Urinary Metabolite Concentrations Research Articles

Association between pesticide exposure and sleep health among a representative sample of US adults: evidence from NHANES 2009\u20132014

BackgroundData suggest that pesticides interact with the melatonin receptor, which may influence sleep. However, the link between pesticides and sleep remains unexplored among the general adult population. This study evaluated unstratified and sex-stratified associations between urinary pesticide exposure (N = 4,478) and self-reported acute household pesticide exposure (N = 14,956), with sleep health outcomes within a nationally representative sample of US adults.MethodsData from the National Health and Nutrition Examination Surveys (NHANES) 2009–2014 were combined for analysis of aim 1 and aim 2. Urinary pesticide metabolite concentrations served as biomarkers of pesticide exposure. Acute household pesticide exposure (if any chemical products were used in the home in the past seven days to control pests) was self-reported (yes/no). Insufficient sleep duration (< 7 h/night) and trouble sleeping (yes/no) were self-reported. Log-binomial regression models that accounted for complex survey weights and adjusted for confounders were used to compute prevalence ratios and 95% CI.ResultsLog urinary 3-phenoxybenzoic acid (3-PBA) was related to a higher probability of insufficient sleep [1.09 (95% CI: 1.00, 1.20), p = 0.04] and trouble sleeping [1.14 (95% CI: 1.02, 1.27), p = 0.02] among males. Self-reported acute household pesticide exposure was associated with a higher probability of insufficient sleep duration [1.16 (95% CI: 1.02, 1.32), p = 0.03] and trouble sleeping [1.20 (95% CI: 1.01, 1.44), p = 0.04] in the unstratified sample. Sex-stratified findings showed that associations between acute household pesticide exposure and trouble sleeping only persisted among males [1.69 (95% CI: 1.27, 2.24), p < .001].ConclusionsIn summary, acute pesticide exposure may be detrimental to adult sleep health, particularly among US males.

Urinary Concentrations of Major Phthalate and Alternative Plasticizer Metabolites in Children of Thailand, Indonesia, and Saudi Arabia, and Associated Risks.

Phthalates are widely used in consumer products and are well-known for adverse endocrine outcomes. Di-(2-ethylhexyl) phthalate (DEHP), one of the most extensively used phthalates, has been rapidly substituted with alternative plasticizers in many consumer products. The aim of this study was to assess urinary phthalate and alternative plasticizer exposure and associated risks in children of three Asian countries with different geographical, climate, and cultural characteristics. Children were recruited from elementary schools of Saudi Arabia (n = 109), Thailand (n = 104), and Indonesia (n = 89) in 2017-2018, and their urine samples were collected. Metabolites of major phthalates and alternative plasticizers were measured in the urine samples by HPLC-MS/MS. Urinary metabolite levels differed substantially between the three countries. Metabolite levels of diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP), di(2-ethylhexyl) terephthalate (DEHTP), and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) were the highest in Saudi children: Median urinary concentrations of oxo-MiNP, OH-MiDP, 5cx-MEPTP, and OH-MINCH were 8.3, 8.4, 128.0, and 2.9 ng/mL, respectively. Urinary DEHP metabolite concentrations were the highest in the Indonesian children. The hazard index (HI) derived for the plasticizers with antiandrogenicity based reference doses (RfDAA) was >1 in 86%, 80%, and 49% of the Saudi, Indonesian, and Thai children, respectively. DEHP was identified as a common major risk driver for the children of all three countries, followed by DnBP and DiBP depending on the country. Among alternative plasticizers, urinary DEHTP metabolites were detected at levels comparable to those of DEHP metabolites or higher among the Saudi children, and about 4% of the Saudi children exceeded the health based human biomonitoring (HBM)-I value. Priority plasticizers that were identified among the children of three countries warrant refined exposure assessment for source identification and relevant exposure reduction measures.

Diurnal variability in urinary volatile organic compound metabolites and its association with oxidative stress biomarkers

Volatile organic compounds (VOCs) are ubiquitous environmental pollutants that are associated with birth defects, leukemia, neurocognitive deficits, reproductive impairment and cancer in humans exposed to these compounds. Exposure to VOCs can be assessed by measuring their metabolites in urine. Little is known, however, about the temporal variability in urinary VOC metabolite (VOCM) concentrations within- and between-individuals. In this study, we determined the variability in the concentrations of 38 VOCMs in urine samples collected from 19 healthy individuals across a period of 44 days. We also measured seven biomarkers of oxidative stress (lipid, protein and DNA damage) in urine to assess the relationship of VOC exposure to oxidative stress. Seventeen VOCMs had detection frequencies (DFs) of >60% in urine, and we limited further data analysis to those compounds. The creatinine-adjusted geometric mean concentrations of VOCMs ranged from 2.70 μg/g to 327 μg/g in spot and 2.60 μg/g to 551 μg/g in first morning void (FMV) urine samples. Calculation of the intra-class correlation coefficients (ICCs) for 17 VOCM concentrations to assess their predictability and repeatability in urinary measurements showed ranges of 0.080–0.425 in spot and 0.050–0.749 in FMV urine samples, revealing notable within-individual variability. Our results suggest that taking only single measurements of VOCM concentrations in urine in epidemiological investigations may lead to exposure misclassification. In addition, VOCM concentrations were significantly and positively correlated with oxidative stress biomarkers. This study thus provides important information for formulating sampling strategies in the biomonitoring of VOC exposure in human populations.

Role of epidemiology in risk assessment: a case study of five ortho-phthalates

BackgroundThe association between environmental chemical exposures and chronic diseases is of increasing concern. Chemical risk assessment relies heavily on pre-market toxicity testing to identify safe levels of exposure, often known as reference doses (RfD), expected to be protective of human health. Although some RfDs have been reassessed in light of new hazard information, it is not a common practice. Continuous surveillance of animal and human data, both in terms of exposures and associated health outcomes, could provide valuable information to risk assessors and regulators. Using ortho-phthalates as case study, we asked whether RfDs deduced from male reproductive toxicity studies and set by traditional regulatory toxicology approaches sufficiently protect the population for other health outcomes.MethodsWe searched for epidemiological studies on benzyl butyl phthalate (BBP), diisobutyl phthalate (DIBP), dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP), and bis(2-ethylhexyl) phthalate (DEHP). Data were extracted from studies where any of the five chemicals or their metabolites were measured and showed a statistically significant association with a health outcome; 38 studies met the criteria. We estimated intake for each phthalate from urinary metabolite concentration and compared estimated intake ranges associated with health endpoints to each phthalate’s RfD.ResultFor DBP, DIBP, and BBP, the estimated intake ranges significantly associated with health endpoints were all below their individual RfDs. For DEHP, the intake range included associations at levels both below and above its RfD. For DCHP, no relevant studies could be identified. The significantly affected endpoints revealed by our analysis include metabolic, neurodevelopmental and behavioral disorders, obesity, and changes in hormone levels. Most of these conditions are not routinely evaluated in animal testing employed in regulatory toxicology.ConclusionWe conclude that for DBP, DIBP, BBP, and DEHP current RfDs estimated based on male reproductive toxicity may not be sufficiently protective of other health effects. Thus, a new approach is needed where post-market exposures, epidemiological and clinical data are systematically reviewed to ensure adequate health protection.

Invited Perspective: How Can Studies of Chemical Mixtures and Human Health Guide Interventions and Policy?

Invited Perspective: How Can Studies of Chemical Mixtures and Human Health Guide Interventions and Policy?

Résistance à l'aspirine : l'ennemi de mon ami est mon ennemi

Low dose aspirin is an efficient antiplatelet agent to decrease the risk of occlusive arterial events, however it is not infallible. Aspirin resistance describe its inability to block the formation of thromboxane A2 in platelets and/or to produce an inhibitory effect on platelet aggregation. Detection of aspirin resistance relies on the results of various platelet function tests or on blood and urinary thromboxane metabolites concentrations, but these methods show very low correlation and reproducibility. Moreover, light-transmission aggregometry using arachidonic acid, known as the reference functional assay, requires technical expertise. The incidence rate of aspirin resistance amoung populations suffering from cardiovascular diseases is about 25%, however there is a wide variability depending on the specificity of the used test and the clinical features of the considered population.Aspirin resistance is associated with the recurrence of arterial occlusive events: the odds ratio is about 4 all tests combined, therefore it could be considered as a risk marker. Evidence is lacking regarding the relevance of these tests to resort an intensification of the antithrombotic treatment, and experts recommend to reserve their use for high-risk situations. Nevertheless several studies have explored the effect of dose increases or intake frequency increases, and revealed encouraging results regarding pharmacodynamic endpoints. The reasons for aspirin resistance are numerous, often remain debate, and can accumulate to result in poor response to aspirin.

The sex-specific association of prenatal phthalate exposure with low birth weight and small for gestational age: A nationwide survey by the Taiwan Maternal and Infant Cohort Study (TMICS)

The Taiwan Maternal and Infant Cohort Study (TMICS) was launched with the aim to assess the effects of prenatal exposure to phthalic acid esters (PAEs) on infant health. A total of 1102 pregnant women were enrolled in this study from 2012 to 2015. All participants completed a structured questionnaire, and provided urine specimens. The urinary concentrations of PAE metabolites in the third trimester were measured using liquid chromatography-electrospray ionization tandem mass spectrometry. Generalized additive model-penalized regression splines and logistic regression models were employed to determine the risk for low birth weight (LBW) or small for gestational age (SGA) among pregnant women exposed to PAEs. After adjustments for other covariates, each incremental unit of ln-transformed mono-n-butyl phthalate (MnBP) for pregnant women increased the odds of SGA in male neonates by 1.44 (95% CI: 0.92–2.23). An inverse association between SGA and maternal MnBP exposure level was observed in female neonates. An increase in one ln-transformed MnBP concentration unit decreased the risk of female SGA to 0.50 (95% CI: 0.24–0.97). In the penalized regression splines, increased risks of LBW/SGA in male neonates were presented while pregnant women exposed to increased MnBP levels. However, an association in the opposite direction was observed between maternal MnBP and LBW or SGA for male and female neonates.This study indicated that high maternal MnBP exposure in the third trimester was associated with LBW or SGA for male infants. Adverse effects on susceptible populations exposed to high levels of PAEs should be of concern.

Untargeted Metabolome- and Transcriptome-Wide Association Study Suggests Causal Genes Modulating Metabolite Concentrations in Urine.

Gene products can affect the concentrations of small molecules (aka “metabolites”), and conversely, some metabolites can modulate the concentrations of gene transcripts. While many specific instances of this interplay have been revealed, a global approach to systematically uncover human gene-metabolite interactions is still lacking. We performed a metabolome- and transcriptome-wide association study to identify genes influencing the human metabolome using untargeted metabolome features, extracted from 1H nuclear magnetic resonance spectroscopy (NMR) of urine samples, and gene expression levels, quantified from RNA-Seq of lymphoblastoid cell lines (LCL) from 555 healthy individuals. We identified 20 study-wide significant associations corresponding to 15 genes, of which 5 associations (with 2 genes) were confirmed with follow-up NMR data. Using metabomatching, we identified the metabolites corresponding to metabolome features associated with the genes, namely, N-acetylated compounds with ALMS1 and trimethylamine (TMA) with HPS1. Finally, Mendelian randomization analysis supported a potential causal link between the expression of genes in both the ALMS1- and HPS1-loci and their associated metabolite concentrations. In the case of HPS1, we additionally observed that TMA concentration likely exhibits a reverse causal effect on HPS1 expression levels, indicating a negative feedback loop. Our study highlights how the integration of metabolomics, gene expression, and genetic data can pinpoint causal genes modulating metabolite concentrations.

The Associations between Blood and Urinary Concentrations of Metal Metabolites, Obesity, Hypertension, Type 2 Diabetes, and Dyslipidemia among US Adults: NHANES 1999-2016.

Background Heavy metals are well known to be associated with cancer outcomes, but its association with obesity and cardiometabolic risk outcomes requires further study. Methods Adult data from the National Health and Examination Survey (NHANES Continuous 1999–2016, n = 12,636 to 32,012) with data for blood or urinary metals concentrations and body mass index were used. The study aim was twofold: (1) to determine the association between heavy metals and obesity and (2) to examine the influence of heavy metals on the relationship between obesity and hypertension, type 2 diabetes, and dyslipidemia. Logistic regression was used to examine the main effects and interaction effects of metals and obesity for the odds of prevalent hypertension, type 2 diabetes, and dyslipidemia. Models were adjusted for age, gender, ethnicity, smoking status, physical active status, and poverty-income ratio, with additional adjustment for creatinine in models with the urinary measures of heavy metals. High-low concentration categories were defined by grouping metal quintiles with the most similar associations with obesity. Results Blood lead had a negative linear association with obesity (odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.37–0.47). In those with obesity, high blood lead was associated with lower risk of prevalent dyslipidemia, while no association was found in those without obesity. The study observed a curvilinear relationship between urinary antimony and obesity with the moderate group having the highest odds of obesity (OR = 1.36, 1.16–1.59). However, the relationship between urinary antimony and prevalent hypertension and dyslipidemia risk was linear, positive, and independent of obesity. While not associated with prevalent obesity risk, high urinary uranium was associated with 30% (P=0.01) higher odds for prevalent type 2 diabetes. Conclusions The impact of environmental factors on obesity and health may be complex, and this study reinforces the heterogeneous relationship between various metals, obesity, and obesity-related metabolic diseases even at levels observed in the general population.

Maternal urinary OPE metabolite concentrations and blood pressure during pregnancy: The HOME study

BackgroundFew studies have examined the association between maternal exposure to organophosphate esters (OPEs) and systolic/diastolic blood pressure (SBP/DBP) during pregnancy. MethodsWe analyzed data from 346 women with a singleton live birth in the HOME Study, a prospective birth cohort in Cincinnati, Ohio, USA. We quantified four OPE metabolites in maternal spot urine samples collected at 16 and 26 weeks pregnancy, standardized by specific gravity. We calculated intraclass correlation coefficients (ICCs). We extracted the first two recorded BP measurements (<20 weeks), the two highest recorded BP measurements (≥20 weeks), and diagnoses of hypertensive disorders of pregnancy (HDP) via chart review. Women with two BP measurements ≥140/90 mmHg or HDP noted in the chart at ≥20 weeks pregnancy were defined as HDP cases. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations as continuous variables or in tertiles with maternal BP and HDP. ResultsICCs of OPEs were 0.17–0.45. Diphenyl phosphate (DPHP) had the highest geometric mean concentration among OPE metabolites. Increasing the average bis(2-chloroethyl) phosphate (BCEP) concentrations were positively associated with two highest recorded DBP ≥20 weeks pregnancy. Compared with women in the 1st DPHP tertile, women in the 3rd tertile at 16 weeks pregnancy had 1.72 mmHg (95% CI: -0.01, 3.46) higher DBP <20 weeks pregnancy, and women in the 3rd tertile of the average DPHP concentrations had 2.25 mmHg (95% CI: 0.25, 4.25) higher DBP ≥20 weeks pregnancy. 33 women (9.5%) were identified with HDP. Di-n-butyl phosphate (DNBP) concentrations at 16 weeks were positively associated with HDP, with borderline significance (RR = 2.98, 95% CI 0.97–9.15). Other OPE metabolites were not significantly associated with HDP. ConclusionMaternal urinary BCEP and DPHP concentrations were associated with increased BP during pregnancy. Maternal urinary DNBP concentrations were associated with HDP, with borderline significance.

Concurrent urinary organophosphate metabolites and acetylcholinesterase activity in Ecuadorian adolescents

BackgroundOrganophosphates are insecticides that inhibit the enzymatic activity of acetylcholinesterase (AChE). Because of this, AChE is considered a physiological marker of organophosphate exposure in agricultural settings. However, limited research exists on the associations between urinary organophosphate metabolites and AChE activity in children. MethodsThis study included 526 participants from 2 exams (April and July–October 2016) of ages 12–17 years living in agricultural communities in Ecuador. AChE activity was measured at both examinations, and organophosphate metabolites, including para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPy), and malathion dicarboxylic acid (MDA) were measured in urine collected in July–October. We used generalized estimating equation generalized linear model (GEEGLM), adjusting for hemoglobin, creatinine, and other demographic and anthropometric covariates, to estimate associations of urinary metabolite concentrations with AChE activity (July–October) and AChE% change between April and July–October. ResultsThe mean (SD) of AChE and AChE% change (April vs July–October) were 3.67 U/mL (0.54) and −2.5% (15.4%), respectively. AChE activity was inversely associated with PNP concentration, whereas AChE% change was inversely associated with PNP and MDA. There was evidence of a threshold: difference was only significant above the 80th percentile of PNP concentration (AChE difference per SD increase of metabolite = −0.12 U/mL [95%CI: 0.20, −0.04]). Likewise, associations with AChE% change were significant only above the 80th percentile of TCPy (AChE % change per SD increase of metabolite = −1.38% [95%CI: 2.43%, −0.32%]) and PNP -2.47% [95%CI: 4.45%, −0.50%]). PNP concentration at ≥80th percentile was associated with elevated ORs for low AChE activity of 2.9 (95% CI: 1.5, 5.7) and for AChE inhibition of ≤ -10% of 3.7 (95% CI: 1.4, 9.8). ConclusionsUrinary organophosphate metabolites, including PNP, TCPy and MDA, particularly at concentrations above the 80th percentile, were associated with lower AChE activity among adolescents. These findings bring attention to the value of using multiple constructs of pesticide exposure in epidemiologic studies.

Urinary Concentrations of Dialkylphosphate Metabolites of Organophosphate pesticides in the Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE)

BackgroundMeasurements of urinary dialkyl phosphate (DAP) metabolites are often used to characterize exposures to organophosphate (OP) insecticides; however, some challenges to using urinary DAP metabolites as an exposure measure exist. OP insecticides have short biological half-lives with measurement in a single urine sample typically only reflecting recent exposure within the last few days. Because of the field staff and participant burden of longitudinal sample collection and the high cost of multiple measurements, typically only one or two urine samples have been used to evaluate OP insecticide exposure during pregnancy, which is unlikely to capture an accurate picture of prenatal exposure. MethodsWe recruited pregnant farmworker women in Chom Thong and Fang, two districts of Chiang Mai province in northern Thailand (N = 330) into the Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE) from 2017 to 2019. We collected up to 6 serial urine samples per participant during gestation and composited the samples to represent early, mid, and late pregnancy. We measured concentrations of urinary DAP metabolites in the composited urine samples and evaluated the within- and between-participant variability of these levels. We also investigated predictors of OP insecticide exposure. ResultsDAP metabolite concentrations in serial composite samples were weakly to moderately correlated. Spearman correlations indicated that composite urine samples were more highly correlated in Fang participants than in Chom Thong participants. The within-person variances (0.064–0.65) exceeded the between-person variances for DETP, DEP, ∑DEAP, DMP, DMTP, ∑DMAP, ∑DAP. The intraclass correlations (ICCs) for the volume-based individual metabolite levels (ng/mL) ranged from 0.10 to 0.66. For ∑DEAP, ∑DMAP, and ∑DAP the ICCs were, 0.47, 0.17, 0.45 respectively. We observed significant differences between participants from Fang compared to those from Chom Thong both in demographic and exposure characteristics. Spearman correlations of composite samples from Fang participants ranged from 0.55 to 0.66 for the ∑DEAP metabolite concentrations in Fang indicating moderate correlation between pregnancy periods. The ICCs were higher for samples from Fang participants, which drove the overall ICCs. ConclusionsCollecting multiple (∼6) urine samples during pregnancy rather than just 1 or 2 improved our ability to accurately assess exposure during the prenatal period. By compositing the samples, we were able to still obtain trimester-specific information on exposure while keeping the analytic costs and laboratory burden low. This analysis also helped to inform how to best conduct future analyses within the SAWASDEE study. We observed two different exposure profiles in participants in which the concentrations and variability in data were highly linked to the residential location of the participants.

A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape.

Background:Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes.Objective:We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development.Methods:The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography–tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) . Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted .Results:We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2-ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs. Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites. Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively. Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations.Discussion:To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort. We identified numerous genes and lncRNAs associated with prenatal phthalate exposure. These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure. https://doi.org/10.1289/EHP8973

Urinary Steroid Profile in Elite Female Athletes in Relation to Serum Androgens and in Comparison With Untrained Controls.

IntroductionIn female athletes, the interpretation of doping tests is complex due to hormonal variations during the menstrual cycle and hormonal contraceptive use, both influencing the urinary steroid profile. Exercise is suggested to affect circulating steroid hormone levels, and in women, the urinary steroid profile differs between in competition testing and out of competition testing. No previous study has investigated the relationship between amount of exercise and the urinary steroid profile in female elite athletes.PurposeTo compare the urinary steroid profile between female Olympic athletes and age- and BMI-matched untrained controls, and to study the urinary steroid profile in relation to serum hormones and amount of exercise.MethodsIn this cross-sectional study conducted at the Women’s Health Research Unit, Karolinska University Hospital, Stockholm, 94 female elite athletes and 86 untrained controls were included. Serum estrogens and testosterone and the urinary steroid profile were analyzed by liquid chromatography–tandem mass spectrometry and gas chromatography-tandem mass spectrometry, respectively. Exercise hours/week were evaluated by questionnaire.ResultsAlthough serum steroid hormones were comparable between groups, the athletes demonstrated approximately 30% lower urinary steroid metabolites of testosterone, epitestosterone, androsterone, etiocholanolone, 5α-androstan-3α, 17β-diol, and 5β-androstan-3α, 17β-diol compared to the controls. The urinary steroid metabolites correlated positively with serum steroid hormones. In the athletes, urinary steroid metabolites: androsterone (rs = −0.28, p = 0.007), epitestosterone (rs = −0.22, p = 0.034), 5αAdiol (rs = −0.31, p = 0.002) and testosterone (rs = −0.24, p = 0.026), were negatively correlated with amount of training (hours per week).ConclusionThe urinary concentrations of steroid metabolites were lower in elite athletes than in sedentary controls, although serum steroids were comparable between groups. Moreover, exercise time was negatively associated with the urinary concentrations. Our findings suggest alternative excretion routes of androgens in the athletes related to training.

Prenatal Maternal Phthalate Exposures and Trajectories of Childhood Adiposity from Four to Twelve Years

BACKGROUND AND AIM: Trajectories of child adiposity have lifelong consequences for future cardiometabolic risk. Prenatal phthalate exposures may affect processes that pre-program later childhood adiposity, but findings from studies examining these associations are conflicting. We examined associations between individual phthalate exposure biomarkers and total phthalate mixture during pregnancy with child adiposity trajectories. METHODS: Data were from 514 mother-child pairs in the PROGRESS cohort of Mexico City. We quantified 15 phthalate metabolites in 2nd and 3rd trimester maternal urine samples and created an average pregnancy measure using the geometric mean. We evaluated the 15 metabolites as nine biomarkers, including four metabolite molar sums. We measured child BMI z-score, bioimpedance-based fat mass index (FMI), and waist-to-height ratio (WHtR) at three visits between four and twelve years of age. We identified trajectories using multivariate latent class growth modeling, considering BMI z-score, FMI, and WHtR as joint indicators of latent adiposity. We then estimated associations of phthalate biomarkers with class membership using multinomial logistic regression. We used quantile g-computation to estimate the effect of the total phthalates mixture and assessed effect modification by sex. RESULTS:We detected three trajectories of child adiposity, “low-stable” remained stable at low adiposity (n=260), “low-high” started low then increased to high (n=147), and “high-high” started high and remained high (n=107). A doubling of the sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), was associated with greater odds of being in the “high-high” trajectory (adjusted odds ratio [OR] = 1.53 [1.08, 2.19]; p = 0.02) in comparison to the “low-stable” group, whereas a doubling in mono(carboxy-isononyl) phthalate (MCNP) was associated with lower odds of being in the “low-high” trajectory (adjusted OR = 0.66 [0.45, 97]; p = 0.03). No sex-specific or total mixtures associations were detected. CONCLUSIONS:Pregnancy urinary concentrations of ΣDEHP metabolites and MCNP were associated with trajectories of child adiposity in opposing directions. KEYWORDS: Phthalates, Children's environmental health, Environmental epidemiology, Mixtures analysis

Maternal urinary organophosphate ester concentrations and blood pressure during pregnancy: The HOME Study

BACKGROUND AND AIM: Organophosphate esters (OPEs) flame retardants found in various consumer products, may be a risk factor of adverse reproductive health outcomes. No study has examined whether gestational exposure to OPEs alters maternal blood pressure (BP) during pregnancy. METHODS: We analyzed data from 346 women who had liveborn singletons without congenital abnormalities in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective birth cohort (Cincinnati, OH, USA). The exposure variables were maternal urinary OPE metabolite concentrations at 16 weeks of gestation, standardized by specific gravity. We extracted the first two recorded maternal BP measures (20 weeks) to assess for chronic hypertension. We also extracted the two highest BP measures (≥20 weeks), and any diagnosis of hypertensive disorders of pregnancy (HDP: gestational hypertension, preeclampsia, and eclampsia) from medical charts. We defined HDP for this analysis as two BP140/90 or HDP noted in the chart at or after 20 weeks gestation. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations with maternal BP and the risk of HDP. RESULTS:Diphenyl phosphate (DPHP) had the highest urinary geometric mean concentration (1.81 µg/L), followed by bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 0.80 µg/L), bis(2-chloroethyl) phosphate (BCEP; 0.61 µg/L), and di-n-butyl phosphate (DNBP; 0.26 µg/L). Thirty women (8.7%) were diagnosed with HDP. Every 10-fold increase of maternal BCEP concentrations was associated with 1.87 mmHg (95%CI 0.05-3.70) increase in the highest diastolic BP≥20 weeks. No urinary metabolites were associated with an increased risk of HDP (RR=1.17, 95%CI: 0.55-2.50 for DPHP; RR=1.68, 95%CI: 0.62-4.58 for BDCIPP; RR= 0.75, 95%CI 0.37-1.53 for BCEP; RR=2.34, 95% CI:0.88-6.24 for DNBP). CONCLUSIONS:Maternal urinary BCEP concentrations may be associated with increased diastolic BP. However, no associations were found between maternal urinary OPE metabolites and an increased risk of HDP. KEYWORDS: Endocrine disrupting chemicals, Pregnancy outcomes, Environmental epidemiology

Variability of urinary organophosphate esters (OPEs) during childhood: The HOME Study

BACKGROUND AND AIM: Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers. Previous research has shown that gestational exposure to OPEs is variable, but no studies have examined the patterns and variability of postnatal exposure to our best knowledge. METHODS: In a prospective birth cohort (HOME Study, Cincinnati, OH, USA), we measured urinary OPE metabolite concentrations three times (16 and 26 weeks of gestation, at delivery) during pregnancy and five times (ages 1, 2, 3, 5, 8 years) during childhood. We log10-transformed creatinine-standardized OPE metabolite concentrations. We calculated Spearman correlation coefficients between postnatal OPE metabolites at each time point. We then used linear mixed models to calculate intraclass correlation coefficients (ICCs) for metabolite concentrations across the five postnatal time points. We further examined the association between three prenatal measures and early childhood (ages 1, 2, 3 years) exposure and subsequent metabolite concentrations at ages 5 and 8 years, including the main effect and the interaction term with the subsequent time points of metabolite measurement using linear mixed models. RESULTS:We detected (2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP) in 79 to 100% of children. The median concentrations (µg/g creatinine) were 0.78-4.76 for BCEP, 4.02-7.42 for BDCIPP, and 2.57-11.48 for DPHP. We found moderate correlations between BCEP and BDCIPP (rs: 0.28-0.49, p 0.001) at all time points. ICCs for metabolites across five postnatal time points, however, indicated poor within-person correlation (0.09–0.25). Prenatal urinary DPHP concentrations were positively associated with postnatal DPHP concentrations at some time points. Positive associations between early (1-3 years) and late childhood concentrations (age 8 years) were found for BCEP and BDCIPP. CONCLUSIONS:We found high within-person variability of OPE exposure within children across the first 8 years of life, suggesting that multiple urine samples are needed to characterize children’s exposures to OPEs. KEYWORDS: Chemical exposures, Endocrine disrupting chemicals, Children's environmental health, Environmental epidemiology

Gestational organophosphate ester exposures and bone mineral density in early adolescence: The HOME Study

BACKGROUND AND AIM: Optimizing bone mineral density (BMD) in adolescence is critical for life-long bone health. Organophosphate esters (OPEs) are synthetic flame retardants and plasticizers that may have osteotoxic effects via endocrine disruption or nuclear receptor agonism. Animal studies suggest that gestation may be a critical period of susceptibility for the impact of OPEs on bone health, but human studies are lacking. We assessed the relation of maternal urinary OPE metabolite concentrations during pregnancy with early adolescent BMD in a prospective birth cohort study. METHODS: We used data from 223 mother-child dyads enrolled in the HOME Study from Cincinnati, OH area, 2003-2006. We measured bis-2-chloroethyl phosphate (BCEP), bis-(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DnBP), and diphenyl phosphate (DPHP) in maternal urine collected at 16- and 26-weeks gestation, and calculated the average of creatinine-adjusted concentrations. We performed dual x-ray absorptiometry in children at age 12 years and calculated height-, age-, sex-, and population ancestry-specific Z-scores for whole body (excluding head), total hip, femoral neck, distal radius, and ultradistal radius areal BMD (aBMD) and spine bone mineral apparent density (BMAD). We estimated covariate-adjusted associations per 2-fold increase in maternal urinary OPE concentrations and assessed effect measure modification by child sex. RESULTS:In adjusted analyses, BDCIPP concentrations were positively associated with aBMD and BMAD Z-scores at most skeletal sites. Z-score differences were between 0.11 and 0.15 and greatest for total hip (β = 0.15, 95% CI: 0.02, 0.29). Associations of DPHP with femoral neck and total hip aBMD differed by child sex. Associations among males were null while DPHP concentrations were inversely associated with femoral neck (β = -0.15, 95% CI: -0.29, -0.02) and total hip (β = -0.15, 95% CI: -0.29, 0.00) aBMD Z-scores among females. CONCLUSIONS:Maternal OPE exposures during gestation may affect early adolescent BMD in a metabolite-, sex-, and bone site-specific manner. KEYWORDS: Chemical exposures, Children's environmental health, Endocrine disrupting chemicals

Environmental pesticide concentrations in air and pregnant women’s urinary pesticide metabolites in the Infants’ Environmental Health Study (ISA)

BACKGROUND AND AIM: We evaluated associations between environmental pesticide concentrations in air and specific urinary pesticide metabolites among pregnant women from the Infants' Environmental Health Study (ISA) in Matina County, Costa Rica. METHODS: We used a Bayesian spatiotemporal model to extrapolate concentrations of the fungicide pyrimethanil and the insecticide chlorpyrifos measured with polyurethane foam passive air samplers (n=48, from 12 schools) across space and time. Using mixed models, we compared them with urinary specific-gravity corrected pesticide metabolite concentrations: 4-hydroxypyrimethanil (OHP, metabolite of pyrimethanil) and 3,5,6-trichloro-2-pyridinol (TCPy, metabolite of chlorpyrifos), repeatedly obtained among 451 pregnant women from the ISA Study (n=951). Pyrimethanil in air, OHP, and TCPy were log-transformed prior to statistical analysis to normalize residuals of models. We considered several covariables. RESULTS:Median (p10-p90) concentrations were: pyrimethanil = 1.33 (0.27-17.0) ng/m3, chlorpyrifos = 15.62 (4.38 - 24.19) ng/m3, OHP = 0.39 (0.06- 2.75) ug/L, and TCPy = 1.63 (0.75-4.27) µg/L. A 10% increase in pyrimethanil in air was associated with a 5.7% (95% CI 4.6, 6.8) increase in urinary OHP (μg/L), women who lived near banana plantations had higher OHP, whilst frequent consumption of rice and beans was associated with lower OHP. In addition, each 1 ng/m3 increase in chlorpyrifos in air was associated with a 1.5% increase in TCPy (μg/L), and women who worked in agriculture tended to have higher TCPy. CONCLUSIONS:Despite the limitations of having limited data on pesticide air concentrations in space and time, and biomonitoring of pesticides with short half-lives, the results of this study indicate environmental air concentrations of pyrimethanil and chlorpyrifos explained to some extent internal pesticide metabolite concentrations in pregnant women. Our results suggest that inhalation of these pesticides is one of the pathways of environmental exposure. Passive air sampling of current-use pesticides seems a promising method to monitor environmental pesticide exposure. KEYWORDS: passive air sampling, pesticides, environmental exposure, biomonitoring

Associations of Phthalates and Phenols, Telomere Length, and Breast Cancer in the Long Island Breast Cancer Study Project

BACKGROUND AND AIM: Exposure to phthalates or phenols has been of concern as associated with breast cancer due to the endocrine disrupting effects of these chemicals. Studies related to the modifying role of cellular aging on these associations are lacking. We aim to evaluate the modifying effect of leukocyte telomere length (LTL), a biomarker of cellular aging, on the associations between phthalate and phenol exposure and breast cancer incidence and mortality. METHODS: We used data from 1268 women whose urinary phthalates and phenols and LTL measurements were available from the Long Island Breast Cancer Study Project. Twenty-two metabolites of phthalates and phenols were measured in the spot urine collected from the study participants. The modifying effect of LTL on the association between each individual metabolite and breast cancer incidence and mortality was estimated using interaction terms between LTL and the individual metabolites in logistic regression models and Cox regression models. Odds ratios, hazard ratios, and corresponding 95% confidence intervals (CI) for a one-unit (ln ug/g creatinine) increase of urinary metabolite concentration were estimated at 10th, 50th, and 90th percentiles of LTL. RESULTS:LTL significantly (P0.05) modified the associations between breast cancer incidence and metabolites for eleven phthalates and phenols. Metabolites were, in general, inversely and positively associated with breast cancer incidence at shorter and at longer LTL, respectively. No statistically significant modifying effect was found for LTL in the association between these metabolites and breast cancer mortality. CONCLUSIONS:Women with longer LTL were more susceptible to exposure to phthalates and phenols in the development of breast cancer. But shorter LTL can still increase the detrimental effect of certain types of phenols to breast cancer. KEYWORDS: Phthalate, Phenol, Breast Cancer, Leukocyte Telomere Length