Atomoxetine and Fluoxetine Activate AMPK-ACC-CPT1 Pathway in Human SH-SY5Y and U-87 MG Cells.

OBJECTIVE: Atomoxetine and fluoxetine are psychopharmacologic agents associated with loss of appetite and weight. Adenosine monophosphate-activated protein kinase (AMPK) is the cellular energy sensor that regulate metabolism and energy, being activated by fasting and inhibited by feeding in the hypothalamus. METHODS: Human brain cell lines (SH-SY5Y and U-87 MG cells) were used to study the outcome of atomoxetine and fluoxetine treatment in the activity of AMPK-acetyl-CoA carboxylase (ACC)- carnitine palmitoyl transferase 1 (CPT1) pathway and upstream regulation by calcium/calmodulin-dependent kinase kinase ß (CaMKKß) using immunoblotting and CPT1 enzymatic activity measures. RESULTS: Phosphorylation of AMPK and ACC increased significantly after atomoxetine and fluoxetine treatment in the first 30-60 minutes of treatment in the two cell lines. Activation of AMPK and inhibition of ACC was associated with an increase by 5-fold of mitochondrial CPT1 activity. Although the neuronal isoform CPT1C could be detected by immunoblotting, activity was not changed by the drug treatments. In addition, the increase in phospho-AMPK and phospho-ACC expression induced by atomoxetine was abolished by treatment with STO-609, a CaMKKß inhibitor, indicating that AMPK-ACC-CPT1 pathway is activated through CaMKKß phosphorylation. CONCLUSION: These findings indicate that at the cellular level atomoxetine and fluoxetine treatments may activate AMPK-ACC-CPT1 pathways through CaMKKß in human SH-SY5Y and U-87 MG cells.

Per2 Expression Regulates the Spatial Working Memory of Mice through DRD1-PKA-CREB Signaling.

Several individuals worldwide show cognitive impairment due to various reasons, including a prolonged lifespan and an altered lifestyle. Various causes, such as broken circadian rhythms and dopamine-related factors, have been proposed to be involved in the development of cognitive impairment. However, the underlying pathways remain elusive. Humans with circadian misalignment often face cognitive impairments, and animals with mutations in circadian rhythm-related genes display impaired cognitive functions. To analyze this in detail, this study aimed to investigate the pathways potentially involved in cognitive impairment using Period2 (Per2) transgenic animals. Spatial working memory performance in Per2 knockout (KO) and wild-type mice was assessed using the Barnes maze and Y-maze. The dopamine-related protein expression levels in the hippocampus were measured by Western blotting and enzyme-linked immunosorbent assay (ELISA). Per2 KO mice exhibited impaired spatial working memory, and the expression levels of dopamine receptor D1 (DRD1), protein kinase A (PKA), and cAMP response element-binding protein (CREB) were higher in Per2 KO mice than in control mice. Additionally, DRD1 expression levels were inversely proportional to those of PER2. Thus, memory tests were again conducted after administration of the DRD1 antagonist SCH-23390. Per2 KO mice recovered from memory impairment, and the levels of PKA and CREB decreased after treatment. The effects of Aß on memory in Per2 mice were also investigated, and we found the increased Aß levels did not influence the memory performance of Per2 mice after SCH-23390 treatment. These results indicate that Per2 expression levels might influence spatial working memory performance via DRD1-PKA-CREB-dependent signaling.

Association Between Sleep Duration and Intelligence Quotient in 6-Year-Old Children.

BACKGROUND: Sufficient sleep during childhood is important for cognitive functions such as learning and successful school performance. This study aimed to investigate the effects of sleep duration on the intelligence quotient (IQ) of 6-year-old children and aimed to analyze whether these effects differed by sex. METHODS: The IQ of 538 6-year-old Korean participants from the cohort study, "The Environment and Development of Children," was measured during follow-up using the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children. The total, verbal, and performance IQ scores were evaluated. The relationship between sleep duration and IQ scores after adjusting for maternal age, maternal educational level, maternal occupation, maternal IQ, exposure to secondhand smoking, gestational age, and monthly age and birth season was also assessed. RESULTS: Longer sleep duration was significantly associated with improved verbal IQ measures (ß 0.55; p value 0.030). After stratifying participants by sex, a significant association was observed between sleep duration and total, verbal, and performance IQ scores in boys (total IQ 2.49, p value 0.012; verbal IQ 0.75, p value: 0.037; performance IQ 0.73, p value 0.048), but not in girls. CONCLUSIONS: The results indicated that only boys show a significant association between IQ scores and sleep duration. These findings support the hypothesis that sleep duration is associated with IQ, in a sex dependent manner. Future studies are needed for a thorough evaluation of the connection between sleep duration and health outcome in young children.

Childhood Obesity-Related Mechanisms: MicroRNome and Transcriptome Changes in a Nested Case-Control Study.

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases.

The Effect of Prenatal Cadmium Exposure on Attention-deficit/Hyperactivity Disorder in 6-Year-old Children in Korea.

OBJECTIVES: Prenatal cadmium (Cd) exposure may be associated with attention-deficit/hyperactivity disorder (ADHD) in children. Therefore, the objective of this study was to examine the relationship between Cd exposure during gestation and ADHD at 6 years of age. METHODS: As part of an ongoing cohort study (the Environment and Development of Children study), 479 mother-child pairs from Seoul, Korea were included for analysis between 2008 and 2011. The whole blood concentration of Cd was analyzed using atomic absorption spectrophotometry. The parents were surveyed about ADHD behaviors in their children at age 6. Multivariable linear regression models were used to investigate the relationship between prenatal exposure to Cd and ADHD at 6 years of age. RESULTS: Increased prenatal Cd concentrations were associated with increased scores for ADHD for girls, but not for boys, at age 6. A 2-fold increase in the prenatal Cd level was significantly associated with a 22.3% (95% confidence interval, 11.6 to 34.1) increase in ADHD in girls at 6 years of age, as indicated by the linear regression model. CONCLUSIONS: Our results identified significant associations between prenatal Cd exposure and ADHD scores in 6-year-old girls.

Prenatal exposure to di-(2-ethylhexyl) phthalate and decreased skeletal muscle mass in 6-year-old children: A prospective birth cohort study.

BACKGROUND/AIM: Phthalate is a well-known endocrine-disrupting chemical that has anti-androgenic effects. Although there are several studies on the relationship between body composition and phthalate, studies that investigated the effects of phthalate on skeletal muscle during childhood are lacking. METHODS: We analyzed data from 481 mother-and-child pairs enrolled in the Environment and Development of Children cohort in South Korea. We examined the association between phthalate metabolites (mono [2-ethyl-5-hydroxyhexyl] phthalate [MEHHP], mono [2-ethyl-5-oxohexyl] phthalate [MEOHP], molar sum of MEHHP and MEOHP [Σ DEHP], and mono-n-butyl phthalate [MnBP]) in prenatal maternal urine and children's urine at the age of 6, and body composition indices (body mass index [BMI] z-score, percentage of fat mass, fat mass index, percentage of skeletal muscle, and the skeletal muscle index [SMI]) measured when the child was 6 years using a bioelectrical impedance analyzer. RESULTS: A 2-fold increase in Σ DEHP and MnBP in the prenatal maternal urine was significantly associated with a -0.07 unit (95% CI: -0.11, -0.03) and -0.09 unit (95% CI: -0.14, -0.03) change in SMI, respectively, in 6-year old girls alone. BMI z-score was also negatively associated with a 2-fold increase in MEHHP and MnBP in prenatal maternal urine as -0.11 unit (95% CI: -0.22, -0.01) and -0.15 unit (95% CI: -0.28, -0.02) change, respectively, only among girls. Among boys, phthalate metabolites in the prenatal and children's urine were not significantly associated with any body composition indices. CONCLUSIONS: Our longitudinal study shows that high levels of prenatal exposure to phthalates are significantly associated with decreased SMI among girls. We can postulate that anti-androgenic effects of phthalates during pregnancy may affect girl offspring's muscle growth.

Childhood Onset of Anti-N-Methyl-D-Aspartate Receptor Encephalitis Without Teratoma Masquerading as a Psychotic Disorder.

Many neurologic disorders manifest as psychiatric symptoms. Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune disease of the brain characterized by numerous neurological and psychiatric features. Despite being rare, its prevalence is rapidly increasing and early management is critical in ensuring successful and sustainable recovery. Therefore, the illness should be considered as a differential diagnosis when clinically assessing patients. This report presents a case of a female child who was hospitalized for acute psychiatric manifestations, which was later confirmed as anti-NMDA receptor encephalitis. She recovered relatively successfully after combined neurological and psychiatric treatment. This report provides information on the clinical course of early onset anti-NMDA receptor encephalitis, including treatment strategy and prognosis.

Neurodevelopment in Early Childhood Affected by Prenatal Lead Exposure and Iron Intake.

No safe threshold level of lead exposure in children has been recognized. Also, the information on shielding effect of maternal dietary iron intake during pregnancy on the adverse effects of prenatal lead exposure on children's postnatal neurocognitive development is very limited. We examined the association of prenatal lead exposure and neurodevelopment in children at 6, 12, 24, and 36 months and the protective action of maternal dietary iron intake against the impact of lead exposure. The study participants comprise 965 pregnant women and their subsequent offspring of the total participants enrolled in the Mothers and Children's environmental health study: a prospective birth cohort study. Generalized linear model and linear mixed model analysis were performed to analyze the effect of prenatal lead exposure and mother's dietary iron intake on children's cognitive development at 6, 12, 24, and 36 months. Maternal late pregnancy lead was marginally associated with deficits in mental development index (MDI) of children at 6 months. Mothers having less than 75th percentile of dietary iron intake during pregnancy showed significant increase in the harmful effect of late pregnancy lead exposure on MDI at 6 months. Linear mixed model analyses showed the significant detrimental effect of prenatal lead exposure in late pregnancy on cognitive development up to 36 months in children of mothers having less dietary iron intake during pregnancy. Thus, our findings imply importance to reduce prenatal lead exposure and have adequate iron intake for better neurodevelopment in children.

Evidence that cognitive deficit in children is associated not only with iron deficiency, but also with blood lead concentration: a preliminary study.

OBJECTIVE: To investigate whether blood lead concentrations are elevated in iron-deficient children, and to examine the association between iron deficiency and/or elevated blood lead concentration and cognitive deficits in children. METHOD: The present study is a component of the Mothers' and Children's Environmental Health (MOCEH) study, a multi-center birth cohort project in Korea that began in 2006. The study cohort consisted of 194 children who underwent testing of blood lead and serum C-reactive proteins (CRPs) and ferritin concentrations, and the Korean version of the Wechsler Preschool and Primary Scale of Intelligence, revised edition (WPPSI-R), at 60 months of age. In addition, the mothers' blood lead concentrations during pregnancy were included in the analyses. Multivariate linear regression analysis was performed to analyze the correlation between high blood lead and low serum ferritin concentrations, after adjustment for covariates, in children, as well as to analyze the association of verbal IQ with serum ferritin and blood lead concentrations. RESULTS: Lead and ferritin concentrations were inversely and significantly associated in children after adjustment for covariates. Moreover, both concentrations were associated with verbal IQ, after adjustment for covariates, and each was associated with cognitive deficits after adjustment for the other. Sobel test statistics showed that blood lead concentration was a significant partial mediator for the relationship between iron deficiency and verbal IQ. CONCLUSION: Due to the results discussed in the present study, cognitive deficit in children seems to be associated not only with iron deficiency, but also with blood lead concentration.

Performance IQ in children is associated with blood cadmium concentration in early pregnancy.

OBJECTIVE: To investigate whether performance IQ in children is associated with maternal blood cadmium concentration in early pregnancy. METHOD: The present study is a component of the Mothers' and Children's Environmental Health (MOCEH) study, a multi-center birth cohort project in Korea that began in 2006. The study cohort consisted of 119 children whose mothers underwent testing of blood cadmium during early pregnancy. All children were evaluated using the Korean version of the Wechsler Preschool and Primary Scale of Intelligence, revised edition (WPPSI-R), at 60 months of age. Multivariate linear regression analysis was performed to analyze the correlation between IQ in children and maternal blood cadmium concentration in early pregnancy, after adjustment for covariates. RESULTS: Maternal blood cadmium concentration during early pregnancy was inversely associated with performance IQ, after adjustment for covariates such as sex, educational levels of both parents, family income, and maternal BMI. Maternal blood cadmium concentration, however, was not associated with cognitive IQ. CONCLUSION: Performance IQ in children is associated with maternal blood cadmium concentration in early pregnancy.

Environmental tobacco smoke exposure and children's intelligence at 8-11 years of age.

BACKGROUND: Evidence supporting a link between postnatal environmental tobacco smoke (ETS) exposure and cognitive problems among children is mounting, but inconsistent. OBJECTIVES: We examined the relationship between ETS exposure, measured using urine cotinine, and IQ scores in Korean school-aged children. METHODS: The participants were 996 children 8-11 years of age recruited from five administrative regions in South Korea. We performed a cross-sectional analysis of urinary cotinine concentrations and IQ scores obtained using the abbreviated form of a Korean version of the Wechsler Intelligence Scales for Children. Associations were adjusted for potential confounders, and estimates were derived with and without adjustment for mother's Full-Scale IQ (FSIQ) score. RESULTS: After adjusting for sociodemographic and developmental covariates, urinary cotinine concentrations were inversely associated with FSIQ, Verbal IQ (VIQ), Performance IQ (PIQ), vocabulary, math, and block design scores. Following further adjustment for maternal IQ, only the VIQ scores remained significantly associated with urinary cotinine concentration (B = -0.31; 95% CI: -0.60, -0.03 for a 1-unit increase in natural log-transformed urine cotinine concentration; p = 0.03). CONCLUSION: Urine cotinine concentrations were inversely associated with children's VIQ scores before and after adjusting for maternal IQ. Further prospective studies with serial measurements of cotinine are needed to confirm our findings.

A psychological analysis of the Korean mothers of cleft lip and palate patients: screening for psychological counseling and neuropsychiatric treatment.

The purpose of this study is to examine the psychological states and the stress levels of the Korean mothers who have cleft lip and palate child patients. The authors explored whether psychological assessments of the mothers with child patients could play a role in screening for psychiatric counseling. Thirty-six mothers of child patients admitted to receive cleft lip and palate surgery at Seoul National University Children's Hospital were recruited as subjects of this study. The 3 questionnaires included in the study were the Beck Depression Inventory, Beck Anxiety Inventory, and Parenting Stress Inventory. We compared these results with those of general population according to the domestic studies. The statistical significances of these results were analyzed using Mann-Whitney method. The average score from the Beck Depression Inventory was 8.89 with standard deviation of 6.08. The average score from the Beck Anxiety Inventory was 9.69 with standard deviation of 6.89. In the Parenting Stress Inventory, the average score was 55.06 and standard deviation was 16.45. However, there were no statistically significant differences between mothers whose children have underwent surgery versus no surgery and mothers whose children had visible versus invisible anomalies. The reliable psychological analysis of depression, anxiety, and stress levels of the mothers of child patients allowed the authors to assess the psychological states of the mothers of child patients. Such assessment can play a vital role in the screening of candidates who need psychiatric treatment or consultation.

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.