Boong-Nyun Kim

Relationship between Environmental Phthalate Exposure and the Intelligence of School-Age Children

Background Concern over phthalates has emerged because of their potential toxicity to humans. Objective We investigated the relationship between the urinary concentrations of phthalate metabolites and children’s intellectual functioning. Methods This study enrolled 667 children at nine elementary schools in five South Korean cities. A cross-sectional examination of urine phthalate concentrations was performed, and scores on neuropsychological tests were obtained from both the children and their mothers. Results We measured mono-2-ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-oxohexyl)phthalate (MEOHP), both metabolites of di(2-ethylhexyl)phthalate (DEHP), and mono-n-butyl phthalate (MBP), a metabolite of dibutyl phthalate (DBP), in urine samples. The geometric mean (ln) concentrations of MEHP, MEOHP, and MBP were 21.3 μg/L [geometric SD (GSD) = 2.2 μg/L; range, 0.5–445.4], 18.0 μg/L (GSD = 2.4; range, 0.07–291.1), and 48.9 μg/L (GSD = 2.2; range, 2.1–1645.5), respectively. After adjusting for demographic and developmental covariates, the Full Scale IQ and Verbal IQ scores were negatively associated with DEHP metabolites but not with DBP metabolites. We also found a significant negative relationship between the urine concentrations of the metabolites of DEHP and DBP and children’s vocabulary subscores. After controlling for maternal IQ, a significant inverse relationship between DEHP metabolites and vocabulary subscale score remained. Among boys, we found a negative association between increasing MEHP phthalate concentrations and the sum of DEHP metabolite concentrations and Wechsler Intelligence Scale for Children vocabulary score; however, among girls, we found no significant association between these variables. Conclusion Controlling for maternal IQ and other covariates, the results show an inverse relationship between phthalate metabolites and IQ scores; however, given the limitations in cross-sectional epidemiology, prospective studies are needed to fully explore these associations.

Regional cerebral perfusion abnormalities in attention deficit/hyperactivity disorder

Abstract.Objective: A voxel based investigation of cerebral blood flow was conducted to identify brain function differences in the resting state between children with Attention Deficit Hyperactivity Disorder (ADHD) and normal controls. Method: Using DSM-IV criteria, we selected 40 children with pure ADHD by various assessment scales, psychometric tools and a neuropsychological battery. All patients were examined by 99mTc-HMPAO brain SPECT. Seventeen normal controls were recruited from age, sex, and IQ-matched children whose previous SPECT, MRI, EEG and psychometric and neuropsychological findings had been normal. Using SPM methods, we compared SPECT images of ADHD patients and those of 17 control subjects on a voxel by voxel basis using t-statistics. Voxels with a p-value of less than 0.01 were considered to be significantly different. Result: Decreased cerebral blood flow in right lateral prefrontal cortex, right middle temporal cortex, both orbital prefrontal cortex and both cerebellar cortices were found in children with ADHD compared to the controls. In addition, the ADHD group showed increased blood flow in some parietal and occipital lobes (posterior brain regions) compared to the control group. Conclusion: Although the results should be interpreted cautiously, this study confirms the presence of functional defects in the prefrontal cortex and reports new problems in the limbic area, somatosensory areas and in the cerebellum during the resting state of brains of ADHD children.

Interaction between GSTM1/GSTT1 Polymorphism and Blood Mercury on Birth Weight

Background Mercury (Hg) is toxic to both the reproductive and nervous systems. In addition, glutathione S-transferases (GSTs), which conjugate glutathione to a variety of electrophilic compounds, are involved in the detoxification of Hg. Objective In this study we examined the association between prenatal exposure to Hg and birth weight as well as the influence of GST polymorphisms. Methods The total Hg concentration in maternal and cord blood was measured from 417 Korean women and newborns in the Mothers and Children’s Environmental Health study from 2006 to 2008. Information on birth weight was collected from the patients’ medical records. The genotyping of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) polymorphisms was carried out using polymerase chain reaction. Regression analysis was performed to determine the association between the blood Hg concentration and birth weight in mothers with GSTM1 and GSTT1 polymorphisms. Results The geometric mean levels of Hg in the maternal blood during late pregnancy and in cord blood were 3.30 μg/L and 5.53 μg/L, respectively. For mothers with the GSTT1 null genotype, elevated Hg levels in maternal blood during late pregnancy were associated with an increased risk of lower birth weight. For mothers with both GSTM1 and GSTT1 null genotype, both maternal and cord blood Hg levels were associated with lower birth weight. Conclusions This study suggests that the interactions of Hg with GSTM1 and GSTT1 polymorphisms play a role in reducing birth weight.

GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice

Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder that affects ∼5% of school-aged children; however, the mechanisms underlying ADHD remain largely unclear. Here we report a previously unidentified association between G protein–coupled receptor kinase–interacting protein-1 (GIT1) and ADHD in humans. An intronic single-nucleotide polymorphism in GIT1, the minor allele of which causes reduced GIT1 expression, shows a strong association with ADHD susceptibility in humans. Git1-deficient mice show ADHD-like phenotypes, with traits including hyperactivity, enhanced electroencephalogram theta rhythms and impaired learning and memory. Hyperactivity in Git1−/− mice is reversed by amphetamine and methylphenidate, psychostimulants commonly used to treat ADHD. In addition, amphetamine normalizes enhanced theta rhythms and impaired memory. GIT1 deficiency in mice leads to decreases in ras-related C3 botulinum toxin substrate-1 (RAC1) signaling and inhibitory presynaptic input; furthermore, it shifts the neuronal excitation-inhibition balance in postsynaptic neurons toward excitation. Our study identifies a previously unknown involvement of GIT1 in human ADHD and shows that GIT1 deficiency in mice causes psychostimulant-responsive ADHD-like phenotypes.

Sparse Brain Network Recovery Under Compressed Sensing

Partial correlation is a useful connectivity measure for brain networks, especially, when it is needed to remove the confounding effects in highly correlated networks. Since it is difficult to estimate the exact partial correlation under the small-n large-p situation, a sparseness constraint is generally introduced. In this paper, we consider the sparse linear regression model with a l1-norm penalty, also known as the least absolute shrinkage and selection operator (LASSO), for estimating sparse brain connectivity. LASSO is a well-known decoding algorithm in the compressed sensing (CS). The CS theory states that LASSO can reconstruct the exact sparse signal even from a small set of noisy measurements. We briefly show that the penalized linear regression for partial correlation estimation is related to CS. It opens a new possibility that the proposed framework can be used for a sparse brain network recovery. As an illustration, we construct sparse brain networks of 97 regions of interest (ROIs) obtained from FDG-PET imaging data for the autism spectrum disorder (ASD) children and the pediatric control (PedCon) subjects. As validation, we check the network reproducibilities by leave-one-out cross validation and compare the clustered structures derived from the brain networks of ASD and PedCon.

Randomized clinical trial for apogeotropic horizontal canal benign paroxysmal positional vertigo

Objective: To determine the immediate and long-term therapeutic efficacies of Gufoni and head-shaking maneuvers in apogeotropic type of benign paroxysmal positional vertigo involving the horizontal semicircular canal (HC-BPPV), a randomized, prospective, sham-controlled study was conducted. Methods: In 10 nationwide dizziness clinics in Korea, 157 consecutive patients (95 women, age range: 18–89 years, mean age ± SD = 59.9 ± 13.6) with apogeotropic HC-BPPV were randomized to Gufoni (n = 52), head-shaking (n = 54), or sham maneuver (n = 51). For Gufoni maneuver, patients underwent ipsilesional side-lying and upward head-turn for migration of the debris toward the vestibule. Immediate responses were determined within 1 hour after a maximum of 2 trials of each maneuver and in the following day. The patients also had weekly follow-ups for 1 month after the initial maneuver. Results: After a maximum of 2 maneuvers on the initial visit day, Gufoni (38/52, 73.1%) and head-shaking (33/53, 62.3%) maneuvers showed better responses than the sham maneuver (17/49, 34.7%). The cumulative therapeutic effects were also better with Gufoni (p < 0.001) and head-shaking (p = 0.026) maneuvers compared with the sham maneuver. However, therapeutic efficacies did not differ between the Gufoni and head-shaking groups in terms of both immediate (p = 0.129) and long-term (p = 0.239) outcomes. Conclusion: Using a prospective randomized trial, we demonstrated that the Gufoni and head-shaking maneuvers are effective in treating apogeotropic HC-BPPV. Classification of evidence: This study provides Class II evidence that Gufoni and head-shaking maneuvers are effective in treating apogeotropic horizontal BPPV up to 1 month after initial treatment. Clinical trial registration: NCT00810641.

Effect of environmental exposure to lead and tobacco smoke on inattentive and hyperactive symptoms and neurocognitive performance in children.

BACKGROUND The present study assessed the association between blood lead and urinary cotinine levels and inattentive and hyperactive symptoms and neurocognitive performance in children. METHODS A total of 667 children (age range 8-11) were recruited from nine schools in five Korean cities. The teachers and parents completed the Korean version of the Attention-deficit/hyperactivity disorder Rating Scales (K-ARS), and the children performed neurocognitive tests. Blood lead and urinary cotinine levels were then measured. RESULTS The inattentive, hyperactive, and total scores of the teacher-rated K-ARS were positively associated with blood lead level, and the results of the continuous performance test (CPT), Stroop Color-Word Test, and Childrens Color Trails Test were inversely associated with urinary cotinine level when controlled for age, gender, fathers educational level, maternal IQ, childs IQ, residential area, birth weight, and cotinine (for lead) or lead (for cotinine). The association between blood lead level and commission errors score on the CPT disappeared when the effect of urinary cotinine level was controlled. CONCLUSIONS These findings indicate that environmental exposure to tobacco smoke in children is associated with poor neurocognitive performance, and low levels of lead are associated with inattention and hyperactivity symptoms.

Association of 4-Repeat Allele of the Dopamine D4 Receptor Gene Exon III Polymorphism and Response to Methylphenidate Treatment in Korean ADHD Children

In the present study, we investigated the association between the 4-repeat allele at the dopamine receptor D4 (DRD4) gene and the response to treatment with methylphenidate (MPH) in Korean children with attention deficit hyperactivity disorder (ADHD). The study subjects were 83 children with ADHD (8.40±1.73 years) who were recruited from two child psychiatric clinics in South Korea. All of the drug-naive ADHD children were treated with MPH for about 8 weeks. An improvement of more than 50% in the ADHD Rating Scale-IV (ARS) scores after 8 weeks of treatment compared with the baseline ARS scores before the treatment was considered as a ‘good response’, whereas an improvement of less than (or equal to?) 50% was considered as a ‘poor response’. After the genotyping for DRD4 was performed, we investigated the association between the genotype at DRD4 and the response to MPH treatment. We performed a comparison of the response to MPH treatment between the two largest groups, viz. the subjects with and without the 4/4 genotype at DRD4. According to the ARS scores of the subjects as assessed by their parents and by their teachers, we found that while 71.1 and 80.0% (32/45 and 24/30), respectively, of those with a good response to MPH treatment showed the 4/4 genotype at DRD4, only 31.6 and 37.7% (12/38 and 20/53), respectively, of those with a poor response to MPH treatment showed the 4/4 genotype at DRD4 (Pearson χ2-values=12.926 and 13.737, respectively, both df=1, and both p<0.01). Our findings support the existence of an association between the 4-repeat allele at DRD4 and good response to MPH in Korean ADHD children.

Prenatal bisphenol A and birth outcomes: MOCEH (Mothers and Children's Environmental Health) study.

Bisphenol A (BPA) is used primarily in the production of polycarbonate plastics and epoxy resins. Widespread exposure to BPA has created a great deal of concern regarding its potential adverse effects on human health. This study examined the relationship between prenatal BPA exposure and birth outcomes, including birth weight, birth length, and ponderal index considering gender difference. A multi-center birth cohort study, Mothers and Childrens Environmental Health (MOCEH) has been established in Korea since 2006. Study subjects are 757 pregnant women from the original cohort, who had their urinary BPA level measured during the third trimester, as well as information on birth outcome, prior medical history, psychosocial status, health behavior, environmental exposure as well as socio-demographic characteristics. Regression analysis was performed to assess the effect of BPA on birth outcome. The geometric mean concentration of BPA in pregnant women was 1.29 μg/L (1.87 μg/g creatinine) during late pregnancy. Urinary BPA concentrations were shown to be higher in women with a higher income level. Univariate regression analysis revealed a significant association between BPA levels and birth weight. In adjusted analysis, the second tertile of maternal BPA exposure exhibited an increase in birth weight, relative to the first tertile (p=0.04). These relationships were more pronounced in male neonates. Also, prenatal exposure to BPA was associated with an increase of ponderal index in total, and especially female neonates. This study shows that the association of prenatal exposure to BPA with anthropometric measures, such as birth weight and birth length, differed by gender. Further study is required to more fully elaborate this relationship between prenatal BPA exposure and birth outcome.

Bisphenol A in relation to behavior and learning of school-age children

BACKGROUND Bisphenol A (BPA) has been shown to affect brain and behavior in rodents and nonhuman primates, but there are few studies focusing on its relationship to human neurobehavior. We aimed to investigate the relationship between environmental exposure to BPA and childhood neurobehavior. METHODS Urinary BPA concentrations and behavioral and learning characteristics were assessed in a general population of 1,089 children, aged 8-11 years. The main outcome measures were the Child Behavior Checklist (CBCL) and the Learning Disability Evaluation Scale (LDES). RESULTS Urinary levels of BPA were positively associated with the CBCL total problems score and negatively associated with the learning quotient from the LDES. The linear association with the CBCL anxiety/depression score and the quadratic association with the LDES listening score were significant after correction for multiple comparisons. CONCLUSIONS Environmental exposure to BPA might be associated with childhood behavioral and learning development. The results suggest possible nonmonotonic relationships.