Metabolomic data presents challenges for epidemiological meta-analysis: a case study of childhood body mass index from the ECHO consortium.

INTRODUCTION: Meta-analyses across diverse independent studies provide improved confidence in results. However, within the context of metabolomic epidemiology, meta-analysis investigations are complicated by differences in study design, data acquisition, and other factors that may impact reproducibility. OBJECTIVE: The objective of this study was to identify maternal blood metabolites during pregnancy (> 24 gestational weeks) related to offspring body mass index (BMI) at age two years through a meta-analysis framework. METHODS: We used adjusted linear regression summary statistics from three cohorts (total N = 1012 mother-child pairs) participating in the NIH Environmental influences on Child Health Outcomes (ECHO) Program. We applied a random-effects meta-analysis framework to regression results and adjusted by false discovery rate (FDR) using the Benjamini-Hochberg procedure. RESULTS: Only 20 metabolites were detected in all three cohorts, with an additional 127 metabolites detected in two of three cohorts. Of these 147, 6 maternal metabolites were nominally associated (P < 0.05) with offspring BMI z-scores at age 2 years in a meta-analytic framework including at least two studies: arabinose (Coefmeta = 0.40 [95% CI 0.10,0.70], Pmeta = 9.7 × 10-3), guanidinoacetate (Coefmeta = - 0.28 [- 0.54, - 0.02], Pmeta = 0.033), 3-ureidopropionate (Coefmeta = 0.22 [0.017,0.41], Pmeta = 0.033), 1-methylhistidine (Coefmeta = - 0.18 [- 0.33, - 0.04], Pmeta = 0.011), serine (Coefmeta = - 0.18 [- 0.36, - 0.01], Pmeta = 0.034), and lysine (Coefmeta = - 0.16 [- 0.32, - 0.01], Pmeta = 0.044). No associations were robust to multiple testing correction. CONCLUSIONS: Despite including three cohorts with large sample sizes (N > 100), we failed to identify significant metabolite associations after FDR correction. Our investigation demonstrates difficulties in applying epidemiological meta-analysis to clinical metabolomics, emphasizes challenges to reproducibility, and highlights the need for standardized best practices in metabolomic epidemiology.

Cross-Sectional Associations between Prenatal Per- and Poly-Fluoroalkyl Substances and Bioactive Lipids in Three Environmental Influences on Child Health Outcomes (ECHO) Cohorts.

Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks' gestation) from three Environmental influences on Child Health Outcomes Program cohorts. Pairwise association estimates across cohorts were obtained through linear mixed models and meta-analysis, adjusting the former for false discovery rates. Associations between the PFAS mixture and bioactive lipids were estimated using quantile g-computation. Pairwise analyses revealed bioactive lipid levels associated with PFDeA, PFNA, PFOA, and PFUdA (p < 0.05) across three enzymatic pathways (cyclooxygenase, cytochrome p450, lipoxygenase) in at least one combined cohort analysis, and PFOA and PFUdA (q < 0.2) in one linear mixed model. The strongest signature revealed doubling in PFOA corresponding with PGD2 (cyclooxygenase pathway; +24.3%, 95% CI: 7.3-43.9%) in the combined cohort. Mixture analysis revealed nine positive associations across all pathways with the PFAS mixture, the strongest signature indicating a quartile increase in the PFAS mixture associated with PGD2 (+34%, 95% CI: 8-66%), primarily driven by PFOS. Bioactive lipids emerged as prenatal PFAS exposure biomarkers, deepening insights into PFAS' influence on pregnancy outcomes.

Associations of urinary polycyclic aromatic hydrocarbon (PAH) metabolites and their mixture with thyroid hormone concentration during pregnancy in the LIFECODES cohort: A repeated measures study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are endocrine disruptors resulting from incomplete combustion. Pregnancy represents a particularly vulnerable period to such exposures, given the significant influence of hormone physiology on fetal growth and pregnancy outcomes. Maternal thyroid hormones play crucial roles in fetal development and pregnancy outcomes. However, limited studies have examined gestational PAH exposure and maternal thyroid hormones during pregnancy. METHODS: Our study included 439 women enrolled in the LIFECODES birth cohort in Boston, aiming to explore the relationship between urinary PAH metabolites and thyroid hormones throughout pregnancy. Urine samples for PAH metabolite analysis and plasma samples for thyroid hormone were measured up to four visits throughout gestation. Single pollutant analyses employed linear mixed effect models to investigate individual associations between each PAH metabolite and thyroid hormone concentration. Sensitivity analyses were conducted to assess potential susceptibility windows and fetal-sex-specific effects of PAH exposure. Mixture analyses utilized quantile g-computation to evaluate the collective impact of eight PAH metabolites on thyroid hormone concentrations. Additionally, Bayesian kernel machine regression (BKMR) was employed to explore potential non-linear associations and interactions between PAH metabolites. Subject-specific random intercepts were incorporated to address intra-individual correlation of serial measurements over time in both single pollutant and mixture analyses. RESULTS: Our findings revealed positive trends in associations between PAH metabolites and thyroid hormones, both individually and collectively as a mixture. Sensitivity analyses indicated that these associations were influenced by the study visit and fetal sex. Mixture analyses suggested non-linear relationships and interactions between different PAH exposures. CONCLUSIONS: This comprehensive investigation underscores the critical importance of understanding the impact of PAH exposures on thyroid hormone physiology during pregnancy. The findings highlight the intricate interplay between environmental pollutants and human pregnancy physiology, emphasizing the need for targeted interventions and public health policies to mitigate adverse outcomes associated with prenatal PAH exposure.

Gestational glyphosate exposure and early childhood neurodevelopment in a Puerto Rico birth cohort.

INTRODUCTION: N-(phosphonomethyl)glycine, or glyphosate, is a non-selective systemic herbicide widely used in agricultural, industrial, and residential settings since 1974. Glyphosate exposure has been inconsistently linked to neurotoxicity in animals, and studies of effects of gestational exposure among humans are scarce. In this study we investigated relationships between prenatal urinary glyphosate analytes and early childhood neurodevelopment. METHODS: Mother-child pairs from the PROTECT-CRECE birth cohort in Puerto Rico with measures for both maternal urinary glyphosate analytes and child neurodevelopment were included for analysis (n = 143). Spot urine samples were collected 1-3 times throughout pregnancy and analyzed for glyphosate and aminomethylphosphonic acid (AMPA), an environmental degradant of glyphosate. Child neurodevelopment was assessed at 6, 12, and 24 months using the Battelle Developmental Inventory, 2nd edition Spanish (BDI-2), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. We used multivariable linear regression to examine associations between the geometric mean of maternal urinary glyphosate analytes across pregnancy and BDI-2 scores at each follow-up. Results were expressed as percent change in BDI-2 score per interquartile range increase in exposure. RESULTS: Prenatal AMPA concentrations were negatively associated with communication domain at 12 months (%change = -5.32; 95%CI: 9.04, -1.61; p = 0.007), and communication subdomain scores at 12 and 24 months. At 24 months, four BDI-2 domains were associated with AMPA: adaptive (%change = -3.15; 95%CI: 6.05, -0.25; p = 0.038), personal-social (%change = -4.37; 95%CI: 7.48, -1.26; p = 0.008), communication (%change = -7.00; 95%CI: 11.75, -2.26; p = 0.005), and cognitive (%change = -4.02; 95%CI: 6.72, -1.32; p = 0.005). Similar trends were observed with GLY concentrations, but most confidence intervals include zero. We found no significant associations at 6 months. CONCLUSIONS: Our results suggest that gestational exposure to glyphosate is associated with adverse early neurodevelopment, with more pronounced delays at 24 months. Given glyphosate's wide usage, further investigation into the impact of gestational glyphosate exposure on neurodevelopment is warranted.

Urinary oxidative stress biomarkers are associated with preterm birth: an Environmental Influences on Child Health Outcomes program study.

BACKGROUND: Preterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States. OBJECTIVE: We leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin. STUDY DESIGN: This study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-F2α, 2,3-dinor-5,6-dihydro-8-iso-prostaglandin-F2α (F2-IsoP-M; the major 8-iso-prostaglandin-F2α metabolite), and prostaglandin-F2α were measured in urine samples obtained during the second and third trimesters of pregnancy. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for the associations between averaged biomarker concentrations for each participant and all preterm births, spontaneous preterm births, nonspontaneous preterm births (births of medically indicated or unknown origin), and categories of preterm birth (early, moderate, and late). Individual oxidative stress biomarkers were examined in separate models. RESULTS: Approximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of F2-IsoP-M was associated with higher odds of all preterm births (odds ratio, 1.29; 95% confidence interval, 1.11-1.51), with a stronger association observed for spontaneous preterm birth (odds ratio, 1.47; 95% confidence interval, 1.16-1.90). An interquartile range increase in averaged concentrations of 8-iso-prostaglandin-F2α was similarly associated with higher odds of all preterm births (odds ratio, 1.19; 95% confidence interval, 0.94-1.50). The results from our meta-analysis were similar to those from the pooled combined cohort analysis. CONCLUSION: Here, oxidative stress, as measured by 8-iso-prostaglandin-F2α, F2-IsoP-M, and prostaglandin-F2α in urine, was associated with increased odds of preterm birth, particularly preterm birth of spontaneous origin and delivery before 34 completed weeks of gestation.

Examining the association between prenatal maternal stress and infant non-nutritive suck.

BACKGROUND: This study examined the relationship between prenatal maternal stress (PREMS) and non-nutritive suck (NNS) and tested its robustness across 2 demographically diverse populations. METHODS: The study involved 2 prospective birth cohorts participating in the national Environmental influences on Child Health Outcomes (ECHO) Program: Illinois Kids Development Study (IKIDS) and ECHO Puerto Rico (ECHO-PROTECT). PREMS was measured during late pregnancy via the 10-item Perceived Stress Scale (PSS-10). NNS was sampled from 1- to 8-week-olds using a custom pacifier for ~5 min. RESULTS: Overall, 237 mother-infant dyads completed this study. Despite several significant differences, including race/ethnicity, income, education, and PREMS levels, significant PREMS-NNS associations were found in the 2 cohorts. In adjusted linear regression models, higher PREMS, measured through PSS-10 total scores, related to fewer but longer NNS bursts per minute. CONCLUSIONS: A significant association was observed between PREMS and NNS across two diverse cohorts. This finding is important as it may enable the earlier detection of exposure-related deficits and, as a result, earlier intervention, which potentially can optimize outcomes. More research is needed to understand how NNS affects children's neurofunction and development. IMPACT: In this double-cohort study, we found that higher maternal perceived stress assessed in late pregnancy was significantly associated with fewer but longer sucking bursts in 1- to 8-week-old infants. This is the first study investigating the association between prenatal maternal stress (PREMS) and infant non-nutritive suck (NNS), an early indicator of central nervous system integrity. Non-nutritive suck is a potential marker of increased prenatal stress in diverse populations. Non-nutritive suck can potentially serve as an early indicator of exposure-related neuropsychological deficits allowing for earlier interventions and thus better prognoses.

Exposures to Organophosphate Esters and Respiratory Morbidity among School-Aged Children with Asthma.

Organophosphate esters (OPEs) are an emerging class of chemicals used in a variety of consumer products as flame retardants, plasticizers, and additives. While prior epidemiologic studies suggest that OPEs may impact respiratory health, results remain inconclusive. We examined associations between urinary biomarkers of OPEs and symptoms of respiratory morbidity in a panel study of 147 predominantly Black school-aged children with asthma living in Baltimore City, Maryland. The study consisted of up to four seasonal, week-long, in-home visits where urine samples and self-reported asthma symptoms were collected on days 4 and 7 (nsamples = 438). We quantified concentrations of nine urinary OPE biomarkers: bis(2-chloroethyl) phosphate (BCEtp), bis(1-chloro-2-propyl) phosphate (BCPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DBuP), di-benzyl phosphate (DBzP), di-o-cresylphosphate (DOCP), di-p-cresylphosphate (DPCP), di-(2-propylheptyl) phthalate (DPHP), and 2,3,4,5-tetrabromo benzoic acid (TBBA). We estimated prevalence odds ratios (POR) of respiratory morbidity symptoms using logistic regression with generalized estimating equations to account for our repeated measure design. We assessed BDCIPP and DPHP as continuous (log2) concentrations and dichotomized exposure of BCEtP, DBuP, and DPCP (detect vs non-detect) based on their lower detection frequencies. We adjusted models for season, visit day, age, gender, caregiver education, health insurance type, exposure to household smoking, atopy, and PM2.5. Higher DPHP concentrations were significantly associated with odds of daytime symptoms (POR: 1.26; 95% CI: 1.04-1.53; p = 0.02) where daytime symptoms consisted of trouble breathing due to asthma, reporting bother caused by asthma, and/or limitation in activities due to asthma. DBuP detection was associated with use of rescue medication on the day of sample collection (POR: 2.36; 95% CI: 1.05-5.29; p = 0.04). We also observed several consistent, albeit non-significant (p > 0.05), positive associations for BCEtP and DPCP and respiratory morbidity measures. This is the first study to evaluate the relationship between OPE biomarkers and respiratory morbidity symptoms in children with asthma, and findings suggest that further studies are warranted to confirm whether these associations are causal.

Calcium supplementation and body mass index modify associations between prenatal phthalate exposure and perinatal bone ultrasound measures among pregnant women.

Phthalates have endocrine activity that may interfere with bone health, particularly during pregnancy and the early postpartum period, when bone resorption increases. We evaluated associations between prenatal phthalate exposure and perinatal bone health among 289 mothers in the ELEMENT birth cohort in Mexico City who were randomized upon recruitment to receive 1,200 mg daily calcium supplementation or placebo throughout pregnancy. Spot urine samples at up to three timepoints during pregnancy were assayed for 9 phthalate metabolites. Bone integrity was assessed by quantitative ultrasound speed of sound (SOS) measurements of the phalange and distal radius at 3, 6, and 8 months of pregnancy and 1, 3, 7, and 12 months postpartum. Geometric means of specific gravity-corrected phthalate concentrations were used as overall measures of prenatal exposure. Linear mixed effect models estimated associations between phthalate exposure and repeated perinatal bone SOS measures, adjusting for age, pre-pregnancy body mass index (BMI), education, parity, calcium supplementation, and month of pregnancy/postpartum. Effect modification by calcium supplementation and BMI were assessed in sensitivity analyses. An interquartile range increase in MEP and MiBP increased pregnancy phalange z-scores (ß: 0.11; 95%CI: 0.003, 0.31 and ß: 0.15; 95%CI: 0.00,0.42, respectively). Higher concentrations of several phthalate metabolites resulted in lower SOS measures among women who received calcium supplements (compared to placebo group) but higher SOS measures among women with a BMI≥25 (compared to BMI<25). These results suggest that phthalate exposure may interfere with bone remodeling during pregnancy, and that consideration of effect modifiers is paramount to fully understand the effects of environmental exposures on bone health.

Prenatal per- and polyfluoroalkyl substances (PFAS) exposure in relation to preterm birth subtypes and size-for-gestational age in the LIFECODES cohort 2006-2008.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals widely used in consumer and industrial products. Numerous studies have linked prenatal PFAS exposures to increased risks of adverse pregnancy outcomes such as preterm birth (PTB) and small-for-gestational age (SGA).However, limited evidence is available for the effects of PFAS on PTB subtypes and large-for-gestational age (LGA). OBJECTIVE: To examine the associations of PFAS with PTB [overall, placental (pPTB), spontaneous (sPTB)], BW Z-score, and size-for-gestational age (SGA, LGA). METHODS: Our nested case-control study included 128 preterm cases and 373 term controls from the LIFECODES cohort between 2006 and 2008 (n = 501). Plasma concentrations of nine PFAS were measured in early pregnancy samples. Logistic regression was used to assess individual PFAS-birth outcome associations, while Bayesian Kernel Machine Regression (BKMR) was used to evaluate the joint effects of all PFAS. Effect modification by fetal sex was examined, and stratified analyses were conducted to obtain fetal sex-specific estimates. RESULTS: Compared to term births, the odds of pPTB were higher from an interquartile range increase in perfluorodecanoic acid (PFDA) (OR = 1.60, 95% CI: 1.00-2.56), perfluorononanoic acid (PFNA) (OR = 1.67, 95% CI: 1.06-2.61), and perfluoroundecanoic acid (PFUA) (OR = 1.77, 95% CI: 1.00-3.12), with stronger associations observed in women who delivered males. BKMR analysis identified PFNA as the most important PFAS responsible for pPTB (conditional PIP = 0.78), with increasing ORs at higher percentiles of PFAS mixture. For LGA, positive associations were observed with PFDA and perfluorooctanoic acid in females only, and with PFUA in males only. BKMR analysis showed increasing, but null effects of PFAS mixture on LGA. CONCLUSIONS: The effect of prenatal exposure to single and multiple PFAS on PTB and LGA depended on fetal sex. Future studies should strongly consider examining PTB subtypes and sex-specific effects of PFAS on pregnancy outcomes.

Cross-sectional associations between phthalates, phenols, and parabens with metabolic syndrome risk during early-to-mid adolescence among a cohort of Mexican youth.

BACKGROUND: Epidemiological studies on children and adults have linked toxicants from plastics and personal care products to metabolic disruption. Yet, the impact of endocrine-disrupting chemicals (EDCs) on adolescent metabolic syndrome (MetS) risk during early and mid-adolescence is unclear. METHODS: To examine the links between exposure to EDCs and MetS risk and its components, cross-sectional data from 344 Mexican youth in early-to-mid adolescence (10-17 years) were analyzed. Urinary biomarker concentrations of phthalates, phenol, and paraben analytes were measured from a single spot urine sample collected in 2015; study personnel obtained anthropometric and metabolic measures. We examined associations between summary phthalates and metabolites, phenol, and paraben analytes with MetS risk z-scores using linear regression, adjusted for specific gravity, sex, age, pubertal status, smoking, alcohol intake, physical activity level, and screen time. As a secondary aim, mediation analysis was conducted to evaluate the role of hormones in the association between summary phthalates with lipids and MetS risk z-scores. RESULTS: The mean (SD) age was 13.2 (1.9) years, and 50.9% were female. Sex-stratified analyses revealed associations between summary phthalates and lipids ratio z-scores, including Σ DEHP [ß = 0.21 (95% CI: 0.04, 0.37; p < 0.01)], phthalates from plastic sources (Σ Plastic) [ß = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], anti-androgenic phthalates (Σ AA) [ß = 0.22 (95% CI: 0.05, 0.39; p < 0.01)], and individual phthalate metabolites (MEHHP, MEOHP, and MECPP) among males. Among females, BPA [ß = 0.24 (95% CI: 0.03, 0.44; p < 0.05)] was positively associated with lipids ratio z-score and one phenol (2,5 DCP) [ß = 0.09 (95% CI: 0.01, 0.18); p < 0.05)] was associated with increased waist circumference z-score. Results showed no evidence of mediation by hormone concentrations in the association between summary phthalates with lipids ratio or MetS risk z-scores. CONCLUSION: Higher EDC exposure was positively associated with serum lipids during adolescence, particularly among males.

A cross-validation based approach for estimating specific gravity in elementary-school aged children using a nonlinear model.

Environmental research often relies on urinary biomarkers which require dilution correction to accurately measure exposures. Specific gravity (SG) and creatinine (UCr) are commonly measured urinary dilution factors. Epidemiologic studies may assess only one of these measures, making it difficult to pool studies that may otherwise be able to be combined. Participants from the National Health and Nutrition Examination Survey 2007-2008 cycle were used to perform k-fold validation of a nonlinear model estimating SG from UCr. The final estimated model was applied to participants from the School Inner-City Asthma Intervention Study, who submitted urinary samples to the Children's Health Exposure Analysis Resource. Model performance was evaluated using calibration metrics to determine how closely the average estimated SG was to the measured SG. Additional models, with interaction terms for age, sex, body mass index, race/ethnicity, relative time of day when sample was collected, log transformed 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and asthma status were estimated and assessed for improvement. The association between monobenzyl phthalate (MBZP) and asthma symptom days, controlling for measured UCr, measured SG, and each estimated SG were compared to assess validity of the estimated SG. The model estimating SG from UCr alone, resulted in a beta estimate of 1.10 (95% CI: 1.01, 1.19), indicating agreement between model-predicted SG and measured SG. Inclusion of age and sex in the model improved estimation (ß = 1.06, 95% CI: 0.98, 1.15). The full model accounting for all interaction terms with UCr resulted in the best agreement (ß = 1.01, 95% CI: 0.93,1.09). Associations between MBZP and asthma symptoms days, controlling for each estimated SG, were within the range of effect estimates when controlling for measured SG and measured UCr (Rate ratios = 1.28-1.34). Our nonlinear modeling provides opportunities to estimate SG in studies that measure UCr or vice versa, enabling data pooling despite differences in urine dilution factors.

A systematic evidence map for the evaluation of noncancer health effects and exposures to polychlorinated biphenyl mixtures.

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty.

Urinary fluoride levels and metal co-exposures among pregnant women in Los Angeles, California.

BACKGROUND: Fluoride is ubiquitous in the United States (US); however, data on biomarkers and patterns of fluoride exposure among US pregnant women are scarce. We examined specific gravity adjusted maternal urinary fluoride (MUFsg) in relation to sociodemographic variables and metal co-exposures among pregnant women in Los Angeles, California. METHODS: Participants were from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort. There were 293 and 490 women with MUFsg measured during first and third trimesters, respectively. An intra-class correlation coefficient examined consistency of MUFsg between trimesters. Kruskal-Wallis and Mann-Whitney U tests examined associations of MUFsg with sociodemographic variables. Covariate adjusted linear regression examined associations of MUFsg with blood metals and specific gravity adjusted urine metals among a subsample of participants within and between trimesters. A False Discovery Rate (FDR) correction accounted for multiple comparisons. RESULTS: Median (IQR) MUFsg was 0.65 (0.5) mg/L and 0.8 (0.59) mg/L, during trimesters one and three respectively. During both trimesters, MUFsg was higher among older participants, those with higher income, and White, non-Hispanic participants than Hispanic participants. MUFsg was also higher for White, non-Hispanic participants than for Black, non-Hispanic participants in trimester three, and for those with graduate training in trimester one. MUFsg was negatively associated with blood mercury in trimester one and positively associated with blood lead in trimester three. MUFsg was positively associated with various urinary metals, including antimony, barium, cadmium, cobalt, copper, lead, nickel, tin, and zinc in trimesters one and/or three. CONCLUSIONS: MUFsg levels observed were comparable to those found in pregnant women in Mexico and Canada that have been associated with poorer neurodevelopmental outcomes. Lower urinary fluoride levels among Hispanic and non-Hispanic Black participants in MADRES compared to non-Hispanic White participants may reflect lower tap water consumption or lower fluoride exposure from other sources. Additional research is needed to examine whether MUFsg levels observed among pregnant women in the US are associated with neurodevelopmental outcomes.

Semiparametric analysis of a generalized linear model with multiple covariates subject to detection limits.

Studies on the health effects of environmental mixtures face the challenge of limit of detection (LOD) in multiple correlated exposure measurements. Conventional approaches to deal with covariates subject to LOD, including complete-case analysis, substitution methods, and parametric modeling of covariate distribution, are feasible but may result in efficiency loss or bias. With a single covariate subject to LOD, a flexible semiparametric accelerated failure time (AFT) model to accommodate censored measurements has been proposed. We generalize this approach by considering a multivariate AFT model for the multiple correlated covariates subject to LOD and a generalized linear model for the outcome. A two-stage procedure based on semiparametric pseudo-likelihood is proposed for estimating the effects of these covariates on health outcome. Consistency and asymptotic normality of the estimators are derived for an arbitrary fixed dimension of covariates. Simulations studies demonstrate good large sample performance of the proposed methods vs conventional methods in realistic scenarios. We illustrate the practical utility of the proposed method with the LIFECODES birth cohort data, where we compare our approach to existing approaches in an analysis of multiple urinary trace metals in association with oxidative stress in pregnant women.

Exposure to Contemporary and Emerging Chemicals in Commerce among Pregnant Women in the United States: The Environmental influences on Child Health Outcome (ECHO) Program.

Prenatal chemical exposures can influence maternal and child health; however, few industrial chemicals are routinely biomonitored. We assessed an extensive panel of contemporary and emerging chemicals in 171 pregnant women across the United States (U.S.) and Puerto Rico in the Environmental influences on Child Health Outcomes (ECHO) Program. We simultaneously measured urinary concentrations of 89 analytes (103 total chemicals representing 73 parent compounds) in nine chemical groups: bactericides, benzophenones, bisphenols, fungicides and herbicides, insecticides, organophosphate esters (OPEs), parabens, phthalates/alternative plasticizers, and polycyclic aromatic hydrocarbons (PAHs). We estimated associations of creatinine-adjusted concentrations with sociodemographic and specimen characteristics. Among our diverse prenatal population (60% non-Hispanic Black or Hispanic), we detected 73 of 89 analytes in ≥1 participant and 36 in >50% of participants. Five analytes not currently included in the U.S. biomonitoring were detected in ≥90% of samples: benzophenone-1, thiamethoxam, mono-2-(propyl-6-carboxy-hexyl) phthalate, monocarboxy isooctyl phthalate, and monohydroxy-iso-decyl phthalate. Many analyte concentrations were higher among women of Hispanic ethnicity compared to those of non-Hispanic White women. Concentrations of certain chemicals decreased with the calendar year, whereas concentrations of their replacements increased. Our largest study to date identified widespread exposures to prevalent and understudied chemicals in a diverse sample of pregnant women in the U.S.

Phthalate biomarkers and associations with respiratory symptoms and healthcare utilization among low-income urban children with asthma.

BACKGROUND: Phthalates are synthetic chemicals present in building materials, personal care products and other consumer goods. Limited studies link phthalates to pediatric asthma incidence; however, their effects on respiratory-related outcomes among those with pre-existing asthma remains unclear. OBJECTIVE: We examined associations between phthalates and asthma symptoms, healthcare use, lung function, and lung inflammation among children with asthma. METHODS: We collected repeated measures of urinary biomarkers for select phthalates and phthalate replacements (MBzP, MCINP, MCIOP, MCPP, MECPTP, MEHHTP, molar sum of DEHP biomarkers [MECPP, MEHHP, MEHP, MEOHP], MEP, MiBP, MnBP) and asthma symptoms, healthcare utilization, lung function, and inflammation among 148 predominantly low-income Black children (5-17 years) with persistent asthma every 3 months for one year. We used generalized estimating equations to assess associations between biomarker concentrations and asthma-related measures adjusting for age, sex, race/ethnicity, caregiver's education level, presence of smokers in the home, and season. We also considered co-exposures to other contaminants previously associated with asthma morbidity. RESULTS: We observed consistent positive associations with individual DEHP biomarkers, the molar sum of DEHP, and BBzP with increased odds of asthma symptoms and with healthcare utilization (adjusted Odds Ratio for general asthma symptoms: ΣDEHP:1.49,95% Confidence Interval, CI:1.08-2.07; BBzP:1.34, CI:1.04-1.73). We observed similar associations between the DEHP phthalate replacement biomarker MEHHTP and most asthma symptoms evaluated; and with select low molecular weight phthalates (DiBP, DBP) and healthcare utilization. Results were similar when controlling for other environmental exposures (e.g., PM2.5, BPA). No associations were observed with lung function or inflammation, and overall, we did not observe consistent evidence of sexually dimorphic effects. CONCLUSION: In the present study, we found evidence to suggest that exposure to select phthalates may be associated with asthma symptoms and healthcare utilization. These findings warrant confirmation given the high asthma burden and widespread and disparate phthalate exposures reported among select populations of color.

Variability and predictors of urinary organophosphate ester concentrations among school-aged children.

Organophosphate esters (OPE) are flame retardants and plasticizers used in a wide range of consumer products. Despite their widespread use, few studies have characterized pediatric exposures. We assessed variability and predictors of OPE exposures in a cohort panel study of 179 predominantly Black school-aged children with asthma in Baltimore City, MD. The study design included up to four seasonal week-long in-home study visits with urine sample collection on days 4 and 7 of each visit (nsamples = 618). We quantified concentrations of 9 urinary OPE biomarkers: bis(2-chloroethyl) phosphate (BCEtp), bis(1-chloro-2-propyl) phosphate, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-benzyl phosphate (DBuP), di-benzyl phosphate, di-o-cresylphosphate, di-p-cresylphosphate (DPCP), di-(2-propylheptyl) phthalate (DPHP), 2,3,4,5-tetrabromo benzoic acid. We assessed potential predictors of exposure, including demographic factors, household characteristics, and cleaning behaviors. We calculated Spearman/tetrachoric correlations and intraclass correlation coefficients (ICCs) to examine within-week and seasonal intra-individual variability, respectively. We assessed OPE predictors using linear models for continuous log2 concentrations (BDCPP and DPHP) and logistic models for odds of detection (BCEtP, DBuP, DPCP), with generalized estimating equations to account for repeated measures. For all OPEs, we observed moderate within-week correlations (rs: 0.31-0.63) and weak to moderate seasonal reliability (ICC: 0.18-0.38). BDCPP and DPHP concentrations were higher in the summer compared to other seasons. DPHP concentrations were lower among males than females (%diff: -53.5%; 95% CI: -62.7, -42.0) and among participants spending >12 h/day indoors compared to ≤12 h (%diff: -20.7%; 95% CI: -32.2, -7.3). BDCPP concentrations were lower among children aged 8-10 years compared to 5-7 years (%diff: -39.1%; 95% CI: -55.9, -15.9) and higher among children riding in a vehicle on the day of sample collection compared to those who had not (%diff: 28.5%; 95% CI: 3.4, 59.8). This study is the first to characterize within-week and seasonal variability and identify predictors of OPE biomarkers among Black school-aged children, a historically understudied population.

Associations between mixtures of urinary phthalate metabolite concentrations and oxidative stress biomarkers among couples undergoing fertility treatment.

Phthalate exposure has been associated with adverse reproductive outcomes and oxidative stress is a potential mechanism by which they act. However, few human studies have explored co-exposure confounding or joint effects. Furthermore, most studies examine associations between biomarkers of exposure and oxidative stress from the same urine sample. We investigated single-exposure, co-exposure-adjusted, and joint associations between phthalate metabolites and oxidative stress in the Environment and Reproductive Health (EARTH) study among couples undergoing fertility treatment. We examined cross-sectional associations in both women and men, and longitudinal associations in women. Urine was collected in the follicular phase (women only) and at the time of fertility procedure (women and men), and analyzed for 11 phthalate metabolites. Urine from the time of fertility procedure was analyzed for oxidative stress biomarkers, including free 8-iso-prostaglandin F2α (8-iso-PGF2α), its primary metabolite (2,3-dinor-5,6-dihydro-15-F2t-isoprostane [F2-IsoP-M]), and prostaglandin F2α (PGF2α). Linear mixed effects models were used to estimate single-exposure associations. Bayesian Kernel Machine Regression (BKMR) was used to adjust for co-exposures and to estimate joint effects. Among women, we observed positive associations between all phthalate metabolites and oxidative stress biomarkers in single-exposure models, but there was clear co-exposure confounding. For instance, in a single-exposure model, we estimated a 63% (95% confidence interval: 51, 77) increase in the 8-iso-PGF2α metabolite per interquartile range (IQR) difference in mono-n-butyl phthalate (MBP) versus a 34% (95% credible interval: 12, 60) increase in co-adjusted models. However, several phthalate metabolites remained associated with oxidative stress in co-exposure models, and the joint effects of all exposures were high (e.g., an 114% increase in the 8-iso-PGF2α metabolite per IQR difference in all exposures). Longitudinal results were also attenuated compared to cross-sectional results in women; however, the joint effect of all exposures and the 8-iso-PGF2α metabolite remained positive and statistically significant (11% increase per IQR difference in all exposures, 95% credible interval: 0.2, 23). In men, associations were generally less pronounced, although the joint effect of the mixture on 8-iso-PGF2α was above the null. Because oxidative stress is related to reproductive success among couples seeking fertility treatment, mitigating phthalate exposure should be considered as a potentially beneficial measure.

Maternal blood metal concentrations are associated with matrix metalloproteinases (MMPs) among pregnant women in Puerto Rico.

BACKGROUND/AIM: Matrix metalloproteinases (MMPs) are important regulators of uterine remodeling, a critical process for healthy pregnancies, and studies have revealed a link between an imbalance in MMPs and adverse birth outcomes. Toxicological studies have indicated that exposure to heavy metals can alter the levels of inflammatory cytokines, including MMPs. Despite growing evidence, the clear association between heavy metal exposure and MMPs has yet to be explored extensively in human populations. To have a better understanding of the association, in this study, we assessed associations between maternal blood metal levels with MMPs among 617 pregnant women in the Puerto Rico PROTECT birth cohort. METHODS: We measured blood concentrations for 11 metals in the first and/or second trimester of pregnancy using ICP-MS. MMPs (MMP1, MMP2, and MMP9) were quantified using a customized Luminex assay. Linear mixed effects models (LMEs) were used to regress MMPs on metals and included random intercepts for study participants to account for correlated repeated outcome measures. Fetal sex effects were estimated using interaction terms between metal exposure variables and fetal sex indicators. RESULTS: We observed significant associations between cesium, manganese, and zinc with all the MMPs that were measured. We also observed differences in metal-MMPs associations by fetal sex. Cobalt was positively associated with MMP1 only in women with male fetuses, and cesium was negatively associated with MMP1 only in women with female fetuses. MMP2 had significant associations with maternal blood metal concentrations only in women with female fetuses. CONCLUSION: Certain metals were significantly associated with MMPs that are responsible for uterine remodeling and healthy pregnancies. Most of these associations differed by fetal sex. This study highlighted significant metal-MMPs associations that may inform research on new avenues for understanding heavy metal-induced adverse birth outcomes and the development of diagnostic tools.

Prenatal maternal pesticide exposure in relation to sleep health of offspring during adolescence.

STUDY OBJECTIVES: The neurobiological processes involved in establishing sleep regulation are vulnerable to environmental exposures as early as seven weeks of gestation. Studies have linked in utero pesticide exposure to childhood sleep-disordered breathing. However, the impact of in utero pesticide exposure on the sleep health of adolescents remains unexplored. MATERIALS AND METHODS: Data from 137 mother-adolescent pairs from a Mexico City cohort were analyzed. We used maternal urinary 3-phenoxybenzoic acid (3-PBA, pyrethroid metabolite) and 3, 5, 6-trichloro-2-pyridinol (TCPy, chlorpyrifos metabolite) from trimester three to estimate in utero pesticide exposure. Among adolescents, we obtained repeated measures of objectively assessed sleep duration, midpoint, and fragmentation using wrist-actigraphy devices for 7 consecutive days in 2015 and 2017. Unstratified and sex-stratified associations between maternal urinary 3-PBA and TCPy and adolescent sleep measures were examined using generalized linear mixed models (GLMMs). We also examined the interactive effects of maternal pesticide exposure and offspring sex on sleep outcomes. RESULTS: 3-PBA and TCPy were detected in 44.4% and 93% of urine samples, respectively. Adjusted findings demonstrated that higher exposure to maternal TCPy was associated with longer sleep duration and later sleep timing. Findings from interaction tests between maternal pesticide exposure and offspring sex were not statistically significant, although adjusted sex-stratified findings showed that the association between TCPy with duration and midpoint was evident only among female offspring. To illustrate, those in the highest tertile of exposure had a 59 minute (95% CI: 12.2, 104.8) (p, trend = 0.004) longer sleep duration and a 0.6 hour (95% CI: 0.01, 1.3) (p, trend = 0.01) later sleep midpoint. We found no significant associations between 3-PBA and sleep outcomes. CONCLUSION: Within a cohort of mother-adolescent pairs, we found associations between maternal prenatal pesticide exposure and longer sleep duration and later sleep timing among adolescent offspring. Further, this association may be female-specific.