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      Attention Deficit/Hyperactivity Disorder and Urinary Nonylphenol Levels: A Case-Control Study in Taiwanese Children

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          Abstract

          Objective

          Nonylphenol (NP) belongs to the family of endocrine disruptors, and it is widely used in industrial applications and is ubiquitous in daily foods. Animal studies have suggested that NP exposure might promote motor hyperactivity, likely by causing deficits in dopaminergic neurons. However, research assessing NP exposure and epidemiology studies on human populations are limited. The aim of this study was to explore the association between child NP exposure and ADHD while considering particular covariants, such as lead levels and dopamine-related gene variations.

          Methods

          A case-control study was conducted on patients with clinically diagnosed ADHD; the Swanson, Nolan and Pelham, Fourth Revision (SNAP-IV) questionnaire was used to identify normal controls aged 4–15 years. Participants were examined for urinary NP concentrations, blood lead levels, and select single-nucleotide polymorphisms of two dopamine-related genes (D4 dopamine receptor, DRD4, and dopamine transporter, DAT1). Socio-demographic variables, maternal lifestyle factors during pregnancy and family medical history were obtained using a questionnaire.

          Results

          A total of 97 children with doctor-diagnosed ADHD and 110 normal controls were enrolled. The blood lead levels in both groups were similar (1.57±0.73 vs. 1.73±0.77 μg/dL, p = 0.15). No significant difference in urinary NP concentration was found between the children with ADHD and the control subjects (4.52±3.22 μg/g cr. vs. 4.64±2.95 μg/g cr., p = 0.43). ADHD was significantly more prevalent among males in this study (male to female ratio: 5:1 for the ADHD group and 1.3:1 for the control group, p<0.01). The analysis was repeated after excluding the females, but this had no effect on the association between NP and ADHD. The regression model, including or excluding females, indicated no increased odds of having ADHD in the context of NP exposure after adjusting for covariants.

          Conclusion

          This study indicated that NP exposure might not promote ADHD in children, even though children in Taiwan had relatively high levels of NP compared to those reported previously and those in developed nations.

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          Most cited references61

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          Molecular genetics of attention-deficit/hyperactivity disorder.

          Stephen V. Faraone, Roy H Perlis, Alysa E Doyle … (2005)
          Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
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            Attention-deficit/hyperactivity disorder: a selective overview.

            Joseph Biederman (2005)
            Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial and clinically heterogeneous disorder that is associated with tremendous financial burden, stress to families, and adverse academic and vocational outcomes. Attention-deficit/hyperactivity disorder is highly prevalent in children worldwide, and the prevalence of this disorder in adults is increasingly recognized. Studies of adults with a diagnosis of childhood-onset ADHD indicate that clinical correlates--demographic, psychosocial, psychiatric, and cognitive features--mirror findings among children with ADHD. Predictors of persistence of ADHD include family history of the disorder, psychiatric comorbidity, and psychosocial adversity. Family studies of ADHD have consistently supported its strong familial nature. Psychiatric disorders comorbid with childhood ADHD include oppositional defiant and conduct disorders, whereas mood and anxiety disorders are comorbid with ADHD in both children and adults. Pregnancy and delivery complications, maternal smoking during pregnancy, and adverse family environment variables are considered important risk factors for ADHD. The etiology of ADHD has not been clearly identified, although evidence supports neurobiologic and genetic origins. Structural and functional imaging studies suggest that dysfunction in the fronto-subcortical pathways, as well as imbalances in the dopaminergic and noradrenergic systems, contribute to the pathophysiology of ADHD. Medication with dopaminergic and noradrenergic activity seems to reduce ADHD symptoms by blocking dopamine and norepinephrine reuptake. Such alterations in dopaminergic and noradrenergic function are apparently necessary for the clinical efficacy of pharmacologic treatments of ADHD.
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              Urinary Concentrations of Bisphenol A and 4-Nonylphenol in a Human Reference Population

              Antonia M Calafat, Zsuzsanna Kuklenyik, John A. Reidy … (2004)
              Bisphenol A (BPA) is used to manufacture polycarbonate plastic and epoxy resins, which are used in baby bottles, as protective coatings on food containers, and for composites and sealants in dentistry. 4-Nonylphenol (NP) is used to make nonylphenol ethoxylates, nonionic surfactants applied as emulsifying, wetting, dispersing, or stabilizing agents in industrial, agricultural, and domestic consumer products. The potential for human exposure to BPA and NP is high because of their widespread use. We measured BPA and NP in archived urine samples from a reference population of 394 adults in the United States using isotope-dilution gas chromatography/mass spectrometry. The concentration ranges of BPA and NP were similar to those observed in other human populations. BPA was detected in 95% of the samples examined at concentrations ≥0.1 μg/L urine; the geometric mean and median concentrations were 1.33 μg/L (1.36 μg/g creatinine) and 1.28 μg/L (1.32 μg/g creatinine), respectively; the 95th percentile concentration was 5.18 μg/L (7.95 μg/g creatinine). NP was detected in 51% of the samples examined ≥0.1 μg/L. The median and 95th percentile concentrations were < 0.1 μg/L and 1.57 μg/L (1.39 μg/g creatinine), respectively. The frequent detection of BPA suggests widespread exposure to this compound in residents of the United States. The lower frequency of detection of NP than of BPA could be explained by a lower exposure of humans to NP, by different pharmacokinetic factors (i.e., absorption, distribution, metabolism, elimination), by the fact that 4-n-nonylphenol—the measured NP isomer—represents a small percentage of the NP used in commercial mixtures, or a combination of all of the above. Additional research is needed to determine the best urinary biomarker(s) to assess exposure to NP. Despite the sample population’s nonrepresentativeness of the U.S. population (although sample weights were used to improve the extent to which the results represent the U.S. population) and relatively small size, this study provides the first reference range of human internal dose levels of BPA and NP in a demographically diverse human population.
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                Author and article information

                Contributors
                Manuel Portolés: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 18 February 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 2
                Electronic Location Identifier: e0149558
                Affiliations
                [1 ]Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang Ming University, Taipei, Taiwan
                [2 ]Department of Pediatrics, Taipei City Hospital, Zhongxiao branch, Taipei, Taiwan
                [3 ]Department of Child and Adolescent Psychiatry, Taipei City Hospital, Songde branch, Taipei, Taiwan
                [4 ]Department of Pediatrics, Taipei City Hospital, Yangming branch, Taipei, Taiwan
                [5 ]Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei, Taiwan
                [6 ]School of Public Health, Taipei Medical University, Taipei, Taiwan
                Hospital Universitario LA FE, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CJY JCD WY MYC BH MLC. Performed the experiments: CJY JCD HCC SHY KWL WY. Analyzed the data: CJY JCD SHY KWL MYC. Contributed reagents/materials/analysis tools: JCD LCC MLC. Wrote the paper: CJY MLC.

                Article
                Publisher ID: PONE-D-15-22907
                DOI: 10.1371/journal.pone.0149558
                PMC ID: 4758720
                PubMed ID: 26890918
                SO-VID: f82be47d-2f84-4955-9c25-61a360937e1d
                Copyright © © 2016 Yu et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 2 June 2015
                Date accepted : 2 February 2016
                Page count
                Figures: 0, Tables: 5, Pages: 15
                Funding
                This study was financially supported by Department of Health, Taipei City Government, and Aiming for the Top University Plan from the Ministry of Education of the Republic of China, Taiwan. The work was also supported by the National Science Council of Taiwan, grant number NSC 96-2314-B-010-020-MY3, and by MOST 103-2319-B-010-001 from the National Core Facility Program for Biotechnology of Taiwan. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Developmental Neuroscience
                Subject: Neurodevelopmental Disorders
                Subject: Adhd
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Neurodevelopmental Disorders
                Subject: Adhd
                Subject: Medicine and Health Sciences
                Subject: Mental Health and Psychiatry
                Subject: Neuropsychiatric Disorders
                Subject: Adhd
                Subject: People and Places
                Subject: Population Groupings
                Subject: Age Groups
                Subject: Children
                Subject: People and Places
                Subject: Population Groupings
                Subject: Families
                Subject: Children
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Urine
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Urine
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Urine
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Urine
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Organic Compounds
                Subject: Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Organic Chemistry
                Subject: Organic Compounds
                Subject: Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neurochemistry
                Subject: Neurotransmitters
                Subject: Biogenic Amines
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Hormones
                Subject: Catecholamines
                Subject: Dopamine
                Subject: Social Sciences
                Subject: Sociology
                Subject: Education
                Subject: Educational Attainment
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Biomarkers
                Subject: Creatinine
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Regression Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Regression Analysis
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