Endocrine Disruptors and Neurobehavioral Disorders

Environmental Pollutants ◽

Autism Spectrum ◽

Organophosphate Pesticides ◽

Hyperactivity Disorder ◽

Experimental Systems ◽

Neural Disorders ◽

This chapter focuses on the role environmental pollutants are playing in the rapidly rising rate of neurodevelopmental disorders in children. The available EDC data are summarized and analyzed in relation to whether or not evidence supports a role for EDCs as contributing to neural disorders. The distinction between endocrine disruption and neurotoxicity is established by focusing on the differences between toxicants, toxins, and altered endocrine/neuroendocrine effects in organizational alterations of the brain. Evidence from experimental systems demonstrating effects of EDCs on the developing brain and the potential roles for EDCs as bad actors in rising rates of autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) are presented in detail. Additional impacts of EDCs on neurodegenerative disorders, including Parkinsons’s disease, are reviewed. The mechanisms of rotenone and paraquat neurodegeneration are compared and contrasted with the evidence and mechanisms of actions for organochlorine and organophosphate pesticides in Parkinsons’s disease.

Understanding the Link Between Allergy and Neurodevelopmental Disorders: A Current Review of Factors and Mechanisms

Frontiers in Neurology ◽

10.3389/fneur.2020.603571 ◽

2021 ◽

Vol 11 ◽

Author(s):

Regena Xin Yi Chua ◽

Michelle Jia Yu Tay ◽

Delicia Shu Qin Ooi ◽

Kewin Tien Ho Siah ◽

Elizabeth Huiwen Tham ◽

...

Keyword(s):

Sleep Disturbances ◽

Environmental Pollutants ◽

Allergic Diseases ◽

Epidemiological Studies ◽

Autism Spectrum ◽

Convincing Evidence ◽

Hyperactivity Disorder ◽

Underlying Mechanisms

Both allergic diseases and neurodevelopmental disorders are non-communicable diseases (NCDs) that not only impact on the quality of life and but also result in substantial economic burden. Immune dysregulation and inflammation are typical hallmarks in both allergic and neurodevelopmental disorders, suggesting converging pathophysiology. Epidemiological studies provided convincing evidence for the link between allergy and neurodevelopmental diseases such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Possible factors influencing the development of these disorders include maternal depression and anxiety, gestational diabetes mellitus, maternal allergic status, diet, exposure to environmental pollutants, microbiome dysbiosis, and sleep disturbances that occur early in life. Moreover, apart from inflammation, epigenetics, gene expression, and mitochondrial dysfunction have emerged as possible underlying mechanisms in the pathogenesis of these conditions. The exploration and understanding of these shared factors and possible mechanisms may enable us to elucidate the link in the comorbidity.

Altered kynurenine pathway metabolites in a mouse model of human attention-deficit hyperactivity/autism spectrum disorders: A potential new biological diagnostic marker

Scientific Reports ◽

10.1038/s41598-019-49781-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Yuki Murakami ◽

Yukio Imamura ◽

Kuniaki Saito ◽

Daisuke Sakai ◽

Jun Motoyama

Keyword(s):

Attention Deficit ◽

Kynurenine Pathway ◽

Autism Spectrum ◽

Behavioral Deficits ◽

Diagnostic Biomarkers ◽

Hyperactivity Disorder ◽

Spectrum Disorders ◽

Almost All ◽

Abstract Deleterious mutations in patchd1 domain containing 1 (PTCHD1) gene have been identified in patients with intellectual disability and/or autism spectrum disorder (ASD). To clarify the causal relationship between Ptchd1 deficiency and behavioral defects relevant to neurodevelopmental disorders, we generated global Ptchd1 knockout (KO) mice. Ptchd1 KO mice displayed hyperlocomotion, increased impulsivity, and lower recognition memory, which resemble attention-deficit hyperactivity disorder (ADHD)-like behaviors. Acute or chronic treatment with atomoxetine ameliorated almost all behavioral deficits in Pthcd1 KO mice. We next determined possible involvement of the kynurenine pathway (KP) metabolites in neurodevelopmental disorders in Ptchd1 KO mice and assessed the potential of KP metabolites as biomarkers for ADHD and/or ASD. Ptchd1 KO mice showed drastic changes in KP metabolite concentrations in the serum and the brain, indicating that the activated KP is associated with ADHD-like behaviors. Our findings indicate that Ptchd1 KO mice can be used as an animal model of human ADHD and/or ASD, and KP metabolites are potential diagnostic biomarkers for neurodevelopmental disorders.

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Science Advances ◽

10.1126/sciadv.aba1187 ◽

2021 ◽

Vol 7 (11) ◽

pp. eaba1187

Author(s):

Rina Baba ◽

Satoru Matsuda ◽

Yuuichi Arakawa ◽

Ryuji Yamada ◽

Noriko Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Neurodevelopmental Disorder ◽

Specific Inhibitor ◽

Autism Spectrum ◽

Poly I:C ◽

Control Of Gene Expression ◽

Epigenetic Machinery ◽

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

Using Sibling Designs to Understand Neurodevelopmental Disorders: From Genes and Environments to Prevention Programming

BioMed Research International ◽

10.1155/2015/672784 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 4

Author(s):

Mark Wade ◽

Heather Prime ◽

Sheri Madigan

Keyword(s):

Broad Class ◽

Psychosocial Health ◽

Recurrence Risk ◽

Autism Spectrum ◽

Functional Neuroanatomy ◽

Early Screening ◽

Environmental Liabilities ◽

Hyperactivity Disorder ◽

Significant Bearing

Neurodevelopmental disorders represent a broad class of childhood neurological conditions that have a significant bearing on the wellbeing of children, families, and communities. In this review, we draw on evidence from two common and widely studied neurodevelopmental disorders—autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD)—to demonstrate the utility of genetically informed sibling designs in uncovering the nature and pathogenesis of these conditions. Specifically, we examine how twin, recurrence risk, and infant prospective tracking studies have contributed to our understanding of genetic and environmental liabilities towards neurodevelopmental morbidity through their impact on neurocognitive processes and structural/functional neuroanatomy. It is suggested that the siblings of children with ASD and ADHD are at risk not only of clinically elevated problems in these areas, but also of subthreshold symptoms and/or subtle impairments in various neurocognitive skills and other domains of psychosocial health. Finally, we close with a discussion on the practical relevance of sibling designs and how these might be used in the service of early screening, prevention, and intervention efforts that aim to alleviate the negative downstream consequences associated with disorders of neurodevelopment.

Attention-deficit/hyperactivity disorder and other neurodevelopmental disorders in offspring of parents with depression and bipolar disorder

Psychological Medicine ◽

10.1017/s0033291721001951 ◽

2021 ◽

pp. 1-8

Author(s):

L. Propper ◽

A. Sandstrom ◽

S. Rempel ◽

E. Howes Vallis ◽

S. Abidi ◽

...

Keyword(s):

Bipolar Disorder ◽

Attention Deficit Hyperactivity Disorder ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Mood Disorder ◽

Attention Deficit ◽

Autism Spectrum ◽

Major Depressive ◽

Hyperactivity Disorder

Abstract Background Offspring of parents with major mood disorders (MDDs) are at increased risk for early psychopathology. We aim to compare the rates of neurodevelopmental disorders in offspring of parents with bipolar disorder, major depressive disorder, and controls. Method We established a lifetime diagnosis of neurodevelopmental disorders [attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disabilities, specific learning disorders, and motor disorders] using the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version in 400 participants (mean age 11.3 + s.d. 3.9 years), including 93 offspring of parents with bipolar disorder, 182 offspring of parents with major depressive disorder, and 125 control offspring of parents with no mood disorder. Results Neurodevelopmental disorders were elevated in offspring of parents with bipolar disorder [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.23–4.47, p = 0.010] and major depressive disorder (OR 1.87, 95% CI 1.03–3.39, p = 0.035) compared to controls. This difference was driven by the rates of ADHD, which were highest among offspring of parents with bipolar disorder (30.1%), intermediate in offspring of parents with major depressive disorder (24.2%), and lowest in controls (14.4%). There were no significant differences in frequencies of other neurodevelopmental disorders between the three groups. Chronic course of mood disorder in parents was associated with higher rates of any neurodevelopmental disorder and higher rates of ADHD in offspring. Conclusions Our findings suggest monitoring for ADHD and other neurodevelopmental disorders in offspring of parents with MDDs may be indicated to improve early diagnosis and treatment.

Graph Ricci Curvatures Reveal Disease-related Changes in Autism Spectrum Disorder

10.1101/2021.11.28.470231 ◽

2021 ◽

Author(s):

Pavithra Elumalai ◽

Yasharth Yadav ◽

Nitin Williams ◽

Emil Saucan ◽

Jürgen Jost ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Resting State ◽

Data Exchange ◽

Meta Analysis ◽

Resting State Fmri ◽

Brain Regions ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders that pose a significant global health burden. Measures from graph theory have been used to characterise ASD-related changes in resting-state fMRI functional connectivity networks (FCNs), but recently developed geometry-inspired measures have not been applied so far. In this study, we applied geometry-inspired graph Ricci curvatures to investigate ASD-related changes in resting-state fMRI FCNs. To do this, we applied Forman-Ricci and Ollivier-Ricci curvatures to compare networks of ASD and healthy controls (N = 1112) from the Autism Brain Imaging Data Exchange I (ABIDE-I) dataset. We performed these comparisons at the brain-wide level as well as at the level of individual brain regions, and further, determined the behavioral relevance of region-specific differences with Neurosynth meta-analysis decoding. We found brain-wide ASD-related differences for both Forman-Ricci and Ollivier-Ricci curvatures. For Forman-Ricci curvature, these differences were distributed across 83 of the 200 brain regions studied, and concentrated within the Default Mode, Somatomotor and Ventral Attention Network. Meta-analysis decoding identified the brain regions showing curvature differences as involved in social cognition, memory, language and movement. Notably, comparison with results from previous non-invasive stimulation (TMS/tDCS) experiments revealed that the set of brain regions showing curvature differences overlapped with the set of brain regions whose stimulation resulted in positive cognitive or behavioural outcomes in ASD patients. These results underscore the utility of geometry-inspired graph Ricci curvatures in characterising disease-related changes in ASD, and possibly, other neurodevelopmental disorders.

Gluten Intolerance and Neurodevelopmental Disorders: Is Nitric Oxide the Common Biomarker Linking These Conditions?

Annals of Nutrition and Metabolism ◽

10.1159/000448664 ◽

2016 ◽

Vol 69 (1) ◽

pp. 54-55 ◽

Cited By ~ 1

Author(s):

Keith Fluegge

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Autism Spectrum ◽

Air Pollutant ◽

Clinical Feature ◽

Nutrient Deficiencies ◽

Hyperactivity Disorder ◽

Spectrum Disorders ◽

The Relationship

Cruchet et al. attempt to tease out the myths and facts surrounding the growing popularity of certain dietary approaches in the management of neurodevelopmental disorders, like attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs). The authors identify a particular exclusionary-type approach that seeks to eliminate dietary gluten. Although the relationship between celiac disease (CD) and ADHD/ASD is not well established, a repeated clinical feature noted in CD is the elevated levels of nitric oxide in serum and urine. Elevated oxidative stress has also been observed in neurodevelopmental conditions, and the author of this correspondence has been the first to propose that chronic, environmental exposure to the air pollutant, nitrous oxide may contribute to these oxidative stress profiles through neural cholinergic perturbation. Therefore, the purpose of this correspondence is to highlight this biochemical connection between these conditions so as to identify the clinical populations who may realize the greatest benefit of these dietary approaches, while minimizing any potential risk of nutrient deficiencies.

Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings

Psychological Medicine ◽

10.1017/s0033291718000521 ◽

2018 ◽

Vol 49 (1) ◽

pp. 84-91 ◽

Cited By ~ 4

Author(s):

Elina Jokiranta-Olkoniemi ◽

Keely Cheslack-Postava ◽

Petteri Joelsson ◽

Auli Suominen ◽

Alan S. Brown ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Neurodevelopmental Disorder ◽

Population Based ◽

Autism Spectrum ◽

Schizophrenia Spectrum Disorders ◽

Hyperactivity Disorder ◽

Increased Risk ◽

Spectrum Disorders

AbstractBackgroundProbands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort.MethodsEvery child born in Finland in 1991–2005 and diagnosed with ADHD in 1995–2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981–2007 and diagnosed in 1981–2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations.Results44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0–2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1–6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5–4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3–4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4–3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4–2.8), and intellectual disability (RR = 2.4; 95% CI 2.0–2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases.ConclusionsThe results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies.

The epigenetic regulation of synaptic genes contributes to the etiology of autism

Reviews in the Neurosciences ◽

10.1515/revneuro-2021-0014 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Annamaria Srancikova ◽

Zuzana Bacova ◽

Jan Bakos

Keyword(s):

Epigenetic Regulation ◽

Autism Spectrum ◽

Prader Willi Syndrome ◽

Epigenetic Mechanisms ◽

Substantial Evidence ◽

Autistic Symptoms ◽

Spectrum Disorders ◽

Abstract Epigenetic mechanisms greatly affect the developing brain, as well as the maturation of synapses with pervasive, long-lasting consequences on behavior in adults. Substantial evidence exists that implicates dysregulation of epigenetic mechanisms in the etiology of neurodevelopmental disorders. Therefore, this review explains the role of enzymes involved in DNA methylation and demethylation in neurodevelopment by emphasizing changes of synaptic genes and proteins. Epigenetic causes of sex-dependent differences in the brain are analyzed in conjunction with the pathophysiology of autism spectrum disorders. Special attention is devoted to the epigenetic regulation of the melanoma-associated antigen-like gene 2 (MAGEL2) found in Prader-Willi syndrome, which is known to be accompanied by autistic symptoms.

Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder

Translational Psychiatry ◽

10.1038/s41398-019-0599-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 12

Author(s):

Olafur O. Gudmundsson ◽

G. Bragi Walters ◽

Andres Ingason ◽

Stefan Johansson ◽

Tetyana Zayats ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Copy Number ◽

Neurodevelopmental Disorder ◽

Copy Number Variant ◽

Pleiotropic Effect ◽

Autism Spectrum ◽

Copy Number Variations ◽

Hyperactivity Disorder

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5–BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10−21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.