expected case counts from Stage I.