Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability.

Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. Results: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

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.

Treatments for ADHD in Children and Adolescents: A Systematic Review.

CONTEXT: Effective treatment of attention-deficit/hyperactivity disorder (ADHD) is essential to improving youth outcomes. OBJECTIVES: This systematic review provides an overview of the available treatment options. DATA SOURCES: We identified controlled treatment evaluations in 12 databases published from 1980 to June 2023; treatments were not restricted by intervention content. STUDY SELECTION: Studies in children and adolescents with clinically diagnosed ADHD, reporting patient health and psychosocial outcomes, were eligible. Publications were screened by trained reviewers, supported by machine learning. DATA EXTRACTION: Data were abstracted and critically appraised by 1 reviewer and checked by a methodologist. Data were pooled using random-effects models. Strength of evidence and applicability assessments followed Evidence-based Practice Center standards. RESULTS: In total, 312 studies reported in 540 publications were included. We grouped evidence for medication, psychosocial interventions, parent support, nutrition and supplements, neurofeedback, neurostimulation, physical exercise, complementary medicine, school interventions, and provider approaches. Several treatments improved ADHD symptoms. Medications had the strongest evidence base for improving outcomes, including disruptive behaviors and broadband measures, but were associated with adverse events. LIMITATIONS: We found limited evidence of studies comparing alternative treatments directly and indirect analyses identified few systematic differences across stimulants and nonstimulants. Identified combination of medication with youth-directed psychosocial interventions did not systematically produce better results than monotherapy, though few combinations have been evaluated. CONCLUSIONS: A growing number of treatments are available that improve ADHD symptoms and other outcomes, in particular for school-aged youth. Medication therapies remain important treatment options but are associated with adverse events.

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.

A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD.

OBJECTIVE: To compare PRC-063 (multilayer-release methylphenidate) and lisdexamfetamine dimesylate (LDX) on the driving performance of young adults with attention deficit hyperactivity disorder (ADHD) in a randomized, double-blind, crossover study. METHOD: Following up to 21 days of each treatment in each treatment course (PRC-063/LDX or LDX/PRC-063), subjects completed a 15-hour driving simulator laboratory assessment. The primary outcome measure was the Tactical Driving Quotient (TDQ) and the Clinical Global Impressions-Improvement (CGI-I) scale was a secondary outcome measure. RESULTS: Forty-four subjects completed the study. PRC-063 and LDX had equivalent effects on driving performance through a 15-hour time period (least square mean difference -0.3 [standard error 1.08], 95% confidence interval [-2.4, 1.8], p = .793). Consistent improvement in CGI-I was observed. The incidence of treatment-emergent adverse events was similar for each treatment sequence. CONCLUSIONS: PRC-063 and LDX had comparable effects on driving performance, from 1 through 15 hours, the last time point measured.

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD.

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (GD 3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.

Prenatal caffeine consumption and neurobehavioral disorders - A systematic review.

Studies have suggested associations between gestational exposure to caffeine and adverse outcomes, however the evidence is still limited. Therefore, a systematic review was conducted to investigate the association between prenatal caffeine exposure and neurobehavioral disorders. The MEDLINE (PubMed), EMBASE, Scopus, Web of Science, and LILACS databases were searched. Observational studies involving women with documented caffeine consumption during pregnancy were eligible for inclusion. The outcomes evaluated were behavioral and intellectual development, Attention Deficit Hyperactivity Disorder, and related behaviors. The data were analyzed by qualitative synthesis. The ROBINS-I tool was employed to assess the risk of bias, and the certainty of evidence was evaluated using GRADE (PROSPERO: CRD42023421164). The search yielded fourteen studies that met the inclusion/exclusion criteria. The sample size among pregnant women ranged from 173 to 64,189, and among children ranged from 88 to 49,190. Maternal caffeine consumption during pregnancy ranged from 0 to 1000 mg/day, with the highest levels observed during mid-pregnancy. Seven studies indicated a potential association between prenatal caffeine exposure and neurobehavioral/neurodevelopment deficits, one study showed that prenatal caffeine exposure improved peer problems, and six studies did not show a significant effect of prenatal caffeine consumption on neurobehavioral disorders. The included studies were classified as moderate for the risk of bias and with very low certainty of evidence. Thus, the evidence is insufficient to confirm with certainty that the prenatal caffeine exposure leads to neurobehavioral disorders. Studies heterogenicity, as well as their variable quality and the presence of several confounding factors, generate uncertainty.

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study.

OBJECTIVE: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. METHODS: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). RESULTS: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. CONCLUSION: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

QT-Interval Prolongation Associated with Supratherapeutic Guanfacine Concentration: A Case Report.

INTRODUCTION: Guanfacine, an alpha-2 adrenergic agonist, is used to treat attention deficit hyperactivity disorder (ADHD). Although cardiovascular effects including hypotension and bradycardia are common adverse effects of guanfacine, the effect of guanfacine on QT intervals remains unclear. The association between the serum concentration of guanfacine and its toxicity has also not been fully investigated. CASE REPORT: This is a case of a 21-year-old woman with ADHD who developed repeated presyncope 1 day before admission. She was taking 3 mg of extended-release guanfacine and 50 mg of sertraline. On admission, she had bradycardia and hypotension. An electrocardiogram (ECG) showed a QT interval of 0.68 s and a QTcF interval of 0.648 s. The QT intervals were manually measured and corrected by the Fridericia formula (QTcF = QT/RR1/3). Although she denied taking an overdose of guanfacine and other drugs, we suspected guanfacine toxicity. The serum guanfacine concentration was 13.0 ng/mL on admission and decreased to 3.2 ng/mL on day 1 and 0.4 ng/mL on day 2. Changes in QTcF intervals and her vital signs correlated with serum guanfacine concentrations. CONCLUSION: Supratherapeutic serum guanfacine concentrations may induce QT prolongation.

Methylphenidate alleviates cognitive dysfunction caused by early manganese exposure: Role of catecholaminergic receptors.

Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and psychomotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attentional and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally induced attentional and psychomotor dysfunction in children more broadly.

Exposure to chlorpyrifos and pyrethroid insecticides and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in preschool children from the Odense Child Cohort.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood psychiatric disorder with severe and lifelong impact on mental health and socioeconomic achievements. Environmental factors may play a role in the increasing incidens rates. Previous studies on associations between prenatal and childhood exposure to organophosphate and pyrethroid insecticides and ADHD symptoms have yielded mixed findings. OBJECTIVES: To investigate associations between prenatal and childhood exposure to chlorpyrifos and pyrethroids and ADHD symptoms in 5-year-old children from the Odense Child Cohort. METHODS: Spot urine samples from pregnant women in gestational week 28 (n = 614) and offspring at 5 years of age (n = 814) were collected and analyzed for the specific metabolite of chlorpyrifos, TCPY (3,5,6-trichloro-2-pyridinol), as well as the generic pyrethroid metabolite, 3-PBA (3-phenoxybenzoic acid). Offspring ADHD symptoms were assessed at age 5 years using the parent reported "ADHD scale" from the "Child Behavior Checklist 1½-5" (n = 1114). Associations between insecticide exposure variables and an ADHD score ≥90th percentile were analyzed using logistic regression for all children and stratified by sex. RESULTS: Most pregnant women had detectable concentrations of 3-PBA (93%) and TCPY (91%) with median concentrations of 0.20 µg/L and 1.62 µg/L, respectively. In children, 3-PBA and TCPY concentrations were detectable in 88% and 82% of the samples, and the median concentrations were 0.17 and 1.16 µg/L. No statistically significant associations were observed between insecticide metabolites and an ADHD score ≥90th percentile at age 5. CONCLUSION: In this relatively large Danish birth cohort study with mainly low dietary insecticide exposure, we found no statistically significant associations between prenatal or childhood exposure to chlorpyrifos or pyrethroids, and excess ADHD-symptom load, in 5-year-old children. Prospective studies with multiple urine samples across vulnerable windows of neurodevelopment is warranted to improve assessment of safe exposure levels, which is particularly relevant for pyrethroids, since their use is increasing.

Susceptible windows of prenatal and postnatal fine particulate matter exposures and attention-deficit hyperactivity disorder symptoms in early childhood.

Few prior studies have explored windows of susceptibility to fine particulate matter (PM2.5) in both the prenatal and postnatal periods and children's attention-deficit/hyperactivity disorder (ADHD) symptoms. We analyzed data from 1416 mother-child pairs from the Spanish INMA (INfancia y Medio Ambiente) Study (2003-2008). Around 5 years of age, teachers reported the number of ADHD symptoms (i.e., inattention, hyperactivity/impulsivity) using the ADHD Diagnostic and Statistical Manual of Mental Disorders. Around 7 years of age, parents completed the Conners' Parent Rating Scales, from which we evaluated the ADHD index, cognitive problems/inattention, hyperactivity, and oppositional subscales, reported as age- and sex-standardized T-scores. Daily residential PM2.5 exposures were estimated using a two-stage random forest model with temporal back-extrapolation and averaged over 1-week periods in the prenatal period and 4-week periods in the postnatal period. We applied distributed lag non-linear models within the Bayesian hierarchical model framework to identify susceptible windows of prenatal or postnatal exposure to PM2.5 (per 5-µg/m3) for ADHD symptoms. Models were adjusted for relevant covariates, and cumulative effects were reported by aggregating risk ratios (RRcum) or effect estimates (ßcum) across adjacent susceptible windows. A similar susceptible period of exposure to PM2.5 (1.2-2.9 and 0.9-2.7 years of age, respectively) was identified for hyperactivity/impulsivity symptoms assessed ~5 years (RRcum = 2.72, 95% credible interval [CrI] = 1.98, 3.74) and increased hyperactivity subscale ~7 years (ßcum = 3.70, 95% CrI = 2.36, 5.03). We observed a susceptibility period to PM2.5 on risk of hyperactivity/impulsivity symptoms ~5 years in gestational weeks 16-22 (RRcum = 1.36, 95% CrI = 1.22, 1.52). No associations between PM2.5 exposure and other ADHD symptoms were observed. We report consistent evidence of toddlerhood as a susceptible window of PM2.5 exposure for hyperactivity in young children. Although mid-pregnancy was identified as a susceptible period of exposure on hyperactivity symptoms in preschool-aged children, this association was not observed at the time children were school-aged.

Cardiovascular Safety of Atomoxetine and Methylphenidate in Patients With Attention-Deficit/Hyperactivity Disorder in Japan: A Self-Controlled Case Series Study.

OBJECTIVE: To investigate the association between atomoxetine or methylphenidate use and arrhythmia, heart failure (HF), stroke, and myocardial infarction (MI) in attention-deficit/hyperactivity disorder (ADHD) patients mainly focused on the people of working age. METHODS: In a self-controlled case series study using a Japanese claims database, we identified events of arrhythmia, HF, stroke, and MI among 15,472 atomoxetine new users and 12,059 methylphenidate new users. Adjusted incidence rate ratios (aIRRs) of outcome events were estimated using multivariable conditional Poisson regression. RESULTS: An increased risk of arrhythmia was observed during the first 7 days after the initial atomoxetine exposure (aIRR 6.22, 95% CI [1.90, 20.35]) and in the subsequent exposure (3.23, [1.58, 6.64]). No association was found between methylphenidate exposure and arrhythmia, nor between atomoxetine or methylphenidate exposure and HF. The limited number of stroke and MI cases prevented thorough analysis. CONCLUSIONS: Clinicians should consider monitoring for arrhythmia after patients initiating or re-initiating atomoxetine.

Stimulant Treatment and Potential Adverse Outcomes in Pediatric Populations With Bipolar Disorder: A Systematic Review of the Literature.

OBJECTIVE: To explore outcomes of stimulant treatment for ADHD in pediatric populations with particular attention to bipolar disorder (BPD). METHOD: We conducted a literature search of PubMed articles published prior to August 25, 2022 that focused on BPD, mania, and psychosis prior to, or as result of, stimulant treatment. We excluded studies: (1) unrelated to stimulants, (2) general stimulant research, (3) articles older than 40 years, (4) study protocols, or (5) case reports. RESULTS: A total of 11 articles met all inclusion/exclusion criteria. Some reports found stimulant treatment safe and well-tolerated in children with comorbid BPD and ADHD. Others found evidence of treatment-emergent mania (TEM), discontinuation, and other adverse events with stimulant treatment. CONCLUSION: Poor outcomes associated with stimulant treatment in pediatric populations with BPD necessitate work to identify patients at risk of serious stimulant-related adverse events. Our results were limited by automated search filters and a pediatric, primarily male sample.

A new mechanistic insight into the association between environmental perfluorooctane sulfonic acid (PFOS) exposure and attention deficit and hyperactivity disorder (ADHD)-like behavior.

Perfluorooctane sulfonic acid (PFOS) is one of the main residual environmental pollutants that threaten human health. PFOS exposure is positively correlated with the prevalence of attention deficit hyperactivity disorder (ADHD); however, the underlying mechanism is unknown. Given that dopamine (DA) is a crucial target for PFOS and that its dysfunction is a key role in ADHD development, it is speculated that PFOS exposure contributes to the occurrence of ADHD to some extent by disrupting DA homeostasis. To establish the relationship between PFOS exposure, DA dysfunction, and ADHD-like behavior, adult zebrafish were exposed to PFOS for 21 days using PFOS concentrations in the serum of patients with ADHD as the reference exposure dose. Results showed that PFOS caused ADHD-like behaviors, with the presence of the slightly elevated percentage of time spent in movement and prolonged time spent in reaching the target zone in the T-maze. Hyperactivity and cognitive ability impairment were more severe with increasing PFOS concentrations. Further investigation showed that PFOS exposure resulted in a decrease in the DA content, accompanied by a decrease in the number of dopaminergic neurons and a disturbance in the transcription profiles of genes associated with the dopaminergic system. Treatment with Ritalin effectively alleviated PFOS-induced ADHD-like behavior and restored DA levels, number of dopaminergic neurons, and expression of DA metabolism-related genes, suggesting that PFOS exposure induced ADHD-like behavior by triggering DA secretion disorder. This study enriches our understanding of the pathogenic mechanisms underlying ADHD development and emphasizes the importance of focusing on the health risks pertaining to environmental exposure.

An Examination of the Relationship Between Exposure to Bisphenol A and Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.

OBJECTIVES: Exposure to environmental toxic agents in the prenatal and/or postnatal periods may play in the acquired development of attention-deficit/hyperactivity disorder (ADHD) in groups with genetic risks. Bisphenol A (BPA) is a widely used industrial chemical with neurotoxic effects. This study examined the relationship between exposure to BPA and clinical ADHD. METHODS: This cross-sectional, case-controlled clinical study compared 45 drug-naive children and adolescents with ADHD and 30 healthy controls in terms of serum BPA levels. Psychiatric comorbidities in the ADHD group were determined using the "Schedule for Affective Disorders and Schizophrenia for school-aged children, lifetime version." The Child Behavior Checklist (CBCL) was also administered to all participants. RESULTS: Serum BPA levels were significantly higher in the ADHD group than in the healthy control group. In addition, significant, weak positive correlation was found between BPA levels and CBCL attention and CBCL total problem scores. CONCLUSIONS: Our results show that BPA may be an environmental toxic agent with a potential role in the etiology of ADHD and particularly attention deficiency. Preventive interventions can be developed if this can be confirmed with longitudinal studies and repeated measurements.

Urinary heavy metals and attention-deficit/hyperactivity symptoms of preschool children: a mixed-exposure analysis.

The neurotoxic effects of certain heavy metals are well established, but only a few studies have investigated the joint effect of concurrent exposure to multiple ones. The study aims to evaluate the association between mixed exposure to neurotoxic metals and the psychosocial behavior of preschool children. Using a stratified sampling strategy, we recruited participants from 105 kindergartens in 41 townships of Taiwan and excluded those with blood lead levels ≥ 3.5 µg/L. The first-morning void urines were collected and analyzed for cadmium, manganese, arsenic, chromium, lead, and nickel concentrations using inductively coupled plasma mass spectrometry. We applied the parentally reported Strengths and Difficulties Questionnaire (SDQ) and Swanson, Nolan, and Pelham IV (SNAP-IV) scales to evaluate the psychosocial behaviors. Multiple linear regressions were utilized to evaluate the associations between each heavy metal and the outcomes, while the mixed effect of concurrent exposure was estimated by using a Quantile g-computation approach. A total of 977 preschool children were included in the study, and the mean (SD) age was 5.7 (0.7) years old. In single pollutant models, we observed adverse effects of urinary manganese, nickel, arsenic, and lead on the specific subsets of SDQ. Furthermore, the combined effect of six heavy metals significantly affected the hyperactivity/inattention symptoms (beta = 0.46, 95% CI: 0.13-0.78, with all metals increased by one quartile), and chromium and lead were the two major contributors. Similar detrimental effects of urinary cadmium and lead were also observed in the SNAP-IV subsets, although the joint effect analysis was not significant. The study provided evidence that concurrent exposure to multiple heavy metals may exert increased risks of hyperactivity/inattention in children compared to single pollutant exposure. Further studies are needed to verify our findings regarding mixed exposure to multiple neurotoxic metals.

Exposure to environmental pollutants and attention-deficit/hyperactivity disorder: an overview of systematic reviews and meta-analyses.

Although heritability estimates suggest a role for genetic components, environmental risk factors have been described as relevant in the etiology of attention deficit/hyperactivity disorder (ADHD). Several studies have investigated the role of toxicological pollution, i.e., air pollution, heavy metals, POPs, and phthalates. Clear evidence for association of ADHD and environmental factors has not been provided yet. To answer this, we have assessed all available systematic reviews and meta-analyses that focused on the association between pollutant exposure and either ADHD diagnosis or symptoms. More than 1800 studies were screened of which 14 found eligible. We found evidence of a significant role for some pollutants, in particular heavy metals and phthalates, in the increased risk of developing ADHD symptoms. However, at the current stage, data from existing literature also do not allow to weight the role of the different environmental pollutants. We also offer a critical examination of the reviews/meta-analyses and provide indications for future studies in this field. PROSPERO registration: CRD42022341496.

l-Arginine/nitric oxide pathway and oxidative stress in adults with ADHD: Effects of methylphenidate treatment.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a mental disorder that was once thought to occur only in children. Meanwhile, it is known that adults can also be affected. The first-line drug in children and adults to treat symptoms of inattention, impulsivity, lack of self-regulation, and hyperactivity is methylphenidate (MPH). Known adverse effects of MPH include cardiovascular problems, such as elevated blood pressure and heart rate. Therefore, biomarkers to monitor potential cardiovascular side effects of MPH are needed. The l-Arginine/Nitric oxide (Arg/NO) pathway is involved in noradrenaline and dopamine release as well as in normal cardiovascular functioning and is therefore a prime candidate for the search of biomarkers. The aim of the present study was to investigate the Arg/NO pathway as well as oxidative stress in adult ADHD patients in plasma and urine and the potential influence of MPH medication. METHODS: In plasma and urine samples of 29 adults with ADHD (39.2 ± 10.9 years) and 32 healthy adults serving as controls (CO) (38.0 ± 11.6 years) the major NO metabolites nitrite and nitrate, Arg, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) as well as malondialdehyde (MDA) were measured by gas chromatography-mass spectrometry. RESULTS: Of the 29 patients with ADHD 14 were currently without MPH treatment (-MPH) and 15 were treated with MPH (+MPH). Plasma nitrate concentrations were significantly higher in patients not treated with MPH vs. CO (-MPH 60.3 µM [46.2-76.0] vs. CO 44.4 µM [35.0-52.7]; p = 0.002), while plasma nitrite tended to be higher in -MPH patients (2.77 µM [2.26-3.27]) vs. CO (2.13 µM [1.50-2.93]; p = 0.053). Additionally, plasma creatinine concentrations were significantly different, with -MPH showing significantly higher concentrations than the other two groups (-MPH 141 µM [128-159]; +MPH 96.2 µM [70.2-140]; Co 75.9 µM [62.0-94.7]; p < 0.001). Urinary creatinine excretion tended to be lowest in -MPH group vs. +MPH and CO (-MPH 11.4 ± 8.88 mM; +MPH 20.7 ± 9.82 mM; 16.6 ± 7.82 mM; p = 0.076). None of the other metabolites, including MDA, a marker of oxidative stress, showed a difference between the groups. CONCLUSION: Adult patients with ADHD, who are not treated with MPH (-MPH), showed varied Arg/NO pathway, but Arg bioavailability seemed to be consistent over the groups. Our findings imply that urinary reabsorption may be increase and/or excretion of nitrite and nitrate may be decreased in ADHD, resulting in an increase in the plasma concentration of nitrite. MPH seems to partially reverse these effects by not yet known mechanisms, and does not affect oxidative stress.

Association of maternal prenatal urinary fluoride levels with ADHD symptoms in childhood.

BACKGROUND: Health concerns about the potential impact of exposure to fluoride via drinking water (DW) on neuropsychological development include behavioral outcomes such as ADHD. OBJECTIVE: We aimed to examine the association between prenatal maternal urinary fluoride and symptoms associated with attention-deficit/hyperactivity disorder (ADHD) at the age of 8 and 11 years. METHOD: Data from 255 to 236 mother-child pairs from the "Infancia y Medio Ambiente" (INMA) birth cohort (Gipuzkoa; Spain) with maternal urinary F adjusted for creatinine (MUFcr) during pregnancy (first and third trimester) and child assessments of ADHD-like symptoms reported by Conners' Rating Scales-Revised at age of 8 and 11 years was available. Clinical approach was also used: cut off criteria (T > 66). Multiple linear regression models were fitted when outcomes were analyzed as continuous, and logistic regression models when the outcomes were analyzed with a categorical clinical approach. Covariates related to maternal characteristics, birth outcomes, childhood, quality of family context and biomarkers of neuro-toxicants were used. RESULTS: No association was found between MUFcr levels during pregnancy and cognitive problems-inattention, hyperactivity or ADHD index score of symptoms at 8 or 11 years. When results were analyzed from the perspective of a clinical approach, at the age of 11 years, there were significant inverse association between MUFcr and being categorized as a cognitive problems-inattention case. ORs were also indicative of a lower risk, although not significant, for ADHD index at age 11. Sensitivity analyses, taking into consideration quality of family context or the levels of other toxicants during pregnancy showed similar results. CONCLUSIONS: Higher levels of MUFcr in pregnant women were associated with a lower risk of cognitive problems-inattention at 11 years. These findings are inconsistent with those from previous studies and indicate the need for other population-based studies to confirm or overturn these results.