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McElrath, Thomas

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McElrath

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Thomas

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McElrath, Thomas
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Now showing 1 - 10 of 17
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    Associations between Maternal Biomarkers of Phthalate Exposure and Inflammation Using Repeated Measurements across Pregnancy
    (Public Library of Science, 2015) Ferguson, Kelly K.; McElrath, Thomas; Mukherjee, Bhramar; Loch-Caruso, Rita; Meeker, John D.
    Phthalate exposure is prevalent in populations worldwide, including pregnant women. Maternal urinary metabolite concentrations have been associated with adverse reproductive outcomes, but underlying mechanisms remain unclear. Here we investigate inflammation as a possible pathway by examining phthalates in association with inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines (IL-1β, IL-6, IL-10, and TNF-α) in a repeated measures analysis of pregnant women (N = 480). Urinary phthalate metabolites and plasma inflammation biomarkers were measured from samples collected at up to four visits per subject during gestation (median 10, 18, 26, and 35 weeks). Associations were examined using mixed models to account for within-individual correlation of measures. Few statistically significant associations or clear trends were observed, although in full models mono-carboxypropyl phthalate (MCPP) was significantly (percent change with interquartile range increase in exposure [%Δ] = 8.89, 95% confidence interval [CI] = 3.28, 14.8), and mono-benzyl phthalate (MBzP) was suggestively (%Δ = 6.79, 95%CI = -1.21, 15.4) associated with IL-6. Overall these findings show little evidence of an association between phthalate exposure and peripheral inflammation in pregnant women. To investigate inflammation as a mechanism of phthalate effects in humans, biomarkers from target tissues or fluids, though difficult to measure in large-scale studies, may be necessary to detect effects.
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    Maternal Smoking during Pregnancy and Daughters’ Preeclampsia Risk
    (Public Library of Science, 2015) Mattsson, Kristina; Källén, Karin; Rignell-Hydbom, Anna; Hansson, Stefan R.; McElrath, Thomas; Cantonwine, David; Rylander, Lars
    Background: An obstetrical paradox is that maternal smoking is protective for the development of preeclampsia. However, there are no prior studies investigating the risk of preeclampsia in women who were exposed to tobacco smoking during their own fetal period. We aimed to study the subsequent risk of preeclampsia in women who were exposed to tobacco smoke in utero, using a national population-based register. Methods: Data were obtained from the Medical Birth Register of Sweden for women who were born in 1982 (smoking data first recorded) or after, who had given birth to at least one child; 153 885 pregnancies were included. Results: The associations between intrauterine smoking exposure (three categories: non-smokers, 1–9 cigarettes/day [moderate exposure], and >9 cigarettes/day [heavy exposure]) and subsequent preeclampsia (n = 5721) were assessed using logistic regressions. In models adjusted for maternal age, parity and own smoking, the odds ratios (OR) for preeclampsia were 1.06 [95% CI: 0.99,1.13 for moderate intrauterine exposure, and 1.18, [95% CI: 1.10,1.27] for heavy exposure. Estimates were slightly strengthened in non-smoking women who experienced heavy intrauterine exposure (adjusted OR 1.24 [95% CI: 1.14,1.34]). Results were no longer statistically significant after adjustment for the woman’s own BMI, gestational age and birthweight Z-scores. Conclusion: These data revealed some evidence of a possible weak positive association between intrauterine smoking exposure and the risk of subsequent preeclampsia, however, results were not significant over all manifestations of preeclampsia and confounder adjustment. The increased risk might be mediated through exposed women’s own BMI or birthweight.
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    Preeclampsia
    (Elsevier BV, 2010) Lee, Soo Bong; Wong, Amy P.; Kanasaki, Keizo; Xu, Yong; Shenoy, Vivek K.; McElrath, Thomas; Whitesides, George; Kalluri, Raghu
    Inadequate invasion of the uterus by cytotrophoblasts is speculated to result in pregnancy-induced disorders such as preeclampsia. However, the molecular mechanisms that govern appropriate invasion of cytotrophoblasts are unknown. Here, we demonstrate that under low-oxygen conditions (2.5% oxygen), 2-methoxyestradiol (2-ME), which is a metabolite of estradiol and is generated by catechol-o-methyltransferase (COMT), induces invasion of cytotrophoblasts into a naturally-derived, extracellular matrix. Neither low-oxygen conditions nor 2-ME alone induces the invasion of cytotrophoblasts in this system; however, low-oxygen conditions combined with 2-ME result in the appropriate invasion of cytotrophoblasts into the extracellular matrix. Cytotrophoblast invasion under these conditions is also associated with a decrease in the expression of hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β3 (TGF-β3), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Pregnant COMT-deficient mice with hypoxic placentas and preeclampsia-like features demonstrate an up-regulation of HIF-1α, TGF-β3, and TIMP-2 when compared with wild-type mice; normal levels are restored on administration of 2-ME, which also results in the resolution of preeclampsia-like features in these mice. Indeed, placentas from patients with preeclampsia reveal lower levels of COMT and higher levels of HIF-1α, TGF-β3, and TIMP-2 when compared with those from normal pregnant women. We demonstrate that low-oxygen conditions of the placenta are a critical co-stimulator along with 2-ME for the proper invasion of cytotrophoblasts to facilitate appropriate vascular development and oxygenation during pregnancy.
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    Statistical methods for modeling repeated measures of maternal environmental exposure biomarkers during pregnancy in association with preterm birth
    (BioMed Central, 2015) Chen, Yin-Hsiu; Ferguson, Kelly K; Meeker, John D; McElrath, Thomas; Mukherjee, Bhramar
    Background: It is of critical importance to evaluate the role of environmental chemical exposures in premature birth. While a number of studies investigate this relationship, most utilize single exposure measurements during pregnancy in association with the outcome. The studies with repeated measures of exposure during pregnancy employ primarily cross-sectional analyses that may not be fully leveraging the power and additional information that the data provide. Methods: We examine 9 statistical methods that may be utilized to estimate the relationship between a longitudinal exposure and a binary, non-time-varying outcome. To exemplify these methods we utilized data from a nested case–control study examining repeated measures of urinary phthalate metabolites during pregnancy in association with preterm birth. Results: The methods summarized may be useful for: 1) Examining sensitive windows of exposure in association with an outcome; 2) Summarizing repeated measures to estimate the relationship between average exposure and an outcome; 3) Identifying acute exposures that may be relevant to the outcome; and 4) Understanding the contribution of temporal patterns in exposure levels to the outcome of interest. In the study of phthalates, changes in urinary metabolites over pregnancy did not appear to contribute significantly to preterm birth, making summary of average exposure across gestation optimal given the current design. Conclusions: The methods exemplified may be of great use in future epidemiologic research projects intended to: 1) Elucidate the complex relationships between environmental chemical exposures and preterm birth; 2) Investigate biological mechanisms in prematurity using repeated measures of maternal factors throughout pregnancy; and 3) More generally, address the relationship between a longitudinal predictor and a binary, non-time-varying outcome. Electronic supplementary material The online version of this article (doi:10.1186/1476-069X-14-9) contains supplementary material, which is available to authorized users.
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    Vitamin D status among preterm and full-term infants at birth
    (Nature Publishing Group, 2013) Burris, Heather H.; Van Marter, Linda; McElrath, Thomas; Tabatabai, Patrik; Litonjua, Augusto A.; Weiss, Scott; Christou, Helen
    Background: Risk factors for maternal vitamin D deficiency and preterm birth overlap but the distribution of 25-hydroxyvitamin D (25(OH)D) levels among preterm infants is not known. We aimed to determine associations between 25(OH)D levels and gestational age. Methods: We measured umbilical cord plasma levels of 25(OH)D from 471 infants born at Brigham and Women’s Hospital in Boston. We used generalized estimating equations to determine whether preterm (<37 weeks’ gestation) or very preterm (<32 weeks’ gestation) infants had greater odds of 25(OH)D levels < 20 ng/ml than more mature infants. We adjusted for potential confounding by season of birth, maternal age, race, marital status and singleton or multiple gestation. Results: Mean cord plasma 25(OH)D level was 34.0 ng/ml (range 4.1 to 95.3, and SD 14.1). Infants born before 32 weeks’ gestation had increased odds of 25(OH)D levels < 20 ng/ml in unadjusted (OR 2.2, 95% CI 1.1, 4.3) and adjusted models (OR 2.4, 95% CI 1.2, 5.3) compared to more mature infants. Conclusion: Infants born < 32 weeks’ gestation are at higher risk than more mature infants for low 25(OH)D levels. Further investigation of the relationships between low 25(OH)D levels and preterm birth and its sequelae is thus warranted.
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    First-Trimester Urine Concentrations of Phthalate Metabolites and Phenols and Placenta miRNA Expression in a Cohort of U.S. Women
    (National Institute of Environmental Health Sciences, 2015) LaRocca, Jessica; Binder, Alexandra; McElrath, Thomas; Michels, Karin
    Background: There is increasing concern that early-life exposure to endocrine-disrupting chemicals (EDCs) can influence the risk of disease development. Phthalates and phenols are two classes of suspected EDCs that are used in a variety of everyday consumer products, including plastics, epoxy resins, and cosmetics. In utero exposure to EDCs may affect disease propensity through epigenetic mechanisms. Objective: The objective of this study was to determine whether prenatal exposure to multiple EDCs is associated with changes in miRNA expression of human placenta, and whether miRNA alterations are associated with birth outcomes. Methods: Our study was restricted to a total of 179 women co-enrolled in the Harvard Epigenetic Birth Cohort and the Predictors of Preeclampsia Study. We analyzed associations between first-trimester urine concentrations of 8 phenols and 11 phthalate metabolites and expression of 29 candidate miRNAs in placenta by qRT-PCR. Results: For three miRNAs—miR-142-3p, miR15a-5p, and miR-185—we detected associations between Σphthalates or Σphenols on expression levels (p < 0.05). By assessing gene ontology enrichment, we determined the potential mRNA targets of these microRNAs predicted in silico were associated with several biological pathways, including the regulation of protein serine/threonine kinase activity. Four gene ontology biological processes were enriched among genes significantly correlated with the expression of miRNAs associated with EDC burden. Conclusions: Overall, these results suggest that prenatal phenol and phthalate exposure is associated with altered miRNA expression in placenta, suggesting a potential mechanism of EDC toxicity in humans. Citation LaRocca J, Binder AM, McElrath TF, Michels KB. 2016. First-trimester urine concentrations of phthalate metabolites and phenols and placenta miRNA expression in a cohort of U.S. women. Environ Health Perspect 124:380–387; http://dx.doi.org/10.1289/ehp.1408409
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    Urinary Concentrations of Bisphenol A and Phthalate Metabolites Measured during Pregnancy and Risk of Preeclampsia
    (National Institute of Environmental Health Sciences, 2016) Cantonwine, David; Meeker, John D.; Ferguson, Kelly K.; Mukherjee, Bhramar; Hauser, Russ; McElrath, Thomas
    Background: Preeclampsia represents a major cause of maternal mortality and morbidity worldwide. Although it is known that the placenta plays a central role in development of preeclampsia, investigation into the contribution of environmental toxicants to the risk of preeclampsia has been sparse. Objectives: In the present study we examined the relationship between longitudinally measured urinary BPA and phthalate metabolite concentrations during gestation and preeclampsia. Methods: A nested case–control study of preterm birth was performed in 2011 from women enrolled in a prospective birth cohort study at Brigham and Women’s Hospital in Boston. There were 50 cases of preeclampsia as part of this study. Urine samples were analyzed for concentrations of BPA and nine phthalate metabolites several times during pregnancy. Adjusted Cox proportional hazard models were used to calculate hazard ratios of preeclampsia in association with an interquartile range increase in BPA and phthalate concentrations and were weighted to reflect results generalizable to the base population. Results: Adjusted hazard ratios indicated that an interquartile range increase of urinary concentrations of BPA (1.53; 95% CI: 1.04, 2.25) and MEP (monoethyl phthalate) (1.72; 95% CI: 1.28, 2.30) at 10 weeks gestation was associated with onset of preeclampsia, whereas significantly elevated hazard ratios were found across gestation for all DEHP [di(2-ethylhexyl) phthalate] metabolites. These relationships differed based on infant sex. Conclusions: Urinary concentrations of BPA and several phthalate metabolites were significantly associated with increased risk of preeclampsia. If validated, these results indicate an environmental contribution of endocrine-disrupting chemicals to preeclampsia and suggest a modifiable means to reduce the mortality and morbidity associated with this condition. Citation: Cantonwine DE, Meeker JD, Ferguson KK, Mukherjee B, Hauser R, McElrath TF. 2016. Urinary concentrations of bisphenol A and phthalate metabolites measured during pregnancy and risk of preeclampsia. Environ Health Perspect 124:1651–1655; http://dx.doi.org/10.1289/EHP188
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    Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors
    (Elsevier BV, 2016) James-Todd, Tamarra; Meeker, John D.; Huang, Tianyi; Hauser, Russ; Ferguson, Kelly K.; Rich-Edwards, Janet; McElrath, Thomas; Seely, Ellen
    Background: Epidemiologic studies suggest phthalate metabolite concentrations are associated with type 2 diabetes. GDM is a strong risk factor for type 2 diabetes. Little is known about phthalates and GDM risk factors (i.e. 1st trimester body mass index (BMI), gestational weight gain (GWG), and 2nd trimester glucose levels). Methods: A total of 350 women participating in Lifecodes pregnancy cohort (Boston, MA), delivered at term and had pregnancy urinary phthalate metabolite concentrations. Nine specific gravity-adjusted urinary phthalate metabolites were evaluated. General linear regression was used to assess associations between quartiles of phthalate metabolites and continuous 1st trimester BMI and late 2nd trimester blood glucose. Linear mixed models were used for total GWG. Multivariable logistic regression was used for phthalate concentrations and categorized GWG and impaired glucose tolerance defined as glucose≥140 mg/dL based on a 50-gram glucose load test. Models were adjusted for potential confounders. Results: There were no associations between 1st trimester urinary phthalate metabolite concentrations and 1st trimester BMI. Mono-ethyl phthalate concentrations averaged across pregnancy were associated with a 2.17 increased odds of excessive GWG (95% CI: 0.98, 4.79). Second trimester mono-ethyl phthalate was associated with increased odds of impaired glucose tolerance (adj. OR: 7.18; 95% CI: 1.97, 26.15). A summary measure of di-2- ethylhexyl phthalate metabolite concentrations were inversely associated with impaired glucose tolerance (adj. OR: 0.25; adj. 95% CI: 0.08, 0.85). Conclusions: Higher exposure to mono-ethyl phthalate, a metabolite of the parent compound of di-ethyl phthalate, may be associated with excessive GWG and impaired glucose tolerance; higher di-2 ethylhexyl phthalate was associated with reduced odds of impaired glucose tolerance.
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    Urinary Phthalate Metabolites and Biomarkers of Oxidative Stress in Pregnant Women: A Repeated Measures Analysis
    (NLM-Export, 2014) Ferguson, Kelly K.; McElrath, Thomas; Chen, Yin-Hsiu; Mukherjee, Bhramar; Meeker, John D.
    Background: Phthalate exposure occurs readily in the environment and has been associated with an array of health end points, including adverse birth outcomes. Some of these may be mediated by oxidative stress, a proposed mechanism for phthalate action. Objectives: In the present study, we explored the associations between phthalate metabolites and biomarkers of oxidative stress measured in urine samples from multiple time points during pregnancy. Methods: Women were participants in a nested case–control study of preterm birth (n = 130 cases, n = 352 controls). Each was recruited early in pregnancy and followed until delivery, providing urine samples at up to four visits. Nine phthalate metabolites were measured to assess exposure, and 8-hydroxydeoxyguanosine and 8-isoprostane were also measured in urine as markers of oxidative stress. Associations were assessed using linear mixed models to account for intraindividual correlation, with inverse selection probability weightings based on case status to allow for greater generalizability. Results: Interquartile range increases in phthalate metabolites were associated with significantly higher concentrations of both biomarkers. Estimated differences were greater in association with monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), and monoisobutyl phthalate (MiBP), compared with di(2-ethylhexyl) phthalate (DEHP) metabolites. Conclusions: Urinary phthalate metabolites were associated with increased oxidative stress biomarkers in our study population of pregnant women. These relationships may be particularly relevant to the study of birth outcomes linked to phthalate exposure. Although replication is necessary in other populations, these results may also be of great importance for a range of other health outcomes associated with phthalates. Citation Ferguson KK, McElrath TF, Chen YH, Mukherjee B, Meeker JD. 2015. Urinary phthalate metabolites and biomarkers of oxidative stress in pregnant women: a repeated measures analysis. Environ Health Perspect 123:210–216; http://dx.doi.org/10.1289/ehp.1307996
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    Prenatal Vitamin Use and Vitamin D Status during Pregnancy, Differences by Race and Overweight Status
    (2014) Burris, Heather H.; Thomas, Ann; Zera, Chloe; McElrath, Thomas
    Objective: We aimed to study whether prenatal vitamin (PNV) use protects against low 25(OH)D levels in all women and particularly in obese and black women who are both at risk of vitamin D deficiency and poor pregnancy outcomes. Study design We studied 1019 women enrolled in a prospective study at Brigham and Women’s Hospital in Boston, 2007–2009. We used multivariable logistic regression to analyze associations of PNV use and odds of vitamin D deficiency defined as 25(OH)D levels < 50 nmol/L. Results: 56% of black and 86% of white women reported pre- and/or post-conceptional PNV use. 75% of black and 19% of white women were vitamin D deficient in the first trimester. PNV use among black women was not associated with vitamin D deficiency (adjusted OR 1.0, 95%CI 0.4, 2.3) but was among white women (3.5, 95%CI 2.1, 5.8)(Interaction P<0.01). Conclusions: Ongoing trials of vitamin D supplementation during pregnancy should consider potential effect modification by race/ethnicity.