Yeni Kim

Phthalates Exposure and Attention-Deficit/Hyperactivity Disorder in School-Age Children

BACKGROUND Very few studies have examined the association between attention-deficit/hyperactivity disorder (ADHD) and phthalate exposure in humans. The aim of this study was to investigate the impact of phthalates on symptoms of ADHD in school-age children. METHODS A cross-sectional examination of urine phthalate concentrations was performed, and scores on measures of ADHD symptoms and neuropsychological dysfunction with regard to attention and impulsivity were obtained from 261 Korean children, age 8-11 years. RESULTS Mono-2-ethylheyl phthalate (MEHP) and mono-2-ethyl-5-oxohexylphthalate (MEOP) for metabolites of Di-2-ethylhexylphthalate (DEHP) and mono-n-butyl phthalate (MNBP) for metabolites of dibutyl phthalate (DBP) were measured in urine samples. The mean concentrations of MEHP, MEOP, and MNBP were 34.0 microg/dL (SD = 36.3; range: 2.1-386.7), 23.4 microg/dL (SD = 23.0; range: .75-244.8), and 46.7 microg/L (SD = 21.4; range: 13.2-159.3), respectively. After adjustment for covariates, teacher-rated ADHD scores were significantly associated with DEHP metabolites but not with DBP metabolites. We also found significant relationships between the urine concentrations of metabolites for DBP and the number of omission and commission errors in continuous performance tests (CPT) after adjustment for covariates. CONCLUSION The present study showed a strong positive association between phthalate metabolites in urine and symptoms of ADHD among school-age children.

Co-exposure to environmental lead and manganese affects the intelligence of school-aged children

BACKGROUND Exposure to environmental levels of lead (Pb) and manganese (Mn) has been associated with detrimental effects to neurodevelopment. However, little is known about the potential association between environmental levels of Pb and Mn on intelligence of children. The aims of the study were to investigate the association of community level of Pb and Mn with the intelligence of school-aged children, and to explore the implications of joint exposure to these two heavy metals. METHODS A cross-sectional examination of blood Pb and Mn concentrations was performed, and the intelligence quotient (IQ) was determined for 261 Korean children aged 8-11 years. RESULTS The mean blood concentrations of Pb and Mn were 1.73 microg/dL (SD=0.8; median=1.55; range=0.42-4.91) and 14.3 microg/L (SD=3.8; median=14.0; range=5.30-29.02), respectively. Both Pb and Mn showed significant linear relationship with full-scale IQ (Pb, beta=-0.174, p=0.005; Mn, beta=-0.123, p=0.042) and verbal IQ (Pb, beta=-0.187, p=0.003; Mn, beta=-0.127, p=0.036). Blood Pb (DeltaR(2)=0.03) and Mn (DeltaR(2)=0.01) explained 4% of the variances of the full-scale IQ and 5% of the variances of the verbal IQ. When Pb and Mn levels were entered as predictive variables, additive increase in the explained variances was observed. Finally, full-scale IQ and verbal IQ of the children with blood Mn>14 microg/L showed significant association with Pb, whereas group with Mn<14 microg/L did not, suggesting effect modification between Pb and Mn. CONCLUSIONS The present study suggests the presence of additive interaction and effect modification between Pb and Mn on the intelligence of school-aged children, suggesting more attention should be paid to preventing the exposure of disadvantaged children to various combinations of toxic materials.

Prenatal Exposure to Phthalates and Infant Development at 6 Months: Prospective Mothers and Children’s Environmental Health (MOCEH) Study

Background: There are increasing concerns over adverse effects of prenatal phthalate exposure on the neurodevelopment of infants. Objectives: Our goal was to explore the association between prenatal di(2-ethylhexyl) phthalate and dibutyl phthalate exposure and the Mental and Psychomotor Developmental Indices (MDI and PDI, respectively) of the Bayley Scales of Infant Development at 6 months, as part of the Mothers and Children’s Environmental Health Study. Methods: Between 2006 and 2009, 460 mother–infant pairs from Seoul, Cheonan, and Ulsan, Korea, participated. Prenatal mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MBP) were measured in one urine sample acquired from each mother during the third trimester of pregnancy. Associations with log-transformed creatinine-corrected phthalate concentrations were estimated using linear regression models adjusted for potential confounders. Results: MDI was inversely associated with the natural log concentrations (micrograms per gram creatinine) of MEHHP [β = –0.97; confidence interval (CI), –1.85 to –0.08] and MEOHP (β = –0.95; CI, –1.87 to –0.03), and PDI was inversely associated with MEHHP (β = –1.20; CI, –2.33 to –0.08). In males, MDI was inversely associated with MEHHP (β = –1.46; CI, –2.70 to –0.22), MEOHP (β = –1.57; CI, –2.87 to –0.28), and MBP (β = –0.93; CI, –1.82 to –0.05); PDI was inversely associated with MEHHP (β = –2.36; CI, –3.94 to –0.79), MEOHP (β = –2.05; CI, –3.71 to –0.39), and MBP (β = –1.25; CI, –2.40 to –0.11). No significant linear associations were observed for females. Conclusions: The results suggest that prenatal exposure to phthalates may be inversely associated with the MDI and PDI of infants, particularly males, at 6 months.

Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D2 receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT2 receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3α/β and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3α/β. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D2- or 5HT2- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Prenatal lead and cadmium co-exposure and infant neurodevelopment at 6 months of age: The Mothers and Children's Environmental Health (MOCEH) study

BACKGROUND This study aimed to explore the developmental effects of prenatal exposure to Pb and Cd on infant cognitive development at 6 months of age. METHODS Between 2006 and 2010, the blood levels of Pb and Cd were measured in 884 mothers during their early and late pregnancy. The mental (MDI) and psychomotor (PDI) development index scores of the infants were assessed using the Bayley Scales of Infant Development. The development index scores were adjusted for birth weight, maternal age, maternal education level, family income, breastfeeding status, and residential area. RESULTS The geometric mean of the maternal blood concentration was 1.36μg/dL (10th percentile=0.83; 90th percentile=2.13; range=0.26-9.10) for Pb and 1.42μg/L (10th percentile=1.01; 90th percentile=2.16; range=0.03-9.87) for Cd during the early pregnancy period and 1.27μg/dL (10th percentile=0.77; 90th percentile=2.10; range=0.12-4.28) for Pb and 1.52μg/L for Cd (10 percentile=1.07; 90th percentile=2.10; range=0.43-3.73) during the late pregnancy period. The prenatal Pb and Cd concentrations during the early pregnancy period showed no association with the adjusted MDI or PDI scores. The antagonistic interaction between the prenatal Pb and Cd levels during the early pregnancy period had a significant effect on the MDI score (B=-4.64, 95% CI=-8.17 to -1.12, p=0.01), but the effect of this interaction did not reach statistical significance for the PDI score (B=-3.69, 95% CI=-7.94 to 0.56, p=0.09). The Pb levels during the late pregnancy period were inversely associated with the MDI score (B=-1.94, 95% CI=-3.60 to -0.29, p=0.02) but not with the PDI score (B=-1.69, 95% CI=-3.65 to 0.27, p=0.09). The prenatal Cd levels during the late pregnancy period showed no association with the MDI or PDI score. However, the MDI score (B=-3.20, 95% CI=-5.35 to -1.06, p<0.01) and the PDI score (B=-2.86, 95% CI=-5.55 to -0.16, p=0.04) of infants with Cd levels >1.51μg/L were significantly associated with the Pb level, whereas there were no such associations for infants with Cd levels <1.51μg/L. These results suggest that there is a synergistic effect modification between Pb and Cd during the late pregnancy period. CONCLUSIONS These findings suggest that there is dose-dependent interaction between prenatal exposure to Pb and prenatal exposure to Cd. The results further demonstrate the biological complexities of examining the neurodevelopmental effects of co-exposure to multiple toxicants.

Calcineurin dephosphorylates glycogen synthase kinase-3 beta at serine-9 in neuroblast-derived cells

This study examined the role of calcineurin, a major calcium‐dependent protein phosphatase, in dephosphorylating Ser‐9 and activating glycogen synthase kinase‐3β (GSK‐3β). Treatment with calcineurin inhibitors increased phosphorylation of GSK‐3β at Ser‐9 in SH‐SY5Y human neuroblastoma cells. The over‐expression of a constitutively active calcineurin mutant, calcineurin A beta (1–401), led to a significant decrease in phosphorylation at Ser‐9, an increase in the activity of GSK‐3β, and an increase in the phosphorylation of tau. Km of calcineurin for a GSK‐3β phosphopeptide was 469.3 μM, and specific activity of calcineurin was 15.2 nmol/min/mg. In addition, calcineurin and GSK‐3β were co‐immunoprecipitated in neuron‐derived cells and brain tissues, and calcineurin formed a complex only with dephosphorylated GSK‐3β. We conclude that in vitro, calcineurin can dephosphorylate GSK‐3β at Ser‐9 and form a stable complex with GSK‐3β, suggesting the possibility that calcineurin regulates the dephosphorylation and activation of GSK‐3βin vivo.

Korean Environmental Health Survey in Children and Adolescents (KorEHS-C): Survey design and pilot study results on selected exposure biomarkers

For the first nationwide representative survey on the environmental health of children and adolescents in Korea, we designed the Korean Environmental Health Survey in Children and Adolescents (KorEHS-C) as a two-phase survey and planned a sampling strategy that would represent the whole population of Korean children and adolescents, based on the school unit for the 6-19 years age group and the household unit for the 5 years or less age group. A pilot study for 351 children and adolescents aged 6 to 19 years in elementary, middle, and high school of two cities was performed to validate several measurement methods and tools, as well as to test their feasibility, and to elaborate the protocols used throughout the survey process. Selected exposure biomarkers, i.e., lead, mercury, cadmium in blood, and bisphenol A, metabolites of diethylhexyl phthalate and di-n-butyl phthalate and cotinine in urine were analyzed. We found that the levels of blood mercury (Median: 1.7 ug/L) and cadmium (Median: 0.30 ug/L) were much higher than those of subjects in Germany and the US, while metabolites of phthalates and bisphenol A showed similar levels and tendencies by age; the highest levels of phthalate metabolites and bisphenol A occurred in the youngest group of children. Specific investigations to elucidate the exposure pathways of major environmental exposure need to be conducted, and the KorEHS-C should cover as many potential environmental hazards as possible.

Relationship between blood manganese levels and children's attention, cognition, behavior, and academic performance—A nationwide cross-sectional study

Manganese (Mn) is neurotoxic at high concentrations. However, Mn is an essential element that can protect against oxidative damage; thus, extremely low levels of Mn might be harmful. Our aim was to examine whether either high or low environmental Mn exposure is related to academic and attention function development among school-aged children. This cross-sectional study included 1089 children 8-11 years of age living in five representative areas in South Korea. Blood Mn, blood lead, and urine cotinine were measured. We assessed IQ with the Wechsler Abbreviated Scale of Intelligence; attention with a computerized continuous performance test called the Attention-deficit/hyperactivity disorder (ADHD) Diagnostic System (ADS), the Korean version of the Stroop Color-Word Test, the Childrens Color Trails Test (CCTT), and the ADHD Rating Scale; academic functions with the Learning Disability Evaluation Scale (LDES); and emotional and behavioral problems with the Korean version of the Child Behavior Checklist (CBCL). We further assessed the presence of ADHD using a highly structured diagnostic interview, the Diagnostic Interview Schedule for Children Version IV (DISC-IV). The median blood concentration of Mn was 14.14 µg/L. We observed a nonlinear association between the CCTT2 completion time and the CPT commission error (F=3.14, p=0.03 and F=4.05, p=0.01, respectively). We divided the data into three groups: lower (<8.154 µg/L), and upper 5th percentile (>21.453 µg/L) and middle 90th percentile to determine whether a lack or overload of Mn could cause adverse effects. After adjusting for urine cotinine, blood lead, childrens IQ, and other potential confounders, the high Mn group showed lower scores in thinking (B=-0.83, p=0.006), reading (B=-0.93, p=0.004), calculations (B=-0.72, p=0.005), and LQ (B=-4.06, p=0.006) in the LDES and a higher commission error in the CPT (B=8.02, p=0.048). The low Mn group showed lower color scores in the Stroop test (B=-3.24, p=0.040). We found that excess Mn in children is associated with lower scores of thinking, reading, calculation, and LQ in the LDES and higher scores of commission error in the ADS test. In contrast, lower Mn in children is associated with lower color scores in the Stroop test. The findings of this cross-sectional study suggest that excess exposure or deficiency of Mn can cause harmful effects in children.

Prenatal exposure to PM10 and NO2 and children's neurodevelopment from birth to 24 months of age: Mothers and Children's Environmental Health (MOCEH) study

INTRODUCTION Previous studies have suggested adverse effects of maternal exposure to air pollution on neurodevelopment in early childhood. OBJECTIVES We aimed to investigate the association between prenatal exposure to particulates of less than 10 μm in diameter (PM10) and nitrogen dioxide (NO2) and neurodevelopment in children during the first 24 months of their lives. METHODS The MOCEH study is a prospective birth cohort study in South Korea. Average exposure levels to PM10 and NO2 during the entire pregnancy were estimated using the inverse distance weighting (IDW) method. A total of 520 mother-child pairs who completed neurodevelopmental assessments using the Korean Bayley Scale of Infant Development II (K-BSID-II) more than once at ages of 6, 12 and 24 months were included. Mental developmental index (MDI) and psychomotor developmental index (PDI) from the K-BSID-II were used as outcome variables. RESULTS There were negative associations between maternal exposure to PM10 and MDI (β=-2.83; p=0.003) and PDI (β=-3.00; p=0.002) throughout the first 24 months of life as determined by the generalized estimating equation (GEE) model. Maternal NO2 exposure was related with impairment of psychomotor development (β=-1.30; p=0.05) but not with cognitive function (β=-0.84; p=0.20). In a multiple linear regression model, there were significant effects of prenatal air pollution exposure on MDI (PM10: β=-4.60; p<0.001, NO2: β=-3.12; p<0.001) and PDI (PM10: β=-7.24; p<0.001, NO2: β=-3.01; p<0.001) at 6 months, but no significant association was found at 12 and 24 months of age. CONCLUSIONS The findings suggest that exposure to air pollution may result in delayed neurodevelopment in early childhood.

Association between blood lead levels (< 5 μg/dL) and inattention-hyperactivity and neurocognitive profiles in school-aged Korean children

OBJECTIVES The association between low blood lead levels (<5 μg/dL) and the inattention-hyperactivity symptoms and neurocognitive profiles of school-aged Korean children was investigated. METHODS We measured blood lead levels in 256 Korean children aged 8-10 years. Teachers completed the Attention-Deficit Hyperactivity Disorder Rating Scale (T-ARS)-IV to assess inattentive and hyperactive symptoms. Parents completed the Korean version of the Learning Disability Evaluation Scale (K-LDES). Children performed neurocognitive tests [The Continuous Performance Test (CPT), the Childrens Color Trails Test, and the Stroop Color and Word Test (SCWT)]. RESULTS A linear regression analysis indicated that the blood lead concentrations were associated with the inattention scores [B=4.8, S.E.=1.6, 95% confidence interval (CI): 1.5-8.0], the hyperactivity subscores (3.1, 1.4, 0.3-5.9), and the total score (7.9, 2.9, 2.1-13.6) on the T-ARS; the number of omission errors on the CPT (20.6, 7.1, 6.5-34.6); the listening (-1.4, 0.7, -2.8 to -0.1), reading (-2.1, 0.7, -3.4 to -0.7), writing (-2.0, 0.7, -3.4 to -0.6), spelling (-2.2, 0.7, -3.7 to -0.7), and calculating (-1.8, 0.7, -3.1 to -0.4) scores on the K-LDES; and the color-word score on the SCWT (-6.7, 3.4, -13.3 to -0.1). A logistic regression analysis indicated that the probability of inattentive and hyperactive symptoms was increased with higher blood lead levels in boys with an odds ratio of 2.768 [B=1.018, S.E.=0.487, p=0.036, 95% CI: 1.066-7.187]. CONCLUSION This study suggests that even low blood lead levels (<5 μg/dL) are associated with inattentive and hyperactivity symptoms and learning difficulties in school-aged children.