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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.

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Exposure to phenols and parabens may contribute to increased maternal inflammation and adverse birth outcomes, but these effects are not well-studied in humans. This study aimed to investigate relationships between concentrations of 8 phenols and 4 parabens with 6 inflammatory biomarkers (C-reactive protein (CRP); matrix metalloproteinases (MMP) 1, 2, and 9; intercellular adhesion molecule-1 (ICAM-1); and vascular cell adhesion molecule-1 (VCAM-1)) measured at two time points in pregnancy in the PROTECT birth cohort in Puerto Rico. Linear mixed models were used, adjusting for covariates of interest. Results are expressed as the percent change in outcome per interquartile range (IQR) increase in exposure. Particularly among phenols, numerous significant negative associations were found, for example, between benzophenone-3 and CRP (-11.21 %, 95 % CI: -17.82, -4.07) and triclocarban and MMP2 (-9.87 %, 95 % CI: -14.05, -5.5). However, significant positive associations were also detected, for instance, between bisphenol-A (BPA) and CRP (9.77 %, 95 % CI: 0.67, 19.68) and methyl-paraben and MMP1 (10.78 %, 95 % CI: 2.17, 20.11). Significant interactions with female fetal sex and the later study visit (at 24-28 weeks gestation) showed more positive associations compared to male fetal sex and the earlier study visit (16-20 weeks gestation). Our results suggest that phenols and parabens may disrupt inflammatory processes pertaining to uterine remodeling and endothelial function, with important implications for pregnancy outcomes. More research is needed to further understand maternal inflammatory status in an effort to improve reproductive and developmental outcomes.

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INTRODUCTION: N-(phosphonomethyl)glycine, or glyphosate, is a non-selective systemic herbicide widely used in agricultural, industrial, and residential settings since 1974. Glyphosate exposure has been inconsistently linked to neurotoxicity in animals, and studies of effects of gestational exposure among humans are scarce. In this study we investigated relationships between prenatal urinary glyphosate analytes and early childhood neurodevelopment. METHODS: Mother-child pairs from the PROTECT-CRECE birth cohort in Puerto Rico with measures for both maternal urinary glyphosate analytes and child neurodevelopment were included for analysis (n = 143). Spot urine samples were collected 1-3 times throughout pregnancy and analyzed for glyphosate and aminomethylphosphonic acid (AMPA), an environmental degradant of glyphosate. Child neurodevelopment was assessed at 6, 12, and 24 months using the Battelle Developmental Inventory, 2nd edition Spanish (BDI-2), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. We used multivariable linear regression to examine associations between the geometric mean of maternal urinary glyphosate analytes across pregnancy and BDI-2 scores at each follow-up. Results were expressed as percent change in BDI-2 score per interquartile range increase in exposure. RESULTS: Prenatal AMPA concentrations were negatively associated with communication domain at 12 months (%change = -5.32; 95%CI: 9.04, -1.61; p = 0.007), and communication subdomain scores at 12 and 24 months. At 24 months, four BDI-2 domains were associated with AMPA: adaptive (%change = -3.15; 95%CI: 6.05, -0.25; p = 0.038), personal-social (%change = -4.37; 95%CI: 7.48, -1.26; p = 0.008), communication (%change = -7.00; 95%CI: 11.75, -2.26; p = 0.005), and cognitive (%change = -4.02; 95%CI: 6.72, -1.32; p = 0.005). Similar trends were observed with GLY concentrations, but most confidence intervals include zero. We found no significant associations at 6 months. CONCLUSIONS: Our results suggest that gestational exposure to glyphosate is associated with adverse early neurodevelopment, with more pronounced delays at 24 months. Given glyphosate's wide usage, further investigation into the impact of gestational glyphosate exposure on neurodevelopment is warranted.

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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.

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Phthalates are ubiquitous environmental exposures that may be implicated in inflammatory processes, as demonstrated by previous in vivo and in vitro studies. Few human studies have substantiated these observations. This study sought to examine whether maternal phthalate exposures impact inflammatory processes, as measured by circulating inflammatory biomarkers, in the PROTECT cohort in northern Puerto Rico. Inflammatory biomarkers included matrix metalloproteinases 1, 2, and 9 (MMPs), C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM), and intercellular cell adhesion molecule-1 (ICAM). Biomarkers were measured in maternal serum samples collected during pregnancy. 19 phthalate metabolites were assessed in urinary samples collected at three study visits across pregnancy. Phthalates with <50 % of measurements above the limit of detection were excluded from analysis. We utilized linear mixed effect models to estimate associations between interquartile range increases in phthalate metabolite concentrations and percent changes in inflammatory biomarkers. Our results revealed significant associations between mono-n-butyl phthalate (MBP) and higher MMP1 by 7.86 % (95 % CI: 0.49, 15.76) and between mono oxononyl phthalate (MONP) and higher MMP2 by 8.30 % (95 % CI: 2.22, 14.75). We observed negative or null associations between phthalate metabolites and MMP2, MMP9, ICAM, VCAM, and CRP. Many results were significantly modified by fetal sex, particularly those between di-2-ethylhexyl phthalate (DEHP) metabolites and MMP1 (p-interaction: MEHHP = 0.01, MEOHP = 0.04, MECPP = 0.01) and MMP2 (p-interaction: MEHHP = 0.03, MEOHP = 0.01, MECPP = 0.01), for which associations were positive among only women carrying female fetuses. MMPs have been previously associated with preeclampsia and hypertensive pregnancy disorders as mediators of artery remodeling. Hence, our findings suggest a potential role for phthalates in mediating the maternal inflammatory response, as well as significant sexual dimorphism in these relationships, which has implications for several adverse pregnancy outcomes.

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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.

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The PROTECT research Center funded by the NIH's National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program was launched in 2010 to explore the impact of exposure to pollutants on the high rate of premature births in Puerto Rico. In September 2017, Hurricanes Irma and María devastated the archipelago, which caused: collapse of the electrical system, collapse of the communication system, limited access to clean water, food, gas, and health services, destruction of public (e.g., hospitals) and private property (e.g., houses) and more than 4500 deaths. Pregnant and postpartum individuals are especially vulnerable to natural disasters. They face difficulty obtaining adequate pre- and post-natal care, are exposed to increased risk of miscarriage, premature delivery, and giving birth to low birth weight babies during and after disasters and are also more likely to suffer physical and mental health problems compared to the general population during and after disasters. A face-to-face questionnaire was administered to PROTECT participants who were pregnant during hurricanes Irma or Maria or who became pregnant shortly after in order to identify hurricane-related sources of stress and other adverse effects. This paper is based on the answers to the open-ended question at the end of the questionnaire where participants were asked to share their experiences during and after the hurricanes. Among the 375 participants who completed the survey, 76 answers to the open-ended question were considered due to data saturation. The answers to the open-ended question were transcribed into a document in order to facilitate the coding process. The transcribed text was analyzed first to identify emerging categories and then coded to identify common themes as well as divergence among participants. The following themes were identified: pregnancy and birth challenges, lack of access to basic services, housing conditions, stressful working conditions, concerns about health, concerns about their children, and positive or protective aspects. The results indicate how the disruption in access to basic services has a unique impact on the physical and mental health of pregnant and post-partum women in an emergency situation. These findings point to the potential benefit of developing specific protocols designed for emergency preparedness aimed at this population, which can inform healthcare providers and community organizations in case of future events.

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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.

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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.

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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.

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Personal care products (PCPs) refer to a wide variety of items commonly characterized as health or beauty products. PCPs contain a number of ingredients, often including a wide range of endocrine disrupting chemicals such as phthalates and parabens. The present study examines the association between self-reported PCP use and prenatal sex-steroids and thyroid hormones levels in women from Puerto Rico. We recruited pregnant women (n = 1070) through the Puerto Rico PROTECT Cohort and collected blood, demographic and pregnancy-related data at recruitment and subsequent visits. PCP use in the 48-h preceding the blood sample was collected through self-reported questionnaires. Nine hormones (corticotropin-releasing hormone [CRH], sex-hormone binding globulin [SHBG], estriol [E3], progesterone, testosterone, thyroid-stimulating hormone [TSH], total triiodothyronine [T3], total thyroxine [T4], and free thyroxine [fT4]) were measured in maternal serum samples at two points during pregnancy. Linear mixed models with random intercepts were used to examine associations between PCP use and serum hormone levels. Use of cosmetics significantly increased with age, household income and education level (p < 0.01). Use of hair products, such as hair dyes and bleach, relaxers, and mousse, was associated with lower levels of all sex steroid hormones compared to non-use: SHBG (%Δ = -7.1, 95%CI: -12.4,-1.8), E3 (%Δ = -23.2, 95%CI: -32.2,-13.0), progesterone (%Δ = -21.5, 95%CI: -29.4,-12.9) and testosterone (%Δ = -21.5, 95%CI: -33.1,-7.8) adjusted for maternal age, education and pre-pregnancy body mass index. Our findings suggest that household income and education level influence PCP use among pregnant women in this study. Use of certain hair products was associated with lower concentrations of sex steroid hormones. Although there are limitations to questionnaire data, characterizing PCP use is inexpensive and may represent exposure from multiple classes of chemicals, including chemicals that may not specifically appear on product labels and/or have not been tested for endocrine disrupting potential, making it a useful complement to chemical biomarker data.

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Background/Aim: Infant non-nutritive suck (NNS) has been used as an early marker of neonatal brain function. Although there is an established relationship between prenatal exposure to certain metals and brain development, the association between metal exposure and NNS has not been explored. Therefore, in this study we assessed associations between maternal urinary metal(loid) concentrations and NNS measurements among infants from the Puerto Rico PROTECT birth cohort. We hypothesized that maternal urinary metal(loid) concentrations are significantly associated with infant NNS measures in a sex-dependent manner. Methods: We measured urinary concentrations of 14 metal(loid)s in pregnant women at up to three time points in pregnancy. The geometric mean of each metal(loid) for each pregnant woman was calculated and used as an exposure measurement across gestation. NNS measurements (duration, frequency, amplitude, bursts/min, cycles/burst, cycles/min) were collected from infants between 4 and 6 (±2 weeks) weeks of age using our custom research pacifier. Linear regression was used to estimate associations between urinary metal(loid) concentrations across pregnancy and continuous NNS variables. Sex-specific effects were estimated using interaction terms between NNS variables and infant sex. Results: We observed significant positive associations between mercury, manganese, and tin with NNS duration (mercury: %Δ = 1.08, 95% CI: 0.42, 1.74; manganese: %Δ = 0.67, 95% CI: 0.15, 1.20; tin: %Δ = 0.83, 95% CI: 0.17, 1.49) and NNS cycles/burst (mercury: %Δ = 1.85, 95% CI: 0.58, 3.11; manganese: (%Δ = 1.37, 95% CI: 0.40, 2.34; tin: %Δ = 1.68, 95% CI: 0.46, 2.91). Furthermore, the association between NNS cycles/min with cadmium (%Δ = 8.06, 95% CI: 3.33, 12.78), manganese (%Δ = 4.44, 95% CI: 1.40, 7.47), and tin (%Δ = 4.50, 95% CI: 0.81, 8.18) were in the opposite direction from its association with zinc (%Δ = -9.30, 95% CI: -14.71, -3.89), as well as with copper (%Δ = -6.58, 95% CI: -12.06, -1.10). For the sex-stratified analysis, the negative associations between metal(loid)s and NNS duration were predominantly driven by male infants; however, the negative associations between metal(loid)s and NNS bursts/min were mainly driven by female infants. Conclusion: We observed significant associations between prenatal metal(loid) exposure and NNS measurements among infants from the ongoing Puerto Rico PROTECT cohort. Similar to previous studies that have demonstrated associations between NNS and subsequent neurodevelopment, this study highlights the potential of NNS as a quantitative index to measure altered neurodevelopment from prenatal metal(loid) exposures. We believe this study will inform future efforts aimed at reducing health risks related to early life metal exposures, such as developing early identification of metal-induced adverse outcomes in child neurodevelopment.

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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.

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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.

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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.

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Background: Evidence suggests exposure to endocrine-disrupting chemicals (EDCs) can influence Metabolic Syndrome (MetS) risk in adults, but it is unclear if EDCs impact women during midlife. We examined if EDCs measured in adult women were predictive of MetS and its components 9 years later. Methods: We measured urinary phthalate metabolites, phenols, and parabens collected in 2008 among 73 females from the ELEMENT study. MetS and its components (Abdominal Obesity, Hypertriglyceridemia, Cholesterolemia, Hypertension, and Hyperglycemia) were assessed in 2017. We regressed log-transformed EDC concentrations on MetS and MetS components using logistic regression, adjusting for age and physical activity. Results: At follow-up, the mean (SD) age was 46.6 (6.3) years; the prevalence of MetS was 34.3%. Sum of dibutyl phthalate metabolites (ΣDBP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP) were associated with an increased odds of hypertriglyceridemia. 2,5-dichlorophenol (2,5 DCP) and 2,4-dichlorophenol (2,4 DCP) were associated with increased odds of hypertriglyceridemia. The odds of hypertension were 4.18 (95% CI: 0.98, 17.7, p < 0.10) and 3.77 (95% CI: 0.76, 18.62, p < 0.10) times higher for every IQR increase in MCOP and propyl paraben, respectively. The odds of hyperglycemia were 0.46 (95% CI: 0.18, 1.17 p < 0.10) times lower for every IQR increase in the sum of di-2-ethylhexyl phthalate metabolites (ΣDEHP), and the odds of abdominal obesity were 0.70 (95% CI: 0.40, 1.21, p < 0.10) lower for every IQR increase in the concentration of triclosan. Conclusion: We found EDCs measured in 2008 were marginally predictive of hypertriglyceridemia and hypertension 9 years later. Results suggest that lower exposure to certain toxicants was related to lower markers of metabolic risk among midlife women.

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BACKGROUND: Infant non-nutritive suck (NNS), or sucking on a pacifier with no nutrients being delivered, has been used as in index of brain function and has been linked to subsequent neurodevelopment. Yet, no data are available connecting NNS to environmental exposures in utero. The goal of this study was to examine the relationship between gestational exposure to phthalates (a group of chemicals found in personal care products, PVC plastics, and other products) and NNS among infants in a birth cohort study in Puerto Rico. METHODS: Urinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. We calculated the geometric mean of each metabolite for each woman as a measure of exposure across gestation. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min. RESULTS: Two hundred and eight mother-infant dyads completed this study We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.

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The prevalence of Attention Deficit/Hyperactivity Disorder (ADHD) has been increasing. Research suggests that exposure to endocrine disrupting chemicals such as phthalates may play a role, but studies of in utero phthalate exposure and ADHD-related symptoms beyond early childhood are limited. We investigated associations between measures of in utero phthalate exposure and ADHD symptoms, such as inattention and impulsivity, in childhood (age 6-11 years, n = 221) and in adolescence (age 9-18 years, n = 200), as well as cross-sectional relationships between phthalate exposure and ADHD symptoms in adolescence (n = 491) among participants in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort. Women provided urine samples up to three times during pregnancy and adolescents provided a urine sample at 9-18 years of age for phthalate metabolite measurement. We administered the Conners' Continuous Performance Test (CPT) when children were age 6-11 years and again at 9-18 years of age. We used multivariable linear regression to examine associations between the geometric mean of phthalate metabolite levels across pregnancy and CPT scores in childhood or adolescence separately, adjusting for age, years schooling (at 9-18 only), maternal education, and specific gravity. Although average in utero phthalate concentrations were not associated with CPT scores in childhood, interquartile range (IQR) increases of in utero MBzP, MCPP, and MBP were associated with 4.2%, 4.7%, and 4.5% (p < 0.05) higher Omissions scores in adolescence, respectively, indicating higher inattention. In utero MiBP levels were also associated with higher Inter-Stimulus Interval (ISI) and Variability scores (5.4% and 5.5% per IQR, p < 0.05) in adolescence. In addition, urinary DEHP metabolite levels during adolescence were cross-sectionally associated with poorer scores on several CPT indices indicating greater inattention. These findings suggest that in utero phthalate exposure may have adverse effects on attention, but these effects may not appear until adolescence, a period of extensive neurodevelopment. Future research investigating the long-term effects of in utero phthalate exposure on attention and ADHD in adolescence, as well as identification of potential mechanisms involved, is needed.

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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.

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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.

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