Faculty Bibliography

Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3-4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.

Substantial effort has been devoted to explaining secular trends in childhood obesity and metabolic risks to unhealthy diet and physical activity. While some studies have suggested these factors may play a role in the obesity epidemic, even these studies have only been able to conclude that these factors have a moderate role. Given that a single-generation transformation in the human genome is even more unlikely to have transformed susceptibility to excess weight gain in early life, we are left with the reality that environmental influences represent important risks for obesity and dysmetabolism. In contrast to diet and physical activity, which can require intensive attention, effort and costs to modify through behavioral and other interventions, government action can fundamentally transform the environment and prevent disease and disability. The costs of regulations to limit environmental obesogens can also be much lower than the benefits to society.

Background: suPAR is an inflammatory mediator that has been linked to the pathogenesis of FSGS and progression of chronic kidney disease in children and adults. Overexpression of suPAR leads to reduced nephron development in preclinical models. This study was designed to measure suPAR in pregnant women to determine the range of fetal exposure to this molecule and its potential influence on antenatal human kidney growth.
Method(s): Pregnant women enrolled in the Children's Health and Environment Study (CHES) provided serum samples obtaining during 1-3 trimesters. Clinical information was obtained from the electronic health record. suPAR levels were determined by ELISA (Virogates, Copenhagen, Denmark). Data are presented as mean+/-SD. Results were analyzed by Pearson correlation and ANOVA.
Result(s): 515 mothers were studied, age 31+/-6 yr, and racial distribution 44% Caucasian, 7% African American, 9 % Asian, and 41% other/unspecified. 46% of the women were Hispanic. 29% had completed a high school education or less and 28% had an annual income <$50,000. There were 464 livebirths, 50.4% girls. The serum suPAR levels (mean, SD, minimum, maximum) are summarized in the Table. The suPAR levels in the subgroup of women who provided more than one sample during pregnancy were closely correlated (r=0.79-0.94, P<0.0001)). The decline in serum suPAR levels from trimester 1 to 3 was highly significant (P<0.001).
Conclusion(s): Maternal suPAR levels are detectable throughout pregnancy but decline from trimester 1 to 3. The levels are highly correlated and steady during the course of pregnancy in an individual woman. There is more than a 10-fold range in suPAR concentration which may contribute to the biological variation in nephron number at birth. Follow-up assessment in the infants will be performed in the prospective Environmental Influences on Child Health Outcomes (ECHO) cohort study. (Table Presented)

Background: Environmental chemical exposures are linked to oxidative stress and kidney injury in children and adults. This applies to short-lived organic compounds such as bisphenol A and phthalates and persistent synthetic chemicals such as perfluoroalkyl acids (PFAAs). Most investigations to date have been conducted in developed countries with few data about environmental chemical exposures in children living in Africa.
Method(s): Clinical and laboratory data about pediatric patients enrolled in the H3 Africa observational cohort study including age, gender, BMI, serum creatinine, eGFR, proteinuria were collected. Serum samples that had been collected at enrollment were retrieved from the Biorepository and analyzed for PFAAs and polybrominated diphenyl ethers (PBDEs) and DDE presticides using established methods. Proteinuria was assessed in a first morning urine sample. Results are presented as mean+/-SD.
Result(s): 86 patients with CKD (41 M:45 F), age 12.6+/-2.6 yr old, were included in this nested case control study. The eGFR was 75+/-4 and the albumin:creatinine ratio was 65+/-186. The chemical exposures are summarized in the Table. There was no association between exposure (log of serum concentration) to PFAAs and proteinuria. However, controlling for age, gender, and BMI, there was an inverse relationship between eGFR and exposure to PFNA, -21.2 [95% CI:-41.6 -0.8] and PFDA -18.3 [95% CI:-35.3 --1.3] ml/min/log unit increase in exposure and a trend towards a similar effect for PFOS. PBDE/DDEs were detected in a small fraction of children and because of small sample size associations with effect markers were not made
Conclusion(s): PFAA exposure is substantially lower in H3 Africa participants than in healthy US children, age 12-19 enrolled in NHANES 2003-2010. However, even at these lower levels of exposure there was an adverse association between select PFAAs and GFR. These studies indicate the feasibility of measuring environmental chemical exposure in developing countries. The impact of these chemical exposures on kidney function will require larger cohorts of children followed for more extended periods of time

BACKGROUND:Walkable neighborhoods are purported to impact a range of cardiometabolic outcomes through increased walking, but there is limited research that examines multiple cardiometabolic outcomes. Additionally, few Walk Score (a novel measure of neighborhood walkability) studies have been conducted in a European context. We evaluated associations between neighborhood Walk Score and selected cardiometabolic outcomes, including obesity, hypertension and heart rate, among adults in the Paris metropolitan area. METHODS AND RESULTS/RESULTS:We used data from the second wave of the RECORD Study on 5993 participants recruited in 2011-2014, aged 34-84 years, and residing in Paris (France). To this existing dataset, we added Walk Score values for participants' residential address. We used multilevel linear models for the continuous outcomes and modified Poisson models were used for our categorical outcomes to estimate associations between the neighborhood Walk Score (both as a continuous and categorical variable) (0-100 score) and body mass index (BMI) (weight/height2 in kg/m2), obesity (kg/m2), waist circumference (cm), systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), hypertension (mmHg), resting heart rate (RHR) (beats per minute), and neighborhood recreational walking (minutes per week). Most participants lived in Walker's Paradise (48.3%). In multivariate models (adjusted for individual variables, neighborhood variables, and risk factors for cardiometabolic outcomes), we found that neighborhood Walk Score was associated with decreased BMI (β: -0.010, 95% CI: -0.019 to -0.002 per unit increase), decreased waist circumference (β: -0.031, 95% CI: -0.054 to -0.008), increased neighborhood recreational walking (β: +0.73, 95% CI: +0.37 to +1.10), decreased SBP (β: -0.030, 95% CI: -0.063 to -0.0004), decreased DBP (β: -0.028, 95% CI: -0.047 to -0.008), and decreased resting heart rate (β: -0.026 95% CI: -0.046 to -0.005). CONCLUSIONS:In this large population-based study, we found that, even in a European context, living in a highly walkable neighborhood was associated with improved cardiometabolic health. Designing walkable neighborhoods may be a viable strategy in reducing cardiovascular disease prevalence at the population level.

BACKGROUND: Large amounts of various chemical contaminants, including perfluoroalkyl substances (PFASs), were released at the time of the World Trade Center (WTC) disaster. Thousands of children who lived and/or attended school near the disaster site were exposed to these substances but few studies have examined the possible consequences related to these exposures. OBJECTIVES: To examine the relationship of PFASs serum levels with cardiometabolic profile in children and adolescents enrolled in the World Trade Center Health Registry (WTCHR) and a matched comparison group. METHODS: We evaluated WTCHR enrollees who resided in New York City and were born between September 11, 1993 and September 10, 2001, and a matched comparison group consisting of individuals who were ineligible for WTCHR participation upon distance of their home, school or work from the WTC and lack of participation in rescue and recovery activities. Matching was based on date of birth, sex, race, ethnicity, and income. We assessed exposure to PFASs, as measured by serum levels and association with cardiometabolic profile as measured by arterial wall stiffness, body mass index, insulin resistance, fasting total cholesterol, HDL, LDL and triglycerides. RESULTS: A total of 402 participants completed the study and serum samples were analyzed from 308 participants, 123 in the WTCHR group and 185 in the comparison group. In multivariable regression analysis, after adjusting for relevant confounders, we observed a significant, positive association of perfluorooctanoic acid (PFOA) with triglycerides (beta coefficient=0.14, 95% CI: 0.02, 0.27, 15.1% change), total cholesterol (beta coefficient=0.09, 95% CI: 0.04, 0.14, 9.2% change), and LDL cholesterol (beta coefficient=0.11, 95% CI: 0.03, 0.19, 11.5% change). Perfluorohexanesulfonic acid levels were associated with decreased insulin resistance (beta coefficient=-0.09, 95% CI: -0.18, -0.003, -8.6% change); PFOA and perfluorononanoic acid were associated with increased brachial artery distensibility. CONCLUSIONS: This research adds to our knowledge of the physical health impacts in a large group of children exposed to the WTC disaster. Abnormal lipid levels in young adults might be an early marker of atherosclerosis and cardiovascular diseases and our findings highlight the importance of conducting longitudinal studies in this population.

Strong evidence now supports the notion that organophosphate pesticides damage the fetal brain and produce cognitive and behavioral dysfunction through multiple mechanisms, including thyroid disruption. A regulatory ban was proposed, but actions to end the use of one such pesticide, chlorpyrifos, in agriculture were recently stopped by the Environmental Protection Agency under false scientific pretenses. This manuscript describes the costs and consequences of this policy failure and notes how this case study is emblematic of a broader dismissal of scientific evidence and attacks on scientific norms. Scientists have a responsibility to rebut and decry these serious challenges to human health and scientific integrity.

Adequate docosahexaenoic acid (DHA) is essential for the optimal growth and development of the fetus. Maternal DHA content fluctuates during pregnancy. The correlation of DHA content with dietary intake might be varied over the course of pregnancy. We aimed to compare the dietary DHA intake, estimated by a DHA-specific semiquantitative food frequency questionnaire (FFQ) against its blood content, among mid- and late-term pregnant women. A total of 804 Chinese pregnant women completed the tailored FFQ and provided fasting venous blood samples. Dietary DHA intake (mg/day) in the previous month was calculated from the FFQ using Chinese Food Composition Table. DHA concentrations (weight percent of total fatty acids) in plasma and erythrocytes were measured by capillary gas chromatography. Spearman correlation coefficients (r_s) between DHA intake and its relative concentrations were calculated. After adjustment for maternal age, pre-pregnancy body mass index, stage of pregnancy, parity, education level, ethnicity, and annual family income per capita, the correlation coefficients of DHA intake with its concentrations in plasma and erythrocytes were 0.35 and 0.33, respectively (p < 0.001). The correlations were relatively stronger among women in late pregnancy (r_s = 0.44 in plasma and 0.39 in erythrocytes) than those in mid-pregnancy (r_s = 0.25 and 0.26). The significant correlations were consistently observed in subgroups stratified by regions, except for erythrocytes in women living in a coastland area. Multiple regression analyses also indicated significant positive linear correlations between DHA intake and its plasma or erythrocytes concentrations (p < 0.001). In conclusion, dietary DHA intake, estimated by the FFQ, was positively correlated with its concentrations in plasma and erythrocytes in Chinese pregnant women, especially for women in late pregnancy, with the exception of the erythrocytes of those living in a coastland area.

BACKGROUND: Early-life exposure to bisphenol A (BPA) has been implicated to play a role in the development of obesity. OBJECTIVE: A systematic review with meta-analyses of experimental rodent studies was conducted to answer the following question: does early-life exposure to BPA affect the obesity-related outcomes body weight, fat (pad) weight, and circulating and tissue levels of triglycerides, free fatty acids (FFA), and leptin? METHODS: The methodology was prespecified in a rigorous protocol using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) approach. Using PubMed and EMBASE, we identified 61 articles that met the inclusion criteria. The risk of bias and the methodological quality of these articles were assessed using the SYRCLE Risk of Bias tool, and a confidence-rating methodology was used to score the quality of evidence. Meta-analyses were performed using random effect models and standardized mean differences (SMDs), or, where possible, mean differences (MDs) were calculated. RESULTS: Overall summary estimates indicated significant positive associations between BPA and fat weight [SMD=0.67 (95% CI: 0.53, 0.81)], triglycerides [SMD=0.97 (95% CI: 0.53, 1.40)], and FFA [SMD=0.86 (95% CI: 0.50, 1.22)], and a nonsignificant positive association with leptin levels [MD=0.37 (95% CI: -0.14, 0.87)] and a significant negative association with body weight were estimated [MD=-0.22 (95% CI: -0.37, -0.06)]. Subgroup analyses revealed stronger positive associations for most outcome measures in males and at doses below the current U.S. reference dose of 50mug/kg/d compared with doses above the reference dose. It should be noted that there was substantial heterogeneity across studies for all outcomes assessed and that there was insufficient information to assess risk of bias for most studies. CONCLUSIONS: Findings from our systematic review suggest that early-life exposure to BPA may increase adiposity and circulating lipid levels in rodents. https://doi.org/10.1289/EHP1233.