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Specht AJ, Zhang X, Antipova OA, Sayam ASM, Nguyen VT, Hoover CG, Punshon T, Jackson BP, Weisskopf MG. Sub-micrometer scale synchrotron x-ray fluorescence measurements of trace elements in teeth compared with laser ablation inductively coupled plasma mass spectrometry. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2025:10.1038/s41370-025-00754-6. [PMID: 39881199 DOI: 10.1038/s41370-025-00754-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/19/2025] [Accepted: 01/20/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND Elemental analysis of teeth allows for exposure assessment during critical windows of development and is increasingly used to link early life exposures and health. The measurement of inorganic elements in teeth is challenging; laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is the most widely used technique. OBJECTIVE Both synchrotron x-ray fluorescence (SXRF) and LA-ICP-MS have the capability to measure elemental distributions in teeth with each having distinct advantages and disadvantages. METHODS In our study, we compared these two methods for teeth elemental quantification. SXRF was able to achieve spatial resolutions of 0.3 µm and is non-destructive while giving similar elemental quantification results to LA-ICP-MS. RESULTS For particular elements, SXRF can offer lower detection limits but depends on the specific beam intensity. The comparison between methods revealed less than 10% disagreement between quantification results from LA-ICP-MS and SXRF. IMPACT Synchrotron x-ray fluorescence can be used to effectively quantify elemental distributions in teeth at a nanoscale resolution and is comparable to current laser ablation inductively coupled plasma mass spectrometry. Both methods offer advantages and disadvantages with LA-ICP-MS offering in-lab analyses, whereas SXRF offers much finer spatial and temporal scales and better detection capabilities. For studies focused on fine scale changes in structure, SXRF is more appropriate than LA-ICP-MS.
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Affiliation(s)
- Aaron J Specht
- School of Health Sciences, Purdue University, West Lafayette, IN, USA.
- Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | | | - Olga A Antipova
- Advanced Photon Source, Argonne National Laboratory, Lemont, IL, USA
| | | | - Vy T Nguyen
- Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Długosz A, Wróblewski M, Błaszak B, Szulc J. The Role of Nutrition, Oxidative Stress, and Trace Elements in the Pathophysiology of Autism Spectrum Disorders. Int J Mol Sci 2025; 26:808. [PMID: 39859522 PMCID: PMC11765825 DOI: 10.3390/ijms26020808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, alongside repetitive behaviors, and atypical sensory-motor patterns. The growing prevalence of ASD has driven substantial advancements in research aimed at understanding its etiology, preventing its onset, and mitigating its impact. This ongoing effort necessitates continuous updates to the body of knowledge and the identification of previously unexplored factors. The present study addresses this need by examining the roles of nutrition, oxidative stress, and trace elements in the pathophysiology of ASD. In this review, an overview is provided of the key dietary recommendations for individuals with ASD, including gluten-free and casein-free (GFCF) diets, ketogenic diets (KDs), and other nutritional interventions. Furthermore, it explores the involvement of oxidative stress in ASD and highlights the significance of trace elements in maintaining neuropsychiatric health. The impact of these factors on molecular and cellular mechanisms was discussed, alongside therapeutic strategies and their efficacy in managing ASD.
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Affiliation(s)
- Anna Długosz
- Department of Food Industry Technology and Engineering, Faculty of Chemical Technology and Engineering, Bydgoszcz University of Science and Technology, 3 Seminaryjna St., 85-326 Bydgoszcz, Poland; (B.B.); (J.S.)
| | - Marcin Wróblewski
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 24 Karłowicza St., 85-092 Bydgoszcz, Poland;
| | - Błażej Błaszak
- Department of Food Industry Technology and Engineering, Faculty of Chemical Technology and Engineering, Bydgoszcz University of Science and Technology, 3 Seminaryjna St., 85-326 Bydgoszcz, Poland; (B.B.); (J.S.)
| | - Joanna Szulc
- Department of Food Industry Technology and Engineering, Faculty of Chemical Technology and Engineering, Bydgoszcz University of Science and Technology, 3 Seminaryjna St., 85-326 Bydgoszcz, Poland; (B.B.); (J.S.)
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3
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Bauer JA, Punshon T, Barr MN, Jackson BP, Weisskopf MG, Bidlack FB, Coker MO, Peacock JL, Karagas MR. Deciduous teeth from the New Hampshire birth cohort study: Early life environmental and dietary predictors of dentin elements. ENVIRONMENTAL RESEARCH 2024; 256:119170. [PMID: 38768888 PMCID: PMC11748168 DOI: 10.1016/j.envres.2024.119170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Sparse research exists on predictors of element concentrations measured in deciduous teeth. OBJECTIVE To estimate associations between maternal/child characteristics, elements measured in home tap water during pregnancy and element concentrations in the dentin of shed deciduous teeth. METHODS Our analysis included 152 pregnant person-infant dyads followed from the second trimester through the end of the first postnatal year from the New Hampshire Birth Cohort Study. During pregnancy and early infancy, we collected dietary and sociodemographic information via surveys, measured elements in home tap water, and later collected naturally exfoliated teeth from child participants. We measured longitudinal deposition of elements in dentin using LA-ICP-MS. Multivariable linear mixed models were used to estimate associations between predictors and dentin element concentrations. RESULTS We measured 12 elements in dentin including those previously reported (Ba, Mn, Pb, Sr, Zn) and less frequently reported (Al, As, Cd, Cu, Hg, Li, and W). A doubling of Pb or Sr concentrations in water was associated with higher dentin Pb or Sr respectively in prenatally formed [9% (95%CI: 3%, 15%); 3% (1%, 6%)] and postnatally formed [10% (2%, 19%); 6% (2%, 10%)] dentin. Formula feeding from birth to 6 weeks or 6 weeks to 4 months was associated with higher element concentrations in postnatal dentin within the given time period as compared to exclusive human milk feeding: Sr: 6 weeks: 61% (36%, 90%) and 4 months: 85% (54%, 121%); Ba: 6 weeks: 35% (3.3%, 77%) and 4 months: 42% (10%, 83%); and Li: 6 weeks: 61% (33%, 95%) and 4 months: 58% (31%, 90%). SIGNIFICANCE These findings offer insights into predictors of dentin elements and potential confounders in exposure-health outcome relationships during critical developmental periods.
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Affiliation(s)
- Julia A Bauer
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA; Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, Chicago, IL, USA.
| | - Tracy Punshon
- Department of Biological Sciences, Dartmouth College, Hanover, NH, USA
| | - Matthew N Barr
- Department of Earth Sciences, Dartmouth College, Hanover, NH, USA
| | - Brian P Jackson
- Department of Earth Sciences, Dartmouth College, Hanover, NH, USA
| | - Marc G Weisskopf
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Modupe O Coker
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA; Department of Oral Biology, School of Dental Medicine, Rutgers University, Newark, NJ, USA
| | - Janet L Peacock
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Margaret R Karagas
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
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Rosa MJ, Gennings C, Curtin P, Alcala CS, Lamadrid-Figueroa H, Tamayo-Ortiz M, Mercado-Garcia A, Torres-Olascoaga L, Téllez-Rojo MM, Wright RO, Arora M, Austin C, Wright RJ. Associations between prenatal metal and metalloid mixtures in teeth and reductions in childhood lung function. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 938:173352. [PMID: 38796021 PMCID: PMC11238599 DOI: 10.1016/j.scitotenv.2024.173352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 04/29/2024] [Accepted: 05/17/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND Metal(oid)s have been cross-sectionally associated with lung function outcomes in childhood but there is limited data on their combined effects starting in utero. Child sex may further modify these effects. OBJECTIVE Examine associations between in utero and early life exposure to metals assessed via novel dentine biomarkers and childhood lung function and explore effect modification by child sex. METHODS Analyses included 291 children enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a longitudinal birth cohort study in Mexico City. Weekly dentine levels of arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), and lead (Pb) were measured from 15 weeks pre-birth to 15 weeks post birth in deciduous children's teeth. Lung function was tested at ages 8-14 years and then modeled as age, height and sex adjusted z-scores. Associations were modeled using lagged weighted quantile sum (LWQS) regression to evaluate the potential for a time-varying mixture effect adjusting for maternal age and education at enrollment and exposure to environmental tobacco smoke in pregnancy. Models were also stratified by sex. RESULTS We identified a window of susceptibility at 12-15 weeks pre-birth in which the metal mixture was associated with lower FVC z-scores in children aged 8-14 years. Cd and Mn were the largest contributors to the mixture effect (70 %). There was also some evidence of effect modification by sex, in which the mean weights and weighted correlations over the identified window was more evident in males when compared to females. In the male stratum, Cd, Mn and additionally Pb also dominated the mixture association. CONCLUSIONS Prenatal metal(oid) exposure was associated with lower lung function in childhood. These findings underscore the need to consider both mixtures and windows of susceptibility to fully elucidate effects of prenatal metal(oid) exposure on childhood lung function.
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Affiliation(s)
- Maria Jose Rosa
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, USA.
| | - Chris Gennings
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | - Cecilia S Alcala
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Hector Lamadrid-Figueroa
- Department of Perinatal Health, Center for Population Health Research, National Institute of Public Health (INSP), Cuernavaca, Morelos, Mexico
| | - Marcela Tamayo-Ortiz
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA
| | - Adriana Mercado-Garcia
- Center for Nutrition and Health Research, National Institute of Public Health (INSP), Cuernavaca, Morelos, Mexico
| | - Libni Torres-Olascoaga
- Center for Nutrition and Health Research, National Institute of Public Health (INSP), Cuernavaca, Morelos, Mexico
| | - Martha María Téllez-Rojo
- Center for Nutrition and Health Research, National Institute of Public Health (INSP), Cuernavaca, Morelos, Mexico
| | - Robert O Wright
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, USA; Kravis Children's Hospital, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA; Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Manish Arora
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Christine Austin
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Rosalind J Wright
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, USA; Kravis Children's Hospital, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA; Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, New York, USA
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5
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Gevezova M, Ivanov Z, Pacheva I, Timova E, Kazakova M, Kovacheva E, Ivanov I, Sarafian V. Bioenergetic and Inflammatory Alterations in Regressed and Non-Regressed Patients with Autism Spectrum Disorder. Int J Mol Sci 2024; 25:8211. [PMID: 39125780 PMCID: PMC11311370 DOI: 10.3390/ijms25158211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/22/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Autism spectrum disorder (ASD) is associated with multiple physiological abnormalities. Current laboratory and clinical evidence most commonly report mitochondrial dysfunction, oxidative stress, and immunological imbalance in almost every cell type of the body. The present work aims to evaluate oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and inflammation-related molecules such as Cyclooxygenase-2 (COX-2), chitinase 3-like protein 1 (YKL-40), Interleukin-1 beta (IL-1β), Interleukin-9 (IL-9) in ASD children with and without regression compared to healthy controls. Children with ASD (n = 56) and typically developing children (TDC, n = 12) aged 1.11 to 11 years were studied. Mitochondrial activity was examined in peripheral blood mononuclear cells (PBMCs) isolated from children with ASD and from the control group, using a metabolic analyzer. Gene and protein levels of IL-1β, IL-9, COX-2, and YKL-40 were investigated in parallel. Our results showed that PBMCs of the ASD subgroup of regressed patients (ASD R(+), n = 21) had a specific pattern of mitochondrial activity with significantly increased maximal respiration, respiratory spare capacity, and proton leak compared to the non-regressed group (ASD R(-), n = 35) and TDC. Furthermore, we found an imbalance in the studied proinflammatory molecules and increased levels in ASD R(-) proving the involvement of inflammatory changes. The results of this study provide new evidence for specific bioenergetic profiles of immune cells and elevated inflammation-related molecules in ASD. For the first time, data on a unique metabolic profile in ASD R(+) and its comparison with a random group of children of similar age and sex are provided. Our data show that mitochondrial dysfunction is more significant in ASD R(+), while in ASD R(-) inflammation is more pronounced. Probably, in the group without regression, immune mechanisms (immune dysregulation, leading to inflammation) begin initially, and at a later stage mitochondrial activity is also affected under exogenous factors. On the other hand, in the regressed group, the initial damage is in the mitochondria, and perhaps at a later stage immune dysfunction is involved.
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Affiliation(s)
- Maria Gevezova
- Department of Medical Biology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.G.); (Z.I.); (M.K.); (E.K.)
- Research Institute at MU-Plovdiv, 4002 Plovdiv, Bulgaria
| | - Zdravko Ivanov
- Department of Medical Biology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.G.); (Z.I.); (M.K.); (E.K.)
| | - Iliana Pacheva
- Department of Pediatrics and Medical Genetics, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (I.P.); (I.I.)
- Pediatrics Clinic, St. George University Hospital, 4002 Plovdiv, Bulgaria;
| | - Elena Timova
- Pediatrics Clinic, St. George University Hospital, 4002 Plovdiv, Bulgaria;
| | - Maria Kazakova
- Department of Medical Biology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.G.); (Z.I.); (M.K.); (E.K.)
- Research Institute at MU-Plovdiv, 4002 Plovdiv, Bulgaria
| | - Eleonora Kovacheva
- Department of Medical Biology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.G.); (Z.I.); (M.K.); (E.K.)
- Research Institute at MU-Plovdiv, 4002 Plovdiv, Bulgaria
| | - Ivan Ivanov
- Department of Pediatrics and Medical Genetics, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (I.P.); (I.I.)
- Pediatrics Clinic, St. George University Hospital, 4002 Plovdiv, Bulgaria;
| | - Victoria Sarafian
- Department of Medical Biology, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; (M.G.); (Z.I.); (M.K.); (E.K.)
- Research Institute at MU-Plovdiv, 4002 Plovdiv, Bulgaria
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Frye RE, Rincon N, McCarty PJ, Brister D, Scheck AC, Rossignol DA. Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis. Neurobiol Dis 2024; 197:106520. [PMID: 38703861 DOI: 10.1016/j.nbd.2024.106520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.
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Affiliation(s)
- Richard E Frye
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Southwest Autism Research and Resource Center, Phoenix, AZ, USA; Rossignol Medical Center, Phoenix, AZ, USA.
| | | | - Patrick J McCarty
- Tulane University School of Medicine, New Orleans, LA 70113, United States of America.
| | | | - Adrienne C Scheck
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, United States of America.
| | - Daniel A Rossignol
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Rossignol Medical Center, Aliso Viejo, CA, USA
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Maitin-Shepard M, O'Tierney-Ginn P, Kraneveld AD, Lyall K, Fallin D, Arora M, Fasano A, Mueller NT, Wang X, Caulfield LE, Dickerson AS, Diaz Heijtz R, Tarui T, Blumberg JB, Holingue C, Schmidt RJ, Garssen J, Almendinger K, Lin PID, Mozaffarian D. Food, nutrition, and autism: from soil to fork. Am J Clin Nutr 2024; 120:240-256. [PMID: 38677518 DOI: 10.1016/j.ajcnut.2024.04.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 04/18/2024] [Accepted: 04/22/2024] [Indexed: 04/29/2024] Open
Abstract
Food and nutrition-related factors have the potential to impact development of autism spectrum disorder (ASD) and quality of life for people with ASD, but gaps in evidence exist. On 10 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships of food and nutrition with ASD. This meeting report summarizes the presentations and deliberations from the meeting. Topics addressed included prenatal and child dietary intake, the microbiome, obesity, food-related environmental exposures, mechanisms and biological processes linking these factors and ASD, food-related social factors, and data sources for future research. Presentations highlighted evidence for protective associations with prenatal folic acid supplementation and ASD development, increases in risk of ASD with maternal gestational obesity, and the potential for exposure to environmental contaminants in foods and food packaging to influence ASD development. The importance of the maternal and child microbiome in ASD development or ASD-related behaviors in the child was reviewed, as was the role of discrimination in leading to disparities in environmental exposures and psychosocial factors that may influence ASD. The role of child diet and high prevalence of food selectivity in children with ASD and its association with adverse outcomes were also discussed. Priority evidence gaps identified by participants include further clarifying ASD development, including biomarkers and key mechanisms; interactions among psychosocial, social, and biological determinants; interventions addressing diet, supplementation, and the microbiome to prevent and improve quality of life for people with ASD; and mechanisms of action of diet-related factors associated with ASD. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and ASD.
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Affiliation(s)
| | | | - Aletta D Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands; Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands
| | - Kristen Lyall
- AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, United States
| | - Daniele Fallin
- Rollins School of Public Health, Emory University, Atlanta, GA, United States
| | - Manish Arora
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Alessio Fasano
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Noel T Mueller
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Xiaobin Wang
- Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Laura E Caulfield
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Aisha S Dickerson
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | | | - Tomo Tarui
- Department of Pediatrics, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Jeffrey B Blumberg
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, United States
| | - Calliope Holingue
- Center for Autism Services, Science and Innovation, Kennedy Krieger Institute and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Rebecca J Schmidt
- Department of Public Health Sciences, the MIND Institute, University of California Davis, Davis, CA, United States
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
| | - Katherine Almendinger
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Pi-I Debby Lin
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States
| | - Dariush Mozaffarian
- Food is Medicine Institute, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, United States.
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8
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Dolatmoradi M, Ellis J, Austin C, Arora M, Vertes A. Detection and Imaging of Exposure-Related Metabolites and Xenobiotics in Hard Tissues by Laser Sampling and Mass Spectrometry. Anal Chem 2024; 96:7022-7029. [PMID: 38669590 DOI: 10.1021/acs.analchem.4c00224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
The utility of two novel laser-based methods, laser ablation electrospray ionization (LAESI) and laser desorption ionization (LDI) from silicon nanopost array (NAPA), is explored via local analysis and mass spectrometry imaging (MSI) of hard tissues (tooth and hair) for the detection and mapping of organic components. Complex mass spectra are recorded in local analysis mode from tooth dentin and scalp hair samples. Nicotine and its metabolites (cotinine, hydroxycotinine, norcotinine, and nicotine) are detected by LAESI-MS in the teeth of rats exposed to tobacco smoke. The intensities of the detected metabolite peaks are proportional to the degree of exposure. Incorporating ion mobility separation in the LAESI-MS analysis of scalp hair enables the detection of cotinine in smoker hair along with other common molecular species, including endogenous steroid hormones and some lipids. Single hair strands are imaged by MALDI-MSI and NAPA-LDI-MSI to explore longitudinal variations in the level of small molecules. Comparing spectra integrated from NAPA-LDI-MSI and MALDI-MSI images reveals that the two techniques provide complementary information. There were 105 and 82 sample-related peaks for MALDI and NAPA, respectively, with an overlap of only 16 peaks, indicating a high degree of complementarity. Enhanced molecular coverage and spatial resolution offered by LAESI-MS and NAPA-LDI-MSI can reveal the distributions of known and potential biomarkers in hard tissues, facilitating exposome research.
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Affiliation(s)
- Marjan Dolatmoradi
- Department of Chemistry, The George Washington University, Washington, District of Columbia 20052, United States
| | - Joanna Ellis
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
- Linus Biotechnology, North Brunswick, New Jersey 08902, United States
| | - Christine Austin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Manish Arora
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
- Linus Biotechnology, North Brunswick, New Jersey 08902, United States
| | - Akos Vertes
- Department of Chemistry, The George Washington University, Washington, District of Columbia 20052, United States
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9
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Frye RE, McCarty PJ, Werner BA, Rose S, Scheck AC. Bioenergetic signatures of neurodevelopmental regression. Front Physiol 2024; 15:1306038. [PMID: 38449786 PMCID: PMC10916717 DOI: 10.3389/fphys.2024.1306038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 02/06/2024] [Indexed: 03/08/2024] Open
Abstract
Background: Studies have linked autism spectrum disorder (ASD) to physiological abnormalities including mitochondrial dysfunction. Mitochondrial dysfunction may be linked to a subset of children with ASD who have neurodevelopmental regression (NDR). We have developed a cell model of ASD which demonstrates a unique mitochondrial profile with mitochondrial respiration higher than normal and sensitive to physiological stress. We have previously shown similar mitochondrial profiles in individuals with ASD and NDR. Methods: Twenty-six ASD individuals without a history of NDR (ASD-NoNDR) and 15 ASD individuals with a history of NDR (ASD-NDR) were recruited from 34 families. From these families, 30 mothers, 17 fathers and 5 typically developing (TD) siblings participated. Mitochondrial respiration was measured in peripheral blood mononuclear cells (PBMCs) with the Seahorse 96 XF Analyzer. PBMCs were exposed to various levels of physiological stress for 1 h prior to the assay using 2,3-dimethoxy-1,4-napthoquinone. Results: ASD-NDR children were found to have higher respiratory rates with mitochondria that were more sensitive to physiological stress as compared to ASD-NoNDR children, similar to our cellular model of NDR. Differences in mitochondrial respiration between ASD-NDR and TD siblings were similar to the differences between ASD-NDR and ASD-NoNDR children. Interesting, parents of children with ASD and NDR demonstrated patterns of mitochondrial respiration similar to their children such that parents of children with ASD and NDR demonstrated elevated respiratory rates with mitochondria that were more sensitive to physiological stress. In addition, sex differences were seen in ASD children and parents. Age effects in parents suggested that mitochondria of older parents were more sensitive to physiological stress. Conclusion: This study provides further evidence that children with ASD and NDR may have a unique type of mitochondrial physiology that may make them susceptible to physiological stressors. Identifying these children early in life before NDR occurs and providing treatment to protect mitochondrial physiology may protect children from experiencing NDR. The fact that parents also demonstrate mitochondrial respiration patterns similar to their children implies that this unique change in mitochondrial physiology may be a heritable factor (genetic or epigenetic), a result of shared environment, or both.
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Affiliation(s)
- Richard E. Frye
- Autism Discovery and Treatment Foundation, Phoenix, AZ, United States
| | | | - Brianna A. Werner
- Creighton University School of Medicine Phoenix Regional Campus, Phoenix, AZ, United States
| | - Shannon Rose
- Arkansas Children’s Research Institute, Little Rock, AR, United States
| | - Adrienne C. Scheck
- Autism Discovery and Treatment Foundation, Phoenix, AZ, United States
- Department of Child Health, University of Arizona College of Medicine—Phoenix, Phoenix, AZ, United States
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10
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Al-Beltagi M. Pre-autism: What a paediatrician should know about early diagnosis of autism. World J Clin Pediatr 2023; 12:273-294. [PMID: 38178935 PMCID: PMC10762597 DOI: 10.5409/wjcp.v12.i5.273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/07/2023] [Accepted: 09/25/2023] [Indexed: 12/08/2023] Open
Abstract
Autism, also known as an autism spectrum disorder, is a complex neurodevelopmental disorder usually diagnosed in the first three years of a child's life. A range of symptoms characterizes it and can be diagnosed at any age, including adolescence and adulthood. However, early diagnosis is crucial for effective management, prognosis, and care. Unfortunately, there are no established fetal, prenatal, or newborn screening programs for autism, making early detection difficult. This review aims to shed light on the early detection of autism prenatally, natally, and early in life, during a stage we call as "pre-autism" when typical symptoms are not yet apparent. Some fetal, neonatal, and infant biomarkers may predict an increased risk of autism in the coming baby. By developing a biomarker array, we can create an objective diagnostic tool to diagnose and rank the severity of autism for each patient. These biomarkers could be genetic, immunological, hormonal, metabolic, amino acids, acute phase reactants, neonatal brainstem function biophysical activity, behavioral profile, body measurements, or radiological markers. However, every biomarker has its accuracy and limitations. Several factors can make early detection of autism a real challenge. To improve early detection, we need to overcome various challenges, such as raising community awareness of early signs of autism, improving access to diagnostic tools, reducing the stigma attached to the diagnosis of autism, and addressing various culturally sensitive concepts related to the disorder.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Tanta 31511, Algahrbia, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr. Sulaiman Al Habib Medical Group, Manama 26671, Manama, Bahrain
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11
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Guo X, Zhai G, Liu J, Zhang X, Zhang T, Cui D, Zhou R, Gao L. Heterogeneity of dynamic synergetic configurations of salience network in children with autism spectrum disorder. Autism Res 2023; 16:2275-2290. [PMID: 37815146 DOI: 10.1002/aur.3037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 09/20/2023] [Indexed: 10/11/2023]
Abstract
Atypical functional connectivity (FC) patterns have been identified in autism spectrum disorders (ASD), especially within salience network (SN) and between SN and default mode network (DMN) and central executive network (CEN). But whether the dynamic configuration of intra-SN and inter-SN (SN with DMN and CEN) FC in ASD is also heterogeneous remains unknown. Based on the resting-state functional magnetic resonance imaging data from 105 ASD and 102 typically-developing controls (TC), we calculated the time-varying FC of intra-SN and inter-SN (SN with DMN and CEN). Then, the joint recurrence features for the time-varying FC were calculated to assess how the SN dynamically recruits different configurations of network segregation and integration in ASD, that is, synergies, from the dynamical systems perspective. We analyzed the differences in synergetic patterns between ASD subtypes obtained by k-means clustering algorithm based on the synergy of SN and TC, and investigated the relationships between synergy of SN and severity of clinical symptoms of ASD for ASD subtypes. Two ASD subtypes were revealed, where the synergy of SN in ASD subtype 1 has lower stability and periodicity compared to the TC, and ASD subtype 2 exhibits the opposite alteration. Synergy of SN for ASD subtype 1 and 2 was found to predict the severity of communication impairments and restricted and repetitive behaviors in ASD, respectively. These results suggest the existence of subtypes with distinct patterns of the synergy of SN in ASD, and provide insight into the complex pathophysiological mechanism of clinical manifestations of ASD.
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Affiliation(s)
- Xiaonan Guo
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
- Hebei Key Laboratory of Information Transmission and Signal Processing, Yanshan University, Qinhuangdao, China
| | - Guangjin Zhai
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
- Hebei Key Laboratory of Information Transmission and Signal Processing, Yanshan University, Qinhuangdao, China
| | - Junfeng Liu
- Department of Neurology, West China Hospital Sichuan University, Chengdu, China
| | - Xia Zhang
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
- Hebei Key Laboratory of Information Transmission and Signal Processing, Yanshan University, Qinhuangdao, China
| | - Tao Zhang
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
- Hebei Key Laboratory of Information Transmission and Signal Processing, Yanshan University, Qinhuangdao, China
| | - Dong Cui
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
- Hebei Key Laboratory of Information Transmission and Signal Processing, Yanshan University, Qinhuangdao, China
| | - Rongjuan Zhou
- Finance Department, Maternity and Child Health Hospital of Qinhuangdao, Qinhuangdao, China
| | - Le Gao
- School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
- Hebei Key Laboratory of Information Transmission and Signal Processing, Yanshan University, Qinhuangdao, China
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12
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Midya V, Alcala CS, Rechtman E, Gregory JK, Kannan K, Hertz-Picciotto I, Teitelbaum SL, Gennings C, Rosa MJ, Valvi D. Machine Learning Assisted Discovery of Interactions between Pesticides, Phthalates, Phenols, and Trace Elements in Child Neurodevelopment. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:18139-18150. [PMID: 37595051 PMCID: PMC10666542 DOI: 10.1021/acs.est.3c00848] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 08/20/2023]
Abstract
A growing body of literature suggests that developmental exposure to individual or mixtures of environmental chemicals (ECs) is associated with autism spectrum disorder (ASD). However, investigating the effect of interactions among these ECs can be challenging. We introduced a combination of the classical exposure-mixture Weighted Quantile Sum (WQS) regression and a machine-learning method termed Signed iterative Random Forest (SiRF) to discover synergistic interactions between ECs that are (1) associated with higher odds of ASD diagnosis, (2) mimic toxicological interactions, and (3) are present only in a subset of the sample whose chemical concentrations are higher than certain thresholds. In a case-control Childhood Autism Risks from Genetics and Environment (CHARGE) study, we evaluated multiordered synergistic interactions among 62 ECs measured in the urine samples of 479 children in association with increased odds for ASD diagnosis (yes vs no). WQS-SiRF identified two synergistic two-ordered interactions between (1) trace-element cadmium (Cd) and the organophosphate pesticide metabolite diethyl-phosphate (DEP); and (2) 2,4,6-trichlorophenol (TCP-246) and DEP. Both interactions were suggestively associated with increased odds of ASD diagnosis in the subset of children with urinary concentrations of Cd, DEP, and TCP-246 above the 75th percentile. This study demonstrates a novel method that combines the inferential power of WQS and the predictive accuracy of machine-learning algorithms to discover potentially biologically relevant chemical-chemical interactions associated with ASD.
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Affiliation(s)
- Vishal Midya
- Department
of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Cecilia Sara Alcala
- Department
of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Elza Rechtman
- Department
of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Jill K. Gregory
- Instructional
Technology Group,Icahn School of Medicine
at Mount Sinai, New York, New York 10029, United States
| | - Kurunthachalam Kannan
- Department
of Pediatrics and Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016, United States
| | - Irva Hertz-Picciotto
- Department
of Public Health Sciences, School of Medicine, University of California at Davis, Davis, California 95616, United States
- UC
Davis MIND (Medical Investigations of Neurodevelopmental Disorders)
Institute, University of California at Davis, Sacramento, California 95817, United States
| | - Susan L. Teitelbaum
- Department
of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Chris Gennings
- Department
of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Maria J. Rosa
- Department
of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Damaskini Valvi
- Department
of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
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13
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Eaves LA, Choi G, Hall E, Sillé FC, Fry RC, Buckley JP, Keil AP. Prenatal Exposure to Toxic Metals and Neural Tube Defects: A Systematic Review of the Epidemiologic Evidence. ENVIRONMENTAL HEALTH PERSPECTIVES 2023; 131:86002. [PMID: 37647124 PMCID: PMC10467818 DOI: 10.1289/ehp11872] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 05/31/2023] [Accepted: 07/25/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND Neural tube defects (NTDs) affect > 300,000 pregnancies worldwide annually. Few nongenetic factors, other than folate deficiency, have been identified that may provide intervenable solutions to reduce the burden of NTDs. Prenatal exposure to toxic metals [arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn) and lead (Pb)] may increase the risk of NTDs. Although a growing epidemiologic literature has examined associations, to our knowledge no systematic review has been conducted to date. OBJECTIVE Through adaptation of the Navigation Guide systematic review methodology, we aimed to answer the question "does exposure to As, Cd, Hg, Mn, or Pb during gestation increase the risk of NTDs?" and to assess challenges to evaluating this question given the current evidence. METHODS We selected available evidence on prenatal As, Cd, Hg, Mn, or Pb exposure and risk of specific NTDs (e.g., spina bifida, anencephaly) or all NTDs via a comprehensive search across MEDLINE, Embase, Web of Science, and TOXLINE databases and applied inclusion/exclusion criteria. We rated the quality and strength of the evidence for each metal. We applied a customized risk of bias protocol and evaluated the sufficiency of evidence of an effect of each metal on NTDs. RESULTS We identified 30 studies that met our criteria. Risk of bias for confounding and selection was high in most studies, but low for missing data. We determined that, although the evidence was limited, the literature supported an association between prenatal exposure to Hg or Mn and increased risk of NTDs. For the remaining metals, the evidence was inadequate to establish or rule out an effect. CONCLUSION The role of gestational As, Cd, or Pb exposure in the etiology of NTDs remains unclear and warrants further investigation in high-quality studies, with a particular focus on controlling confounding, mitigating selection bias, and improving exposure assessment. https://doi.org/10.1289/EHP11872.
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Affiliation(s)
- Lauren A. Eaves
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill (UNC-Chapel Hill), Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, North Carolina, USA
| | - Giehae Choi
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Emily Hall
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Fenna C.M. Sillé
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Rebecca C. Fry
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill (UNC-Chapel Hill), Chapel Hill, North Carolina, USA
- Institute for Environmental Health Solutions, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jessie P. Buckley
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Alexander P. Keil
- Department of Epidemiology, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, North Carolina, USA
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14
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Wang C, Li Y, Wang L, Liu S, Yang S. A study of EEG non-stationarity on inducing false memory in different emotional states. Neurosci Lett 2023; 809:137306. [PMID: 37244446 DOI: 10.1016/j.neulet.2023.137306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/11/2023] [Accepted: 05/16/2023] [Indexed: 05/29/2023]
Abstract
False memory leads to inaccurate decisions and unnecessary challenges. Researchers have conventionally used electroencephalography (EEG) to study false memory under different emotional states. However, EEG non-stationarity has scarcely been investigated. To address this problem, this study utilized the nonlinear method of recursive quantitative analysis to analyze the non-stationarity of EEG signals. Deese-Roediger-McDermott paradigm experiments were used to induce false memory wherein semantic words were highly correlated. The EEG signals of 48 participants with false memory associated with different emotional states were collected. Recurrence rate (RR), determination rate (DET), and entropy recurrence (ENTR) data were generated to characterize EEG non-stationarity. Behavioral outcomes exhibited significantly higher false-memory rates in the positive group than in the negative group. The prefrontal, temporal, and parietal regions yielded significantly higher RR, DET, and ENTR values than other brain regions in the positive group. However, only the prefrontal region had significantly higher values than other brain regions in the negative group. Therefore, positive emotions enhance non-stationarity in brain regions associated with semantics compared with negative emotions, leading to a higher false-memory rate. This suggests that non-stationary alterations in brain regions under different emotional states are correlated with false memory.
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Affiliation(s)
- Chen Wang
- Hebei Key Laboratory of Bioelectromagnetics and Neural Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300131, China
| | - Ying Li
- Hebei Key Laboratory of Bioelectromagnetics and Neural Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300131, China; State Key Laboratory of Reliable and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300130, China.
| | - Lingyue Wang
- Hebei Key Laboratory of Bioelectromagnetics and Neural Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300131, China
| | - Shuo Liu
- Hebei Key Laboratory of Bioelectromagnetics and Neural Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300131, China
| | - Shuo Yang
- Hebei Key Laboratory of Bioelectromagnetics and Neural Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300131, China; State Key Laboratory of Reliable and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300130, China.
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15
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Arora A, Becker M, Marques C, Oksanen M, Li D, Mastropasqua F, Watts ME, Arora M, Falk A, Daub CO, Lanekoff I, Tammimies K. Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep 2023; 13:10519. [PMID: 37386098 PMCID: PMC10310850 DOI: 10.1038/s41598-023-37488-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 06/22/2023] [Indexed: 07/01/2023] Open
Abstract
Research continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.
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Affiliation(s)
- Abishek Arora
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Martin Becker
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Cátia Marques
- Department of Chemistry - BMC, Uppsala University, Uppsala, Sweden
| | - Marika Oksanen
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Danyang Li
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Francesca Mastropasqua
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Michelle Evelyn Watts
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden
| | - Manish Arora
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Anna Falk
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Lund Stem Cell Center, Division of Neurobiology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Carsten Oliver Daub
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Science for Life Laboratory, Stockholm, Sweden
| | - Ingela Lanekoff
- Department of Chemistry - BMC, Uppsala University, Uppsala, Sweden
| | - Kristiina Tammimies
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, Visionsgatan 4, 171 56, Solna, Stockholm, Sweden.
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden.
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16
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Yen TL, Huang TN, Lin MH, Hsu TT, Lu MH, Shih PY, Ellegood J, Lerch J, Hsueh YP. Sex bias in social deficits, neural circuits and nutrient demand in Cttnbp2 autism models. Brain 2023; 146:2612-2626. [PMID: 36385662 PMCID: PMC10232293 DOI: 10.1093/brain/awac429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/04/2022] [Accepted: 11/04/2022] [Indexed: 09/02/2023] Open
Abstract
Autism spectrum disorders caused by both genetic and environmental factors are strongly male-biased neuropsychiatric conditions. However, the mechanism underlying the sex bias of autism spectrum disorders remains elusive. Here, we use a mouse model in which the autism-linked gene Cttnbp2 is mutated to explore the potential mechanism underlying the autism sex bias. Autism-like features of Cttnbp2 mutant mice were assessed via behavioural assays. C-FOS staining identified sex-biased brain regions critical to social interaction, with their roles and connectivity then validated by chemogenetic manipulation. Proteomic and bioinformatic analyses established sex-biased molecular deficits at synapses, prompting our hypothesis that male-biased nutrient demand magnifies Cttnbp2 deficiency. Accordingly, intakes of branched-chain amino acids (BCAA) and zinc were experimentally altered to assess their effect on autism-like behaviours. Both deletion and autism-linked mutation of Cttnbp2 result in male-biased social deficits. Seven brain regions, including the infralimbic area of the medial prefrontal cortex (ILA), exhibit reduced neural activity in male mutant mice but not in females upon social stimulation. ILA activation by chemogenetic manipulation is sufficient to activate four of those brain regions susceptible to Cttnbp2 deficiency and consequently to ameliorate social deficits in male mice, implying an ILA-regulated neural circuit is critical to male-biased social deficits. Proteomics analysis reveals male-specific downregulated proteins (including SHANK2 and PSD-95, two synaptic zinc-binding proteins) and female-specific upregulated proteins (including RRAGC) linked to neuropsychiatric disorders, which are likely relevant to male-biased deficits and a female protective effect observed in Cttnbp2 mutant mice. Notably, RRAGC is an upstream regulator of mTOR that senses BCAA, suggesting that mTOR exerts a beneficial effect on females. Indeed, increased BCAA intake activates the mTOR pathway and rescues neuronal responses and social behaviours of male Cttnbp2 mutant mice. Moreover, mutant males exhibit greatly increased zinc demand to display normal social behaviours. Mice carrying an autism-linked Cttnbp2 mutation exhibit male-biased social deficits linked to specific brain regions, differential synaptic proteomes and higher demand for BCAA and zinc. We postulate that lower demand for zinc and BCAA are relevant to the female protective effect. Our study reveals a mechanism underlying sex-biased social defects and also suggests a potential therapeutic approach for autism spectrum disorders.
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Affiliation(s)
- Tzu-Li Yen
- Molecular and Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11529, Taiwan, ROC
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - Tzyy-Nan Huang
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - Ming-Hui Lin
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - Tsan-Ting Hsu
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - Ming-Hsuan Lu
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - Pu-Yun Shih
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - Jacob Ellegood
- Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada
- Department of Medical Biophysics, The University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Jason Lerch
- Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada
- Department of Medical Biophysics, The University of Toronto, Toronto, Ontario M5G 1L7, Canada
- Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford OX3 9DU, UK
| | - Yi-Ping Hsueh
- Molecular and Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11529, Taiwan, ROC
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, ROC
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17
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Martinez M, Harry GJ, Haynes EN, Lin PID, Oken E, Horton MK, Wright RO, Arora M, Austin C. Quantitative fluoride imaging of teeth using CaF emission by laser induced breakdown spectroscopy. JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY 2023; 38:303-314. [PMID: 36776552 PMCID: PMC9906802 DOI: 10.1039/d2ja00134a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 09/15/2022] [Indexed: 05/18/2023]
Abstract
In this work, we propose the use of molecular emission of calcium fluoride (CaF) by laser induced breakdown spectroscopy (LIBS) to obtain quantitative fluoride distribution images of teeth. LIBS has proved to be an efficient technique to detect low amounts of fluoride in solids, and human teeth have the advantage being a matrix rich in calcium. We used new calibration material from sintered hydroxyapatite pellets doped with fluoride to determine the optimized LIBS conditions of argon flow at 1 L min-1 and using the green emission bands of CaF in 530 nm, and obtained a calibration curve between 0 and 400 μg g-1, and LOD of 18 μg g-1. This methodology was applied within a rat model of fluoride exposure and showed increasing tooth-fluoride with increased exposure dose. To demonstrate applicability of this method in human teeth, we quantified fluoride distribution in teeth from three children from non-fluorinated and fluorinated water regions. Samples from children living in fluoridated water regions showed higher fluoride concentrations in dentine formed after birth, compared to a child from a non-fluoridated region. Teeth have been used as biomarkers for environmental exposure and this new method opens the opportunity in epidemiology research to study critical windows of early life exposure to fluoride as well.
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Affiliation(s)
- Mauro Martinez
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai New York NY USA
| | - G Jean Harry
- Mechanistic Toxicology Branch, Division of National Toxicology Program, National Institute of Environmental Health Sciences Research Triangle Park NC USA
| | - Erin N Haynes
- Department of Epidemiology, College of Public Health, University of Kentucky Lexington KY USA
| | - Pi-I D Lin
- Division of Chronic Disease Research Across the Life Course, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute Boston MA USA
| | - Emily Oken
- Division of Chronic Disease Research Across the Life Course, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute Boston MA USA
| | - Megan K Horton
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai New York NY USA
| | - Robert O Wright
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai New York NY USA
| | - Manish Arora
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai New York NY USA
| | - Christine Austin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai New York NY USA
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18
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Associations between Elemental Metabolic Dynamics and Default Mode Network Functional Connectivity Are Altered in Autism. J Clin Med 2023; 12:jcm12031022. [PMID: 36769671 PMCID: PMC9917994 DOI: 10.3390/jcm12031022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Autism is a neurodevelopmental condition associated with atypical social communication, cognitive, and sensory faculties. Recent advances in exposure biology suggest that biomarkers of elemental uptake and metabolism measured in hair samples can yield an effective signal predictive of autism diagnosis. Here, we investigated if elemental biomarkers in hair were associated with functional connectivity in regions of the default mode network (DMN) previously linked to autism. In a study sample which included twin pairs with concordant and discordant diagnoses for autism, our analysis of hair samples and neuroimaging data supported two general findings. First, independent of autism diagnosis, we found a broad pattern of association between elemental biomarkers and functional connectivity in the DMN, which primarily involved dynamics in zinc metabolism. Second, we found that associations between the DMN and elemental biomarkers, particularly involving phosphorus, calcium, manganese, and magnesium, differed significantly in autistic participants from control participants. In sum, these findings suggest that functional dynamics in elemental metabolism relate broadly to persistent patterns of functional connectivity in the DMN, and that these associations are altered in the emergence of autism.
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19
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Escobedo-Monge MF, Barrado E, Parodi-Román J, Escobedo-Monge MA, Torres-Hinojal MC, Marugán-Miguelsanz JM. Copper/Zinc Ratio in Childhood and Adolescence: A Review. Metabolites 2023; 13:metabo13010082. [PMID: 36677007 PMCID: PMC9862945 DOI: 10.3390/metabo13010082] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/26/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
Both copper (Cu) and zinc (Zn) are crucial micronutrients for human growth and development. This literature review covered the last five years of available evidence on the Cu/Zn ratio in children and adolescents. We searched PubMed, Web of Science, Google Scholar, Cochrane Library, and Science Direct for publications between 2017 and 2022, especially in English, although publications in other languages with abstracts in English were included. The main terms used were "copper", "zinc", "copper-zinc", and "zinc-copper" ratios. Cu and Zn determinations made in blood, plasma, or serum were included. This review comprises several cross-sectional and case-control studies with substantial results. The bibliographic search generated a compilation of 19 articles, in which 63.2% of the studies mostly reported a significantly higher Cu/Zn ratio, and 57.9% of them informed significantly lower levels of Zn. We conclude that children and adolescents with acute and chronic conditions are at greater risk of developing elevated Cu/Zn ratios, related to altered nutritional, infectious, and inflammatory status.
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Affiliation(s)
- Marlene Fabiola Escobedo-Monge
- Faculty of Medicine, University of Valladolid, Avenida Ramón y Cajal, 7, 47005 Valladolid, Spain
- Correspondence: ; Tel.: +34-639-590-467
| | - Enrique Barrado
- Department of Analytical Chemistry, Science Faculty, Campus Miguel Delibes, University of Valladolid, Calle Paseo de Belén, 7, 47011 Valladolid, Spain
| | - Joaquín Parodi-Román
- Science Faculty, University of Cadiz, Paseo de Carlos III, 28, 11003 Cádiz, Spain
| | | | | | - José Manuel Marugán-Miguelsanz
- Department of Pediatrics, Faculty of Medicine, University of Valladolid, Section of Gastroenterology and Pediatric Nutrition, University Clinical Hospital of Valladolid, Avenida Ramón y Cajal, 7, 47005 Valladolid, Spain
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20
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Błażewicz A, Grabrucker AM. Metal Profiles in Autism Spectrum Disorders: A Crosstalk between Toxic and Essential Metals. Int J Mol Sci 2022; 24:ijms24010308. [PMID: 36613749 PMCID: PMC9820494 DOI: 10.3390/ijms24010308] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/15/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Since hundreds of years ago, metals have been recognized as impacting our body's physiology. As a result, they have been studied as a potential cure for many ailments as well as a cause of acute or chronic poisoning. However, the link between aberrant metal levels and neuropsychiatric illnesses such as schizophrenia and neurodevelopmental disorders, such as autism spectrum disorders (ASDs), is a relatively new finding, despite some evident ASD-related consequences of shortage or excess of specific metals. In this review, we will summarize past and current results explaining the pathomechanisms of toxic metals at the cellular and molecular levels that are still not fully understood. While toxic metals may interfere with dozens of physiological processes concurrently, we will focus on ASD-relevant activity such as inflammation/immune activation, mitochondrial malfunction, increased oxidative stress, impairment of axonal myelination, and synapse formation and function. In particular, we will highlight the competition with essential metals that may explain why both the presence of certain toxic metals and the absence of certain essential metals have emerged as risk factors for ASD. Although often investigated separately, through the agonistic and antagonistic effects of metals, a common metal imbalance may result in relation to ASD.
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Affiliation(s)
- Anna Błażewicz
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 20-093 Lublin, Poland
| | - Andreas M. Grabrucker
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland
- Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, V94 T9PX Limerick, Ireland
- Correspondence: ; Tel.: +353-61-237756
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21
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Austin C, Curtin P, Arora M, Reichenberg A, Curtin A, Iwai-Shimada M, Wright RO, Wright RJ, Remnelius KL, Isaksson J, Bölte S, Nakayama SF. Elemental Dynamics in Hair Accurately Predict Future Autism Spectrum Disorder Diagnosis: An International Multi-Center Study. J Clin Med 2022; 11:jcm11237154. [PMID: 36498727 PMCID: PMC9740182 DOI: 10.3390/jcm11237154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy (n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age.
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Affiliation(s)
- Christine Austin
- Linus Biotechnology Inc., New York, NY 10013, USA
- Environmental Medicine and Public Health, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Paul Curtin
- Linus Biotechnology Inc., New York, NY 10013, USA
- Environmental Medicine and Public Health, Mount Sinai School of Medicine, New York, NY 10029, USA
- Correspondence: (P.C.); (M.A.)
| | - Manish Arora
- Linus Biotechnology Inc., New York, NY 10013, USA
- Environmental Medicine and Public Health, Mount Sinai School of Medicine, New York, NY 10029, USA
- Correspondence: (P.C.); (M.A.)
| | - Abraham Reichenberg
- Environmental Medicine and Public Health, Mount Sinai School of Medicine, New York, NY 10029, USA
- Seaver Autism Center, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Austen Curtin
- Linus Biotechnology Inc., New York, NY 10013, USA
- Environmental Medicine and Public Health, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Miyuki Iwai-Shimada
- Exposure Dynamics Research Section, Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan
| | - Robert O. Wright
- Environmental Medicine and Public Health, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Rosalind J. Wright
- Environmental Medicine and Public Health, Mount Sinai School of Medicine, New York, NY 10029, USA
- Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Karl Lundin Remnelius
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women’s and Children’s Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, 11330 Stockholm, Sweden
| | - Johan Isaksson
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women’s and Children’s Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, 11330 Stockholm, Sweden
- Department of Medical Sciences, Child and Adolescent Psychiatry Unit, Uppsala University, 75185 Uppsala, Sweden
| | - Sven Bölte
- Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women’s and Children’s Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, 11330 Stockholm, Sweden
- Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, 11861 Stockholm, Sweden
- Curtin Autism Research Group, Curtin School of Allied Health, Curtin University, Perth, WA 6102, Australia
| | - Shoji F. Nakayama
- Exposure Dynamics Research Section, Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan
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22
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Makris KC, Charisiadis P, Delplancke T, Efthymiou N, Giuliani A. Diurnal Nonlinear Recurrence Metrics of Skin Temperature and Their Association with Metabolic Hormones in Contrasting Climate Settings: A Randomized Cross-Over Trial. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:15195. [PMID: 36429912 PMCID: PMC9690349 DOI: 10.3390/ijerph192215195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 06/16/2023]
Abstract
The urban overheating phenomenon in Mediterranean cities is a societal challenge with vast implications for the protection of public health. An additional analysis of the pilot TEMP randomized 2 × 2 cross-over trial was set up, using wearable sensor-based skin temperature measurements (n = 14). The study objectives were to: (i) assess the recurrence patterns of skin temperature measurements in individuals spending time in two climatologically contrasting settings (urban versus mountainous), and (ii) evaluate the association between the diurnal nonlinear recurrence quantification analysis (RQA) metrics and metabolic hormone levels. The intervention was a short-term stay (5-7 days) in a mountainous, climate-cooler setting (range 600-900 m altitude), which is about a 1 h drive from the main urban centres of Cyprus. The RQA analysis showed a blunting phenomenon on the nonlinear temporal dynamics of skin temperature time series observed in the urban setting. Compared with the mountainous setting, a more stable (and thus less adaptive) profile of skin temperature dynamics in the urban setting appeared, being less deterministic and with a smaller degree of complexity. No significant (p > 0.05) associations were observed between the leptin or cortisol and any of the skin temperature dynamical descriptors. However, there were marginal associations between the adiponectin and laminarity (beta = 0.24, 95%CI: -0.02, 0.50, p = 0.07) and with determinism (beta = 0.23, 95%CI: -0.037, 0.50, p = 0.09). We found dysregulations in skin temperature temporal dynamics of the study population while residing in the urban setting when compared with the cooler mountainous setting; these dysregulations took the form of reduced cycle duration and complexity, while skin temperature dynamics became less responsive to perturbations and less regular in magnitude. More research is needed to better understand heat stress temporal dynamics and their influence on human health. Trial registration: This trial is registered with ClinicalTrials.gov; number: NCT03625817.
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Affiliation(s)
- Konstantinos C. Makris
- Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, 3041 Limassol, Cyprus
| | - Pantelis Charisiadis
- Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, 3041 Limassol, Cyprus
| | - Thibaut Delplancke
- Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, 3041 Limassol, Cyprus
| | - Nikolaos Efthymiou
- Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, 3041 Limassol, Cyprus
| | - Alessandro Giuliani
- Environment and Health Department, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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23
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Ding E, Wang Y, Liu J, Tang S, Shi X. A review on the application of the exposome paradigm to unveil the environmental determinants of age-related diseases. Hum Genomics 2022; 16:54. [DOI: 10.1186/s40246-022-00428-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/29/2022] [Indexed: 11/11/2022] Open
Abstract
AbstractAge-related diseases account for almost half of all diseases among adults worldwide, and their incidence is substantially affected by the exposome, which is the sum of all exogenous and endogenous environmental exposures and the human body’s response to these exposures throughout the entire lifespan. Herein, we perform a comprehensive review of the epidemiological literature to determine the key elements of the exposome that affect the development of age-related diseases and the roles of aging hallmarks in this process. We find that most exposure assessments in previous aging studies have used a reductionist approach, whereby the effect of only a single environmental factor or a specific class of environmental factors on the development of age-related diseases has been examined. As such, there is a lack of a holistic and unbiased understanding of the effect of multiple environmental factors on the development of age-related diseases. To address this, we propose several research strategies based on an exposomic framework that could advance our understanding—in particular, from a mechanistic perspective—of how environmental factors affect the development of age-related diseases. We discuss the statistical methods and other methods that have been used in exposome-wide association studies, with a particular focus on multiomics technologies. We also address future challenges and opportunities in the realm of multidisciplinary approaches and genome–exposome epidemiology. Furthermore, we provide perspectives on precise public health services for vulnerable populations, public communications, the integration of risk exposure information, and the bench-to-bedside translation of research on age-related diseases.
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24
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Yasuda H, Tsutsui T. Metallomics analysis for early assessment and individualized intervention of neurodevelopmental disorders. METALLOMICS : INTEGRATED BIOMETAL SCIENCE 2022; 14:6695310. [PMID: 36087072 DOI: 10.1093/mtomcs/mfac067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 07/28/2022] [Indexed: 11/12/2022]
Abstract
The children today are in the midst of the epidemic of neurodevelopmental disorders. In this metallomics study for the scalp hair samples of total 2550 children with autistic disorders (2108 males and 442 females aged 0-15 year), it was demonstrated that near one half of the infantile individuals aged 0-3 year are suffering from zinc deficiency and toxic metal burdens. Zinc level correlated closely to the index of zinc/iron ratio more than zinc/copper ratio. Furthermore, there were significant relationships between zinc deficiency and toxic metal burdens such as lead and aluminum which were inversely associated with not only zinc level but also zinc/iron ratio with higher regression coefficients of r = -0.486 and -0.551 (p < 0.00001), respectively. High-significant inverse association was detected between zinc and molybdenum concentration (r = -0.509) and also between zinc/iron ratio and molybdenum (r = -0.548). These findings suggest that infantile zinc deficiency relates to the high burdens of not only toxic but also some essential metals such as molybdenum, iron and manganese and that these various mineral imbalances play principal roles to the etiology of neurodevelopmental disorders. We expect that the early assessment and intervention of the mineral imbalances (or dis-homeostasis) in individual child open an avenue for evidence-based individualized treatment of neurodevelopmental disorders and also of the comorbid immune disorders, in near future.
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Affiliation(s)
- Hiroshi Yasuda
- La Belle Vie Research Laboratory, Tokyo; Japan.,Institute of Nature and Environmental Technology, Kanazawa University, Kanazawa, Japan
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25
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Alteration in Gut Microbiota Associated with Zinc Deficiency in School-Age Children. Nutrients 2022; 14:nu14142895. [PMID: 35889856 PMCID: PMC9319427 DOI: 10.3390/nu14142895] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/01/2022] [Accepted: 07/11/2022] [Indexed: 12/10/2022] Open
Abstract
Zinc deficiency could lead to a dynamic variation in gut microbial composition and function in animals. However, how zinc deficiency affects the gut microbiome in school-age children remains unclear. The purpose of this study was to profile the dynamic shifts in the gut microbiome of school-age children with zinc deficiency, and to determine whether such shifts are associated with dietary intake. A dietary survey, anthropometric measurements, and serum tests were performed on 177 school-age children, and 67 children were selected to explore the gut microbial community using amplicon sequencing. School-age children suffered from poor dietary diversity and insufficient food and nutrient intake, and 32% of them were zinc deficient. The inflammatory cytokines significantly increased in the zinc deficiency (ZD) group compared to that in the control (CK) group (p < 0.05). There was no difference in beta diversity, while the Shannon index was much higher in the ZD group (p < 0.05). At the genus level, Coprobacter, Acetivibrio, Paraprevotella, and Clostridium_XI were more abundant in the ZD group (p < 0.05). A functional predictive analysis showed that the metabolism of xenobiotics by cytochrome P450 was significantly depleted in the ZD group (p < 0.05). In conclusion, gut microbial diversity was affected by zinc deficiency with some specific bacteria highlighted in the ZD group, which may be used as biomarkers for further clinical diagnosis of zinc deficiency.
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26
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Jensen AR, Lane AL, Werner BA, McLees SE, Fletcher TS, Frye RE. Modern Biomarkers for Autism Spectrum Disorder: Future Directions. Mol Diagn Ther 2022; 26:483-495. [PMID: 35759118 PMCID: PMC9411091 DOI: 10.1007/s40291-022-00600-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2022] [Indexed: 11/19/2022]
Abstract
Autism spectrum disorder is an increasingly prevalent neurodevelopmental disorder in the world today, with an estimated 2% of the population being affected in the USA. A major complicating factor in diagnosing, treating, and understanding autism spectrum disorder is that defining the disorder is solely based on the observation of behavior. Thus, recent research has focused on identifying specific biological abnormalities in autism spectrum disorder that can provide clues to diagnosis and treatment. Biomarkers are an objective way to identify and measure biological abnormalities for diagnostic purposes as well as to measure changes resulting from treatment. This current opinion paper discusses the state of research of various biomarkers currently in development for autism spectrum disorder. The types of biomarkers identified include prenatal history, genetics, neurological including neuroimaging, neurophysiologic, and visual attention, metabolic including abnormalities in mitochondrial, folate, trans-methylation, and trans-sulfuration pathways, immune including autoantibodies and cytokine dysregulation, autonomic nervous system, and nutritional. Many of these biomarkers have promising preliminary evidence for prenatal and post-natal pre-symptomatic risk assessment, confirmation of diagnosis, subtyping, and treatment response. However, most biomarkers have not undergone validation studies and most studies do not investigate biomarkers with clinically relevant comparison groups. Although the field of biomarker research in autism spectrum disorder is promising, it appears that it is currently in the early stages of development.
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Affiliation(s)
- Amanda R Jensen
- Section on Neurodevelopmental Disorders, Barrow Neurological Institute at Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA
| | - Alison L Lane
- Section on Neurodevelopmental Disorders, Barrow Neurological Institute at Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA
| | - Brianna A Werner
- Section on Neurodevelopmental Disorders, Barrow Neurological Institute at Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA
| | - Sallie E McLees
- Section on Neurodevelopmental Disorders, Barrow Neurological Institute at Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA
| | - Tessa S Fletcher
- Section on Neurodevelopmental Disorders, Barrow Neurological Institute at Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA.,Department of Child Health, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
| | - Richard E Frye
- Section on Neurodevelopmental Disorders, Barrow Neurological Institute at Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, AZ, 85016, USA.
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27
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Curtin P, Neufeld J, Curtin A, Arora M, Bölte S. Altered Periodic Dynamics in the Default Mode Network in Autism and Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry 2022; 91:956-966. [PMID: 35227462 PMCID: PMC9119910 DOI: 10.1016/j.biopsych.2022.01.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Altered resting-state functional connectivity in the default mode network (DMN) is characteristic of both autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Standard analytical pipelines for resting-state functional connectivity focus on linear correlations in activation time courses between neural networks or regions of interest. These features may be insensitive to temporally lagged or nonlinear relationships. METHODS In a twin cohort study comprising 292 children, including 52 with a diagnosis of ASD and 70 with a diagnosis of ADHD, we applied nonlinear analytical methods to characterize periodic dynamics in the DMN. Using recurrence quantification analysis and related methods, we measured the prevalence, duration, and complexity of periodic processes within and between DMN regions of interest. We constructed generalized estimating equations to compare these features between neurotypical children and children with ASD and/or ADHD while controlling for familial relationships, and we leveraged machine learning algorithms to construct models predictive of ASD or ADHD diagnosis. RESULTS In within-pair analyses of twins with discordant ASD diagnoses, we found that DMN signal dynamics were significantly different in dizygotic twins but not in monozygotic twins. Considering our full sample, we found that these patterns allowed a robust predictive classification of both ASD (81.0% accuracy; area under the curve = 0.85) and ADHD (82% accuracy; area under the curve = 0.87) cases. CONCLUSIONS These findings indicate that synchronized periodicity among regions comprising the DMN relates both to neurotypical function and to ASD and/or ADHD, and they suggest generally that a dynamical analysis of network interconnectivity may be a useful methodology for future neuroimaging studies.
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Affiliation(s)
- Paul Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Janina Neufeld
- Center of Neurodevelopmental Disorders at Karolinska Institutet, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
| | - Austen Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Manish Arora
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sven Bölte
- Center of Neurodevelopmental Disorders at Karolinska Institutet, Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Curtin Autism Research Group, Curtin School of Allied Health, Curtin University, Perth, Western Australia, Australia
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28
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Sauer AK, Hagmeyer S, Grabrucker AM. Prenatal Zinc Deficient Mice as a Model for Autism Spectrum Disorders. Int J Mol Sci 2022; 23:ijms23116082. [PMID: 35682762 PMCID: PMC9181257 DOI: 10.3390/ijms23116082] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 02/06/2023] Open
Abstract
Epidemiological studies have shown a clear association between early life zinc deficiency and Autism Spectrum Disorders (ASD). In line with this, mouse models have revealed prenatal zinc deficiency as a profound risk factor for neurobiological and behavioral abnormalities in the offspring reminiscent of ASD behavior. From these studies, a complex pathology emerges, with alterations in the gastrointestinal and immune system and synaptic signaling in the brain, as a major consequence of prenatal zinc deficiency. The features represent a critical link in a causal chain that leads to various neuronal dysfunctions and behavioral phenotypes observed in prenatal zinc deficient (PZD) mice and probably other mouse models for ASD. Given that the complete phenotype of PZD mice may be key to understanding how non-genetic factors can modify the clinical features and severity of autistic patients and explain the observed heterogeneity, here, we summarize published data on PZD mice. We critically review the emerging evidence that prenatal zinc deficiency is at the core of several environmental risk factors associated with ASD, being mechanistically linked to ASD-associated genetic factors. In addition, we highlight future directions and outstanding questions, including potential symptomatic, disease-modifying, and preventive treatment strategies.
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Affiliation(s)
- Ann Katrin Sauer
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland; (A.K.S.); (S.H.)
- Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, V94 T9PX Limerick, Ireland
| | - Simone Hagmeyer
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland; (A.K.S.); (S.H.)
| | - Andreas M. Grabrucker
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland; (A.K.S.); (S.H.)
- Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, V94 T9PX Limerick, Ireland
- Correspondence: ; Tel.: +353-61-237756
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Diurnal Variation in Biomarkers of Exposure to Endocrine-Disrupting Chemicals and Their Association with Oxidative Damage in Norwegian Adults: The EuroMix Study. TOXICS 2022; 10:toxics10040181. [PMID: 35448442 PMCID: PMC9028082 DOI: 10.3390/toxics10040181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/27/2022] [Accepted: 04/02/2022] [Indexed: 11/23/2022]
Abstract
Much evidence on the adverse health effects of endocrine-disrupting chemicals (EDCs) has accumulated during recent decades. EDCs are commonly found in various foods and personal care products (PCP). Data documenting a diurnally varying EDC metabolism in humans is scarce. This study examined (i) the time-of-day effect on the diurnal magnitude and variance of urinary biomarkers of exposure to EDCs, and (ii) the association between EDC exposures and oxidative damage in a Norwegian adult subpopulation. This was a cross-sectional panel study using biobanked samples from the EuroMix project. During a typical weekday, participants were asked to collect all day’s urine voids and record dietary and PCP habitual uses in a diary. Collected time stamps of urine voids were classified into three distinct periods in the day (morning 6 a.m.−12 p.m., mid-day 12 p.m.−6 p.m., evening 6 p.m.−6 a.m.). Questionnaires regarding demographic characteristics, personal care product usage, and dietary habits were completed. Urinary levels of EDCs (phthalates, parabens, and bisphenols) were measured using mass spectrometry and adjusted for urinary volume using specific gravity. Urinary 4-hydroxynonenal (4HNE), a lipid peroxidation marker, was measured using an immunoassay kit. Linear mixed-effect models identified EDCs under the influence of a diurnal variation effect that was adjusted for dietary habits and PCP use and examined associations between EDC and 4HNE. p-values were FDR-adjusted. Most phthalates appeared to be diurnally varying with higher urinary levels towards the evening (q < 0.001) than those measured during mid-day; this strong diurnal variation effect was not present for parabens and bisphenols. Significant (q < 0.001) positive associations were observed between all phthalates, parabens, and bisphenols (except bisphenol S) and 4HNE. This study’s findings highlighted the diurnal variation of excretion for certain EDC, but not for others, in real-life conditions. The degree of EDC chronotoxicity in distinct diurnal windows of the day warrants further investigation with longitudinal human studies.
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Dunn EC, Mountain RV, Davis KA, Shaffer I, Smith ADAC, Roubinov DS, Den Besten P, Bidlack FB, Boyce WT. Association Between Measures Derived From Children's Primary Exfoliated Teeth and Psychopathology Symptoms: Results From a Community-Based Study. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2022.803364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mental disorders are among the most disabling health conditions globally. However, there remains a lack of valid, reliable, noninvasive, and inexpensive biomarkers to identify (at an early age) people who are at the greatest risk of experiencing a future mental health condition. Exfoliated primary teeth, when used in combination with established and emerging tools (e.g., family history, imaging, genetics, epigenetics), may provide important additional insights about vulnerability to mental illness. Teeth are especially promising because they develop in parallel with the brain and maintain a permanent record of environmental insults occurring during prenatal and perinatal development. Despite their potential, few empirical studies have investigated features of exfoliated teeth in relation to mental health. Here, we used micro-CT imaging to test the hypothesis that measures derived from exfoliated primary incisors associated with psychopathology symptoms in a community-based sample of children (n = 37). We found that enamel volume (β = −0.77, 95% CI, −1.35 to −0.18, P = 0.01) had large negative associations with internalizing symptoms, and enamel mineral density (β = 0.77, 95% CI, 0.18–1.35, P = 0.01) had large positive associations with internalizing behavioral symptoms, even after stringent control for multiple testing. Pulp volume (β = −0.50, 95% CI, −0.90 to −0.09, P = 0.02) had a moderately-large negative association with externalizing behavioral symptoms, though these associations did not survive multiple testing correction. These results support the ongoing investigation of teeth as potential novel biomarkers of mental health risk.
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31
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Amolegbe SM, Carlin DJ, Henry HF, Heacock ML, Trottier BA, Suk WA. Understanding exposures and latent disease risk within the National Institute of Environmental Health Sciences Superfund Research Program. Exp Biol Med (Maywood) 2022; 247:529-537. [PMID: 35253496 DOI: 10.1177/15353702221079620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Understanding the health effects of exposures when there is a lag between exposure and the onset of disease is an important and challenging topic in environmental health research. The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) is a National Institutes of Health (NIH) grant program that uses a multidisciplinary approach to support biomedical and environmental science and engineering research. Because of the multidisciplinary nature of the program, SRP grantees are well-positioned to study exposure and latent disease risk across humans, animal models, and various life stages. SRP-funded scientists are working to address the challenge of connecting exposures that occur early in life and prior to conception with diseases that manifest much later, including developing new tools and approaches to predict how chemicals may affect long-term health. Here, we highlight research from the SRP focused on understanding the health effects of exposures with a lag between exposure and the onset of the disease as well as provide future directions for addressing knowledge gaps for this highly complex and challenging topic. Advancing the knowledge of latency to disease will require a multidisciplinary approach to research, the need for data sharing and integration, and new tools and computation approaches to make better predications about the timing of disease onset. A better understanding of exposures that may contribute to later-life diseases is essential to supporting the implementation of prevention and intervention strategies to reduce or modulate exposures to reduce disease burden.
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Affiliation(s)
- Sara M Amolegbe
- Superfund Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27560, USA
| | - Danielle J Carlin
- Superfund Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27560, USA
| | - Heather F Henry
- Superfund Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27560, USA
| | - Michelle L Heacock
- Superfund Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27560, USA
| | - Brittany A Trottier
- Superfund Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27560, USA
| | - William A Suk
- Superfund Research Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC 27560, USA
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32
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Alsufiani HM, Alkhanbashi AS, Laswad NAB, Bakhadher KK, Alghamdi SA, Tayeb HO, Tarazi FI. Zinc deficiency and supplementation in autism spectrum disorder and Phelan-McDermid syndrome. J Neurosci Res 2022; 100:970-978. [PMID: 35114017 DOI: 10.1002/jnr.25019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 12/02/2021] [Accepted: 01/07/2022] [Indexed: 01/05/2023]
Abstract
Approximately 1 in 36 children are diagnosed with autism spectrum disorder (ASD). The disorder is four times more common in males than in females. Zinc deficiency and mutations in SHANK2 and SHANK3 (members of a family of excitatory postsynaptic scaffolding proteins) are all risk factors that may contribute to the pathophysiology of the disease. The presence of shankopathies (loss of one copy of the SHANK3 gene) can lead to the development of Phelan-McDermid syndrome (PMDS)-a rare genetic disorder characterized by developmental delay, intellectual disability, poor motor tone, and ASD-like symptoms. We reviewed the relationship between zinc, ASD, and PMDS as well as the effect of zinc supplementation in improving symptoms of ASD and PMDS based on 22 studies published within 6 years (2015-2020). Zinc deficiency (assessed by either dietary intake, blood, hair, or tooth matrix) was shown to be highly prevalent in ASD and PMDS patients as well as in preclinical models of ASD and PMDS. Zinc supplements improved the behavioral deficits in animal models of ASD and PMDS. Clinical trials are still needed to validate the beneficial therapeutic effects of zinc supplements in ASD and PMDS patients.
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Affiliation(s)
- Hadeil M Alsufiani
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Experimental Biochemistry Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Alaa S Alkhanbashi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Norah A Bin Laswad
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Khulood K Bakhadher
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shareefa A Alghamdi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Haythum O Tayeb
- Division of Neurology, Department of Internal Medicine, The Neuroscience Research Unit, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Frank I Tarazi
- Department of Psychiatry and Neuroscience, Harvard Medical School and McLean Hospital, Belmont, Massachusetts, USA
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33
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Ma J, Wu J, Li H, Wang J, Han J, Zhang R. Association Between Essential Metal Elements and the Risk of Autism in Chinese Han Population. Biol Trace Elem Res 2022; 200:505-515. [PMID: 33797704 DOI: 10.1007/s12011-021-02690-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 03/23/2021] [Indexed: 12/27/2022]
Abstract
Essential metal elements (EMEs) have essential roles in neurological development and maintenance of human homeostasis. We performed a case-control study to explore association between the risk of autism spectrum disorder (ASD) and the 11 EMEs [Calcium (Ca), potassium (K), magnesium (Mg), sodium (Na), manganese (Mn), selenium (Se), cobalt (Co), Molybdenum (Mo), copper (Cu), zinc (Zn), and iron (Fe)] in serum. Ninety-two autistic subjects (cases) and age-sex-matched healthy subjects (controls = 91) from Beijing, China were recruited. In addition, totally 109 mothers of recruited children participated in this study. ICP-AES and ICP-MS were applied to determine the concentration of 11 EMEs in serum. The concentrations of Ca, K, and Mg were significantly higher in the cases than in the controls (OR [95% CI]: 1.031 [1.006-1.058] for Ca; 1.081 [1.046-1.118] for K; 1.161 [1.012-1.331] for Mg), while the concentrations of Zn and Cu were significantly lower (0.997 [0.995-0.999] for Cu; 0.996 [0.992-1.000] for Zn). Clear dose-response relationships between EMEs concentrations and the risk of ASD, as well as the correlation between EME concentrations and the severity of ASD were observed for most of the above EMEs. Six and seven specific correlated pairs between mothers and children were found in the cases and controls separately. The overall profiles of the EMEs were changed in the cases as compared to the controls. This study suggested that the higher levels of Ca, K, and Mg and lower levels of Zn and Cu may be associated with an elevated risk of ASD.
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Affiliation(s)
- Jiahui Ma
- Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, People's Republic of China
| | - Jing Wu
- Peking University Medical and Health Analysis Center, Peking University, Beijing, 100191, People's Republic of China
| | - Haibin Li
- Heart Center & Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People's Republic of China
| | - Jingyu Wang
- School of Public Health, Peking University, Beijing, 100191, People's Republic of China
| | - Jisheng Han
- Neuroscience Research Institute, Peking University, Beijing, 100191, People's Republic of China
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100191, People's Republic of China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People's Republic of China
| | - Rong Zhang
- Neuroscience Research Institute, Peking University, Beijing, 100191, People's Republic of China.
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100191, People's Republic of China.
- Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People's Republic of China.
- Autism Research Center of Peking University Health Science Center, Beijing, 100191, People's Republic of China.
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34
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Dong HY, Feng JY, Li HH, Yue XJ, Jia FY. Non-parental caregivers, low maternal education, gastrointestinal problems and high blood lead level: predictors related to the severity of autism spectrum disorder in Northeast China. BMC Pediatr 2022; 22:11. [PMID: 34980074 PMCID: PMC8722278 DOI: 10.1186/s12887-021-03086-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/20/2021] [Indexed: 12/18/2022] Open
Abstract
Background The prevalence of autism spectrum disorder (ASD) has increased rapidly in recent years. Environmental factors may play an important role in the pathogenesis of ASD. These factors may include socioeconomic factors, nutritional factors, heavy metal exposure, air pollution, etc. Our aim is to analyze possible environmental factors associated with the severity of ASD. Methods All participating children were divided into two groups (mild and moderate/severe) according to the severity of their symptoms, as determined by their Childhood Autism Rating Scale (CARS) scores. The socioeconomic, demographic factors and the nutritional factors that may affect the severity of ASD were included in the logistic regression to analyze whether they were predictors that affected the severity of ASD. Results Logistic regression showed that caregivers(P = 0.042), maternal education (P = 0.030), gastrointestinal problems (P = 0.041) and a high serum concentration of lead (P = 0.003) were statistically significantly associated with ASD severity. Conclusion Many environmental factors affect the severity of ASD. We concluded that non-parental caregivers, low maternal education, gastrointestinal problems and high blood lead level maybe predictors that affected the severity of ASD in northeast China.
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Affiliation(s)
- Han-Yu Dong
- Department of Developmental and Behavioral Pediatrics, the First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
| | - Jun-Yan Feng
- Department of Developmental and Behavioral Pediatrics, the First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
| | - Hong-Hua Li
- Department of Developmental and Behavioral Pediatrics, the First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
| | - Xiao-Jing Yue
- Department of Developmental and Behavioral Pediatrics, the First Hospital of Jilin University, Changchun, 130021, Jilin Province, China
| | - Fei-Yong Jia
- Department of Developmental and Behavioral Pediatrics, the First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
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35
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Zhou Y, Gao J. Why not try to predict autism spectrum disorder with crucial biomarkers in cuproptosis signaling pathway? Front Psychiatry 2022; 13:1037503. [PMID: 36405901 PMCID: PMC9667021 DOI: 10.3389/fpsyt.2022.1037503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/17/2022] [Indexed: 01/24/2023] Open
Abstract
The exact pathogenesis of autism spectrum disorder (ASD) is still unclear, yet some potential mechanisms may not have been evaluated before. Cuproptosis is a novel form of regulated cell death reported this year, and no study has reported the relationship between ASD and cuproptosis. This study aimed to identify ASD in suspected patients early using machine learning models based on biomarkers of the cuproptosis pathway. We collected gene expression profiles from brain samples from ASD model mice and blood samples from humans with ASD, selected crucial genes in the cuproptosis signaling pathway, and then analysed these genes with different machine learning models. The accuracy, sensitivity, specificity, and areas under the receiver operating characteristic curves of the machine learning models were estimated in the training, internal validation, and external validation cohorts. Differences between models were determined with Bonferroni's test. The results of screening with the Boruta algorithm showed that FDX1, DLAT, LIAS, and ATP7B were crucial genes in the cuproptosis signaling pathway for ASD. All selected genes and corresponding proteins were also expressed in the human brain. The k-nearest neighbor, support vector machine and random forest models could identify approximately 72% of patients with ASD. The artificial neural network (ANN) model was the most suitable for the present data because the accuracy, sensitivity, and specificity were 0.90, 1.00, and 0.80, respectively, in the external validation cohort. Thus, we first report the prediction of ASD in suspected patients with machine learning methods based on crucial biomarkers in the cuproptosis signaling pathway, and these findings may contribute to investigations of the potential pathogenesis and early identification of ASD.
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Affiliation(s)
- Yu Zhou
- Department of Child Rehabilitation Division, Huai'an Maternal and Child Health Care Center, Huai'an, China.,Affiliated Hospital of Yang Zhou University Medical College, Huai'an Maternal and Child Health Care Center, Huai'an, China
| | - Jing Gao
- Department of Child Rehabilitation Division, Huai'an Maternal and Child Health Care Center, Huai'an, China.,Affiliated Hospital of Yang Zhou University Medical College, Huai'an Maternal and Child Health Care Center, Huai'an, China
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36
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Sauer AK, Malijauskaite S, Meleady P, Boeckers TM, McGourty K, Grabrucker AM. Zinc is a key regulator of gastrointestinal development, microbiota composition and inflammation with relevance for autism spectrum disorders. Cell Mol Life Sci 2021; 79:46. [PMID: 34936034 PMCID: PMC11072240 DOI: 10.1007/s00018-021-04052-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/31/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022]
Abstract
Gastrointestinal (GI) problems and microbiota alterations have been frequently reported in autism spectrum disorders (ASD). In addition, abnormal perinatal trace metal levels have been found in ASD. Accordingly, mice exposed to prenatal zinc deficiency display features of ASD-like behavior. Here, we model GI development using 3D intestinal organoids grown under zinc-restricted conditions. We found significant morphological alterations. Using proteomic approaches, we identified biological processes affected by zinc deficiency that regulate barrier permeability and pro-inflammatory pathways. We confirmed our results in vivo through proteomics studies and investigating GI development in zinc-deficient mice. These show altered GI physiology and pro-inflammatory signaling, resulting in chronic systemic and neuroinflammation, and gut microbiota composition similar to that reported in human ASD cases. Thus, low zinc status during development is sufficient to compromise intestinal barrier integrity and activate pro-inflammatory signaling, resulting in changes in microbiota composition that may aggravate inflammation, altogether mimicking the co-morbidities frequently observed in ASD.
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Affiliation(s)
- Ann Katrin Sauer
- Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Bernal Institute, Analog Devices Building AD3-018, Castletroy, Limerick, V94PH61, Ireland
- Bernal Institute, University of Limerick, Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, Limerick, Ireland
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
| | - Sigita Malijauskaite
- Bernal Institute, University of Limerick, Limerick, Ireland
- Department of Chemical Sciences, University of Limerick, Limerick, Ireland
| | - Paula Meleady
- School of Biotechnology and National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Tobias M Boeckers
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
- DZNE, Ulm Unit, Ulm, Germany
| | - Kieran McGourty
- Bernal Institute, University of Limerick, Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, Limerick, Ireland
- Department of Chemical Sciences, University of Limerick, Limerick, Ireland
| | - Andreas M Grabrucker
- Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Bernal Institute, Analog Devices Building AD3-018, Castletroy, Limerick, V94PH61, Ireland.
- Bernal Institute, University of Limerick, Limerick, Ireland.
- Health Research Institute (HRI), University of Limerick, Limerick, Ireland.
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37
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Network Dynamics in Elemental Assimilation and Metabolism. ENTROPY 2021; 23:e23121633. [PMID: 34945939 PMCID: PMC8700619 DOI: 10.3390/e23121633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/29/2021] [Accepted: 12/01/2021] [Indexed: 11/16/2022]
Abstract
Metabolism and physiology frequently follow non-linear rhythmic patterns which are reflected in concepts of homeostasis and circadian rhythms, yet few biomarkers are studied as dynamical systems. For instance, healthy human development depends on the assimilation and metabolism of essential elements, often accompanied by exposures to non-essential elements which may be toxic. In this study, we applied laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to reconstruct longitudinal exposure profiles of essential and non-essential elements throughout prenatal and early post-natal development. We applied cross-recurrence quantification analysis (CRQA) to characterize dynamics involved in elemental integration, and to construct a graph-theory based analysis of elemental metabolism. Our findings show how exposure to lead, a well-characterized toxicant, perturbs the metabolism of essential elements. In particular, our findings indicate that high levels of lead exposure dysregulate global aspects of metabolic network connectivity. For example, the magnitude of each element's degree was increased in children exposed to high lead levels. Similarly, high lead exposure yielded discrete effects on specific essential elements, particularly zinc and magnesium, which showed reduced network metrics compared to other elements. In sum, this approach presents a new, systems-based perspective on the dynamics involved in elemental metabolism during critical periods of human development.
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38
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Frye RE, Lionnard L, Singh I, Karim MA, Chajra H, Frechet M, Kissa K, Racine V, Ammanamanchi A, McCarty PJ, Delhey L, Tippett M, Rose S, Aouacheria A. Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder. Transl Psychiatry 2021; 11:527. [PMID: 34645790 PMCID: PMC8514530 DOI: 10.1038/s41398-021-01647-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/20/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.
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Affiliation(s)
- Richard E Frye
- Phoenix Children's Hospital, Phoenix, AZ, USA.
- University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA.
| | - Loïc Lionnard
- Institut des Sciences de l'Evolution de Montpellier, UMR 5554 CNRS, UM, IRD, EPHE, Université de Montpellier, Place Eugène Bataillon, 34095, Montpellier cedex 05, France
| | - Indrapal Singh
- Phoenix Children's Hospital, Phoenix, AZ, USA
- University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - Mohammad A Karim
- Phoenix Children's Hospital, Phoenix, AZ, USA
- University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - Hanane Chajra
- Clariant Active ingredients, 195 Route d'Espagne, 31036, Toulouse Cedex 1, France
| | - Mathilde Frechet
- Clariant Active ingredients, 195 Route d'Espagne, 31036, Toulouse Cedex 1, France
| | - Karima Kissa
- LPHI, CNRS, INSERM, Emergence of Haematopoietic Stem Cells and Cancer, Univ Montpellier, Montpellier, France
| | - Victor Racine
- QuantaCell SAS, 2 allée du Doyen Georges Brus, 33600, Pessac, France
| | - Amrit Ammanamanchi
- Phoenix Children's Hospital, Phoenix, AZ, USA
- University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - Patrick John McCarty
- Phoenix Children's Hospital, Phoenix, AZ, USA
- University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - Leanna Delhey
- Arkansas Children's Research Institute, Little Rock, AR, USA
| | - Marie Tippett
- Arkansas Children's Research Institute, Little Rock, AR, USA
| | - Shannon Rose
- Arkansas Children's Research Institute, Little Rock, AR, USA
| | - Abdel Aouacheria
- Institut des Sciences de l'Evolution de Montpellier, UMR 5554 CNRS, UM, IRD, EPHE, Université de Montpellier, Place Eugène Bataillon, 34095, Montpellier cedex 05, France
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39
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Makris KC. Desynchronized circadian clock and exposures to xenobiotics are associated with differentiated disease phenotypes: The interface of desynchronized circadian clock and exposures to xenobiotics would lead to adverse response and recovery. Bioessays 2021; 43:e2100159. [PMID: 34585760 DOI: 10.1002/bies.202100159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023]
Abstract
A paradigm shift in the human chronotoxicity of xenobiotics would study two-sided desynchronized phenomena of interfacial interactions between cyclic or periodic environmental insults and the endogenous response and recovery profile. These systems-based networks are under the influence of well-synchronized biological clocks and their metabolic regulators. This perspective argues in favor of addressing the concept of synchronization in studies involving critical life windows of susceptibility, or circadian rhythms, or 24-hour (periodic) diurnal rhythms and answering whether these disruptions in synchronization would affect response and recovery or disease phenotypes associated with environmental insults, e.g., xenobiotics. Synchronization or synchrony is defined as the totality of elements that appear during the same time period within a system, including the network of interactions between the system's elements. Desynchronized interfaces during critical life windows or in time-repeated exposure events would likely lead to initiating a cascade of adverse health effects associated with differentiated disease phenotypes.
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Affiliation(s)
- Konstantinos Christos Makris
- Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, Cyprus
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40
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Zhang J, Li X, Shen L, Khan NU, Zhang X, Chen L, Zhao H, Luo P. Trace elements in children with autism spectrum disorder: A meta-analysis based on case-control studies. J Trace Elem Med Biol 2021; 67:126782. [PMID: 34049201 DOI: 10.1016/j.jtemb.2021.126782] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 03/30/2021] [Accepted: 05/10/2021] [Indexed: 12/25/2022]
Abstract
Autism spectrum disorder (ASD) is a common childhood neurodevelopmental disorder that may be related to trace elements. However, reports on the relationship between them are still inconsistent. In this article, we conducted a meta-analysis on this issue. We searched the PubMed, EMBASE, and Cochrane databases as of November 15, 2019. A random-effects model was used, and subgroups of studies were analyzed using samples of different measurements. Twenty-two original articles were identified (18 trace elements, including a total of 1014 children with ASD and 999 healthy controls). In autistic children, the overall levels of barium (Ba), mercury (Hg), lithium (Li), and lead (Pb) were higher. There were significant differences in the levels of copper (Cu) in the hair and serum between autistic children and the control group. The levels of Hg, Li, Pb and selenium (Se) in the hair of autistic children were higher than those of healthy children, while the levels of zinc (Zn) in the blood were lower. Excessive exposure to toxic heavy metals and inadequate intake of essential metal elements may be associated with ASD. Preventing excessive exposure to toxic metals and correcting poor dietary behaviors may be beneficial for the prevention and treatment of the disease.
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Affiliation(s)
- Jun Zhang
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring Control Ministry of Education, Guizhou Medical University, 550025, PR China
| | - Xi Li
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring Control Ministry of Education, Guizhou Medical University, 550025, PR China
| | - Liming Shen
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518060, PR China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, PR China.
| | - Naseer Ullah Khan
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518060, PR China
| | - Xiao Zhang
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring Control Ministry of Education, Guizhou Medical University, 550025, PR China
| | - Lulu Chen
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring Control Ministry of Education, Guizhou Medical University, 550025, PR China
| | - Huan Zhao
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring Control Ministry of Education, Guizhou Medical University, 550025, PR China
| | - Peng Luo
- School of Public Health, Key Laboratory of Environmental Pollution Monitoring Control Ministry of Education, Guizhou Medical University, 550025, PR China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China.
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41
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Frye RE, Cakir J, Rose S, Palmer RF, Austin C, Curtin P. Physiological mediators of prenatal environmental influences in autism spectrum disorder. Bioessays 2021; 43:e2000307. [PMID: 34260745 DOI: 10.1002/bies.202000307] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 12/27/2022]
Abstract
Recent research has pointed to the importance of the prenatal environment in the etiology of autism spectrum disorder (ASD) but the biological mechanisms which mitigate these environmental factors are not clear. Mitochondrial metabolism abnormalities, inflammation and oxidative stress as common physiological disturbances associated with ASD. Network analysis of the scientific literature identified several leading prenatal environmental factors associated with ASD, particularly air pollution, pesticides, the microbiome and epigenetics. These leading prenatal environmental factors were found to be most associated with inflammation, followed by oxidative stress and mitochondrial dysfunction. Other prenatal factors associated with ASD not identified by the network analysis were also found to be significantly associated with these common physiological disturbances. A better understanding of the biological mechanism which mediate the effect of prenatal environmental factors can lead to insights of how ASD develops and the development of targeted therapeutics to prevent ASD from occuring.
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Affiliation(s)
- Richard E Frye
- Section on Neurodevelopmental Disorders, Division of Neurology, Barrow Neurological Institute at Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, Arizona, 85016, USA.,Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, 85004, USA
| | - Janet Cakir
- Department of Applied Ecology, North Carolina State University, Raleigh, North Carolina, 27695, USA
| | - Shannon Rose
- Arkansas Children's Research Institute, Little Rock, Arkansas, 72202, USA.,Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA
| | - Raymond F Palmer
- Department of Family and Community Medicine, University of Texas Health Science Center, San Antonio, Texas, 78229, USA
| | - Christine Austin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA
| | - Paul Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA
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42
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Talvio K, Kanninen KM, White AR, Koistinaho J, Castrén ML. Increased iron content in the heart of the Fmr1 knockout mouse. Biometals 2021; 34:947-954. [PMID: 34089433 PMCID: PMC8313461 DOI: 10.1007/s10534-021-00320-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/24/2021] [Indexed: 11/12/2022]
Abstract
Trace elements have important functions in several processes involved in cellular homeostasis and survival. Dysfunctional metal ion homeostasis can make an important impact on cellular defence mechanisms. We assessed the concentrations of 23 trace minerals in different tissues (brain, spleen, heart and liver) of Fmr1 knockout (KO) mice that display the main phenotype of Fragile X syndrome (FXS), an intellectual disability syndrome and the best-known monogenic model of autism spectrum disorder (ASD). Altogether, seven minerals—Cu, Fe, K, Mg, Mn, Na, and P—were above the detection limit with the analysis revealing increased iron content in the heart of Fmr1 KO mice. In addition, levels of iron were higher in the cerebellum of the transgenic mouse when compared to wild type controls. These results implicate a role for dysregulated iron homeostasis in FXS tissues and suggest that defective iron-related mechanisms contribute to increased tissue vulnerability in FXS.
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Affiliation(s)
- Karo Talvio
- Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, 00290, Helsinki, Finland
| | - Katja M Kanninen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Anthony R White
- Department of Pathology, University of Melbourne, Melbourne, VIC, Australia.,Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Jari Koistinaho
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.,Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Maija L Castrén
- Faculty of Medicine, Physiology, University of Helsinki, P.O. Box 63, 00290, Helsinki, Finland.
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43
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Shih PY, Hsieh BY, Lin MH, Huang TN, Tsai CY, Pong WL, Lee SP, Hsueh YP. CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors. Cell Rep 2021; 31:107700. [PMID: 32492416 DOI: 10.1016/j.celrep.2020.107700] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 03/29/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
Synaptic dysregulation is a critical feature of autism spectrum disorders (ASDs). Among various autism-associated genes, cortactin binding protein 2 (CTTNBP2) is a cytoskeleton regulator predominantly expressed in neurons and highly enriched at dendritic spines. Here, using Cttnbp2 knockout and ASD-linked mutant mice, we demonstrate that Cttnbp2 deficiency reduces zinc levels in the brain, alters synaptic protein targeting, impairs dendritic spine formation and ultrastructure of postsynaptic density, and influences neuronal activation and autism-like behaviors. A link to autism, the NMDAR-SHANK pathway, and zinc-related regulation are three features shared by CTTNBP2-regulated synaptic proteins. Zinc supplementation rescues the synaptic expression of CTTNBP2-regulated proteins. Moreover, zinc supplementation and administration of D-cycloserine, an NMDAR coagonist, improve the social behaviors of Cttnbp2-deficient mice. We suggest that CTTNBP2 controls the synaptic expression of a set of zinc-regulated autism-associated genes and influences NMDAR function and signaling, providing an example of how genetic and environmental factor crosstalk controls social behaviors.
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Affiliation(s)
- Pu-Yun Shih
- Molecular and Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Bing-Yuan Hsieh
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Ming-Hui Lin
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Tzyy-Nan Huang
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Ching-Yen Tsai
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Wen-Li Pong
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Sue-Ping Lee
- Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Yi-Ping Hsueh
- Molecular and Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China.
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44
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Frye RE, Cakir J, Rose S, Palmer RF, Austin C, Curtin P, Arora M. Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder. J Pers Med 2021; 11:218. [PMID: 33803789 PMCID: PMC8003154 DOI: 10.3390/jpm11030218] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/17/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
We propose that the mitochondrion, an essential cellular organelle, mediates the long-term prenatal environmental effects of disease in autism spectrum disorder (ASD). Many prenatal environmental factors which increase the risk of developing ASD influence mitochondria physiology, including toxicant exposures, immune activation, and nutritional factors. Unique types of mitochondrial dysfunction have been associated with ASD and recent studies have linked prenatal environmental exposures to long-term changes in mitochondrial physiology in children with ASD. A better understanding of the role of the mitochondria in the etiology of ASD can lead to targeted therapeutics and strategies to potentially prevent the development of ASD.
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Affiliation(s)
- Richard E. Frye
- Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
| | - Janet Cakir
- Department of Applied Ecology, North Carolina State University, Raleigh, NC 27695, USA;
| | - Shannon Rose
- Department of Pediatrics, Arkansas Children’s Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA;
| | - Raymond F. Palmer
- Department of Family and Community Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA;
| | - Christine Austin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.A.); (P.C.); (M.A.)
| | - Paul Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.A.); (P.C.); (M.A.)
| | - Manish Arora
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.A.); (P.C.); (M.A.)
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45
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Yasuda H, Tsutsui T, Suzuki K. Metallomics Analysis for Assessment of Toxic Metal Burdens in Infants/Children and Their Mothers: Early Assessment and Intervention Are Essential. Biomolecules 2020; 11:biom11010006. [PMID: 33374671 PMCID: PMC7822439 DOI: 10.3390/biom11010006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Accumulation of toxic metals in infants/children is of serious concern worldwide, from the viewpoint of their harmful effects on the normal growth and development. This metallomics study investigates the extent of toxic metal burdens in infants/children and the relationship to those in their mothers for 77 child/mother pair subjects. For mercury, its geometric mean concentration in infants/children was of similar level to that in their mothers, and a high-significant close correlation was observed between infants/children and their mothers (β = 0.758, r = 0.539, p < 0.0001). A significant but less intimate mother/child relationship was observed for arsenic (β = 0.301, r = 0.433), lead (β = 0.444, r = 0.471) and aluminum (β = 0.379, r = 0.451). Remarkably, the burden levels of lead, cadmium and aluminum in infants/children were approximately three times higher than those in their mothers (p < 0.0001), and the burden levels in some individuals were several tens of times higher than in the mothers. In contrast, some essential metal levels such as zinc, magnesium and calcium in infants/children were significantly lower than those in their mothers, and 29 individuals (37.7%) in the child subjects were estimated to be zinc-deficient. In addition, significant inverse correlations were observed between zinc and lead (r = −0.267, p = 0.019), and magnesium and arsenic (r = −0.514, p < 0.0001). These findings suggest that these toxic metal burdens and essential metal deficiencies in infants/children are of serious concern for their neurodevelopment, indicating that the early assessment and intervention are crucial. It is expected that larger epidemiological and intervention studies will provide a reasonable and essential pathway for intervention of neurodevelopment disorders.
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Affiliation(s)
- Hiroshi Yasuda
- La Belle Vie Research Laboratory, Tokyo 103-0006, Japan;
- Correspondence: (H.Y.); (K.S.)
| | | | - Katsuhiko Suzuki
- Faculty of Sport Sciences, Waseda University, Tokorozawa 359-1192, Japan
- Correspondence: (H.Y.); (K.S.)
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46
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Huang TN, Shih YT, Lin SC, Hsueh YP. Social behaviors and contextual memory of Vcp mutant mice are sensitive to nutrition and can be ameliorated by amino acid supplementation. iScience 2020; 24:101949. [PMID: 33437936 PMCID: PMC7786123 DOI: 10.1016/j.isci.2020.101949] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 11/01/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023] Open
Abstract
Both genetic variations and nutritional deficiency are associated with autism spectrum disorders and other neurological disorders. However, it is less clear whether or how nutritional deficiency and genetic variations influence each other under pathogenic conditions. "Valosin-containing protein" (VCP, also known as p97) is associated with multiple neurological disorders and regulates dendritic spine formation by controlling endoplasmic reticulum formation and protein synthesis efficiency. Increased protein synthesis ameliorates the dendritic spine defects of Vcp-deficient neurons. Therefore, we investigated if Vcp-deficient mice are sensitive to nutritional conditions. Here, we show that social interaction and contextual memory of Vcp-deficient mice are indeed influenced by different dietary protein levels. Moreover, leucine supplementation ameliorates the behavioral deficits and dendritic spine density of Vcp-deficient mice, strengthening evidence for the role of protein synthesis in VCP function. Our study illustrates that genetic variation and nutrient factors cross-talk to influence neuronal and behavioral phenotypes.
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Affiliation(s)
- Tzyy-Nan Huang
- Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei 11529, Taiwan, Republic of China
| | - Yu-Tzu Shih
- Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei 11529, Taiwan, Republic of China
| | - Si-Cih Lin
- Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei 11529, Taiwan, Republic of China
| | - Yi-Ping Hsueh
- Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei 11529, Taiwan, Republic of China
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47
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Behl S, Mehta S, Pandey MK. Abnormal Levels of Metal Micronutrients and Autism Spectrum Disorder: A Perspective Review. Front Mol Neurosci 2020; 13:586209. [PMID: 33362464 PMCID: PMC7759187 DOI: 10.3389/fnmol.2020.586209] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/20/2020] [Indexed: 12/16/2022] Open
Abstract
The aim of the present review is to summarize the prevalence of abnormal levels of various metal micronutrients including copper (Cu), iron (Fe), magnesium (Mg), zinc (Zn), and selenium (Se) in Autism Spectrum Disorder (ASD) using hair, nail and serum samples. A correlation of selected abnormal metal ions with known neurodevelopmental processes using Gene Ontology (GO) term was also conducted. Data included in this review are derived from ASD clinical studies performed globally. Metal ion disparity data is also analyzed and discussed based on gender (Male/Female) to establish any gender dependent correlation. Finally, a rational perspective and possible path to better understand the role of metal micronutrients in ASD is suggested.
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Affiliation(s)
- Supriya Behl
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, United States
| | - Sunil Mehta
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, United States
| | - Mukesh K Pandey
- Department of Radiology, Mayo Clinic, Rochester, MN, United States
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48
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Arora M, Giuliani A, Curtin P. Biodynamic Interfaces Are Essential for Human–Environment Interactions. Bioessays 2020; 42:e2000017. [DOI: 10.1002/bies.202000017] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 07/15/2020] [Indexed: 12/28/2022]
Affiliation(s)
- Manish Arora
- Department of Environmental Medicine and Public Health Icahn School of Medicine at Mount Sinai New York 10029 USA
| | - Alessandro Giuliani
- Environment and Health Department Istituto Superiore di Sanità Rome 00161 Italy
| | - Paul Curtin
- Department of Environmental Medicine and Public Health Icahn School of Medicine at Mount Sinai New York 10029 USA
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49
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Frye RE, Cakir J, Rose S, Delhey L, Bennuri SC, Tippett M, Palmer RF, Austin C, Curtin P, Arora M. Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder. Transl Psychiatry 2020; 10:223. [PMID: 32636364 PMCID: PMC7341836 DOI: 10.1038/s41398-020-00905-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/11/2020] [Accepted: 06/16/2020] [Indexed: 12/21/2022] Open
Abstract
Neurodevelopmental regression (NDR) is a subtype of autism spectrum disorder (ASD) that manifests as loss of previously acquired developmental milestones. Early life dysregulation of nutritional metals and/or exposure to toxic metals have been associated with ASD, but the underlying biological mechanisms by which metals influence neurodevelopment remain unclear. We hypothesize that metals influences neurodevelopment through dysregulation of bioenergetics. Prenatal and early postnatal metal exposures were measured using validated tooth-matrix biomarkers in 27 ASD cases (13 with NDR) and 7 typically-developing (TD) controls. Mitochondrial respiration and glycolysis were measured in peripheral blood mononuclear cells using the Seahorse XF96. Children with ASD demonstrated lower prenatal and postnatal Copper (Cu) and prenatal Nickel concentrations and Copper-to-Zinc (Cu/Zn) ratio as compared with TD children. Children with ASD and NDR showed greater metal-related disruption of cellular bioenergetics than children with ASD without NDR. For children with ASD and NDR mitochondrial respiration decreased as prenatal Manganese concentration increased and increased as prenatal Zinc concentration increased; glycolysis decreased with increased exposure to prenatal Manganese and Lead and postnatal Manganese. For children with ASD without a history of NDR, glycolysis increased with increased postnatal exposure to Tin. Language and communication scores in children with ASD were positively related to prenatal Cu exposure and Cu/Zn ratio. This study suggests that prenatal nutritional metals may be important for neurodevelopment in children with ASD, and that exposure to toxic metals and differences in nutritional metal exposures is associated with dysregulation of cellular bioenergetics, particularly in the NDR subtype of ASD.
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Affiliation(s)
- Richard E. Frye
- grid.427785.b0000 0001 0664 3531Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ USA ,grid.134563.60000 0001 2168 186XUniversity of Arizona College of Medicine – Phoenix, Phoenix, AZ USA
| | - Janet Cakir
- grid.40803.3f0000 0001 2173 6074North Carolina State University, Raleigh, NC USA
| | - Shannon Rose
- grid.488749.eArkansas Children’s Research Institute, Little Rock, AR USA ,grid.241054.60000 0004 4687 1637Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Leanna Delhey
- grid.488749.eArkansas Children’s Research Institute, Little Rock, AR USA ,grid.241054.60000 0004 4687 1637Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Sirish C. Bennuri
- grid.488749.eArkansas Children’s Research Institute, Little Rock, AR USA ,grid.241054.60000 0004 4687 1637Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Marie Tippett
- grid.488749.eArkansas Children’s Research Institute, Little Rock, AR USA ,grid.241054.60000 0004 4687 1637Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Raymond F. Palmer
- grid.267309.90000 0001 0629 5880Department of Family and Community Medicine, University of Texas Health Science Center, San Antonio, TX USA
| | - Christine Austin
- grid.59734.3c0000 0001 0670 2351Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Paul Curtin
- grid.59734.3c0000 0001 0670 2351Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Manish Arora
- grid.59734.3c0000 0001 0670 2351Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY USA
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50
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Curtin P, Austin C, Curtin A, Gennings C, Figueroa-Romero C, Mikhail KA, Botero TM, Goutman SA, Feldman EL, Arora M. Dysregulated biodynamics in metabolic attractor systems precede the emergence of amyotrophic lateral sclerosis. PLoS Comput Biol 2020; 16:e1007773. [PMID: 32294079 PMCID: PMC7159190 DOI: 10.1371/journal.pcbi.1007773] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 03/04/2020] [Indexed: 11/19/2022] Open
Abstract
Evolutionarily conserved mechanisms maintain homeostasis of essential elements, and are believed to be highly time-variant. However, current approaches measure elemental biomarkers at a few discrete time-points, ignoring complex higher-order dynamical features. To study dynamical properties of elemental homeostasis, we apply laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) to tooth samples to generate 500 temporally sequential measurements of elemental concentrations from birth to 10 years. We applied dynamical system and Information Theory-based analyses to reveal the longest-known attractor system in mammalian biology underlying the metabolism of nutrient elements, and identify distinct and consistent transitions between stable and unstable states throughout development. Extending these dynamical features to disease prediction, we find that attractor topography of nutrient metabolism is altered in amyotrophic lateral sclerosis (ALS), as early as childhood, suggesting these pathways are involved in disease risk. Mechanistic analysis was undertaken in a transgenic mouse model of ALS, where we find similar marked disruptions in elemental attractor systems as in humans. Our results demonstrate the application of a phenomological analysis of dynamical systems underlying elemental metabolism, and emphasize the utility of these measures in characterizing risk of disease. The metabolism of essential elements in early life is essential to healthy growth and development. Elemental homeostasis is typically studied by characterizing distributions of elemental concentrations at the level of the population. Here, we introduce a new method of characterizing elemental metabolism at the level of the individual. Using tooth-based biomarkers, we tracked the longitudinal trajectory of essential elements throughout childhood at weekly temporal resolution from birth through approximately 10 years of life. We analyzed these trajectories to identify the formation of stable dynamic states (attractors) and transitions between these states throughout development. We found that metabolic dynamics were specific to discrete elemental pathways; copper metabolism typically involved the formation of multiple discrete states throughout childhood, whereas other elements, such as zinc, tended to persist in a single stable dynamic throughout development. Next, we compared elemental biodynamics in neurologically healthy cases and subjects that were later diagnosed with amyotrophic lateral sclerosis (ALS). We found these patterns were dysregulated in ALS, and also found similar results in a mouse model of ALS. Overall, our results provide a novel approach to characterize elemental biodynamics throughout development, and emphasize that the dysregulation of these processes may be predictive of later onset of disease.
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Affiliation(s)
- Paul Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- * E-mail: (PC); (MA)
| | - Christine Austin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Austen Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Chris Gennings
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | | | - Kristen A. Mikhail
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States of America
| | - Tatiana M. Botero
- Department of Cariology, Restorative Sciences and Endodontics, School of Dentistry University of Michigan, Ann Arbor, MI, United States of America
| | - Stephen A. Goutman
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States of America
| | - Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States of America
| | - Manish Arora
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- * E-mail: (PC); (MA)
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