Faculty Bibliography

OBJECTIVE: Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal hypothyroxinemia (gestational weeks 6-18) and autistic symptoms in children. METHODS: The mother-and-child cohort of the Generation R Study (Rotterdam, the Netherlands) began prenatal enrollment between 2002 and 2006. At a mean gestational age of 13.4 weeks (standard deviation=1.9, range=5.9-17.9), maternal thyroid function tests (serum thyrotropin [TSH], free thyroxine [fT4], and thyroid peroxidase [TPO] antibodies) were assessed in 5,100 women. We defined severe maternal hypothyroxinemia as fT4<5th percentile with normal TSH. Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS). We defined a probable autistic child by a PDP score>98th percentile and SRS score in the top 5% of the sample (n=81, 2.0%). RESULTS: Severe maternal hypothyroxinemia (n=136) was associated with an almost 4-fold increase in the odds of having a probable autistic child (adjusted odds ratio=3.89, 95% confidence interval [CI]=1.83-8.20, p<0.001). Using PDP scores, children of mothers with severe hypothyroxinemia had higher scores of autistic symptoms by age 6 years (adjusted B=0.23, 95% CI=0.03-0.37); SRS results were similar. No risk was found for children of TPO-antibody-positive mothers (n=308). INTERPRETATION: We found a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring. Findings are concordant with epidemiological, biological, and experimental data on autism. Although these findings cannot establish causality, they open the possibility of preventive interventions.

Exposure to maternal hypothyroxinemia during pregnancy, which is characterized by low free T4 but normal thyroid-stimulating hormone (TSH) levels, can negatively affect the foetus. This review provides an overview of present findings concerning the association between maternal hypothyroxinemia during pregnancy and childhood cognitive functioning. Possible causes of maternal hypothyroxinemia and potential mechanisms underlying this association are also discussed. Clinical and epidemiological studies suggest that maternal hypothyroxinemia in the first half of pregnancy but not later in pregnancy impairs cognitive development in infancy and childhood. Animal models confirm that the first half of pregnancy may constitute a sensitive period in which maternal hypothyroxinemia alters neurogenesis and causes neuronal migration errors in the developing foetal brain. However, observational studies in humans cannot demonstrate causality of the association between hypothyroxinemia and neurodevelopment. In the only completed randomized trial of antenatal thyroid screening and subsequent levothyroxine treatment of mild maternal subclinical thyroid dysfunction, including hypothyroxinemia, the interventions did not affect offspring intelligence quotient (IQ). More randomized trials are needed investigating whether screening for hypothyroxinemia and its treatment earlier in the first trimester of pregnancy can improve child cognitive functioning or prevent neurodevelopmental changes. Long-term observational studies should identify molecular, neuroanatomical and neurophysiological factors involved in the association between maternal hypothyroxinemia and offspring cognitive functioning. Information on such mechanisms can be used for the development of innovative prevention and intervention studies that address maternal hypothyroxinemia and its potential consequences.

It has been shown in adults that individual differences in intelligence are related to the integrity of the interaction between parietal and frontal brain regions. Since connectivity between distant brain regions strengthens during childhood, it is unclear when in the course of development this relationship emerges. Thus, the goal of this study was to determine whether parietal-frontal functional connectivity is associated with intelligence in young children. We performed independent component analyses on resting-state fMRI data of 115 children (6-8 years old) to select seed and target regions for a seed/target region correlation analysis. We found that higher nonverbal intelligence was associated with increased functional connectivity between right parietal and right frontal regions, and between right parietal and dorsal anterior cingulate regions. The association between intelligence and functional connectivity between certain brain regions was stronger in girls than boys. In conclusion, we found that connectivity between the parietal and frontal lobes is critically involved in intelligence in young children.

BACKGROUND: Neuroimaging findings have provided evidence for a relation between variations in brain structures and attention deficit/hyperactivity disorder (ADHD). However, longitudinal neuroimaging studies are typically confined to children who have already been diagnosed with ADHD. In a population-based study, we aimed to characterize the prospective association between brain structures measured during infancy and executive function and attention deficit/hyperactivity problems assessed at preschool age. METHODS: In the Generation R Study, the corpus callosum length, the gangliothalamic ovoid diameter (encompassing the basal ganglia and thalamus), and the ventricular volume were measured in 784 6-week-old children using cranial postnatal ultrasounds. Parents rated executive functioning at 4 years using the behavior rating inventory of executive function-preschool version in five dimensions: inhibition, shifting, emotional control, working memory, and planning/organizing. Attention deficit/hyperactivity problems were assessed at ages 3 and 5 years using the child behavior checklist. RESULTS: A smaller corpus callosum length during infancy was associated with greater deficits in executive functioning at 4 years. This was accounted for by higher problem scores on inhibition and emotional control. The corpus callosum length during infancy did not predict attention deficit/hyperactivity problem at 3 and 5 years, when controlling for the confounders. We did not find any relation between gangliothalamic ovoid diameter and executive function or Attention deficit/hyperactivity problem. CONCLUSIONS: Variations in brain structures detectible in infants predicted subtle impairments in inhibition and emotional control. However, in this population-based study, we could not demonstrate that early structural brain variations precede symptoms of ADHD.

Context: Bisphenol A (BPA) is an environmental endocrine disruptor that has been linked to many reproductive disorders in animal models and humans. One such disorder is polycystic ovary syndrome (PCOS), which has been correlated with increased BPA levels in adult women. However, little is known about the role of serum BPA in adolescents with PCOS and its correlation with the metabolic profile. Objectives: To measure BPA levels in adolescent with PCOS as compared to a body mass index (BMI)-matched control group. To correlate serum BPA levels with disease severity, as measured by biochemical and radiologic features. Design: A retrospective chart review of clinical, biochemical, and ultrasonographic data in adolescents with PCOS and controls. Serum BPA was measured and compared between groups and correlated with biochemical (testosterone, insulin resistance) and ovarian ultrasound findings. Setting: Urban tertiary academic medical center. Participants: Study groups included 15 overweight/obese adolescent females with PCOS (mean age 15.27 years, mean BMI 32.84) and 14 BMI-matched female controls (mean age 14.1 years, mean BMI 31). Results: Biochemical data showed a mean free testosterone of 7.06 pg/mL and mean LH:FSH ratio of 1.93 in the PCOS group as compared to mean testosterone of 4.51 pg/mL and mean LH:FSH ratio of 1.12 in the control group (P=0.08 and 0.012, respectively). The index of insulin resistance (HOMA-IR) was 1.65 in the PCOS group and 1.82 in the control group (P=0.75). Serum BPA levels were 0.624 +/-1.29 ng/mL in the PCOS group versus 0.28 +/-0.11 ng/mL in controls (P=0.325). No correlation was found between serum BPA levels and biochemical and radiologic markers of PCOS severity. Conclusions: The results of this exploratory study pose many interesting questions about BPA exposure in adolescents. Although the results are not statistically significant, both adult studies and animal models have shown a strong correlation between serum BPA and severity of PCOS. The weaker relationship in adolescents may be explained in part by shorter duration of exposure to BPA in years. Further studies are warranted to clarify the correlation of PCOS and the endocrine disruptor BPA in a larger setting

BACKGROUND: Di-2-ethylhexylphthalate (DEHP) is an ester of phthalic acid commonly found in processed foods. DEHP may contribute to obesity and insulin resistance in children and adolescents, yet dietary exposures have been not been studied in this vulnerable subpopulation. OBJECTIVE: To assess diet and its relation to urinary phthalates in a nationally representative sample of US children and adolescents. DESIGN: Cross-sectional analysis of 24-h dietary recall and urinary phthalate metabolites from 2743 6-19 year olds participating in the 2003-8 National Health and Nutrition Examination Surveys. Regression analyses examined relationships of food consumption with log-transformed metabolite concentrations, examined as low-molecular weight, high molecular weight and di-2-ethylhexylphthalate categories, controlling for urinary creatinine, age group, body mass index category, race/ethnicity, caloric intake and gender. RESULTS: We identified a -0.04% (95% CI: -0.08, -0.01) increment in di-2-ethylhexylphthalate metabolite concentration/additional gram fruit consumption, a +0.01% increment/additional calorie dietary intake (95% CI: +0.003, +0.02), and a +0.09% (95% CI: +0.02, +0.17) increment/additional gram meat/poultry/fish consumption. Soy consumption (-0.40% increment/additional gram consumed, 95% CI: -0.66, -0.14) was inversely associated with di-2-ethylhexylphthalate, while poultry (+0.23% increment/additional gram consumed, 95% CI: +0.12, +0.35) was positively associated. Findings were robust to examination of metabolite concentrations per unit body mass index and weight, and inclusion of fasting time. CONCLUSIONS: Diet contributes to urinary phthalate concentrations in children and adolescents. Further study is needed to examine the implications of di-2-ethylhexylphthalate exposure, especially earlier in life, when more permanent metabolic changes may occur.

Background: Children's blood lead levels have declined worldwide, especially after the removal of lead in gasoline. However, significant exposure remains, particularly in low- and middle-income countries. To date, there have been no global estimates of the costs related to lead exposure in children in developing countries.Objective: Our main aim was to estimate the economic costs attributable to childhood lead exposure in low- and middle-income countries.Methods: We developed a regression model to estimate mean blood lead levels in our population of interest, represented by each 1-year cohort of children < 5 years of age. We used an environmentally attributable fraction model to estimate lead-attributable economic costs and limited our analysis to the neurodevelopmental impacts of lead, assessed as decrements in IQ points. Our main outcome was lost lifetime economic productivity due to early childhood exposure.Results: We estimated a total cost of $977 billions of international dollars in low- and middle-income countries, with economic losses equal to $134.7 billion in Africa [4.03% of gross domestic product (GDP)], $142.3 billion in Latin America and the Caribbean (2.04% of GDP), and $699.9 billion in Asia (1.88% of GDP). Our sensitivity analysis indicates a total economic loss in the range of $728.6-1162.5 billion.Conclusions: We estimated that, in low- and middle-income countries, the burden associated with childhood lead exposure amounts to 1.20% of world GDP in 2011. For comparison, in the United States and Europe lead-attributable economic costs have been estimated at $50.9 and $55 billion, respectively, suggesting that the largest burden of lead exposure is now borne by low- and middle-income countries.Citation: Attina TM, Trasande L. 2013. Economic costs of childhood lead exposure in low- and middle-income countries. Environ Health Perspect 121:1097-1102; http://dx.doi.org/10.1289/ehp.1206424.

BACKGROUND Di-2-ethylhexylphthalate (DEHP) is an environmental chemical commonly found in processed foods. Phthalate exposures, in particular to DEHP, have been associated with insulin resistance in adults, but have not been studied in adolescents. METHODS: Using cross-sectional data from 766 fasting 12- to 19-year-olds in the 2003-2008 NHANES, we examined associations of phthalate metabolites with continuous and categorical measures of homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Controlling for demographic and behavioral factors, diet, continuous age, BMI category, and urinary creatinine, for each log (roughly threefold) increase in DEHP metabolites, a 0.27 increase (95% confidence interval 0.14-0.40; P < .001) in HOMA-IR was identified. Compared with the first tertile of DEHP metabolite in the study population (14.5% insulin resistant), the third tertile had 21.6% prevalence (95% confidence interval 17.2%-26.0%; P = .02). Associations persisted despite controlling for bisphenol A, another endocrine-disrupting chemical commonly found in foods, and HOMA-IR and insulin resistance were not significantly associated with metabolites of lower molecular weight phthalates commonly found in cosmetics and other personal care products. CONCLUSIONS: Urinary DEHP concentrations were associated with increased insulin resistance in this cross-sectional study of adolescents. This study cannot rule out the possibility that insulin-resistant children ingest food with higher phthalate content, or that insulin-resistant children excrete more DEHP.

OBJECTIVE: To examine associations of urinary phthalate levels with blood pressure (BP) and serum triglyceride and lipoprotein levels in children. STUDY DESIGN: We performed a cross-sectional analysis of a subsample of US children aged 6-19 years who participated in the National Health and Nutrition Examination Survey between 2003 and 2008. We quantified exposure to 3 families of phthalates-low molecular weight, high molecular weight and di-2-ethylhexylphthalate (DEHP)-based on molar concentration of urinary metabolites. We assessed descriptive, bivariate, and multivariate associations with BP and lipid levels. RESULTS: Controlling for an array of sociodemographic and behavioral factors, as well as diet and body mass index, levels of metabolites of DEHP, a phthalate commonly found in processed foods, were associated with higher age-, sex-, and height-standardized BP. For each log unit (roughly 3-fold) increase in DEHP metabolites, a 0.041 SD unit increase in systolic BP z-score was identified (P = .047). Metabolites of low molecular weight phthalates commonly found in cosmetics and personal care products were not associated with BP. Phthalate metabolites were not associated with triglyceride levels, high-density lipoprotein level, or prehypertension. CONCLUSIONS: Dietary phthalate exposure is associated with higher systolic BP in children and adolescents. Further work is needed to confirm these associations, as well as to evaluate opportunities for intervention.