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Results of Projects Used to Test CHEAR Processes

The following are selected examples of the work completed to develop and test CHEAR operational and quality control procedures for submission and review of proposals, and coordination and standardization of laboratory and data exposure analyses. CHEAR invited four investigators with ongoing studies of children’s health to submit a proposal to pilot test addition of chemical exposure analysis to their study design. The pilot proposals were submitted to the CHEAR proposal review process, and the post approval process for laboratory and data analyses. The results of these pilot tests are included in our research highlights.

Urinary polycyclic aromatic hydrocarbon metabolite associations with biomarkers of inflammation, angiogenesis, and oxidative stress in pregnant women

Kelly K. Ferguson, Thomas F. McElrath, Gerry G. Pace, David Weller, Lixia Zeng, Subramaniam Pennathur, David E. Cantonwine, John D. Meeker

M-CHEAR: Michigan Children's Health Exposure Analysis Resource Laboratory Hub

Environmental exposure to polycyclic aromatic hydrocarbons (PAHs) is prevalent and may adversely impact pregnancy and development of the fetus. The purpose of this exploratory study was to examine urinary PAH metabolites in potential association with mediators of these outcomes. To do so, we measured a panel of 12 inflammatory, angiogenic, and oxidative stress biomarkers in plasma or urine from women in their third trimester of pregnancy (n = 200). Urinary PAH metabolites were highly detectable (>88%) in the study population, and most were higher in women who had lower education levels, higher body mass index, and who were African American. Some PAH metabolites showed consistent positive associations with the plasma inflammation marker C-reactive protein (CRP) and the urinary oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane. For example, an interquartile range increase in 2-hydroxynapthalene was associated with a 35% increase in CRP (95% confidence interval = -0.13, 83.2), a 14% increase in 8-OHdG (95% confidence interval = 0.59, 30.1), and a 48% increase in 8-isoprostane (95% confidence interval = 16.7, 87.0). These data suggest that exposure to PAHs may cause systemic changes during pregnancy that could lead to adverse pregnancy or developmental outcomes; however, these results should be corroborated in a larger study population.

This work is published in Environmental Science and Technology. 2017;51(8):4652-4660.


Urinary trace metals individually and in mixtures in association with preterm birth

Stephani S. Kim, John D. Meeker, Rachel Carroll, Shanshan Zhao, Michael J. Mourgas, Michael J. Richards, Max Aung, David E. Cantonwine, Thomas F. McElrath, Kelly K. Ferguson

M-CHEAR: Michigan Children's Health Exposure Analysis Resource Laboratory Hub

One in ten infants born in the United States is born preterm, or prior to 37 weeks gestation. Exposure to elevated levels of metals, such as lead and arsenic, has been linked to higher risk of preterm birth (PTB), but consequences of lower levels of exposure and less studied metals are unclear. We examined the associations between 17 urinary trace metals individually and in mixtures in relation to PTB. The LIFECODES birth cohort enrolled pregnant women at <15 weeks gestation at Brigham and Women's Hospital in Boston. We selected cases of PTB (n = 99) and unmatched controls (n = 291) and analyzed urine samples for a panel of trace metals (median: 26 weeks gestation). We used logistic regression models to calculate the odds ratio (OR) for PTB and subtypes of PTB based on presentation at delivery. Subtypes included spontaneous and placental PTB. We used elastic net (ENET) regularization to identify individual metals or pairwise interactions that had the strongest associations with PTB, and principal components analysis (PCA) to identify classes of exposures associated with the outcome. We observed increased odds of PTB (OR: 1.41, 95% Confidence Interval [CI]: 1.12, 1.78) in association with an interquartile range difference in urinary copper (Cu). We also observed an increased OR for selenium (OR: 1.33, 95% CI: 0.98, 1.81). ENET selected Cu as the most important trace metal associated with PTB. PCA identified 3 principal components (PCs) that roughly reflected exposure to toxic metals, essential metals, and metals with seafood as a common source of exposure. PCs reflecting essential metals were associated with increased odds of overall and spontaneous PTB. Maternal urinary copper in the third trimester was associated with increased risk of PTB, and statistical analyses for mixtures indicated that after accounting for correlation this metal was the most important statistical predictor of the outcome.

This work is published in Environment International. 2018;121 (Pt 1):582-590.


Perinatal lead (Pb) exposure’s effect on DNA methylation in human umbilical cord blood

Christine A. Rygiel, Jaclyn M. Goodrich, Wei Perng, Tamara R. Jones, Maritsa Solano, Howard Hu, Martha M. Tellez-Rojo, Karen E. Peterson, Dana C. Dolinoy

M-CHEAR: Michigan Children's Health Exposure Analysis Resource Laboratory Hub

Early life exposure to lead (Pb) can influence health through epigenetic modifications including DNA methylation. The aim of this study is to identify differentially methylated CpG positions associated with prenatal Pb exposure in human cord blood leukocytes. The Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project utilizes a series of longitudinal birth cohorts to examine the impact of Pb exposure during sensitive periods of development. In this study, we selected 97 ELEMENT participants with archived umbilical cord blood samples for methylation analysis via the Infinium MethylationEPIC BeadChip, which quantifies total methylation at >850,000 CpG sites. Maternal blood lead levels (BLLs) at each trimester (T1: 6.56 ± 5.27 ug/dL; T2: 5.89 ± 4.83 ug/dL; T3: 6.20 ± 4.48 ug/dL), umbilical cord BLLs (4.82 ± 3.71 ug/dL) at birth, and patella (9.45 ± 9.96 ug/g) and tibia (7.19 ± 9.61 ug/g) bone Pb levels one-month post pregnancy were measured. Differentially methylated positions (DMPs) by Pb level were identified using linear regression, controlling for sex and estimated umbilical cord cell-type composition. We employed a false discovery rate of 5% (q50 significant pathways enriched for differential methylation by maternal BLL in each trimester, including neurological system processes, chemical stimuli in sensory perception, and transmembrane receptor activities. Further studies are needed to quantify gene expression to help determine if methylation alterations are promoting transcriptomic alterations, as well as investigate if these findings are tissue-specific or persistent later in life.

This work was presented at the 2019 Society of Toxicology Annual Meeting, March 10–14, in Baltimore, Maryland.


Page last updated: 
May 22, 2019