Inflammation and oxidative stress play major roles in healthy and pathological pregnancy. Environmental exposure to chemical pollutants may adversely affect maternal and fetal health in pregnancy by ...dysregulating these critical underlying processes of inflammation and oxidative stress. Oxylipins are bioactive lipids that play a major role in regulating inflammation and increasing lines of evidence point towards an importance in pregnancy. The biosynthetic production of oxylipins requires oxygenation of polyunsaturated fatty acids, which can occur through several well-characterized enzymatic and nonenzymatic pathways. This review describes the state of the science of epidemiologic evidence on oxylipin production in pregnancy and its association with 1) key pregnancy outcomes and 2) environmental exposures. We searched PubMed for studies of pregnancy that measured one or more oxylipin analytes during pregnancy or delivery. We evaluated oxylipin associations with three categories of adverse pregnancy outcomes, including preeclampsia, preterm birth, and fetal growth restriction, along with several categories of environmental pollutants. The majority of studies evaluated one to two oxylipins, most of which focused on oxylipins produced from nonenzymatic processes of oxidative stress. However, an increasing number of recent studies have leveraged technological advancements to profile a large number of oxylipins produced from distinct biosynthetic pathways. Although the literature indicated robust evidence that oxylipins produced via nonenzymatic pathways are associated with pregnancy outcomes and environmental exposures, evidence for enzymatically produced oxylipins showed that associations may differ between biosynthetic pathways. Along with summarizing this evidence, we review promising therapeutic options to regulate oxylipin production and provide a set of recommendations for future epidemiologic studies in these research areas. Further evidence is needed to improve our understanding of how oxylipins may act as key biological mediators for the adverse effects of environmental pollutants on pregnancy outcomes.
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).
Arsenic can impair immune function. Timing of exposure can influence potential immunotoxicity of arsenic exposure. We examined the association between drinking water arsenic concentrations (W-As) ...measured repeatedly during different exposure windows in early life and serum concentrations of IgG antibodies against diphtheria and tetanus toxoids (diphtheria and tetanus antibody).
A prospective cohort of pregnant women was recruited in Bangladesh (2008–2011). Averaged W-As levels were calculated for: pregnancy (W-Aspregnancy): ≤16 weeks gestation and <1 month; toddlerhood (W-Astoddlerhood): 12 and 20–40 months; and early childhood (W-Aschildhood): 4–5 years. Serum was collected from 502 vaccinated children at age 5 and concentrations of diphtheria and tetanus toxoid IgG (i.e. antibody) were quantified. Antibody concentrations >0.1 IU/mL were considered clinically sufficient for protection. Associations were estimated using linear and logistic regression models.
Inverse associations were observed between W-Aspregnancy and serum diphtheria antibody levels, while null associations were observed between W-As and tetanus antibody. Children within the highest versus lowest tertile of W-Aspregnancy had 91% greater odds of having clinically insufficient concentrations of diphtheria antibody (Odds ratio:1.91, 95% confidence interval (CI): 1.03, 3.56). Among females, a doubling in W-Aspregnancy was associated with 12.3% (95%CI: −20.1%, −4.5%) lower median concentrations of diphtheria antibody. Tetanus antibody was only associated with W-Aspregnancy among females (percent change in median: −9.5%, 95%CI: −17.6%, −1.3%). Among children who were stunted or underweight, a doubling in W-Aspregnancy was associated with decreased diphtheria antibody of 19.8% (95%CI: −32%, −7.5%) and 14.3% (95%CI: −26.7%, −2%), respectively.
Among vaccinated children, W-As measured during pregnancy was associated with decreased diphtheria antibody levels, but not tetanus antibody. However, W-As measured during toddlerhood and early childhood were not associated with either antibody outcome. Children's sex and malnutrition status were important effect modifiers of W-As for both diphtheria and tetanus antibody levels, highlighting the importance of these factors and the timing of the exposure when evaluating the effect of arsenic on humoral immunity.
•Drinking water arsenic was negatively associated with vaccine-related diphtheria antibody.•Null associations were observed between tetanus antibody titers and drinking water arsenic.•Pregnancy appeared to be the most susceptible period for arsenic-related immunotoxicity.•Arsenic-related effects were most pronounced in females, or children that were stunted growth or underweight.
Guidance is lacking for how to combine urinary biomarker data across studies that use different measures of urinary dilution, that is, creatinine or specific gravity.
Among 741 pregnant participants ...from four sites of The Infant Development and Environment Study (TIDES) cohort, we assessed the relation of maternal urinary di-2-ethylhexyl phthalate (DEHP) concentrations with preterm birth. We compared scenarios in which all sites measured either urinary creatinine or specific gravity, or where measure of dilution differed by site. In addition to a scenario with no dilution adjustment, we applied and compared three dilution-adjustment approaches: a standard regression-based approach for creatinine, a standard approach for specific gravity (Boeniger method), and a more recently developed approach that has been applied to both (covariate-adjusted standardization method). For each scenario and dilution-adjustment method, we estimated the association between a doubling in the molar sum of DEHP (∑DEHP) and odds of preterm birth using logistic regression.
All dilution-adjustment approaches yielded comparable associations (odds ratio OR) that were larger in magnitude than when we did not perform dilution adjustment. A doubling of ∑DEHP was associated with 9% greater odds of preterm birth (OR = 1.09, 95% confidence interval CI = 0.91, 1.30) when applying no dilution-adjustment method, whereas dilution-adjusted point estimates were higher, and similar across all scenarios and methods: 1.13-1.20 (regression-based), 1.15-1.18 (Boeniger), and 1.14-1.21 (covariate-adjusted standardization).
In our applied example, we demonstrate that it is possible and straightforward to combine urinary biomarker data across studies when measures of dilution differ.
•We evaluated class-specific mixtures of phenol, phthalate, and organophosphate ester biomarkers in maternal urine.•We assessed the bioactive lipids called oxylipins from several biosynthetic ...pathways in maternal plasma.•Higher consumer product chemicals were associated with certain pro-inflammatory oxylipins.•Consumer product chemicals may promote inflammation related to lipid metabolism during pregnancy.
Exposure to consumer product chemicals during pregnancy may increase susceptibility to pregnancy disorders by influencing maternal inflammation. However, effects on specific inflammatory pathways have not been well characterized. Oxylipins are a diverse class of lipids that act as important mediators and biomarkers of several biological pathways that regulate inflammation. Adverse pregnancy outcomes have been associated with circulating oxylipin levels in pregnancy. In this study, we aimed to determine the longitudinal associations between plasma oxylipins and urinary biomarkers of three classes of consumer product chemicals among pregnant women.
Data come from a study of 90 pregnant women nested within the LIFECODES cohort. Maternal plasma and urine were collected at three prenatal visits. Plasma was analyzed for 61 oxylipins, which were grouped according to biosynthetic pathways that we defined by upstream: 1) fatty acid precursor, including linoleic, arachidonic, docosahexaenoic, or eicosapentaenoic acid; and 2) enzyme pathway, including cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450 (CYP). Urine was analyzed for 12 phenol, 12 phthalate, and 9 organophosphate ester (OPE) biomarkers. Linear mixed effect models were used for single-pollutant analyses. We implemented a novel extension of quantile g-computation for longitudinal data to examine the joint effect of class-specific chemical mixtures on individual plasma oxylipin concentrations.
We found that urinary biomarkers of consumer product chemicals were positively associated with pro-inflammatory oxylipins from several biosynthetic pathways. Importantly, these associations depended upon the chemical class of exposure biomarker. We estimated positive associations between urinary phenol biomarkers and oxylipins produced from arachidonic acid by LOX enzymes, including several important pro-inflammatory hydroxyeicosatetraenoic acids (HETEs). On average, mean concentrations of oxylipin produced from the arachidonic acid/LOX pathway were 48%–71% higher per quartile increase in the phenol biomarker mixture. For example, a simultaneous quartile increase in all urinary phenols was associated with 53% higher (95% confidence interval CI: 11%, 111%) concentrations of 12-HETE. The positive associations among phenols were primarily driven by methyl paraben, 2,5-dichlorophenol, and triclosan. Additionally, we observed that phthalate and OPE metabolites were associated with higher concentrations of oxylipins produced from linoleic acid by CYP enzymes, including the pro-inflammatory dihydroxy-octadecenoic acids (DiHOMEs). Associations among DiHOME oxylipins were driven by metabolites of benzylbutyl and di-isodecyl phthalate, and by the metabolite of tris(1,3-dichloro-2-propyl) phosphate among OPEs. We also observed inverse associations between phthalate and OPE metabolites and oxylipins produced from other pathways; however, adjusting for a plasma indicator of dietary fatty acid intake attenuated those results.
Our findings support the hypothesis that consumer product chemicals may have diverse impacts on inflammation processes in pregnancy. Certain pro-inflammatory oxylipins were generally higher among participants with higher urinary chemical biomarker concentrations. Associations varied by class of chemical and by the biosynthetic pathway of oxylipin production, indicating potential specificity in the inflammatory effects of these environmental chemicals during pregnancy that warrant investigation in larger studies.
Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity.BACKGROUNDOrganophosphate esters (OPEs), ...used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity.Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA) measures of growth.OBJECTIVESOur study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA) measures of growth.In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models.METHODSIn the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models.Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng/mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17, abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng/mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94).RESULTSMost OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng/mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17, abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng/mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94).In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.CONCLUSIONSIn a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.
Lower socioeconomic status (SES) and elevated psychosocial stress are known contributors to adverse pregnancy outcomes; however, biological mechanisms linking these factors to adverse pregnancy ...outcomes are not well-characterized. Oxidative stress may be an important, yet understudied mechanistic pathway. We used a pooled study design to examine biological, behavioral, and social factors as predictors of prenatal oxidative stress biomarkers.
Leveraging four pregnancy cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program spanning multiple geographic regions across the United States (U.S.) (N = 2082), we measured biomarkers of oxidative stress in urine samples at up to three time points during pregnancy, including 8-isoprostane-prostaglandin F2α (8-isoPGF2α), its major metabolite, 2,3-dinor-5,6-dihydro-15-F2t-isoprostane, and prostaglandin F2α (PGF2α). Maternal age, pre-pregnancy body mass index, marital/partnered status, parity, and smoking status were included as biological and behavioral factors while race/ethnicity, maternal education, and stressful life events were considered social factors. We examined associations between each individual biological, behavioral, and social factor with oxidative stress biomarkers using multivariable-adjusted linear mixed models.
Numerous biological, behavioral, and social factors were associated with elevated levels of 8-isoPGF2α, its major metabolite, and PGF2α. Pregnant people who were current smokers relative to non-smokers or had less than a high school education relative to a college degree had 11.04% (95% confidence interval CI = −1.97%, 25.77%) and 9.13% (95% CI = -1.02%, 20.32%) higher levels of 8-isoPGF2α, respectively.
Oxidative stress biomarkers are elevated among pregnant people with higher socioeconomic disadvantage and may represent one pathway linking biological, behavioral, and social factors to adverse pregnancy and child health outcomes, which should be explored in future work.
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•Oxidative stress biomarkers were elevated among pregnant people with higher socioeconomic disadvantage.•Associations were strongest for the chemical fraction of 8-iso-PGF2α.•Oxidative stress may link socioeconomic status to adverse pregnancy outcomes.
Arsenic alters immunological parameters including antibody formation and antigen-driven T-cell proliferation.
We evaluated the cross-sectional relationship between urinary arsenic and the ...seroprevalence of hepatitis B (HBV) infection in the United States using data from six pooled cycles of the National Health and Nutrition Examination Survey (2003–2014, N = 12,447).
Using serological data, participants were classified as susceptible, immune due to vaccination, or immune due to past natural infection. We used multinomial logistic regression to evaluate the association between urinary DMA and HBV classification. A sensitivity analysis using total urinary arsenic (TUA) was also conducted. Both DMA and TUA were adjusted for arsenobetaine using a residual regression method
A 1-unit increase in the natural logarithm (ln) of DMA was associated with 40% greater adjusted odds of having immunity due to natural infection compared to being susceptible (Odds Ratio aOR: 1.40, 95% Confidence Intervals CI 1.15, 1.69), 65% greater odds of having immunity due to a natural infection (aOR: 1.65, 95% CI: 1.34, 2.04) and 18% greater odds of being susceptible (aOR: 1.18, 95% CI: 1.05, 1.33) compared to being immune due to vaccination after adjusting for creatinine, age, sex, race, income, country of birth, BMI, survey cycle, serum cotinine, recent seafood intake, and self-reported HBV immunization status.
In the U.S. general public, higher urinary arsenic levels were associated with a greater odds of having a serological classification consistent with a past natural hepatitis B infection after adjusting for other risk factors. Additionally, higher urinary arsenic levels were linked to a greater odds of not receiving hepatitis B vaccinations. Given the cross-sectional nature of this analysis, more research is needed to test the hypothesis that environmentally relevant exposure to arsenic modulates host susceptibility to hepatitis B virus.
•Serology tests discern between hepatitis B infections and hepatitis B vaccinations.•Urinary arsenic concentrations are used as a biomarker of recent exposure.•Arsenic biomarkers were linked to serology indicative of hepatitis B infection.
Polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that are hepatotoxic and immunotoxic. PAH exposure may modulate hepatitis B immunology.
We used data from 6 cycles of the ...National Health and Nutrition Examination Survey (2003–2014) to evaluate the associations between urinary PAH metabolites and hepatitis B serology.
This analysis included individuals who self-reported receiving ≥3 doses of hepatitis B vaccine and urinary PAH metabolites (i.e. 1-napthol, 2-napthol, 3-fluorene, 2-fluorene, 1-phenanthrene, 1-pyrene, and total PAH sum of all metabolites). Separate logistic regression models assessed the association between hepatitis B vaccination status (i.e. individuals who were immune due to vaccination or susceptible) and tertiles of urinary PAH. Models were adjusted for age, gender, race/ethnicity, survey cycle, family income to poverty ratio, BMI, country of birth, serum cotinine, and urinary creatinine.
Among participants who reported receiving ≥3 doses of vaccine and had no antibodies indicating a history of hepatitis B infection and/or current hepatitis B infection, dose-response relationships were observed where individuals with the lowest odds of serology indicating a response to the hepatitis B vaccine (i.e., anti-HBs+, anti-HBc-, and HBsAg−) were in the highest tertile of 2-Napthol (adjusted Odds Ratio aOR: 0.70, 95% confidence interval CI: 0.54, 0.91), 3-Napthol (aOR: 0.68, 95% CI: 0.53, 0.87), 2-Fluorene (aOR: 0.61, 95% CI: 0.54, 0.86), 1-Phenanthrene (aOR: 0.79, 95% CI: 0.65, 0.97), 1-Pyrene (aOR): 0.68, 95% CI: 0.55, 0.83), and total PAH (aOR: 0.73, 95% CI: 0.56, 0.95) had the compared to the lowest tertile.
This cross-sectional study supports a hypothesis that PAH exposures experienced by the general US population may modulate hepatitis B vaccine induced immunity. Given the ubiquity of PAH exposures in the US, additional research is warranted to explore the effects of chronic PAH exposures on hepatitis B related humoral immunity.
•Polycyclic aromatic hydrocarbons (PAHs) are immunotoxic and hepatotoxic.•PAH exposure was associated with hepatitis B vaccine serology.•Higher PAH exposure was related to lower odds of serology indicating vaccination.•Age modified the effect of PAHs on hepatitis B vaccination serology.
Reductions in fetal growth are associated with adverse outcomes at birth and later in life. However, identifying fetuses with pathologically small growth remains challenging. Definitions of ...small-for-gestational age are often used as a proxy to identify those experiencing pathologic growth (ie, fetal growth restriction). However, this approach is subject to limitation as most newborns labeled small-for-gestational age are constitutionally, not pathologically, small. Incorporating repeated ultrasound measures to examine fetal growth trajectories may help distinguish pathologic deviations in growth from normal variability, beyond a simple definition of small-for-gestational age.
This study aimed to characterize phenotypes of growth using ultrasound trajectories of fetal growth among small-for-gestational-age births.
This study identified and described trajectories of fetal growth among small-for-gestational-age births (<10th percentile weight for gestational age; n=245) in the LIFECODES Fetal Growth Study using univariate and multivariate trajectory modeling approaches. Available ultrasound measures of fetal growth (estimated fetal weight, head circumference, abdominal circumference, and femur length) from health records were abstracted. First, univariate group-based trajectory modeling was used to define trajectories of estimated fetal weight z scores during gestation. Second, group-based multi-trajectory modeling was used to identify trajectories based on concurrent measures of head circumference, abdominal circumference, and femur length z scores. Last, how these trajectories were related to patient demographics, pregnancy characteristics, and birth outcomes compared with those observed among appropriate-for-gestational-age controls was described.
Of note, 3 univariate trajectories of estimated fetal weight and 4 multivariate trajectories of fetal growth among small-for-gestational-age births were identified. In our univariate approach, infants with the smallest estimated fetal weight trajectory throughout pregnancy had poorer outcomes, including the highest risk of neonatal intensive care unit admission. The remaining univariate trajectory groups did not have an elevated risk of adverse birth outcomes relative to appropriate-for-gestational-age controls. In our multivariate approach, 2 groups at increased or moderately increased risk of neonatal intensive care unit admission were identified, including infants that remained extremely small for all parameters throughout pregnancy and those who had disproportionately smaller femur length and abdominal circumference compared with head circumference. The remaining multivariate trajectory groups did not have an elevated risk of adverse birth outcome relative to appropriate-for-gestational-age controls.
Latent class group-based trajectory modeling applied to ultrasound measures of fetal growth may help distinguish pathologic vs constitutional growth profiles among newborns born small-for-gestational age. Although trajectories cannot be fully characterized until delivery, limiting the direct clinical application of these methods, they may still contribute to the development of approaches for separating growth restriction from constitutional smallness.
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