Faculty Bibliography

INTRODUCTION: Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. PURPOSE: To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). METHODS: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. RESULTS: The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618 000 additional assisted reproductive technology procedures, costing euro4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of euro130 million (sensitivity analysis, euro117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of euro848 million annually (sensitivity analysis, euro313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of euro7.96 billion. CONCLUSIONS: EDCs may contribute substantially to male reproductive disorders and diseases, with nearly euro15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

CONTEXT: Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. OBJECTIVE: The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. DESIGN: An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. RESULTS: The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555-5463) in 2010 with associated costs of euro24.6 million (sensitivity analysis: euro24.6-86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of euro835 million (sensitivity analysis: euro835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and euro15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with euro607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of euro1.54 billion. CONCLUSIONS: EDC exposures in the EU contribute substantially to obesity and diabetes, with a moderate probability of >euro18 billion costs per year. This is a conservative estimate; the results emphasize the need to control EDC exposures.

OBJECTIVE: Maternal prepregnancy obesity is associated with several poor infant health outcomes; however, studies that investigated motor development have been inconsistent. Thus, maternal prepregnancy weight status and infants' gross motor development were examined. METHODS: Participants consisted of 4,901 mother-infant pairs from the Upstate KIDS study, a longitudinal cohort in New York. Mothers indicated dates when infants achieved each of six gross motor milestones when infants were 4, 8, 12, 18, and 24 months old. Failure time modeling under a Weibull distribution was utilized to compare time to achievement across three levels of maternal prepregnancy BMI. Hazard ratios (HR) below one indicate a lower "risk" of achieving the milestone and translate to later achievement. RESULTS: Compared to infants born to thin and normal-weight mothers (BMI < 25), infants born to mothers with obesity (BMI > 30) were slower to sit without support (HR = 0.91, P = 0.03) and crawl on hands and knees (HR = 0.86, P < 0.001), after adjusting for maternal and birth characteristics. Increased gestational age was associated with faster achievement of all milestones, but additional adjustment did not impact results. CONCLUSIONS: Maternal prepregnancy obesity was associated with a slightly longer time for infant to sit and crawl, potentially due to a compromised intrauterine environment or reduced physically active play.

BACKGROUND:Cesarean delivery may reduce placental-fetal transfusion and thus increase the risk of early childhood anemia compared with vaginal delivery, but this notion has not been carefully studied in longitudinal cohorts. OBJECTIVE:The aim was to assess the association of cesarean delivery with anemia in infants and children in 2 longitudinal Chinese birth cohorts from different socioeconomic settings. DESIGN/METHODS:Cohort 1 was recruited from 5 counties in northeastern China and cohort 2 from 21 counties or cities in southeastern China. Cohort 1 involved 17,423 infants born during 2006-2009 to mothers with early pregnancy baseline hemoglobin concentrations ranging from 100 to 177 g/L, whereas cohort 2 involved 122,777 children born during 1993-1996 to mothers with baseline hemoglobin concentrations ranging from 60 to 190 g/L. The main outcomes were anemia at 6 and 12 mo in cohort 1 and at 58 mo in cohort 2. Multiple logistic regressions were used to estimate adjusted ORs of anemia for cesarean compared with vaginal delivery. Stratified analyses were performed by pre- and postlabor cesarean delivery and according to maternal baseline hemoglobin concentration (≤109, 110-119, 120-129, and ≥130 g/L). RESULTS:Cesarean delivery was not associated with anemia at 6 mo in cohort 1 (adjusted OR: 1.05; 95% CI: 0.93, 1.19); however, cesarean delivery was associated with increased anemia at 12 mo in cohort 1 (adjusted OR: 1.19; 95% CI: 1.04, 1.37) and at 58 mo in cohort 2 (adjusted OR: 1.11; 95% CI: 1.08, 1.15). The positive associations for anemia at 12 and 58 mo were consistent across maternal hemoglobin subgroups and persisted for cesarean delivery subtypes. CONCLUSION/CONCLUSIONS:Cesarean delivery is likely associated with anemia in children, which suggests a possible need for exploring changes in obstetric care that might prevent anemia in cesarean-delivered children.

During early childhood, girls outperform boys on key dimensions of cognitive functions, including inhibitory control, sustained attention, and working memory. The role of parenting in these sex differences is unknown despite evidence that boys are more sensitive to the effects of the early environment. In this study, we measured parental sensitivity at 14 and 36 months of age, and children's cognitive and executive functions (sustained attention, inhibitory control, and forward/backward memory) at 52 months of age, in a longitudinal cohort (N=752). Boys scored significantly lower than girls on inhibitory control (more Go/NoGo "commission errors") and short-term memory (forward color recall task), but boys did not differ from girls on attention (Go/NoGo "omission errors") or working memory (backward color recall task). In stratified analyses, parental sensitivity at 36 months of age was negatively associated with number of errors of commission (p=.05) and omission (p=.02) in boys, whereas child's age was the only significant predictor of commission and omission errors in girls. A combined analysis of both sexes confirmed an interaction between sex and parenting for omission errors (p=.03). The results indicate that sex differences in cognitive functions are evident in preschoolers, although not across all dimensions we assessed. Boys appear to be more vulnerable to early parenting effects, but only in association with omission errors (attention) and not with the other cognitive function dimensions.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAH) are produced by the burning and processing of fuel oils, and have been associated with oxidant stress, insulin resistance and hypertension in adults. Few studies have examined whether adolescents are susceptible to cardiovascular effects of PAHs. OBJECTIVE: To study associations of PAH exposure with blood pressure (BP) and brachial artery distensibility (BAD), an early marker of arterial wall stiffness, in young boys attending three schools in Jeddah, Saudi Arabia in varying proximity to an oil refinery. METHODS: Air samples collected from the three schools were analyzed for PAHs. PAH metabolites (total hydroxyphenanthrenes and 1-hydroxypyrene) were measured in urine samples from 184 adolescent males, in whom anthropometrics, heart rate, pulse pressure, brachial artery distensibility and blood pressure were measured. Descriptive, bivariate and multivariable analyses were performed to assess relationships of school location and urinary PAH metabolites with cardiovascular measures. RESULTS: Total suspended matter was significantly higher (444+/-143mug/m(3)) at the school near the refinery compared to a school located near a ring road (395+/-65mug/m(3)) and a school located away from vehicle traffic (232+/-137mug/m(3)), as were PAHs. Systolic (0.47 SD units, p=0.006) and diastolic (0.53 SD units, p<0.001) BP Z-scores were highest at the school near the refinery, with a 4.36-fold increase in prehypertension (p=0.001), controlling for confounders. No differences in pulse pressure, BAD and heart rate were noted in relationship to school location. Urinary total hydroxyphenanthrenes and 1-hydroxypyrene were not associated with cardiovascular outcomes. CONCLUSIONS: Proximity to an oil refinery in Saudi Arabia is associated with prehypertension and increases in PAH and particulate matter exposures. Further study including insulin resistance measurements, better control for confounding, and longitudinal measurement is indicated.

BACKGROUND: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. METHODS: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 mum (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. RESULTS: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 mug/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. CONCLUSIONS: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.

Temperament and psychopathology are intimately related; however, research on the prospective associations between positive emotionality, defined as a child's positive mood states and high engagement with the environment, and psychopathology is inconclusive. We examined the longitudinal relation between positive emotionality and internalizing problems in young children from the general population. Furthermore, we explored whether executive functioning mediates any observed association. Within a population-based Dutch birth cohort, we observed positive emotionality in 802 children using the laboratory temperament assessment battery at age 3 years. Child behavior checklist (CBCL) internalizing problems (consisting of Emotionally Reactive, Anxious/Depressed, and Withdrawn scales) were assessed at age 6 years. Parents rated their children's executive functioning at ages 4 years. Children with a lower positive emotionality at age 3 had a higher risk of withdrawn problems at age 6 years (OR = 1.20 per SD decrease in positive emotionality score, 95 % CI: 1.01, 1.42). This effect was not explained by preexisting internalizing problems. This association was partly mediated by more problems in the shifting domain of executive functioning (p < 0.001). We did not find any relation between positive emotionality and the CBCL emotionally reactive or anxious/depressed scales. Although the effect sizes were moderate, our results suggest that low levels of positive emotionality at preschool age can result in children's inflexibility and rigidity later in life. The inflexibility and rigidity are likely to affect the child's drive to engage with the environment, and thereby lead to withdrawn problems. Further research is needed to replicate these findings.