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Associations between Maternal Biomarkers of Phthalate Exposure and Inflammation Using Repeated Measurements across Pregnancy.

ABSTRACT: Phthalate exposure is prevalent in populations worldwide, including pregnant women. Maternal urinary metabolite concentrations have been associated with adverse reproductive outcomes, but underlying mechanisms remain unclear. Here we investigate inflammation as a possible pathway by examining phthalates in association with inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines (IL-1?, IL-6, IL-10, and TNF-?) in a repeated measures analysis of pregnant women (N = 480). Urinary phthalate metabolites and plasma inflammation biomarkers were measured from samples collected at up to four visits per subject during gestation (median 10, 18, 26, and 35 weeks). Associations were examined using mixed models to account for within-individual correlation of measures. Few statistically significant associations or clear trends were observed, although in full models mono-carboxypropyl phthalate (MCPP) was significantly (percent change with interquartile range increase in exposure [%?] = 8.89, 95% confidence interval [CI] = 3.28, 14.8), and mono-benzyl phthalate (MBzP) was suggestively (%? = 6.79, 95%CI = -1.21, 15.4) associated with IL-6. Overall these findings show little evidence of an association between phthalate exposure and peripheral inflammation in pregnant women. To investigate inflammation as a mechanism of phthalate effects in humans, biomarkers from target tissues or fluids, though difficult to measure in large-scale studies, may be necessary to detect effects.

SUBMITTER: Ferguson KK

PROVIDER: S-EPMC4552851 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Associations between Maternal Biomarkers of Phthalate Exposure and Inflammation Using Repeated Measurements across Pregnancy.

Ferguson Kelly K KK McElrath Thomas F TF Mukherjee Bhramar B Loch-Caruso Rita R Meeker John D JD

PloS one 20150828 8

Phthalate exposure is prevalent in populations worldwide, including pregnant women. Maternal urinary metabolite concentrations have been associated with adverse reproductive outcomes, but underlying mechanisms remain unclear. Here we investigate inflammation as a possible pathway by examining phthalates in association with inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines (IL-1β, IL-6, IL-10, and TNF-α) in a repeated measures analysis of pregnant women (N = 480 ...[more]

PMID: 26317519

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Project description:BackgroundMediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease.ObjectiveWe examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress.MethodsThis nested case-control study of preterm birth (n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure-mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure-mediator interaction.ResultsWe observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure-mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure-mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively.ConclusionsThis demonstrates mediation of the phthalate-preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure-mediator interaction may exist. Citation: Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488-494; http://dx.doi.org/10.1289/EHP282.

Project description:BACKGROUND:Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women. OBJECTIVES:We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection. METHODS:Data were obtained from pregnant women (n = 439) participating in a nested case-control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy. RESULTS:Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation. CONCLUSIONS:These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women. Citation: Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808-1815;?http://dx.doi.org/10.1289/EHP170.

Project description: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 [%?]?=?-2.07; 95% confidence interval [CI]?=?-4.16, 0.01), butyl paraben (%??=?-2.76; 95% CI?=?-5.25, -0.26) and triclosan (%??=?-2.53; 95% CI?=?-4.75, -0.30), and triclocarban at levels above the LOD (%??=?-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 (%??=?-3.14; 95% CI?=?-6.12, -0.06), and a suggestive positive association between total thyroxine (T4) and methyl paraben (%??=?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.

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

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

Dataset Information

Associations between Maternal Biomarkers of Phthalate Exposure and Inflammation Using Repeated Measurements across Pregnancy.

Publications

Associations between Maternal Biomarkers of Phthalate Exposure and Inflammation Using Repeated Measurements across Pregnancy.

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