Urinary trace metals, maternal circulating angiogenic biomarkers, and preeclampsia: a single-contaminant and mixture-based approach.
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ABSTRACT: Background
Exposures to toxic metals and deficiencies in essential metals disrupt placentation and may contribute to preeclampsia. However, effects of exposure to combinations of metals remain unknown.Objective
We investigated the relationship between urinary trace metals, circulating angiogenic biomarkers, and preeclampsia using the LIFECODES birth cohort.Methods
Urine samples collected during pregnancy were analyzed for 17 trace metals and plasma samples were analyzed for soluble fms-like tyrosine-1 (sFlt-1) and placental growth factor (PlGF). Cox proportional hazard models were used to estimate the hazard ratios (HR) of preeclampsia associated with urinary trace metals. Linear regression models were used to estimate the relationship between urinary trace metals and angiogenic biomarkers. Principal components analysis (PCA) was used to identify groups of metals and interactions between principal components (PCs) loaded by toxic and essential metals were examined.Results
In single-contaminant models, several toxic and essential metals were associated with lower PlGF and higher sFlt-1/PlGF ratio. Detection of urinary chromium was associated with preeclampsia: HR (95% Confidence Interval [CI]) = 3.48 (1.02, 11.8) and an IQR-increase in urinary selenium was associated with reduced risk of preeclampsia (HR: 0.28, 95% CI: 0.08, 0.94). Using PCA, 3 PCs were identified, characterized by essential metals (PC1), toxic metals (PC2), and seafood-associated metals (PC3). PC1 and PC2 were associated with lower PlGF levels, but not preeclampsia risk in the overall cohort.Conclusions
Trace urinary metals may be associated with adverse profiles of angiogenic biomarkers and preeclampsia.
SUBMITTER: Bommarito PA
PROVIDER: S-EPMC6624941 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Exposure to metals increases risk for pregnancy complications. Extracellular vesicle (EV) miRNA contribute to maternal-foetal communication and are dysregulated in pregnancy complications. However, metal impacts on maternal circulating EV miRNA during pregnancy are unknown. Our objective was to investigate the impact of multiple metal exposures on EV miRNA in maternal circulation during pregnancy in the MADRES Study. Associations between urinary concentrations of nine metals and 106 EV miRNA in maternal plasma during pregnancy were investigated using robust linear regression (N = 231). Primary analyses focused on metal-miRNA associations in early pregnancy (median: 12.3 weeks gestation). In secondary analyses, we investigated associations with late pregnancy miRNA counts (median: 31.8 weeks gestation) in a subset of participants (N = 184) with paired measures. MiRNA associated with three or more metals (PFDR<0.05) were further investigated using Bayesian Kernel Machine Regression (BKMR), an environmental mixture method. Thirty-five miRNA were associated (PFDR<0.05) with at least one metal in early pregnancy. One association (an inverse association between cobalt and miR-150-5p) remained statistically significant when evaluating late pregnancy miRNA counts. Eight miRNA (miR-302b-3p, miR-199a-5p, miR-188-5p, miR-138-5p, miR-212-3p, miR-608, miR-1272, miR-19b-3p) were associated with three metals (barium, mercury, and thallium) in early pregnancy, and their predicted target genes were enriched in pathways important for placental development. Results were consistent when using BKMR. Early pregnancy exposure to barium, mercury, and thallium may have short-term impacts on a common set of EV miRNA which target pathways important for placental development.
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Project description:Background: Preeclampsia (PE) is a placental disease characterized by hypertension and proteinuria in pregnant women, which is associated with a high maternal and infantile morbidity. However, circulating biomarkers able to predict the prognosis of PE are lacking. Methods: Thirty-eight women were included in the study. They consisted of 19 patients with PE (13 with severe PE and 6 women with non-severe PE) and 19 gestational age-matched normal pregnancy controls. We measured coagulation pathway, endothelial responses and microparticle release and circulating gene expression in PE patient groups and normotensive controls. Results: The measurement of markers associated with coagulation pathway, endothelial activation and circulating microparticles enabled to discriminate PE from normal pregnancy but were not sufficient to distinguish severe from non-severe PE. PE patients also exhibited a specific transcriptional program distinct from that of control women and subtle differences were observed between severe and non-severe PE. Functional annotation of the up-modulated signature in PE highlighted two main functions related to ribosome and complement. Importantly, we found that 8 genes were specifically up-modulated in severe preeclampsia. Among these genes, the expression of VSIG4 was significantly increased in patients with severe preeclampsia in comparison with controls and patients with non-severe preeclampsia. Conclusion: Using transcriptional signatures of blood samples, we identified the gene encoding the estrogen receptor as a potential diagnostic marker of severe preeclampsia. In addition, the determination of this gene may improve the prognostic assessment of severe preeclampsia. Thirty-eight women were included in the study: 19 patients with PE, including 6 women with non-severe PE and 13 with severe PE, and 19 women with normal pregnancy (NP) selected according to age, weight, smoking status, race, gestational age at the inclusion, and blood pH (Table 1 of manuscript). Women with NP had no history of medical illness or medication, and received routing prenatal care. The diagnostic of PE was based on a blood pressure of M-bM-^IM-% 140/90 mmHg taken twice, uricemia above normal laboratory range (120-420 M-BM-5mol/L), and proteinuria higher than 300 mg in a 24 hour-collection, occurring after 20 gestational weeks in previously normotensive women (Table 2). The criteria used to define severe PE included one of the following conditions: a blood pressure higher than 160/110 mmHg, a proteinuria higher than 1500 mg/24h), a multisystem disorder, maternal cerebral symptoms (seizures, stroke) or intrauterine growth restriction below the 3M-BM-0 percentile. Women with multiple gestations, fetal congenital malformations/chromosomal abnormalities, recent infection, antiphospholipid antibodies, trauma, drug or alcohol abuse during pregnancy, preexisting hypertension, thrombophilia with PE history, or women receiving anticoagulant or antiaggregation therapy were excluded from the study. Two microarrays (one non-severe PE and one normal) were discarded from the analysis for technical reasons. Thus, only 36 microarrays are included here.
2014-05-14 | E-GEOD-48424 | biostudies-arrayexpress
Project description:Background Preeclampsia is a leading contributor to maternal and perinatal morbidity and mortality. In mice experiments, manganese (Mn) and selenium (Se) are protective whereas cadmium (Cd) is promotive for preeclampsia. Epidemiologic findings on these chemical elements have been inconsistent. To confirm experimental findings in mice, we examined associations of trace minerals (Mn and Se) and heavy metals (Cd, lead [Pb], and mercury [Hg]) with preeclampsia in a birth cohort. Methods and Results A total of 1274 women from the Boston Birth Cohort (enrolled since 1998) had complete data on the exposures and outcome. We measured Mn, Se, Cd, Pb, and Hg from red blood cells collected within 24 to 72 hours after delivery. We ascertained preeclampsia diagnosis from medical records. We used Poisson regression with robust variance models to estimate prevalence ratios (PRs) and 95% CIs. A total of 115 (9.0%) women developed preeclampsia. We observed evidence of a dose-response trend for Mn (P for trend<0.001) and to some extent for Cd (P for trend=0.009) quintiles. After multivariable adjustment, a 1 SD increment in Mn was associated with 32% lower risk of developing preeclampsia (PR=0.68; 95% CI, 0.54-0.86), whereas a 1 SD increment in Cd was associated with 15% higher risk of preeclampsia (PR=1.15; 95% CI, 0.98-1.36). Null associations were observed for Se, Pb, and Hg. Conclusions Findings from our cohort, consistent with evidence from mice experiments and human studies, indicate that women with lower blood concentration of Mn or higher Cd are more likely to develop preeclampsia.
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Project description:Background: Preeclampsia (PE) is a placental disease characterized by hypertension and proteinuria in pregnant women, which is associated with a high maternal and infantile morbidity. However, circulating biomarkers able to predict the prognosis of PE are lacking. Methods: Thirty-eight women were included in the study. They consisted of 19 patients with PE (13 with severe PE and 6 women with non-severe PE) and 19 gestational age-matched normal pregnancy controls. We measured coagulation pathway, endothelial responses and microparticle release and circulating gene expression in PE patient groups and normotensive controls. Results: The measurement of markers associated with coagulation pathway, endothelial activation and circulating microparticles enabled to discriminate PE from normal pregnancy but were not sufficient to distinguish severe from non-severe PE. PE patients also exhibited a specific transcriptional program distinct from that of control women and subtle differences were observed between severe and non-severe PE. Functional annotation of the up-modulated signature in PE highlighted two main functions related to ribosome and complement. Importantly, we found that 8 genes were specifically up-modulated in severe preeclampsia. Among these genes, the expression of VSIG4 was significantly increased in patients with severe preeclampsia in comparison with controls and patients with non-severe preeclampsia. Conclusion: Using transcriptional signatures of blood samples, we identified the gene encoding the estrogen receptor as a potential diagnostic marker of severe preeclampsia. In addition, the determination of this gene may improve the prognostic assessment of severe preeclampsia.
2014-05-14 | GSE48424 | GEO
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Project description:We aim to establish a prediction model for pregnancy outcomes through a combinatorial analysis of circulating biomarkers and maternal characteristics to effectively identify pregnant women with higher risks of preeclampsia in the first and third trimesters within the Asian population. A total of two hundred and twelve pregnant women were screened for preeclampsia through a multicenter study conducted in four recruiting centers in Taiwan from 2017 to 2020. In addition, serum levels of sFlt-1/PlGF ratio, miR-181a, miR-210 and miR-223 were measured and transformed into multiples of the median. We thus further developed statistically validated algorithmic models by designing combinations of different maternal characteristics and biomarker levels. Through the performance of the training cohort (0.848 AUC, 0.73-0.96 95% CI, 80% sensitivity, 85% specificity, p < 0.001) and the validation cohort (0.852 AUC, 0.74-0.98 95% CI, 75% sensitivity, 87% specificity, p < 0.001) from one hundred and fifty-two women with a combination of miR-210, miR-181a and BMI, we established a preeclampsia prediction model for the first trimester. We successfully identified pregnant women with higher risks of preeclampsia in the first and third trimesters in the Asian population using the established prediction models that utilized combinatorial analysis of circulating biomarkers and maternal characteristics.
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Project description:Placental dysfunction underlies a spectrum of perinatal pathologies, including preeclampsia and fetal growth restriction. Angiogenesis-related factors, including sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor), play an important role in placental dysfunction; altered levels are detectable several weeks before onset of pregnancy complications. In vitro diagnostic tests for these biomarkers can improve early diagnosis and facilitate prediction of maternal and fetal outcomes. We assessed evidence for combining angiogenic biomarkers with other biomarkers or clinical parameters to predict maternal/fetal outcomes in pregnant women with placental dysfunction. Pooled information on placental perfusion (ultrasonography, mean arterial pressure), clinical characteristics, and biomarker levels (PlGF) can improve first-trimester prediction and preeclampsia diagnosis. Angiogenic factors (sFlt-1/PlGF ratio; PlGF alone) with or without clinical characteristics can facilitate second-/third-trimester prediction of early-onset and late-onset preeclampsia. A combination of increased sFlt-1/PlGF ratio and ultrasound can rule out early fetal growth restriction. The sFlt-1/PlGF ratio is also a reliable tool for discriminating between pregnancy-related hypertensive disorders, including superimposed preeclampsia and gestational hypertension. Analysis of angiogenic factors with or without uterine Doppler substantially improves sensitivity and specificity for predicting adverse outcomes and iatrogenic preterm delivery. We propose to extend the American College of Obstetricians and Gynecologists definition of preeclampsia in the future to include the combination of new-onset hypertension and new-onset of altered angiogenic factors (sFlt-1/PlGF ratio or PlGF alone). In summary, altered angiogenic biomarkers indicate placental dysfunction, and their implementation into clinical practice will help reduce the considerable burden of morbidity and mortality associated with adverse pregnancy outcomes as a consequence of angiogenic-placental syndrome.
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Project description:BackgroundReliable biomarkers are needed to improve preeclampsia (PE) prediction accuracy. With the investigational tool of peptidomics, we aimed to identify and validate potential serum peptide biomarkers in cohorts suspected for PE development in middle or late pregnancy.MethodsTotally 195 serum samples were prospectively collected from pregnant women with PE-related syndromes who were followed up for PE development until delivery. Serum peptidomic analysis was performed in the discovery cohort of 115 samples using matrix-assisted laser desorption ionization-time of flight coupled with Linear Trap Quadropole Orbitrap mass spectrometry. The candidate biomarkers were further validated using an in-house developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method in an independent validation cohort of 80 serum samples.ResultsWe identified 8 peptides that were differentially expressed and originated from fibrinogen alpha chain (FGA), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and complement component 3. In the subsequent LC-MS/MS quantitation analysis, the levels of the three peptides (FGA-1033.4, ITIH4-2026.9, ITIH4-2051.1) exhibited a significant difference between the PE-positive and PE-negative groups. Further, the three-peptide panel yielded an area under the ROC curve (AUC) of 0.985 [95% confidence interval (CI) 0.965-1.000] and 0.923 (95% CI 0.845-1.000) in the discovery and validation cohorts respectively, with negative predictive values of 98.1-98.8% and positive predictive values of 73.1-85.3% that were much improved when compared with that of soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio.ConclusionsWe have discovered and validated a novel three-peptide biomarker panel predictive for the occurrence PE in pregnant women.
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