Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

An Industry-Relevant Metal Mixture, Iron Status, and Reported Attention-Related Behaviors in Italian Adolescents.

BACKGROUND: Exposure to environmental metals has been consistently associated with attention and behavioral deficits in children, and these associations may be modified by coexposure to other metals or iron (Fe) status. However, few studies have investigated Fe status as a modifier of a metal mixture, particularly with respect to attention-related behaviors. METHODS: We used cross-sectional data from the Public Health Impact of Metals Exposure study, which included 707 adolescents (10-14 years of age) from Brescia, Italy. Manganese, chromium, and copper were quantified in hair samples, and lead was quantified in whole blood, using inductively coupled plasma mass spectrometry. Concentrations of Fe status markers (ferritin, hemoglobin, transferrin) were measured using immunoassays or luminescence assays. Attention-related behaviors were assessed using the Conners Rating Scales Self-Report Scale-Long Form, Parent Rating Scales Revised-Short Form, and Teacher Rating Scales Revised-Short Form. We employed Bayesian kernel machine regression to examine associations of the metal mixture with these outcomes and evaluate Fe status as a modifier. RESULTS: Higher concentrations of the metals and ferritin were jointly associated with worse self-reported attention-related behaviors: metals and ferritin set to their 90th percentiles were associated with 3.0% [ß=0.03; 95% credible interval (CrI): -0.01, 0.06], 4.1% (ß=0.04; 95% CrI: 0.00, 0.08), and 4.1% (ß=0.04; 95% CrI: 0.00, 0.08) higher T-scores for self-reported attention deficit/hyperactivity disorder (ADHD) index, inattention, and hyperactivity, respectively, compared with when metals and ferritin were set to their 50th percentiles. These associations were driven by hair manganese, which exhibited nonlinear associations with all self-reported scales. There was no evidence that Fe status modified the neurotoxicity of the metal mixture. The metal mixture was not materially associated with any parent-reported or teacher-reported scale. CONCLUSIONS: The overall metal mixture, driven by manganese, was adversely associated with self-reported attention-related behavior. These findings suggest that exposure to multiple environmental metals impacts adolescent neurodevelopment, which has significant public health implications. https://doi.org/10.1289/EHP12988.

Evaluating how occupational exposure to organophosphates and pyrethroids impacts ADHD severity in Egyptian male adolescents.

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by deficits in attention and hyperactivity/impulsivity that cause impairments to daily living. An area of long-standing concern is understanding links between environmental toxicants, including pesticides, and the development or worsening of ADHD. OBJECTIVES: The present study evaluated associations between occupational pesticide exposure, specifically organophosphate (OP) pesticides, chlorpyrifos (CPF) and the pyrethroids (PYR) alpha-cypermethrin (αCM) and lambda-cyhalothrin (λCH), and symptoms of ADHD in a longitudinal study among Egyptian adolescent males. METHODS: Participants (N = 226, mean age = 17) were Egyptian adolescent males who either applied pesticides or were non-applicators. Urinary trichloro-2-pyridinol (TCPy) was measured as a specific metabolite biomarker of exposure to chlorpyrifos. Urinary 3-phenoxybenzoic acid (3-PBA) was measured as a general metabolite biomarker of exposure to pyrethroids, while urinary cis-3-(2,2- dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA) was measured as a specific biomarker of exposure to αCM and lambda cyhalothric acid (λCH acid) measured as a specific biomarker of exposure to λCH. Ordinal logistic regression models controlling for age were used to determine the likelihood of ADHD development (measured via parent-reported ADHD symptoms) as the level of biomarkers of pesticide exposure increased. RESULTS: Cis-DCCA was the only biomarker associated with higher likelihood ADHD symptoms (> 0.60 vs. 0-0.17 µg/g creatinine; OR = 2.82, 95% CI: 1.29-6.14). All participants reported clinical levels of ADHD symptoms when compared to national norms used in the United States. TCPy, trans-DCCA and λCH acid were not associated with risk of ADHD symptoms after controlling for levels of cis-DCCA. No other metabolites were associated with the number of ADHD symptoms. There were no interaction effects found for exposure to both OPs and Pyrethroids. DISCUSSION: The results suggest that exposure to the pyrethroid αCM is associated with more ADHD symptoms. Methodological and cultural considerations in need of further study are discussed.

Maternal exposure to pesticides and autism or attention-deficit/hyperactivity disorders in offspring: A meta-analysis.

OBJECTIVE: To analyze the association between maternal pesticide exposure and autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorders (ADHD) in offspring. METHOD: Five databases including PubMed, Embase, Web of Science, Medline, as well as PsycINFO were systematically retrieved for the records related to pesticide exposure during pregnancy and ASD and ADHD in offspring before August 30, 2022. The pesticide category, maternal age and window of exposure as the main subgroups were presented. RESULTS: 949 studies were initially identified, and 19 studies were eventually included. Eleven were on ASD, seven were on ADHD, and one was on both disorders. Maternal pesticide exposure was positively related to ASD (pooled OR = 1.19 (95%CI: 1.04 to 1.36)) and ADHD (pooled OR = 1.20 (95%CI: 1.04 to 1.38)) in offspring. In the subgroup analysis, organophosphorus pesticides (OPs) (pooled OR = 1.14 (95%CI: 1.04 to 1.24)), pyrethroid (pooled OR = 1.40 (95%CI: 1.09 to 1.80)), and maternal age ≥30 years old (pooled OR = 1.24 (95%CI: 1.10 to 1.40)) increased the risk of ASD in offspring. Maternal organochlorine pesticides (OCPs) exposure was a risk factor for ADHD in offspring (pooled OR = 1.22 (95%CI: 1.03 to 1.45)). CONCLUSION: Maternal pesticide exposure increased the risk of ASD and ADHD in offspring. Moreover, OPs, pyrethroid, and maternal age ≥30 years old were found to be risk factors affecting children's ASD. Maternal exposure to OCPs increased the risk of ADHD in offspring. Our findings contribute to our understanding of health risks related to maternal pesticide exposure and indicate that the in utero developmental period is a vulnerable window-of-susceptibility for ASD and ADHD risk in offspring. These findings should guide policies that limit maternal exposure to pesticides, especially for pregnant women living in agricultural areas.

Organophosphorus Pesticide Exposure at 17 Weeks' Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study.

Prenatal organophosphorus pesticides (OPs) are ubiquitous and have been linked to adverse neurodevelopmental outcomes. However, few studies have examined prenatal OPs in relation to diagnosed attention-deficit/hyperactivity disorder (ADHD), with only two studies exploring this relationship in a population primarily exposed through diet. In this study, we used a nested case-control study to evaluate prenatal OP exposure and ADHD diagnosis in the Norwegian Mother, Father, and Child Cohort Study (MoBa). For births that occurred between 2003 and 2008, ADHD diagnoses were obtained from linkage of MoBa participants with the Norwegian Patient Registry (N = 297), and a reference population was randomly selected from the eligible population (N = 552). Maternal urine samples were collected at 17 weeks' gestation and molar sums of diethyl phosphates (ΣDEP) and dimethyl phosphates metabolites (ΣDMP) were calculated. Multivariable adjusted logistic regression models were used to estimate the association between prenatal OP metabolite exposure and child ADHD diagnosis. Additionally, multiplicative effect measure modification (EMM) by child sex was assessed. In most cases, mothers in the second and third tertiles of ΣDMP and ΣDEP exposure had slightly lower odds of having a child with ADHD, although confidence intervals were wide and included the null. EMM by child sex was not observed for either ΣDMP or ΣDEP. In summary, we did not find evidence that OPs at 17 weeks' gestation increased the odds of ADHD in this nested case-control study of ADHD in MoBa, a population primarily experiencing dietary exposure.

Parental smoking exposure before and during pregnancy and offspring attention-deficit/hyperactivity disorder risk: A Chinese child and adolescent cohort study.

Background: Previous studies revealed that maternal smoking exposure during pregnancy was an essential risk factor for offspring developing attention-deficit/hyperactivity disorder (ADHD). The impact of paternal smoking exposure 1 year before pregnancy on offspring ADHD risk is still unclear. Methods: The present study included 2,477 school-age children and their parents from the Shanghai Child and Adolescent Health Cohort who had complete data for offspring ADHD diagnosis and parents' smoking exposure before and during pregnancy information. A multivariate logistic regression model and Firth's logistic regression model were used to determine the associations of paternal smoking and parental smoke exposure patterns before and during pregnancy with offspring ADHD risk. Results: Children whose fathers smoked before pregnancy had a higher risk of developing ADHD [odds ratio (OR) = 2.59, 95% confidence interval (CI): 1.35-4.98] compared to those whose fathers had never been exposed to smoking. Similarly, parents who were exposed to smoking or second-hand smoke before pregnancy had 1.96 times (OR = 1.96, 95% CI: 1.19-3.22) more likely to have offspring with ADHD. Moreover, children whose parents were exposed to smoking both before and during pregnancy were 2.01 times (OR = 2.01, 95% CI: 1.29-3.12) more likely to develop ADHD. Conclusion: Paternal smoking before pregnancy and parental smoking exposure 1 year ahead of and throughout pregnancy were all risk factors for offspring developing ADHD.

The protective effect of thymoquinone or/and thymol against monosodium glutamate-induced attention-deficit/hyperactivity disorder (ADHD)-like behavior in rats: Modulation of Nrf2/HO-1, TLR4/NF-κB/NLRP3/caspase-1 and Wnt/ß-Catenin signaling pathways in rat model.

Both thymoquinone (TQ) and thymol (T) have been proved to possess a positive impact on human health. In this research, we aimed to investigate the effect of these compounds separately and together on the Attention-deficit/hyperactivity disorder (ADHD)-like behavior induced by monosodium glutamate (MSG) in rats. Forty male, Spargue Dawley rat pups (postnatal day 21), were randomly allocated into five groups: Normal saline (NS), MSG, MSG+TQ, MSG+T, and MSG+TQ+T. MSG (0.4 mg/kg/day), TQ (10 mg/kg/day) and T (30 mg/kg/day) were orally administered for 8 weeks. The behavioral tests proved that rats treated with TQ and/or T showed improved locomotor, attention and cognitive functions compared to the MSG group with more pronounced effect displayed with their combination. All treated groups showed improvement in MSG-induced aberrations in brain levels of GSH, IL-1ß, TNF-α, GFAP, glutamate, calcium, dopamine, norepinephrine, Wnt3a, ß-Catenin and BDNF. TQ and/or T treatment also enhanced the mRNA expression of Nrf2, HO-1 and Bcl2 while reducing the protein expression of TLR4, NFκB, NLRP3, caspase 1, Bax, AIF and GSK3ß as compared to the MSG group. However, the combined therapy showed more significant effects in all measured parameters. All of these findings were further confirmed by the histopathological examinations. Current results concluded that the combined therapy of TQ and T had higher protective effects than their individual supplementations against MSG-induced ADHD-like behavior in rats.

Vinpocetine, a PDE1 modulator, regulates markers of cerebral health, inflammation, and oxidative stress in a rat model of prenatal alcohol-induced experimental attention deficit hyperactivity disorder.

Prenatal alcohol exposure (PAE) has been shown to induce symptomatology associated with attention deficit hyperactivity disorder (ADHD) by altering neurodevelopmental trajectories. Phosphodiesterase-1 (PDE1) is expressed centrally and has been used in various experimental brain conditions. We investigated the role of vinpocetine, a PDE1 inhibitor, on behavioral phenotypes and important biochemical deficits associated with a PAE rat model of ADHD. Protein markers of cerebral health (synapsin-IIa, BDNF, and pCREB), inflammation (IL-6, IL-10, and TNF-α), and oxidative stress (TBARS, GSH, and SOD) were analyzed in three brain regions (frontal cortex, striatum, and cerebellum). Hyperactivity, inattention, and anxiety introduced in the offspring due to PAE were assayed using open-field, Y-maze, and elevated plus maze, respectively. Administration of vinpocetine (10 & 20 mg/kg, p.o. [by mouth]) to PAE rat offspring for 4 weeks resulted in improvement of the behavioral profile of the animals. Additionally, levels of protein markers such as synapsin-IIa, BDNF, pCREB, IL-10, SOD, and GSH were found to be significantly increased, with a significant reduction in markers such as TNF-α, IL-6, and TBARS in selected brain regions of vinpocetine-treated animals. Vinpocetine, a selective PDE1 inhibitor, rectified behavioral phenotypes associated with ADHD, possibly by improving cerebral function, reducing brain inflammation, and reducing brain oxidative stress. This study provides preliminary analysis and suggests that the PDE1 enzyme may be an important pharmacological tool to study ADHD as a result of PAE.

Nicotine and the developing brain: Insights from preclinical models.

Use of tobacco products during pregnancy is associated with increased risk for neurodevelopmental disorders in the offspring. Preclinical models of developmental nicotine exposure have offered valuable insights into the neurobiology of nicotine's effects on the developing brain and demonstrated lasting effects of developmental nicotine exposure on brain structure, neurotransmitter signaling and behavior. These models have facilitated discovery of novel compounds as candidate treatments for attention deficit hyperactivity disorder, a neurodevelopmental disorder associated with prenatal nicotine exposure. Using these models the significance of heritability of behavioral phenotypes from the nicotine-exposed pregnant female or adult male to multiple generations of descendants has been demonstrated. Finally, research using the preclinical models has demonstrated synergistic interactions between developmental nicotine exposure and repetitive mild traumatic brain injury that contribute to "worse" outcomes from the injury in individuals with attention deficit hyperactivity disorder associated with developmental nicotine exposure.

Epilepsy in Pregnancy-Management Principles and Focus on Valproate.

An estimated 60 million people worldwide suffer from epilepsy, half of whom are women. About one-third of women with epilepsy are of childbearing age. The childbirth rate in women with epilepsy is about 20-40% lower compared to that of the general population, which may be partly due to a lower number of these women being in relationships. Lower fertility in women with epilepsy may be linked to the disease itself, but it is mainly a result of the treatment provided. Valproate, as an antiepileptic drug inhibiting histone deacetylases, may affect the expression of genes associated with cell cycle control and cellular differentiation. Evidently, this drug is associated with the risk of malformations although other antiepileptic drugs (AEDs) may also trigger birth defects, however, to a lower degree. Valproate (and to a certain degree other AEDs) may induce autism spectrum disorders and attention deficit hyperactivity disorder. The main mechanism responsible for all negative effects of prenatal exposure to valproate seems inhibition of histone deacetylases. Animal studies show a reduction in the expression of genes involved in social behavior and an increase in hippocampal cytokines. Valproate-induced oxidative stress may also contribute to neural tube defects. Interestingly, paternal exposure to this AED in mice may trigger neurodevelopmental disorders as well although a population-based cohort study does not confirm this effect. To lower the risk of congenital malformations and neurodevelopmental disorders, a single AED at the optimal dose and supplementation with folic acid is recommended. VPA should be avoided in women of childbearing age and especially during pregnancy.

The relationship between persistent organic pollutants and Attention Deficit Hyperactivity Disorder phenotypes: Evidence from task-based neural activity in an observational study of a community sample of Canadian mother-child dyads.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs), widespread in North America, is associated with increased Attention Deficit/Hyperactivity Disorder (ADHD) symptoms and may be a modifiable risk for ADHD phenotypes. However, the effects of moderate exposure to POPs on task-based inhibitory control performance, related brain function, and ADHD-related symptoms remain unknown, limiting our ability to develop interventions targeting the neural impact of common levels of exposure. OBJECTIVES: The goal of this study was to examine the association between prenatal POP exposure and inhibitory control performance, neural correlates of inhibitory control and ADHD-related symptoms. METHODS: Prospective data was gathered in an observational study of Canadian mother-child dyads, with moderate exposure to POPs, including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), as part of the GESTation and the Environment (GESTE) cohort in Sherbrooke, Quebec, Canada. The sample included 87 eligible children, 46 with maternal plasma samples, functional magnetic resonance imaging (fMRI) data of Simon task performance at 9-11 years, and parental report of clinical symptoms via the Behavioral Assessment System for Children 3 (BASC-3). Simon task performance was probed via drift diffusion modeling, and parameter estimates were related to POP exposure. Simon task-based fMRI data was modeled to examine the difference in incongruent vs congruent trials in regions of interest (ROIs) identified by meta analysis. RESULTS: Of the 46 participants with complete data, 29 were male, and mean age was 10.42 ± 0.55 years. Increased POP exposure was associated with reduced accuracy (e.g. PCB molar sum rate ratio = 0.95; 95% CI [0.90, 0.99]), drift rate (e.g. for PCB molar sum ß = -0.42; 95% CI [-0.77, -0.07]), and task-related brain activity (e.g. in inferior frontal cortex for PCB molar sum ß = -0.35; 95% CI [-0.69, -0.02]), and increased ADHD symptoms (e.g. hyperactivity PCB molar sum ß = 2.35; 95%CI [0.17, 4.53]), supporting the possibility that prenatal exposure to POPs is a modifiable risk for ADHD phenotypes. DISCUSSION: We showed that exposure to POPs is related to task-based changes in neural activity in brain regions important for inhibitory control, suggesting a biological mechanism underlying previously documented associations between POPs and neurobehavioral deficits found in ADHD phenotypes.

Bupropion Use Disorder by Chewing.

INTRODUCTION: Bupropion is a widely used antidepressant that plays an essential role in treating mental disorders. Due to its structural similarities with psychostimulants, bupropion is suggested to have addictive potential. Several case reports have been published addressing its misuse in recent years, mainly through nasal insufflation and intravenous administration. Most of the reported cases cited a history of substance use disorder. METHODS: Written informed consent was obtained from the patient to write this case report. CASE PRESENTATION: We present a case with alcohol use disorder and attention deficit hyperactivity disorder, who developed a substance use disorder to bupropion while chewing it in doses up to 2250 mg, in an attempt to get "high" with no history of seizures. DISCUSSION: Our case suggests that bupropion can also be misused by chewing even at high doses and that it can lead to a substance use disorder. Its use in various indications in treating mental disorders and its over-the-counter accessibility, along with a lower risk of stigmatization, could increase the prevalence of bupropion misuse. It is essential to know the medical consequences of bupropion misuse as there is increasing data on its addictive potential. More information is needed to clarify the impact of the route of administration on drug metabolism and adverse effects.

Neurotoxicity of pesticides in the context of CNS chronic diseases.

Following the introduction and application of pesticides in human life, they have always been along with health concerns both in acute poisoning and chronic toxicities. Neurotoxicity of pesticides in chronic exposures has been known as one of the most important human health problems, as most of these chemicals act through interacting with some elements of nervous system. Pesticide-induced neurotoxicity can be defined in different categories of neurological disorders including neurodegenerative (Alzheimer, Parkinson, amyotrophic lateral sclerosis, multiple sclerosis), neurodevelopmental (attention deficit hyperactivity disorder, autism spectrum disorders, developmental delay, and intellectual disability), neurobehavioral and neuropsychiatric (depression/suicide attempt, anxiety/insomnia, and cognitive impairment) disorders some of which are among the most debilitating human health problems. In this review, neurotoxicity of pesticides in the mentioned categories and sub-categories of neurological diseases have been systematically presented in relation to different route of exposures including general, occupational, environmental, prenatal, postnatal, and paternal.

Gestational Exposure to Organophosphate Pesticides and Longitudinally Assessed Behaviors Related to Attention-Deficit/Hyperactivity Disorder and Executive Function.

The brain's prefrontal cortex directs higher-order cognitive and behavioral processes that are important for attention, working memory, and inhibitory control. We investigated whether gestational exposure to organophosphate (OP) pesticides was associated with these abilities in childhood and early adolescence. Between 1999 and 2000, we enrolled pregnant women in a birth cohort drawn from an agricultural region of California. We measured dialkyl phosphate (DAP) metabolites of OP pesticides in maternal pregnancy urine samples (13 and 26 weeks) and estimated associations with behaviors related to attention-deficit/hyperactivity disorder and executive function, assessed longitudinally; 351 families provided neurodevelopmental outcome data at any point when the child was aged 7-12 years. We assessed function across multiple dimensions (e.g., working memory, attention), methods (e.g., behavior reports, child assessment), and reporters (e.g., mothers, teachers, child self-reports). Higher gestational DAP concentrations were consistently associated with behaviors related to attention-deficit/hyperactivity disorder and executive function. For example, a 10-fold increase in gestational DAP concentration was associated with poorer longitudinally assessed Behavior Rating Inventory of Executive Function scores, as reported by mothers (ß = 4.0 (95% confidence interval: 2.1, 5.8); a higher score indicates more problems), and Weschler Intelligence Scale for Children-Fourth Edition Working Memory scores (a 3.8-point reduction; ß = -3.8 (95% confidence interval: -6.2, -1.3)). Reducing gestational exposure to OP pesticides through public health policy is an important goal.

Association of Prenatal, Early Postnatal, or Current Exposure to Secondhand Smoke With Attention-Deficit/Hyperactivity Disorder Symptoms in Children.

Importance: Few studies have investigated the association between the exposure window (prenatal, early postnatal, and current period) of secondhand smoke (SHS) and attention-deficit/hyperactivity disorder (ADHD) symptoms and subtypes in children. Objective: To evaluate the associations of prenatal, early postnatal, or current SHS exposure with ADHD symptoms and subtypes among school-aged children. Design, Setting, and Participants: In this cross-sectional study, 48 612 children aged 6 to 18 years from elementary and middle schools in Liaoning province, China, between April 2012 and January 2013 were eligible for participation. Data on SHS exposure and ADHD symptoms and subtypes for each child were collected via questionnaires administered to parents or guardians by school teachers. Data were analyzed from September 14 to December 2, 2020. Main Outcomes and Measures: The ADHD symptoms and subtypes (inattention, hyperactivity-impulsivity, and combined) were measured based on a validated tool developed from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). Generalized linear mixed models were evaluated to estimate the association of SHS exposure with ADHD symptoms and subtypes. Results: A total of 45 562 participants completed the questionnaires and were included in this study (22 905 girls [50.3%]; mean [SD] age, 11.0 [2.6] years; 2170 [4.8%] with ADHD symptoms). Compared with their unexposed counterparts, children who were ever exposed (odds ratio [OR], 1.50; 95% CI, 1.36-1.66) or always exposed to SHS (OR, 2.88; 95% CI, 2.55-3.25) from pregnancy to childhood had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.46 [95% CI, 1.31-1.62] to 2.94 [95% CI, 2.09-4.13]). Compared with their unexposed counterparts, children with SHS exposure had higher odds of having ADHD symptoms when exposed in the prenatal period (OR, 2.28; 95% CI, 2.07-2.51), early postnatal period (OR, 1.47; 95% CI, 1.29-1.68), or current period (OR, 1.20; 95% CI, 1.09-1.31). Compared with their unexposed counterparts, children whose fathers smoked 10 or more cigarettes/d on both weekdays and weekends had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.48 [95% CI, 1.28-1.70] to 2.25 [95% CI, 1.29-3.93]). Conclusions and Relevance: Being exposed to SHS from pregnancy to childhood was associated with higher odds of having ADHD symptoms and subtypes among school-aged children, and the associations were somewhat stronger for SHS exposure during prenatal and early postnatal periods. Our findings highlight the important public health implications of reducing SHS exposure, which may decrease the health and economic burdens of individuals with ADHD.

DNA methylation of GFI1 as a mediator of the association between prenatal smoking exposure and ADHD symptoms at 6 years: the Hokkaido Study on Environment and Children's Health.

BACKGROUND: Prenatal smoking exposure has been associated with childhood attention-deficit/hyperactivity disorder (ADHD). However, the mechanism underlying this relationship remains unclear. We assessed whether DNA methylation differences may mediate the association between prenatal smoking exposure and ADHD symptoms at the age of 6 years. RESULTS: We selected 1150 mother-infant pairs from the Hokkaido Study on the Environment and Children's Health. Mothers were categorized into three groups according to plasma cotinine levels at the third trimester: non-smokers (≤ 0.21 ng/mL), passive smokers (0.21-11.48 ng/mL), and active smokers (≥ 11.49 ng/mL). The children's ADHD symptoms were determined by the ADHD-Rating Scale at the age of 6 years. Maternal active smoking during pregnancy was significantly associated with an increased risk of ADHD symptoms (odds ratio, 1.89; 95% confidence interval, 1.14-3.15) compared to non-smoking after adjusting for covariates. DNA methylation of the growth factor-independent 1 transcriptional repressor (GFI1) region, as determined by bisulfite next-generation sequencing of cord blood samples, mediated 48.4% of the total effect of the association between maternal active smoking during pregnancy and ADHD symptoms. DNA methylation patterns of other genes (aryl-hydrocarbon receptor repressor [AHRR], cytochrome P450 family 1 subfamily A member 1 [CYP1A1], estrogen receptor 1 [ESR1], and myosin IG [MYO1G]) regions did not exert a statistically significant mediation effect. CONCLUSIONS: Our findings demonstrated that DNA methylation of GFI1 mediated the association between maternal active smoking during pregnancy and ADHD symptoms at the age of 6 years.

Evaluation of the German biographic screening interview for fetal alcohol spectrum disorder (BSI-FASD).

Alcohol consumption during pregnancy may lead to permanent damage in the offspring, including fetal alcohol spectrum disorders (FASD), which have an estimated prevalence of 1-8% worldwide. In adulthood, diagnosing FASD is time-consuming and costly. This study aimed to evaluate the discriminatory power of a German screening instrument for FASD in adults-the biographic screening interview (BSI-FASD). In an open-label comparative cohort study wherein a one-time survey was administered per participant, we compared 22 subjects with confirmed FASD with control groups of 15 subjects diagnosed with attention deficit hyperactivity disorder (ADHD), 20 subjects with alcohol or opiate dependence, 18 subjects with depression, and 31 controls without prenatal alcohol exposure. The BSI-FASD was found to be resource-efficient, user-friendly, comprehensible, and easily applicable. It provided an overall good convergent and discriminant validity with a sensitivity of 0.77 (adapted 0.86) and specificities between 0.70 and 1.00. The BSI-FASD subdomains differed in their power to differentiate FASD from the groups. This study established that the BSI-FASD is an efficient instrument to screen adults with suspected FASD. The BSI-FASD may facilitate future diagnostic evaluation and thereby contribute to improved treatment of affected individuals.

Fetal methylphenidate exposure induced ADHD-like phenotypes and decreased Drd2 and Slc6a3 expression levels in mouse offspring.

Methylphenidate (MPD) is used as a first-line treatment for attention-deficit/hyperactivity disorder (ADHD). The number of prescriptions for ADHD patients is increasing, suggesting that the number of fertile women using such medication might be also increasing. The purpose of this study was to clarify the effects of MPD exposure during the fetal period on infant development, behavior, learning, and memory in mice. Expression levels of candidate genes associated with ADHD were also determined in the brain of pups born to MDP-treated dams who were administered MPD orally at a dose of 2.5, 7.5, or 15 mg/kg daily from gestational day 1 to the day before delivery. Offspring aged 6-8 weeks were subjected to the spontaneous locomotor activity, elevated plus-maze, and passive avoidance tests and therapeutic treatments with MPD or atomoxetine. Fetal MPD exposure induced ADHD-like phenotypes, such as hyperactivity and impulsivity, in mouse offspring, which were suppressed by treatment with MPD and atomoxetine. These mice showed decreased Drd2 and Slc6a3 expression levels in the brain, which are often observed in ADHD model animals. Our results suggest that continuous use of MPD during pregnancy induces ADHD phenotypes in the offspring.

Synergistic efficacy and diminished adverse effect profile of composite treatment of several ADHD medications.

Although attention-deficit/hyperactivity disorder (ADHD) is widely studied, problems regarding the adverse effect risks and non-responder problems still need to be addressed. Combination pharmacotherapy using standard dose regimens of existing medication is currently being practiced mainly to augment the therapeutic efficacy of each drug. The idea of combining different pharmacotherapies with different molecular targets to alleviate the symptoms of ADHD and its comorbidities requires scientific evidence, necessitating the investigation of their therapeutic efficacy and the mechanisms underlying the professed synergistic effects. Here, we injected male ICR mice with MK-801 to induce ADHD behavioral condition. We then modeled a "combined drug" using sub-optimal doses of methylphenidate, atomoxetine, and fluoxetine and investigated the combined treatment effects in MK-801-treated mice. No sub-optimal dose monotherapy alleviated ADHD behavioral condition in MK-801-treated mice. However, treatment with the combined drug attenuated the impaired behavior of MK-801-treated animals. Growth impediment, sleep disturbances, or risk of substance abuse were not observed in mice treated subchronically with the combined drugs. Finally, we observed that the combined ADHD drug rescued alterations in p-AKT and p-ERK1/2 levels in the prefrontal cortex and hippocampus, respectively, of MK-801-treated mice. Our results provide experimental evidence of a possible new pharmacotherapy option in ameliorating the ADHD behavioral condition without the expected adverse effects. The detailed mechanism of action underlying the synergistic therapeutic efficacy and reduced adverse reaction by combinatorial drug treatment should be investigated further in future studies.

Maternal smoking during pregnancy and physiological anxiety in children with attention deficit hyperactivity disorder.

Our objective was to explore the relationship between mother smoking during pregnancy and physiological anxiety of children with Attention deficit-hyperactivity disorder. Cognitive profile was evaluated by Wechsler Intelligence Scale for Children, physiological anxiety by Children's Manifest Anxiety Scale. Mother's smoking was evaluated by the Fagerström test for nicotine dependence. Ninety-seven children with Attention Deficit-Hyperactivity Disorder combined type, 70 inattentive, and 48 hyperactive-impulsive, and 130 controls were studied. We found a higher frequency of high smoking dependence in mothers of children with Attention Deficit-Hyperactivity Disorder-combined type, and Attention Deficit Hyperactivity Disorder-hyperactive type in the Fagerström test; and a significant correlation between physiological anxiety in children with Attention Deficit Hyperactivity Disorder-combined type, with high and moderate maternal smoking level during pregnancy. In conclusion, data suggests, with caution a brain alteration of infants, induced by nicotine exposure during pregnancy in children with Attention Deficit Hyperactivity Disorder-combined type, and Attention Deficit Hyperactivity Disorder-hyperactive type.