Publications by authors named "John D Meeker"

270 Publications

Preterm birth and PM in Puerto Rico: evidence from the PROTECT birth cohort.

Environ Health 2021 Jun 11;20(1):69. Epub 2021 Jun 11.

Department of Civil and Environmental Engineering, Tufts University, Anderson Hall, 200 College Avenue, Medford, MA, 02155, USA.

Background: Preterm birth (PTB, birth before 37 weeks of gestation) has been associated with adverse health outcomes across the lifespan. Evidence on the association between PTB and prenatal exposure to air pollutants is inconsistent, and is especially lacking for ethnic/racial minority populations.

Methods: We obtained data on maternal characteristics and behaviors and PTB and other birth outcomes for women participating in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort, who lived in municipalities located along the North Coast of Puerto Rico. We assessed pre-natal PM exposures for each infant based on the nearest US Environmental Protection Agency monitor. We estimated prenatal phthalate exposures as the geometric mean of urinary measurements obtained during pregnancy. We then examined the association between PM and PTB using modified Poisson regression and assessed modification of the association by phthalate exposure levels and sociodemographic factors such as maternal age and infant gender.

Results: Among 1092 singleton births, 9.1% of infants were born preterm and 92.9% of mothers had at least a high school education. Mothers had a mean (standard deviation) age of 26.9 (5.5) years and a median (range) of 2.0 (1.0-8.0) pregnancies. Nearly all women were Hispanic white, black, or mixed race. Median (range) prenatal PM concentrations were 6.0 (3.1-19.8) μ g/m. Median (interquartile range) prenatal phthalate levels were 14.9 (8.9-26.0) and 14.5 (8.4-26.0), respectively, for di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP). An interquartile range increase in PM was associated with a 1.2% (95% CI 0.4, 2.1%) higher risk of PTB. There was little difference in PTB risk in strata of infant sex, mother's age, family income, history of adverse birth outcome, parity, and pre-pregnancy body mass index. Pregnancy urinary phthalate metabolite levels did not modify the PM-PTB association.

Conclusion: Among ethnic minority women in Puerto Rico, prenatal PM exposure is associated with a small but significant increase in risk of PTB.
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http://dx.doi.org/10.1186/s12940-021-00748-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196435PMC
June 2021

Performance of urine, blood, and integrated metal biomarkers in relation to birth outcomes in a mixture setting.

Environ Res 2021 Jun 10;200:111435. Epub 2021 Jun 10.

University of Michigan School of Public Health, Department of Environmental Health Sciences, Ann Arbor, MI, United States. Electronic address:

Background: Studies on the health effects of metal mixtures typically utilize biomarkers measured in a single biological medium, such as blood or urine. However, the ability to evaluate mixture effects are limited by the uncertainty whether a unified medium can fully capture exposure for each metal. Therefore, it is important to compare and assess metal mixtures measured in different media in epidemiology studies.

Objectives: The aim of this study was to examine the mixture predictive performance of urine and blood metal biomarkers and integrated multi-media biomarkers in association with birth outcomes.

Methods: In our analysis of 847 women from the Puerto Rico PROTECT Cohort, we measured 10 essential and non-essential metals in repeated and paired samples of urine and blood during pregnancy. For each metal, we integrated exposure estimates from paired urine and blood biomarkers into multi-media biomarkers (MMBs), using intraclass-correlation coefficient (ICC) and weighted quantile sum (WQS) approaches. Using Ridge regressions, four separate Environmental risk scores (ERSs) for metals in urine, blood, MMB, and MMB were computed as a weighted sum of the 10 metal concentrations. We then examined associations between urine, blood, and multi-media biomarker ERSs and birth outcomes using linear and logistic regressions, adjusting for maternal age, maternal education, pre-pregnancy body mass index (BMI), and second-hand smoke exposure. The performance of each ERS was evaluated with continuous and tertile estimates and 95% confidence intervals of the odds ratio of preterm birth using area under the curve (AUC).

Results: Pb was the most important contributor of blood ERS as well as the two integrated multi-media biomarker ERSs. Individuals with high ERS (3rd tertile) showed increased odds of preterm birth compared to individuals with low ERS (1st tertile), with 2.8-fold (95% CI, 1.49 to 5.40) for urine (specific gravity corrected); 3.2- fold (95% CI, 1.68 to 6.25) for blood; 3.9-fold (95% CI, 1.72 to 8.66) for multi-media biomarkers composed using ICC; and 5.2-fold (95% CI, 2.34 to 11.42) for multi-media biomarkers composed using WQS. The four ERSs had comparable predictive performances (AUC ranging from 0.64 to 0.68) when urine is examined with specific gravity corrected concentrations.

Conclusions: Within a practical metal panel, measuring metals in either urine or blood may be an equally good approach to evaluate the metals as a mixture. Applications in practical study design require validation of these methods with other cohorts, larger panels of metals and within the context of other adverse health effects of interest.
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http://dx.doi.org/10.1016/j.envres.2021.111435DOI Listing
June 2021

A prospective study of maternal 25-hydroxyvitamin D (25OHD) in the first trimester of pregnancy and second trimester heavy metal levels.

Environ Res 2021 08 19;199:111351. Epub 2021 May 19.

Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA.

Background: Vitamin D facilitates the absorption of calcium but may also increase absorption of other metals; the literature is conflicting.

Objective: To examine whether 25OHD in the first trimester of pregnancy was associated with subsequent metals levels in the late second trimester of pregnancy.

Methods: We used data from a sample of women in the LIFECODES pregnancy cohort (N = 381). 25-hydroxyvitamin D (25OHD) was measured with a chemiluminescence immunoassay in plasma samples drawn at 10 weeks of gestation. A panel of 17 metals and elements was measured in urine collected at 26 weeks of gestation. We used linear or logistic regression to estimate associations between 25OHD (dichotomous, linear, and in tertiles) and either urinary metal concentrations or the proportion of samples below the limit of detection, respectively. Multivariable models included urinary specific gravity, age, race/ethnicity, education, body mass index, insurance type, gestational age, and season.

Results: After multivariable adjustment, low 25OHD was associated with a 47% increase in lead level, a 60% increase in tin level, and 1.58 times the odds of detectable tungsten. A 10 ng/ml increase in 25OHD was associated with a 12% decrease in tin and an 8% increase in molybdenum. While we had a small sample size, we found some evidence of effect modification by race. Women who reported their race as Black or were classified in the other race category, who also had low 25OHD, had 40% higher thallium than women with higher 25OHD and were more likely to have detectable beryllium and tungsten. These metals were not associated with low 25OHD in women who reported their race as White. Tin and lead were higher in women with low 25OHD in all race groups.

Discussion: In total, further research is warranted to determine if vitamin D levels alter metal levels, and to elucidate the shape of the association for each metal across a range of corresponding 25OHD levels, and longitudinally, across pregnancy. This is especially true for pregnant people as exposure to metals during pregnancy has health consequences for the fetus.
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http://dx.doi.org/10.1016/j.envres.2021.111351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308798PMC
August 2021

Prenatal Exposure to Glyphosate and Its Environmental Degradate, Aminomethylphosphonic Acid (AMPA), and Preterm Birth: A Nested Case-Control Study in the PROTECT Cohort (Puerto Rico).

Environ Health Perspect 2021 May 19;129(5):57011. Epub 2021 May 19.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Background: Glyphosate (GLY) is the most heavily used herbicide in the world. Despite nearly ubiquitous exposure, few studies have examined prenatal GLY exposure and potentially adverse pregnancy outcomes. Preterm birth (PTB) is a risk factor for neonatal mortality and adverse health effects in childhood.

Objectives: We examined prenatal exposure to GLY and a highly persistent environmental degradate of GLY, aminomethylphosphonic acid (AMPA), and odds of PTB in a nested case-control study within the ongoing Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort in northern Puerto Rico.

Methods: GLY and AMPA in urine samples collected at (Visit 1) and (Visit 3) wk gestation (53 cases/194 randomly selected controls) were measured using gas chromatography tandem mass spectrometry. Multivariable logistic regression was used to estimate associations with PTB (delivery completed gestation).

Results: Detection rates in controls were 77.4% and 77.5% for GLY and 52.8% and 47.7% for AMPA, and geometric means (geometric standard deviations) were 0.44 (2.50) and 0.41 for GLY and 0.25 (3.06) and 0.20 for AMPA, for Visits 1 and 3, respectively. PTB was significantly associated with specific gravity-corrected urinary GLY and AMPA at Visit 3, whereas associations with levels at Visit 1 and the Visits 1-3 average were largely null or inconsistent. Adjusted odds ratios (ORs) for an interquartile range increase in exposure at Visit 3 were 1.35 (95% CI: 0.99, 1.83) and 1.67 (95% CI: 1.26, 2.20) for GLY and AMPA, respectively. ORs for Visit 1 and the visit average were closer to the null.

Discussion: Urine GLY and AMPA levels in samples collected near the 26th week of pregnancy were associated with increased odds of PTB in this modestly sized nested case-control study. Given the widespread use of GLY, multiple potential sources of AMPA, and AMPA's persistence in the environment, as well as the potential for long-term adverse health effects in preterm infants, further investigation in other populations is warranted. https://doi.org/10.1289/EHP7295.
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http://dx.doi.org/10.1289/EHP7295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132611PMC
May 2021

Exposure to obesogenic endocrine disrupting chemicals and obesity among youth of Latino or Hispanic origin in the United States and Latin America: A lifecourse perspective.

Obes Rev 2021 Jun 5;22 Suppl 3:e13245. Epub 2021 May 5.

Center for Nutrition and Health Research, National Institute of Public Health, Mexico City, Mexico.

Following a 2019 workshop led by the Center for Global Health Studies at the Fogarty International Center on the topic of childhood obesity prevention and research synergies transpiring from cross-border collaborations, we convened a group of experts in the United States and Latin America to conduct a narrative review of the epidemiological literature on the role of obesogenic endocrine disrupting chemicals (EDCs) in the etiology of childhood obesity among Latino youth in the United States and Latin America. In addition to summarizing and synthesizing results from research on this topic published within the last decade, we place the findings within a lifecourse biobehavioral framework to aid in identification of unique exposure-outcome relationships driven by both biological and behavioral research, identify inconsistencies and deficiencies in current literature, and discuss the role of policy regulations, all with the goal of identifying viable avenues for prevention of early life obesity in Latino/Hispanic populations.
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http://dx.doi.org/10.1111/obr.13245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217151PMC
June 2021

Individual and joint effects of phthalate metabolites on biomarkers of oxidative stress among pregnant women in Puerto Rico.

Environ Int 2021 09 23;154:106565. Epub 2021 Apr 23.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA. Electronic address:

Exposures to phthalate compounds have been linked to adverse birth outcomes, potentially through oxidative stress mechanisms. We explored associations between mixtures of biomarkers of phthalate and phthalate replacement metabolites and oxidative stress using lipid peroxidation biomarker 8-iso-prostaglandin-F2α (8-iso-PGF2α). As 8-iso-PGF2α can be generated via both chemical (nonenzymatic) and enzymatic lipid peroxidation pathways, we calculated the ratio of 8-iso-PGF2α/prostaglandin F2α in an attempt to distinguish the potential contributions of the two pathways. Urinary biomarker measurements were taken from 775 pregnant women in the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) longitudinal birth cohort at up to three time points during gestation (16-20, 20-24, and 24-28 weeks gestation). Adaptive elastic net with pairwise linear interaction terms (adENET-I) was used to determine individual phthalate metabolites and phthalate interactions that were predictive of lipid oxidative stress biomarkers, and to subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual at each study visit. Repeated ERS were then used in linear mixed effects models to test for associations between biomarkers of phthalate mixtures and biomarkers of oxidative stress. We also used Bayesian kernel machine regression (BKMR) to explore nonlinearity and interactions between phthalate metabolites within the mixture. An increase from the first to fourth quartile of phthalate ERS derived from adENET-I was associated with a 96.7% increase (95% CI: 74.0, 122) in the hypothesized chemical fraction of 8-iso-PGF2α and a 268% increase (95% CI: 139, 465) in the hypothesized enzymatic fraction of 8-iso-PGF2α. BKMR analyses also suggested strong linear associations between the phthalate mixture and biomarkers of lipid oxidative stress. Various phthalates displayed nonlinear relationships with both chemical and enzymatic fractions of 8-iso-PGF2α, and we observed some evidence of interactions between metabolites in the mixture. In conclusion, exposure to phthalate mixtures was strongly associated with linear increases in biomarkers of lipid oxidative stress, and differences observed between hypothesized chemical and enzymatic lipid peroxidation outcomes highlight the need to critically assess pathways of 8-iso-PGF2α generation in relation to environmental exposures.
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http://dx.doi.org/10.1016/j.envint.2021.106565DOI Listing
September 2021

Maternal lipidomic signatures in relation to spontaneous preterm birth and large-for-gestational age neonates.

Sci Rep 2021 Apr 14;11(1):8115. Epub 2021 Apr 14.

Department of Environmental Health Sciences, University of Michigan, School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA.

Lipidome-wide metabolites may be useful biomarkers of pregnancy outcomes. We sought to characterize maternal lipidomic signatures associated with preterm birth and neonatal anthropometric parameters. Plasma samples were collected 24-28 weeks gestation, and lipidomic profiling was quantified using high-performance liquid chromatography tandem mass spectrometry. Lipid metabolites were analyzed individually and as whole lipid classes and subgroups based on degree of hydrocarbon chain saturation. Associations were estimated using linear and logistic regression. After false discovery adjustment (q < 0.15), four plasmenyl-phosphatidylethanolamines and three free fatty acids associated with increased risk for spontaneous preterm birth. Five phosphatidylinositols, two phosphatidylglycerols, and one phosphatidic acid were associated with large for gestational age neonates. The saturated plasmenyl-phosphatidylethanolamines held the association with increased risk for spontaneous preterm birth. Both the mono- and poly-unsaturated free fatty acids held the association for increased risk for spontaneous preterm birth. Mono- and poly-unsaturated phosphatidylinositols were associated with large for gestational age neonates. Whole lipid classes (plasmenyl-phophatidylcholines and plasmenyl-phosphatidylethanolamines) were associated with increased risk for large for gestational age at delivery. This study provides evidence that finer omics-scale analysis of the maternal lipidome may be more informative biomarkers of pregnancy outcomes compared to whole class level lipid analysis.
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http://dx.doi.org/10.1038/s41598-021-87472-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046995PMC
April 2021

Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI).

Epigenetics 2021 Apr 2:1-16. Epub 2021 Apr 2.

Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins University, Baltimore, USA.

The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate -value <0.1), near the genes , and . Lead-associated sites were enriched (FDR -value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR -value <0.1), one of which was near the gene . Manganese-associated sites were enriched for cellular metabolism pathways (FDR -value<0.1). Effect estimates for DNA methylation sites associated ( < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.
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http://dx.doi.org/10.1080/15592294.2021.1897059DOI Listing
April 2021

Cross-Sectional Estimation of Endogenous Biomarker Associations with Prenatal Phenols, Phthalates, Metals, and Polycyclic Aromatic Hydrocarbons in Single-Pollutant and Mixtures Analysis Approaches.

Environ Health Perspect 2021 Mar 24;129(3):37007. Epub 2021 Mar 24.

Department of Environmental Health Sciences, U-M School of Public Health, Ann Arbor, Michigan, USA.

Background: Humans are exposed to mixtures of toxicants that can impact several biological pathways. We investigated the associations between multiple classes of toxicants and an extensive panel of biomarkers indicative of lipid metabolism, inflammation, oxidative stress, and angiogenesis.

Methods: We conducted a cross-sectional study of 173 participants (median 26 wk gestation) from the LIFECODES birth cohort. We measured exposure analytes of multiple toxicant classes [metals, phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs)] in urine samples. We also measured endogenous biomarkers (eicosanoids, cytokines, angiogenic markers, and oxidative stress markers) in either plasma or urine. We estimated pair-wise associations between exposure analytes and endogenous biomarkers using multiple linear regression after adjusting for covariates. We used adaptive elastic net regression, hierarchical Bayesian kernel machine regression, and sparse-group LASSO regression to evaluate toxicant mixtures associated with individual endogenous biomarkers.

Results: After false-discovery adjustment (), single-pollutant models yielded 19 endogenous biomarker signals associated with phthalates, 13 with phenols, 17 with PAHs, and 18 with trace metals. Notably, adaptive elastic net revealed that phthalate metabolites were selected for several positive signals with the cyclooxygenase (), cytochrome p450 (), and lipoxygenase () pathways. Conversely, the toxicant classes that exhibited the greatest number of negative signals overall in adaptive elastic net were phenols () and metals ().

Discussion: This study characterizes cross-sectional endogenous biomarker signatures associated with individual and mixtures of prenatal toxicant exposures. These results can help inform the prioritization of specific pairs or clusters of endogenous biomarkers and exposure analytes for investigating health outcomes. https://doi.org/10.1289/EHP7396.
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http://dx.doi.org/10.1289/EHP7396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990518PMC
March 2021

Investigating the impact of Hurricane Maria on an ongoing birth cohort in Puerto Rico.

Popul Environ 2020 Sep 17;42(1):95-111. Epub 2020 Mar 17.

University of Michigan, Department of Environmental Health Sciences - Ann Arbor, Michigan.

Prior to Hurricane Maria, Puerto Rico already had 200+ hazardous waste sites, significant contamination of water resources, and among the highest rates of preterm birth in the US. To address these issues, the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) Center was formed in 2010 to investigate prenatal environmental exposures, particularly phthalates, and adverse birth outcomes. Recent work from the PROTECT study confirms that in utero exposure to certain phthalates is associated with shorter gestation and increased risk of preterm birth. However, previous research also suggests that pregnant women who experience a natural disaster such as Hurricane Maria are at higher risk of adverse birth outcomes, but it is unknown whether this is due to stress, hazardous exposures, or a combination of factors. Thus, the aim of this analysis was to characterize hurricane-related changes in phthalate exposures and experiences within the PROTECT cohort. Among 176 participants who were pregnant during or within 5 months after Maria, 122 completed a questionnaire on hurricane-related experiences. Questionnaire results and biomarkers of exposure suggest that participants did not have regular access to fresh foods and water during hurricane recovery, and almost half reported structural damage to their home. In addition, biomarker concentrations of phthalates commonly used in food packaging were higher among participants post-hurricane, while phthalates commonly used in personal care products were lower compared to pre-hurricane levels. Hurricane-related increases in phthalate exposure, as well as widespread structural damage, food and water shortages, and long-term absence of electricity and cell phone service, likely increased the risk of adverse birth outcomes among this already vulnerable population.
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http://dx.doi.org/10.1007/s11111-020-00345-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967016PMC
September 2020

Associations of gestational phthalate exposure and non-nutritive suck among infants from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study.

Environ Int 2021 07 16;152:106480. Epub 2021 Mar 16.

University of Michigan School of Public Health, Department of Environmental Health Sciences, Ann Arbor, Michigan, USA.

Background: Infant non-nutritive suck (NNS), or sucking on a pacifier with no nutrients being delivered, has been used as in index of brain function and has been linked to subsequent neurodevelopment. Yet, no data are available connecting NNS to environmental exposures in utero. The goal of this study was to examine the relationship between gestational exposure to phthalates (a group of chemicals found in personal care products, PVC plastics, and other products) and NNS among infants in a birth cohort study in Puerto Rico.

Methods: Urinary phthalate metabolite levels were measured in women at up to three time points in pregnancy as a measure of in utero exposure to the child. We calculated the geometric mean of each metabolite for each woman as a measure of exposure across gestation. Infants had their NNS sampled using our custom research pacifier between 4-6 (± 2 weeks) weeks of age, yielding the following NNS dependent measures: cycles/burst, frequency, amplitude, bursts/min, and cycles/min.

Results: Two hundred and eight mother-infant dyads completed this study We used multiple linear regression to assess associations between individual phthalate metabolites and NNS measurements, adjusting for infant sex, birthweight, and urinary specific gravity. An interquartile range (IQR) increase in mono carboxyisononyl phthalate across pregnancy was associated with 3.5% (95%CI: -6.2, -0.8%) lower NNS frequency and 8.9% (0.6, 17.3%) higher NNS amplitude. Similarly, an IQR increase in mono-2-ethylhexyl phthalate was also associated with 3.4% (-6.5, -0.2%) lower NNS frequency, while an IQR increase in di-2-ethylhexyl terephthalate metabolites was associated with 11.2% (2.9, 19.5%) higher NNS amplitude. Gestational exposure to phthalates may alter NNS amplitude and frequency in full-term infants. These findings indicate that the infants may be increasing their NNS amplitude to compensate for their slower NNS frequency. These preliminary findings could have important clinical implications for earlier detection of exposure-related deficits in neurofunction as well as implications for subsequent neurodevelopment and related interventions.
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http://dx.doi.org/10.1016/j.envint.2021.106480DOI Listing
July 2021

Exposure to Phenols, Phthalates, and Parabens and Development of Metabolic Syndrome Among Mexican Women in Midlife.

Front Public Health 2021 26;9:620769. Epub 2021 Feb 26.

Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, United States.

Evidence suggests exposure to endocrine-disrupting chemicals (EDCs) can influence Metabolic Syndrome (MetS) risk in adults, but it is unclear if EDCs impact women during midlife. We examined if EDCs measured in adult women were predictive of MetS and its components 9 years later. We measured urinary phthalate metabolites, phenols, and parabens collected in 2008 among 73 females from the ELEMENT study. MetS and its components (Abdominal Obesity, Hypertriglyceridemia, Cholesterolemia, Hypertension, and Hyperglycemia) were assessed in 2017. We regressed log-transformed EDC concentrations on MetS and MetS components using logistic regression, adjusting for age and physical activity. At follow-up, the mean (SD) age was 46.6 (6.3) years; the prevalence of MetS was 34.3%. Sum of dibutyl phthalate metabolites (ΣDBP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP) were associated with an increased odds of hypertriglyceridemia. 2,5-dichlorophenol (2,5 DCP) and 2,4-dichlorophenol (2,4 DCP) were associated with increased odds of hypertriglyceridemia. The odds of hypertension were 4.18 (95% CI: 0.98, 17.7, < 0.10) and 3.77 (95% CI: 0.76, 18.62, < 0.10) times higher for every IQR increase in MCOP and propyl paraben, respectively. The odds of hyperglycemia were 0.46 (95% CI: 0.18, 1.17 < 0.10) times lower for every IQR increase in the sum of di-2-ethylhexyl phthalate metabolites (ΣDEHP), and the odds of abdominal obesity were 0.70 (95% CI: 0.40, 1.21, < 0.10) lower for every IQR increase in the concentration of triclosan. We found EDCs measured in 2008 were marginally predictive of hypertriglyceridemia and hypertension 9 years later. Results suggest that lower exposure to certain toxicants was related to lower markers of metabolic risk among midlife women.
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http://dx.doi.org/10.3389/fpubh.2021.620769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952420PMC
May 2021

Gestational and peripubertal phthalate exposure in relation to attention performance in childhood and adolescence.

Environ Res 2021 05 25;196:110911. Epub 2021 Feb 25.

Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Mexico.

The prevalence of Attention Deficit/Hyperactivity Disorder (ADHD) has been increasing. Research suggests that exposure to endocrine disrupting chemicals such as phthalates may play a role, but studies of in utero phthalate exposure and ADHD-related symptoms beyond early childhood are limited. We investigated associations between measures of in utero phthalate exposure and ADHD symptoms, such as inattention and impulsivity, in childhood (age 6-11 years, n = 221) and in adolescence (age 9-18 years, n = 200), as well as cross-sectional relationships between phthalate exposure and ADHD symptoms in adolescence (n = 491) among participants in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort. Women provided urine samples up to three times during pregnancy and adolescents provided a urine sample at 9-18 years of age for phthalate metabolite measurement. We administered the Conners' Continuous Performance Test (CPT) when children were age 6-11 years and again at 9-18 years of age. We used multivariable linear regression to examine associations between the geometric mean of phthalate metabolite levels across pregnancy and CPT scores in childhood or adolescence separately, adjusting for age, years schooling (at 9-18 only), maternal education, and specific gravity. Although average in utero phthalate concentrations were not associated with CPT scores in childhood, interquartile range (IQR) increases of in utero MBzP, MCPP, and MBP were associated with 4.2%, 4.7%, and 4.5% (p < 0.05) higher Omissions scores in adolescence, respectively, indicating higher inattention. In utero MiBP levels were also associated with higher Inter-Stimulus Interval (ISI) and Variability scores (5.4% and 5.5% per IQR, p < 0.05) in adolescence. In addition, urinary DEHP metabolite levels during adolescence were cross-sectionally associated with poorer scores on several CPT indices indicating greater inattention. These findings suggest that in utero phthalate exposure may have adverse effects on attention, but these effects may not appear until adolescence, a period of extensive neurodevelopment. Future research investigating the long-term effects of in utero phthalate exposure on attention and ADHD in adolescence, as well as identification of potential mechanisms involved, is needed.
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http://dx.doi.org/10.1016/j.envres.2021.110911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119354PMC
May 2021

Psychosocial status modifies the effect of maternal blood metal and metalloid concentrations on birth outcomes.

Environ Int 2021 04 3;149:106418. Epub 2021 Feb 3.

University of Michigan School of Public Health, Department of Environmental Health Sciences, Ann Arbor, MI, United States. Electronic address:

Background: Metal exposure and psychosocial stress in pregnancy have each been associated with adverse birth outcomes, including preterm birth and low birth weight, but no study has examined the potential interaction between them.

Objectives: We examined the modifying effect of psychosocial stress on the association between metals and birth outcomes among pregnant women in Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study.

Methods: In our analysis of 682 women from the PROTECT study, we measured 16 essential and non-essential metals in blood samples at two time points. We administered questionnaires to collect information on depression, perceived stress, social support, and life experience during pregnancy. Using K-means clustering, we categorized pregnant women into one of two groups: "good" and "poor" psychosocial status. We then evaluated whether the effect of blood metals (geometric average) on adverse birth outcomes (gestational age, preterm birth [overall and spontaneous], birth weight z-score, small for gestation [SGA], large for gestation [LGA]) vary between two clusters of women, adjusting for maternal age, maternal education, pre-pregnancy body mass index (BMI), and second-hand smoke exposure.

Results: Blood manganese (Mn) was associated with an increased odds ratio (OR) of overall preterm birth (OR/interquartile range [IQR] = 2.76, 95% confidence interval [CI] = 1.25, 6.12) and spontaneous preterm birth (OR/IQR: 3.68, 95% CI: 1.20, 6.57) only among women with "poor" psychosocial status. The association between copper (Cu) and SGA was also statistically significant only among women having "poor" psychosocial status (OR/IQR: 2.81, 95% CI: 1.20, 6.57). We also observed associations between nickel (Ni) and preterm birth and SGA that were modified by psychosocial status during pregnancy.

Conclusions: Presence of "poor" psychosocial status intensified the adverse associations between Mn and preterm birth, Cu and SGA, and protective effects of Ni on preterm. This provides evidence that prenatal psychosocial stress may modify vulnerability to metal exposure.
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http://dx.doi.org/10.1016/j.envint.2021.106418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897320PMC
April 2021

The use of dried blood spots for characterizing children's exposure to organic environmental chemicals.

Environ Res 2021 04 25;195:110796. Epub 2021 Jan 25.

University of Washington, School of Public Health, Department of Environmental and Occupational Health, Seattle, WA, USA.

Biomonitoring is a commonly used tool for exposure assessment of organic environmental chemicals with urine and blood samples being the most commonly used matrices. However, for children's studies, blood samples are often difficult to obtain. Dried blood spots (DBS) represent a potential matrix for blood collection in children that may be used for biomonitoring. DBS are typically collected at birth to screen for several congenital disorders and diseases; many of the states that are required to collect DBS archive these spots for years. If the archived DBS can be accessed by environmental health researchers, they potentially could be analyzed to retrospectively assess exposure in these children. Furthermore, DBS can be collected prospectively in the field from children ranging in age from newborn to school-aged with little concern from parents and minimal risk to the child. Here, we review studies that have evaluated the measurement of organic environmental toxicants in both archived and prospectively collected DBS, and where available, the validation procedures that have been performed to ensure these measurements are comparable to traditional biomonitoring measurements. Among studies thus far, the amount of validation has varied considerably with no studies systematically evaluating all parameters from field collection, shipping and storage contamination and stability to laboratory analysis feasibility. These validation studies are requisite to ensure reliability of the measurement and comparability to more traditional matrices. Thus, we offer some recommendations for validation studies and other considerations before DBS should be adopted as a routine matrix for biomonitoring.
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http://dx.doi.org/10.1016/j.envres.2021.110796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988293PMC
April 2021

Maternal Urinary Metal and Metalloid Concentrations in Association with Oxidative Stress Biomarkers.

Antioxidants (Basel) 2021 Jan 15;10(1). Epub 2021 Jan 15.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.

Metal exposure has been associated with a wide range of adverse birth outcomes and oxidative stress is a leading hypothesis of the mechanism of action of metal toxicity. We assessed the relationship between maternal exposure to essential and non-essential metals and metalloids in pregnancy and oxidative stress markers, and sought to identify windows of vulnerability and effect modification by fetal sex. In our analysis of 215 women from the PROTECT birth cohort study, we measured 14 essential and non-essential metals in urine samples at three time points during pregnancy. The oxidative stress marker 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite 2,3-dinor-5,6-dihydro-15-15-F2t-IsoP, as well as prostaglandin F2α (PGF2α), were also measured in the same urine samples. Using linear mixed models, we examined the main effects of metals on markers of oxidative stress as well as the visit-specific and fetal sex-specific effects. After adjustment for covariates, we found that a few urinary metal concentrations, most notably cesium (Cs) and copper (Cu), were associated with higher 8-iso-PGF2α with effect estimates ranging from 7.3 to 14.9% for each interquartile range, increase in the metal concentration. The effect estimates were generally in the same direction at the three visits and a few were significant only among women carrying a male fetus. Our data show that higher urinary metal concentrations were associated with elevated biomarkers of oxidative stress. Our results also indicate a potential vulnerability of women carrying a male fetus.
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http://dx.doi.org/10.3390/antiox10010114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830802PMC
January 2021

Association of biomarkers of exposure to metals and metalloids with maternal hormones in pregnant women from Puerto Rico.

Environ Int 2021 02 13;147:106310. Epub 2020 Dec 13.

Department of Environmental Health Sciences, School of Public Health, University of Michigan Ann Arbor, MI, USA. Electronic address:

Background: Metal(loid)s have been associated to adverse birth outcomes in experimental and epidemiological studies, but the underlying mechanism(s) are not well understood. Endocrine disruption may be a mechanism by which the metal(loid)s impact birth outcomes.

Methods: Pregnant women were recruited through the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT). Urine, blood, demographic and pregnancy-related data were collected at recruitment and subsequent visits. Sixteen metal(loid)s were analyzed in urine and blood samples, while nine maternal hormones (corticotropin-releasing hormone (CRH), sex-hormone binding globulin (SHBG), estriol (E3), progesterone, testosterone, thyroid-stimulating hormone (TSH), total triiodothyronine (T3), total thyroxine (T4), and free thyroxine (fT4)) were measured in serum samples from 815 singleton pregnancies. Linear mixed models with random intercepts were used to examine associations between metal(loid)s in blood and urine with hormone concentrations.

Results: Arsenic blood concentrations were significantly associated with increased levels in CRH (%Δ: 23.0, 95%CI: 8.4-39.6) and decreased levels in testosterone (%Δ: 16.3, 95%CI: 26.2-5.1). Cobalt, manganese, and lead blood concentrations were associated with small increases in SHBG (%Δ range: 3.3-4.2), E3 (%Δ range: 3.9-8.7) and progesterone (%Δ range: 4.1-6.3) levels, respectively. Nickel blood concentration was inversely associated with testosterone levels (%Δ 13.3, 95%CI: 18.7-7.6). Significant interactions were detected for the association between nickel and study visit in relation to CRH (p < 0.02) and testosterone levels (p < 0.01).

Conclusion: Our analysis suggests that metal(loid)s may act as endocrine disruptors by altering prenatal hormone levels. This disruption may depend on specific windows of exposure during pregnancy. Additionally, some essential metal(loid)s such as managense and cobalt may be contributors to adverse maternal and fetal outcomes. The study of metal(loid)s as endocrine disruptors is in the early stages of epidemiological research and future studies are needed to further investigate these associations.
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http://dx.doi.org/10.1016/j.envint.2020.106310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856269PMC
February 2021

In utero and peripubertal metals exposure in relation to reproductive hormones and sexual maturation and progression among boys in Mexico City.

Environ Health 2020 11 25;19(1):124. Epub 2020 Nov 25.

Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA.

Background: Endocrine disrupting chemicals (EDCs) such as metals have been reported to alter circulating reproductive hormone concentrations and pubertal development in animals. However, the relationship has rarely been investigated among humans, with the exception of heavy metals, such as Pb and Cd. Our aim was to investigate measures of in utero and peripubertal metal exposure in relation to reproductive hormone concentrations and sexual maturation and progression among boys from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohorts.

Methods: Our analysis included 118 pregnant women and their male children from the ELEMENT study. Essential and non-essential metals were measured in urine collected from the mothers during the third trimester of pregnancy and their male children at 8-14 years. Reproductive hormone concentrations [serum testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone-binding globulin (SHBG)] were measured in blood samples from the children at 8-14 years. We also assessed Tanner stages for sexual maturation (genital, pubic hair development, and testicular volume), at two time points (8-14, 10-18 years). We used linear regression to independently examine urinary metal concentrations in relation to each peripubertal reproductive hormones adjusting for child age and BMI. Generalized estimation equations (GEEs) were used to evaluate the association of in utero and peripubertal metal exposures with sexual maturation and progression during follow-up based on Tanner staging and testicular volume.

Results: In utero and prepubertal concentrations of some urinary metals were associated with increased concentrations of peripubertal reproductive hormones, especially non-essential metal(loid)s As and Cd (in utero), and Ba (peripubertal) as well as essential metal Mo (in utero) in association with testosterone. More advanced pubic hair developmental stage and higher testicular volume at the early teen visit was observed for boys with higher non-essential metal concentrations, including in utero Al and peripubertal Ba, and essential metal Zn concentration (peripubertal). These metals were also associated with slower pubertal progression between the two visits.

Conclusion: These findings suggest that male reproductive development may be associated with both essential and non-essential metal exposure during in utero and peripubertal windows.
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http://dx.doi.org/10.1186/s12940-020-00672-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688001PMC
November 2020

Application of an analytical framework for multivariate mediation analysis of environmental data.

Nat Commun 2020 11 6;11(1):5624. Epub 2020 Nov 6.

Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, US.

Diverse toxicological mechanisms may mediate the impact of environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. In this study, we introduce an analytical framework for multivariate mediation analysis to identify mediation pathways (q = 61 mediators) in the relationship between environmental toxicants (p = 38 analytes) and gestational age at delivery. Our analytical framework includes: (1) conducting pairwise mediation for unique exposure-mediator combinations, (2) exposure dimension reduction by estimating environmental risk scores, and (3) multivariate mediator analysis using either Bayesian shrinkage mediation analysis, population value decomposition, or mediation pathway penalization. Dimension reduction demonstrates that a one-unit increase in phthalate risk score is associated with a total effect of 1.07 lower gestational age (in weeks) at delivery (95% confidence interval: 0.48-1.67) and eicosanoids from the cytochrome p450 pathway mediated 26% of this effect (95% confidence interval: 4-63%). Eicosanoid products derived from the cytochrome p450 pathway may be important mediators of phthalate toxicity.
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http://dx.doi.org/10.1038/s41467-020-19335-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648785PMC
November 2020

Early Gestational Exposure to High-Molecular-Weight Phthalates and Its Association with 48-Month-Old Children's Motor and Cognitive Scores.

Int J Environ Res Public Health 2020 11 4;17(21). Epub 2020 Nov 4.

Research Unit in Occupational Health, Mexican Social Security Institute, Mexico City 06720, Mexico.

In utero phthalate exposure has been associated with neurodevelopmental disorders, nevertheless, trimester-specific susceptibility remains understudied. Our aim was to identify susceptible windows to the effects of gestational High-Molecular-Weight Phthalates (HMWP) exposure on 48 months' neurodevelopment. We measured six HMWP metabolites (MEHP, MEHHP, MEOHP, MECPP, MBzP and MCPP) in urine samples collected during each trimester from women in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort ( = 218). We assessed children's motor (MS), cognitive (GCI) and memory (MeS) abilities using McCarthy Scales of Children's Abilities (MSCA). We used linear regression models to examine associations between trimester-specific phthalate metabolites and MSCA scores, adjusted for sex, gestational age, breastfeeding, and maternal IQ. Although phthalate concentrations were similar across trimesters, first and second trimester phthalates were inversely associated with MS and GCI, with first trimester associations with MS being the strongest and statistically significant. Stronger associations were seen with MS and GCI among boys compared to girls, however interaction terms were not statistically significant. Our results suggest that early gestation is a sensitive window of exposure to HMWP for neurodevelopment, particularly in boys. Regulations on phthalate content in food as well as pregnancy consumption guidelines are necessary to protect future generations.
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http://dx.doi.org/10.3390/ijerph17218150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662459PMC
November 2020

Prenatal Metal Mixtures and Birth Weight for Gestational Age in a Predominately Lower-Income Hispanic Pregnancy Cohort in Los Angeles.

Environ Health Perspect 2020 11 3;128(11):117001. Epub 2020 Nov 3.

Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

Background: Reduced fetal growth increases the risk for adverse health outcomes. Growing evidence suggests that metal exposures contribute to reduced fetal growth, but little is known about the effects of complex metal mixtures.

Objectives: We investigated the impact of a complex mixture of metals on birth weight for gestational age (BW for GA) in the Maternal and Developmental Risks from Environmental and Social Stressors study, a predominately lower-income Hispanic pregnancy cohort in Los Angeles, California.

Methods: Cadmium (Cd), cobalt (Co), mercury (Hg), nickel (Ni), molybdenum (Mo), lead (Pb), antimony (Sb), tin (Sn), and thallium (Tl) were measured by inductively coupled plasma mass spectrometry (ICP-MS) in maternal urine samples collected in early pregnancy (median GA: 13.1 wk). Speciated urinary arsenic (As) ( As) was measured by high-performance liquid chromatography coupled to ICP-MS. Primary analyses focused on a mixture of seven metals that have previously been associated individually with fetal growth (i.e., As, Cd, Co, Hg, Ni, Pb, Tl) (). In exploratory analyses, we additionally examined three metals that have been less studied in relation to fetal growth (i.e., Mo, Sb, Sn). Covariate-adjusted Bayesian kernel machine regression was used to investigate metal mixture associations with BW for GA -scores.

Results: In primary analyses, Hg and Ni ranked highest as predictors of BW for GA. An inverse linear association was estimated for Hg, whereas a positive association was estimated for Ni at low-to-moderate concentrations. A potential interaction between Hg and Ni was also identified. In our exploratory analysis, Sb ranked highest as a predictor of BW for GA, followed by Hg and Ni.

Conclusions: Our findings suggest that in this understudied population, Hg may reduce fetal growth, whereas Ni may promote fetal growth. We also identified Sb as a potential metal of concern for this population, which merits additional investigation. https://doi.org/10.1289/EHP7201.
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http://dx.doi.org/10.1289/EHP7201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608819PMC
November 2020

Prenatal metal mixtures and fetal size in mid-pregnancy in the MADRES study.

Environ Res 2021 05 28;196:110388. Epub 2020 Oct 28.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: Fetal growth is predictive of health later in life. Both toxic and essential metals influence fetal growth, but most studies have focused on these elements individually and used birth weight as an indicator of fetal growth. The objective of the current study was to investigate the impact of a mixture of metals on fetal size in mid-pregnancy in a predominately lower income Hispanic pregnancy cohort in Los Angeles.

Methods: For our primary analysis, we focused on six elements that have previously been associated individually with fetal size, including arsenic (As), barium (Ba), cadmium (Cd), mercury (Hg), molybdenum (Mo), and tin (Sn), measured in maternal urine samples collected in early pregnancy (median: 12.4 weeks gestation). In an exploratory analysis, we additionally included cobalt (Co), nickel (Ni), antimony (Sb), and thallium (Tl). Using covariate-adjusted Bayesian Kernel Machine Regression (BKMR) as our main mixture modeling approach, we examined the impact of these metals on fetal biometry measures obtained between 18 and 22 weeks gestation, with a focus on estimated fetal weight (EFW).

Results: BKMR identified Mo and Ba as the mixture components that contributed most to associations with EFW. Linear associations were observed for both metals. An increase in Mo from the 25th to 75th percentile was associated with a 0.114 (95% credible interval (CI): 0.019, 0.247) SD higher EFW, equivalent to a 7.4 g difference. Similar associations were observed between Mo and the other fetal measures evaluated. In contrast, an increase in Ba from the 25th to 75th percentile was associated with a -0.076 (95% CI: 0.217, 0.066) SD lower EFW, equivalent to a 4.9 g difference. Similar inverse associations were observed for Ba in relation to abdominal circumference and biparietal diameter. BKMR also identified a possible interaction between Ba and Mo in relation to head circumference, suggesting that the positive associations between Mo and this outcome may be attenuated at high levels of Ba, which was consistent with findings from linear regression (P = 0.03). In an exploratory analysis accounting for a larger mixture of metals, Mo and Ba consistently contributed most to associations with EFW. An inverse association was also identified between Sb and EFW.

Conclusions: Our results suggest that Mo may promote fetal growth, while Ba and Sb may reduce fetal growth, in this population.
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http://dx.doi.org/10.1016/j.envres.2020.110388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079562PMC
May 2021

Association of personal exposure to power-frequency magnetic fields with pregnancy outcomes among women seeking fertility treatment in a longitudinal cohort study.

Fertil Steril 2020 11 6;114(5):1058-1066. Epub 2020 Oct 6.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan. Electronic address:

Objective: To assess for the first time the potential relationships of personal exposure to magnetic fields (MF) with pregnancy outcomes among a cohort of women from a fertility clinic, addressing, through study design, some of the primary limitations of previous studies on this topic.

Design: Longitudinal preconception prospective cohort.

Setting: Fertility center.

Patient(s): Our analysis included 119 women recruited from 2012 to 2018, who underwent in vitro fertilization (IVF) (n = 163 cycles) and/or intrauterine insemination (IUI) (n = 123 cycles).

Intervention(s): Women wore personal exposure monitors continuously for up to three consecutive 24-hour time periods separated by several weeks.

Main Outcome Measure(s): Implantation, clinical pregnancy, live birth, and pregnancy loss.

Result(s): The median and maximum of the overall daily mean (daily peak) MF exposure levels were 1.10 mG (2.14 mG) and 15.54 mG (58.73 mG), respectively. MF exposure metrics were highest among women who changed environments four or more times per day. Overall, no statistically significant associations between MF exposure metrics and fertility treatment or pregnancy outcomes were observed in crude or adjusted models. Effect estimates, both positive and negative, varied by outcome and the exposure metric, including the way in which exposure was modeled.

Conclusion(s): Personal MF exposures were not associated with fertility treatment outcomes or pregnancy outcomes. Despite its limited size, strengths of the study include a longitudinal repeated-measures design, the collection of personal MF exposure data across multiple days, and carefully documented outcome and covariate information among a potentially susceptible study population.
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http://dx.doi.org/10.1016/j.fertnstert.2020.05.044DOI Listing
November 2020

Reproductive outcomes associated with flame retardants among couples seeking fertility treatment: A paternal perspective.

Environ Res 2021 01 22;192:110226. Epub 2020 Sep 22.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA. Electronic address:

Background: Polybrominated diphenyl ethers (PBDEs) have been phased out of production for nearly a decade yet are still frequently detected in serum of U.S. adults. PBDE concentrations have been associated with adverse reproductive outcomes and laboratory studies suggest hydroxylated-BDEs (OH-BDEs) may act as endocrine disruptors. We set out to assess the joint effects of paternal and maternal serum PBDE concentrations on in vitro fertilization (IVF) outcomes and the association between paternal serum OH-BDE concentrations and IVF outcomes.

Methods: This analysis included 189 couples (contributing 285 IVF cycles) recruited between 2006 and 2016 from a longitudinal cohort based at Massachusetts General Hospital Fertility Center who completed at least one IVF cycle and had an available blood sample at study entry. Congeners (47, 99, 100, 153, and 154) and OH-BDEs (3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49) were quantified in serum. Log-transformed PBDEs and OH-BDEs were modeled in quartiles for associations with IVF outcomes using multivariable generalized mixed models and cluster weighted generalized estimating equations.

Results: Lipid-adjusted concentrations of PBDEs and OH-BDEs were higher in females than in male partners. There were no clear patterns of increases in risk of adverse IVF outcomes associated with PBDEs and OH-BDEs. However, some decreases in associations with IVF outcomes were observed in isolated quartiles.

Conclusions: Our assessment of couple level exposure is unique and highlights the importance of including male and female exposures in the assessment of the influence of environmental toxicants on pregnancy outcomes.
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http://dx.doi.org/10.1016/j.envres.2020.110226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736216PMC
January 2021

Polycyclic aromatic hydrocarbon exposure results in altered CRH, reproductive, and thyroid hormone concentrations during human pregnancy.

Sci Total Environ 2020 Dec 11;749:141581. Epub 2020 Aug 11.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA. Electronic address:

Polycyclic aromatic hydrocarbons (PAHs) are byproducts of incomplete combustion reactions and are ubiquitous in the environment, leading to widespread human exposure via inhalation and ingestion pathways. PAHs have been implicated as endocrine disrupting compounds in previous animal and in vitro studies, but human studies are currently lacking. Pregnant women and their developing fetuses are particularly susceptible populations to environmental contaminants, in part because alterations in hormone physiology during gestation can have adverse consequences on the health of the pregnancy. We utilized data on 659 pregnant women from the PROTECT longitudinal birth cohort in Puerto Rico to assess associations between repeated measures of 8 urinary hydroxylated PAH (OH-PAH) metabolites and 9 serum hormones during gestation. Urine samples were collected at 3 study visits (median gestational ages of 18, 22, and 26 weeks at each visit, respectively) and serum samples were collected at the first and third study visits. Linear mixed effects models were used to ascertain longitudinal associations between OH-PAHs and hormones, and sensitivity analyses were employed to assess potential nonlinearity and differences in associations on the basis of fetal sex and timing of biomarker measurement. Among the multiple positive associations we observed between OH-PAHs and CRH, estriol, progesterone, T3, and the ratio of T3 to T4, and inverse associations with testosterone, the most notable are a 24.3% increase (95% CI: 13.0, 36.7) in CRH with an interquartile range (IQR) increase in 1-hydroxyphenanthrene and a 17.2% decrease (95% CI: 8.13, 25.4) in testosterone with an IQR increase in 1-hydroxynapthalene. Many associations observed were dependent on fetal sex, and some relationships showed evidence of nonlinearity. These findings demonstrate the importance of studying PAH exposures during pregnancy and highlight the potential complexity of their impacts on the physiology of human pregnancy.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755823PMC
December 2020

Cohort profile: Center for Research on Early Childhood Exposure and Development in Puerto Rico.

BMJ Open 2020 07 19;10(7):e036389. Epub 2020 Jul 19.

Department of Civil and Environmental Engineering, Northeastern University, Boston, Massachusetts, USA.

Purpose: Puerto Rican children experience high rates of asthma and obesity. Further, infants born in Puerto Rico are more at risk for being born prematurely compared with infants on the mainland USA. Environmental exposures from multiple sources during critical periods of child development, potentially modified by psychosocial factors, may contribute to these adverse health outcomes. To date, most studies investigating the health effects of environmental factors on infant and child health have focused on single or individual exposures.

Participants: Infants currently in gestation whose mother is enrolled in Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort, and infants and children already born to mothers who participated in the PROTECT study.

Findings To Date: Data collection and processing remains ongoing. Demographic data have been collected on 437 mother-child pairs. Birth outcomes are available for 420 infants, neurodevelopmental outcomes have been collected on 319 children. Concentrations of parabens and phenols in maternal spot urine samples have been measured from 386 mothers. Center for Research on Early Childhood Exposure and Development mothers have significantly higher urinary concentrations of dichlorophenols, triclosan and triclocarban, but lower levels of several parabens compared with reference values from a similar population drawn from the National Health and Nutrition Examination Survey.

Future Plans: Data will continue to be collected through recruitment of new births with a target of 600 children. Seven scheduled follow-up visits with existing and new participants are planned. Further, our research team continues to work with healthcare providers, paediatricians and early intervention providers to support parent's ability to access early intervention services for participants.
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http://dx.doi.org/10.1136/bmjopen-2019-036389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371225PMC
July 2020

Urinary Concentrations of Phthalate Metabolite Mixtures in Relation to Serum Biomarkers of Thyroid Function and Autoimmunity among Women from a Fertility Center.

Environ Health Perspect 2020 06 9;128(6):67007. Epub 2020 Jun 9.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women.

Objective: We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity.

Methods: This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005-2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (, ) and triiodothyronine (, ), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores.

Results: We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of , , , and [absolute difference: ; 95% confidence interval (CI): , ; ; absolute difference: ; 95% CI: , ; ; absolute difference: ; 95% CI: 0.54, ; ; and absolute difference: ; 95% CI: , ; , respectively]. Using BKMR, we observed that mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was the primary contributor to these negative associations. DEHP and non-DEHP factor scores were not associated with serum TSH, TgAb, or TPOAb.

Conclusions: Mixtures of urinary DEHP metabolites were inversely associated with serum biomarkers of thyroid function but not with autoimmunity, which were within normal ranges for healthy adult women. https://doi.org/10.1289/EHP6740.
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http://dx.doi.org/10.1289/EHP6740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282564PMC
June 2020

Exploring reproductive associations of serum polybrominated diphenyl ether and hydroxylated brominated diphenyl ether concentrations among women undergoing in vitro fertilization.

Hum Reprod 2020 05;35(5):1199-1210

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Study Question: Are serum concentrations of polybrominated diphenyl ethers (PBDEs) and hydroxylated brominated diphenyl ethers (OH-BDEs) associated with IVF endpoints?

Summary Answer: Positive associations were observed for BDE153 and several OH-BDEs with IVF endpoints.

What Is Known Already: PBDEs have been voluntarily phased out of production in the USA and EU due to their persistence and toxicity to humans and ecosystems. PBDEs have been associated with implantation failure among women undergoing IVF, yet some animal studies suggest greater toxicity from their metabolites, OH-BDEs.

Study Design, Size, Duration: We evaluated a subset of 215 women (contributing 330 IVF cycles) enrolled between 2005 and 2016 in a longitudinal cohort based at Massachusetts General Hospital Fertility Center.

Participants/materials, Setting, Methods: The following PBDEs were quantified: 47, 99, 100, 153 and 154 and the following OH-BDEs: 3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49. Clinical endpoints of IVF treatments were abstracted from electronic medical records. Associations of log-transformed PBDEs and OH-BDEs with IVF outcomes were assessed using multivariable generalized mixed models and cluster weighted generalized estimating equation models adjusted for lipids, age, BMI, race, year of sample collection, IVF protocol and FSH levels. Outcomes were adjusted to represent a percent change in outcome with an increase equal to the magnitude of the difference between the 75th and 25th percentiles for each specific compound (interquartile range (IQR) increase).

Main Results And The Role Of Chance: Detection frequencies were highest for congeners 47 and 153 (82% ≥ method detection limit (MDL)) and metabolites 3 and 5-OH-BDE47 and 4-OH-BDE49 (92% > MDL). PBDE and OH-BDE geometric mean concentrations declined by up to 80% between participants recruited in 2005 and those recruited in 2016. An IQR increase of BDE153 was associated with an increase in the probability of implantation (relative risk (RR) = 1.26, 95% CI: 1.16, 1.36), clinical pregnancy (RR = 1.32, 95% CI: 1.19, 1.46) and live birth (RR = 1.34; 95% CI: 1.15, 1.54). An IQR increase in 3 and 5-OH-BDE47 was associated with increased probabilities of implantation (RR = 1.52; 95% CI: 1.11, 2.09), clinical pregnancy (RR = 1.66; 95% CI: 1.17, 2.36), and live birth (RR = 1.61; 95% CI: 1.07, 2.40). When models were stratified by race (White (86%)/Other race (14%)), associations remained positive for White women, yet inverse associations were observed for Other race women. An IQR increase in BDE47 was associated with a 46% decreased probability of clinical pregnancy (95% CI: 0.31, 0.95) for Other race women.

Limitations, Reasons For Caution: Despite the long half-lives of PBDEs and OH-BDEs, exposure misclassification is possible for women who underwent multiple treatment cycles over several months or years. It is also possible another medium, such as follicular fluid would be optimal to characterize exposure. We also tested associations for multiple congeners and metabolites with multiple outcomes.

Wider Implications Of The Findings: Detections of serum concentrations of PBDEs and OH-BDEs were highest in the early years of the study and suggests that the phase-out of these compounds has contributed to a decrease in exposure. The negative associations found for PBDEs and IVF outcomes among other race women suggests the potential for racial disparity. Potential racial disparities in PBDE exposure and exploration of alternative flame retardants with reproductive health outcomes should be the focus of future investigations.

Study Funding/competing Interest(s): Funding for this research was supported by the National Institutes of Environmental Health Sciences (NIEHS) [R01 ES009718, ES022955, ES000002 and 009718T32ES007069]. The authors have no conflicts of interest.
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http://dx.doi.org/10.1093/humrep/deaa063DOI Listing
May 2020

Exposure to Endocrine-Disrupting Chemicals During Pregnancy Is Associated with Weight Change Through 1 Year Postpartum Among Women in the Early-Life Exposure in Mexico to Environmental Toxicants Project.

J Womens Health (Larchmt) 2020 11 1;29(11):1419-1426. Epub 2020 Apr 1.

Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

The postpartum period may be a vulnerable life stage for a woman's cardiometabolic health. We examined associations of exposure to common endocrine-disrupting chemicals (EDCs) during pregnancy with weight from delivery through 1 year postpartum among 199 women in Mexico City. During each trimester of pregnancy, we collected a urine sample to assay bisphenol A (BPA), mono--butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), mono-3-carboxypropyl phthalate (MCPP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and monoethyl phthalate (MEP). We calculated summary scores for di-2-ethylhexyl phthalate metabolites (ΣDEHP) and dibutyl phthalate metabolites (ΣDBP). We calculated the geometric mean of each EDC across pregnancy for use in the analysis. At delivery and three additional times during the first year postpartum, we measured the women's weight. We used mixed-effects linear regression models to estimate associations of each EDC with weight at delivery (kg) and weight change (kg/year) from delivery through 1 year postpartum. Covariates included urinary specific gravity, maternal age, parity, height, first trimester body mass index, and gestational age at enrollment. Mean ± standard deviation weight change during the first postpartum year was -0.49 ± 4.04 kg. The EDCs were inversely associated with weight at delivery, but positively associated with weight change through 1 year postpartum. For example, each interquartile range of urinary ΣDEHP corresponded with 1.38 (95% confidence interval: 0.44-2.33) kg lower weight at delivery and 1.01 (0.41--1.61) kg/year slower rate of weight loss. We observed similar associations for other EDCs. Prenatal exposure to EDCs is associated with lower weight at delivery, but slower rate of weight loss through the first postpartum year.
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http://dx.doi.org/10.1089/jwh.2019.8078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703250PMC
November 2020

Urinary trace metals in association with fetal ultrasound measures during pregnancy.

Environ Epidemiol 2020 Apr;4(2)

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Toxic metals have been associated with lower birth weight while essential metals have been associated with higher birth weight. Evidence for other metals is either inconsistent or limited in terms of number of studies. This study analyzed 17 urinary metals, individually and as a mixture, and their association with measures of fetal growth in the LIFECODES birth cohort. Ultrasound was used to measure abdominal circumference, head circumference, and femur length and measures were used to calculate estimated fetal weight at ~26 and ~35 weeks. We calculated the z-score based on gestational age at scan, and estimated fetal weight (EFW) was combined with birth weight for longitudinal analyses. Metals were measured in samples collected at ~26 weeks. We used linear mixed effects models to examine associations between metals and repeated measures of each outcome, controlling for covariates. Principal components analysis reduced the biomarkers to predictors that may share some commonality. We found that an interquartile range increase in selenium was inversely associated with femur length z-score as well as other growth outcomes. Other essential metals, however, were associated with an increase in growth. Finally, the PCA component comprised of arsenic, mercury, and tin was associated with decreased head circumference z-score (-0.14 [95% CI: -0.23, -0.05]).
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http://dx.doi.org/10.1097/ee9.0000000000000075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083213PMC
April 2020