Background Preeclampsia is a prevalent and enigmatic disease, in part characterized by poor remodeling of the spiral arteries. However, preeclampsia does not always clinically present when remodeling ...has failed to occur. Hypotheses surrounding the “second hit” that is necessary for the clinical presentation of the disease focus on maternal inflammation and oxidative stress. Yet, the studies to date that have investigated these factors have used cross-sectional study designs or small study populations. Objective In the present study, we sought to explore longitudinal trajectories, beginning early in gestation, of a panel of inflammation and oxidative stress markers in women who went on to have preeclamptic or normotensive pregnancies. Study Design We examined 441 subjects from the ongoing LIFECODES prospective birth cohort, which included 50 mothers who experienced preeclampsia and 391 mothers with normotensive pregnancies. Participants provided urine and plasma samples at 4 time points during gestation (median, 10, 18, 26, and 35 weeks) that were analyzed for a panel of oxidative stress and inflammation markers. Oxidative stress biomarkers included 8-isoprostane and 8-hydroxydeoxyguanosine. Inflammation biomarkers included C-reactive protein, the cytokines interleukin-1β, -6, and -10, and tumor necrosis factor-α. We created Cox proportional hazard models to calculate hazard ratios based on time of preeclampsia diagnosis in association with biomarker concentrations at each of the 4 study visits. Results In adjusted models, hazard ratios of preeclampsia were significantly ( P <.01) elevated in association with all inflammation biomarkers that were measured at visit 2 (median, 18 weeks; hazard ratios, 1.31–1.83, in association with an interquartile range increase in biomarker). Hazard ratios at this time point were the most elevated for C-reactive protein, for interleukin-1β, -6, and -10, and for the oxidative stress biomarker 8-isoprostane (hazard ratio, 1.68; 95% confidence interval, 1.14–2.48) compared to other time points. Hazard ratios for tumor necrosis factor-α were consistently elevated at all 4 of the study visits (hazard ratios, 1.49–1.63; P <.01). In sensitivity analyses, we observed that these associations were attenuated within groups typically at higher risk of experiencing preeclampsia, which include African American mothers, mothers with higher body mass index at the beginning of gestation, and pregnancies that ended preterm. Conclusions This study provides the most robust data to date on repeated measures of inflammation and oxidative stress in preeclamptic compared with normotensive pregnancies. Within these groups, inflammation and oxidative stress biomarkers show different patterns across gestation, beginning as early as 10 weeks. The start of the second trimester appears to be a particularly important time point for the measurement of these biomarkers. Although biomarkers alone do not appear to be useful in the prediction of preeclampsia, these data are useful in understanding the maternal inflammatory profile in pregnancy before the development of the disease and may be used to further develop an understanding of potentially preventative measures.
Preeclampsia represents a major cause of maternal mortality and morbidity worldwide. Although it is known that the placenta plays a central role in development of preeclampsia, investigation into the ...contribution of environmental toxicants to the risk of preeclampsia has been sparse.
In the present study we examined the relationship between longitudinally measured urinary BPA and phthalate metabolite concentrations during gestation and preeclampsia.
A nested case-control study of preterm birth was performed in 2011 from women enrolled in a prospective birth cohort study at Brigham and Women's Hospital in Boston. There were 50 cases of preeclampsia as part of this study. Urine samples were analyzed for concentrations of BPA and nine phthalate metabolites several times during pregnancy. Adjusted Cox proportional hazard models were used to calculate hazard ratios of preeclampsia in association with an interquartile range increase in BPA and phthalate concentrations and were weighted to reflect results generalizable to the base population.
Adjusted hazard ratios indicated that an interquartile range increase of urinary concentrations of BPA (1.53; 95% CI: 1.04, 2.25) and MEP (monoethyl phthalate) (1.72; 95% CI: 1.28, 2.30) at 10 weeks gestation was associated with onset of preeclampsia, whereas significantly elevated hazard ratios were found across gestation for all DEHP di(2-ethylhexyl) phthalate metabolites. These relationships differed based on infant sex.
Urinary concentrations of BPA and several phthalate metabolites were significantly associated with increased risk of preeclampsia. If validated, these results indicate an environmental contribution of endocrine-disrupting chemicals to preeclampsia and suggest a modifiable means to reduce the mortality and morbidity associated with this condition.
Cantonwine DE, Meeker JD, Ferguson KK, Mukherjee B, Hauser R, McElrath TF. 2016. Urinary concentrations of bisphenol A and phthalate metabolites measured during pregnancy and risk of preeclampsia. Environ Health Perspect 124:1651-1655; http://dx.doi.org/10.1289/EHP188.
One in ten infants born in the United States is born preterm, or prior to 37 weeks gestation. Exposure to elevated levels of metals, such as lead and arsenic, has been linked to higher risk of ...preterm birth (PTB), but consequences of lower levels of exposure and less studied metals are unclear. We examined the associations between 17 urinary trace metals individually and in mixtures in relation to PTB. The LIFECODES birth cohort enrolled pregnant women at <15 weeks gestation at Brigham and Women's Hospital in Boston. We selected cases of PTB (n = 99) and unmatched controls (n = 291) and analyzed urine samples for a panel of trace metals (median: 26 weeks gestation). We used logistic regression models to calculate the odds ratio (OR) for PTB and subtypes of PTB based on presentation at delivery. Subtypes included spontaneous and placental PTB. We used elastic net (ENET) regularization to identify individual metals or pairwise interactions that had the strongest associations with PTB, and principal components analysis (PCA) to identify classes of exposures associated with the outcome. We observed increased odds of PTB (OR: 1.41, 95% Confidence Interval CI: 1.12, 1.78) in association with an interquartile range difference in urinary copper (Cu). We also observed an increased OR for selenium (OR: 1.33, 95% CI: 0.98, 1.81). ENET selected Cu as the most important trace metal associated with PTB. PCA identified 3 principal components (PCs) that roughly reflected exposure to toxic metals, essential metals, and metals with seafood as a common source of exposure. PCs reflecting essential metals were associated with increased odds of overall and spontaneous PTB. Maternal urinary copper in the third trimester was associated with increased risk of PTB, and statistical analyses for mixtures indicated that after accounting for correlation this metal was the most important statistical predictor of the outcome.
•We analyzed 17 urinary trace metals in collaboration with the Children's Health and Exposure Assessment Resource (CHEAR).•Urinary Cu concentrations from third trimester were associated with increased odds of preterm birth in single pollutant model•Elevated concentrations of essential trace metals, Se and Zn, also had a positive association with increased odds of preterm birth•ENET and PCA results confirmed findings from the single pollutant models.
Diverse toxicological mechanisms may mediate the impact of environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. In this study, we ...introduce an analytical framework for multivariate mediation analysis to identify mediation pathways (q = 61 mediators) in the relationship between environmental toxicants (p = 38 analytes) and gestational age at delivery. Our analytical framework includes: (1) conducting pairwise mediation for unique exposure-mediator combinations, (2) exposure dimension reduction by estimating environmental risk scores, and (3) multivariate mediator analysis using either Bayesian shrinkage mediation analysis, population value decomposition, or mediation pathway penalization. Dimension reduction demonstrates that a one-unit increase in phthalate risk score is associated with a total effect of 1.07 lower gestational age (in weeks) at delivery (95% confidence interval: 0.48-1.67) and eicosanoids from the cytochrome p450 pathway mediated 26% of this effect (95% confidence interval: 4-63%). Eicosanoid products derived from the cytochrome p450 pathway may be important mediators of phthalate toxicity.
Background: A number of phenols and parabens are added to consumer products for a variety of functions, and have been found at detectable levels in the majority of the U.S. population. Among other ...functions, thyroid hormones are essential in fetal neurodevelopment, and could be impacted by the endocrine disrupting effects of phenols and parabens. The present study investigated the association between ten maternal urinary phenol and paraben biomarkers (bisphenol S, triclosan, triclocarban, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, and ethyl, butyl, methyl and propyl paraben) and four plasma thyroid hormones in 439 pregnant women in a case–control sample nested within a cohort study based in Boston, MA. Methods: Urine and blood samples were collected from up to four visits during pregnancy (median weeks of gestation at each visit: Visit 1: 9.64, Visit 2: 17.9, Visit 3: 26.0, Visit 4: 35.1). Linear mixed models were constructed to take into account the repeated measures jointly, followed by multivariate linear regression models stratified by gestational age to explore potential windows of susceptibility. Results: We observed decreased total triiodothyronine (T3) in relation to an IQR increase in benzophenone-3 (percent change %Δ = −2.07; 95% confidence interval CI = −4.16, 0.01), butyl paraben (%Δ = −2.76; 95% CI = −5.25, −0.26) and triclosan (%Δ = −2.53; 95% CI = −4.75, −0.30), and triclocarban at levels above the LOD (%Δ = −5.71; 95% CI = −10.45, −0.97). A 2.41% increase in T3 was associated with an IQR increase in methyl paraben (95% CI = 0.58, 4.24). We also detected a negative association between free thyroxine (FT4) and propyl paraben (%Δ = −3.14; 95% CI = −6.12, −0.06), and a suggestive positive association between total thyroxine (T4) and methyl paraben (%Δ = 1.19; 95% CI = −0.10, 2.47). Gestational age-specific multivariate regression analyses showed that the magnitude and direction of some of the observed associations were dependent on the timing of exposure. Conclusion: Certain phenols and parabens were associated with altered thyroid hormone levels during pregnancy, and the timing of exposure influenced the association between phenol and paraben, and hormone concentrations. These changes may contribute to downstream maternal and fetal health outcomes. Additional research is required to replicate the associations, and determine the potential biological mechanisms underlying the observed associations.
•Phenol and paraben urinary biomarker concentrations were measured at four time points in pregnant women•Exposure urinary biomarker concentrations were associated with changes in thyroid hormone levels, particularly triiodothyronine•Some differences in the associations were observed across time points in pregnancy
An increase in telomere shortening in gestational tissues has been proposed as a mechanism involved in the timing for the initiation of parturition. An increase in very short telomeres with ...increasing gestational age has been observed in mice; this study sought to explore this phenomenon in human pregnancies. Specifically, this study addressed the hypothesis that prior to labor, the quantity of very short telomeres (<3 kilobase (kb) lengths) increases in human placental tissue as term gestation approaches. The primary outcome was the quantity of very short telomeres present in placental tissue. Quantitative measurements of very short telomeres were performed using real-time polymerase chain reaction (qPCR) adaptation of the telomere restriction fragment technique. Placental tissue from 69 pregnant individuals were included. Mean gestational age was 39.1 weeks (term) and 36.2 weeks (preterm). For term versus preterm placentas, the observed increase in very short telomeres were as follows: 500 bp telomeres increased by 1.67-fold (p < 0.03); 1 kb telomeres increased 1.67-fold (p < 0.08); and 3 kb telomeres increased 5.20-fold (p < 0.001). This study confirms a significant increase in very short telomeres in human placental tissue at term; thereby supporting the hypothesis that telomere shortening at term contributes to the mechanism that determine the length of pregnancy thereby leading to onset of parturition.
Puerto Rico has higher rates of a range of endocrine-related diseases and disorders compared to the United States. However, little is known to date about human exposures to known or potential ...endocrine disrupting chemicals (EDCs) in Puerto Rico. We recruited 105 pregnant women in Northern Puerto Rico who provided urine samples and questionnaire data at three times (18 ± 2, 22 ± 2, and 26 ± 2 weeks) during gestation. We measured the urinary concentrations of five phenols and three parabens: 2,4-dichlorophenol (24-DCP), 2,5-dichlorophenol (25-DCP), benzophenone-3 (BP-3), bisphenol A (BPA), triclosan (TCS), butyl paraben (B-PB), methyl paraben (M-PB), and propyl paraben (P-PB). The frequent detection of these chemicals suggests that exposure is highly prevalent among these Puerto Rican pregnant women. Urinary concentrations of TCS, BP-3, and 25-DCP were higher than among women of reproductive age in the US general population, while concentrations of BPA, 24-DCP, and parabens were similar. Intraclass correlation coefficients (ICC) varied widely between biomarkers; BPA had the lowest ICC (0.24) and BP-3 had the highest (0.62), followed by 25-DCP (0.49) and TCS (0.47). We found positive associations between biomarker concentrations with self-reported use of liquid soap (TCS), sunscreen (BP-3), lotion (BP-3 and parabens), and cosmetics (parabens). Our results can inform future epidemiology studies and strategies to reduce exposure to these chemicals or their precursors.
•BPA is an endocrine disruptor but may also cause oxidative stress and inflammation.•We used repeated measures models to examine BPA in relation to biomarkers of each.•BPA was associated with modest ...increases in biomarkers of oxidative stress.•BPA was associated with increases in IL-6, an indicator of systemic inflammation.
Bisphenol-A (BPA) exposure occurs commonly and may adversely impact pregnancy. Endocrine disruption is posited as the primary mechanism of action, but oxidative stress and inflammation pathways may also be important. We investigated associations between BPA exposure and oxidative stress and inflammation in 482 pregnant women. Participants were recruited early in pregnancy and provided urine and plasma at up to four visits. We measured total BPA and two biomarkers of oxidative stress (8-hydroxydeoxyguanosine and 8-isoprostane) in urine from each visit. Inflammation markers, including C-reactive protein and four cytokines were measured in plasma from the same time points. In adjusted models, an interquartile range increase in BPA was associated with significant increases in both oxidative stress biomarkers (5–9% increase). Additionally, we observed significantly higher IL-6 concentrations in association with an interquartile range increase in BPA (8.95% increase). These systemic changes consequent to BPA exposure may mediate adverse birth outcomes and/or fetal development.
Increasing scientific evidence suggests that exposure to phthalates during pregnancy may be associated with an elevated risk of adverse reproductive outcomes such as preterm birth. Maternal endocrine ...disruption across pregnancy may be one pathway mediating some of these relationships. We investigated whether urinary phthalate metabolites were associated with maternal serum thyroid (free thyroxine FT4, free triiodothyronine FT3, and thyroid-stimulating hormone TSH), and sex (estradiol, progesterone, and sex hormone-binding globulin SHBG) hormone levels at multiple time points during pregnancy.
Preliminary data (n = 106) were obtained from an ongoing prospective birth cohort in Northern Puerto Rico. We collected urine and serum sample at the first and third study visits that occurred at 18 +/- 2 and 26 +/- 2 weeks of gestation, respectively. To explore the longitudinal relationships between urinary phthalate metabolites and serum thyroid and sex hormone concentrations, we used linear mixed models (LMMs) adjusted for prepregnancy body mass index (BMI) and maternal age. An interaction term was added to each LMM to test whether the effect of urinary phthalate metabolites on serum thyroid and sex hormone levels varied by study visit. In cross-sectional analyses, we stratified BMI- and age-adjusted linear regression models by study visit.
In adjusted LMMs, we observed significant inverse associations between mono-3-carboxypropyl phthalate (MCPP) and FT3 and between mono-ethyl phthalate (MEP) and progesterone. In cross-sectional analyses by study visit, we detected stronger and statistically significant inverse associations at the third study visit between FT3 and MCPP as well as mono-carboxyisooctyl phthalate (MCOP); also at the third study visit, significant inverse associations were observed between FT4 and metabolites of di-(2-ethylhexyl) phthalate (DEHP). The inverse association between MEP and progesterone was consistent across study visits.
In this group of pregnant women, urinary phthalate metabolites may be associated with altered maternal serum thyroid and sex hormone levels, and the magnitude of these effects may depend on the timing of exposure during gestation.
Eicosanoids are a class of bioactive lipids produced from the oxygenation of polyunsaturated fatty acid precursors, including the primary omega-6 fatty acids (linoleic acid LA and arachidonic acid ...AA) and omega-3 fatty acids (docosahexaenoic acid DHA and eicosapentaenoic acid EPA) 12. Namely, 1 participant previously categorized as AGA was recategorized as SGA, and 2 participants previously categorized as LGA were recategorized as AGA. ...our final distribution of outcome groups was 31 SGA cases, 31 AGA controls, and 28 LGA cases. Eicosanoid quantification A panel of eicosanoids and fatty acids was measured in plasma samples by the Mass Spectrometry Research and Support Group at the National Institute of Environmental Health Sciences (Research Triangle, NC, US) in 2018. The eicosanoid pathway is defined by a fatty acid precursor—linoleic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA)—that is metabolized by an enzyme—cytochrome P450 (CYP), lipoxygenase (LOX), or cyclooxygenase (COX).
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