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Tytuł:
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The role of Hipk2-p53 pathways in arsenic-induced autistic behaviors: A translational study from rats to humans.
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Autorzy:
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Zhou H; Department of Pediatrics, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, 550002, China; Department of Neurology, Children's Hospital of Fudan University, Shanghai, 201102, China.
Lin Y; Global Health Institute & Nicholas School of the Environment, Duke University, Durham, NC, 27705, USA.
Zhao W; Department of Pediatrics, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, 550002, China.
Teng Y; Global Health Research Center, Duke Kunshan University, Jiangsu Province, China.
Cui Y; Department of Pediatrics, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, 550002, China.
Wang T; Department of Neurology, Children's Hospital of Fudan University, Shanghai, 201102, China.
Li C; Department of Neurology, Children's Hospital of Fudan University, Shanghai, 201102, China.
Jiang YH; Department of Genetics and Pediatrics, Yale School of Medicine, New Haven, CT, 06520, USA.
Zhang JJ; Global Health Institute & Nicholas School of the Environment, Duke University, Durham, NC, 27705, USA; Global Health Research Center, Duke Kunshan University, Jiangsu Province, China. Electronic address: .
Wang Y; Department of Neurology, Children's Hospital of Fudan University, Shanghai, 201102, China. Electronic address: .
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Źródło:
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Environmental pollution (Barking, Essex : 1987) [Environ Pollut] 2020 Dec; Vol. 267, pp. 115568. Date of Electronic Publication: 2020 Aug 31.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Barking, Essex, England : Elsevier Applied Science Publishers, c1987-
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MeSH Terms:
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Arsenic*/toxicity
Autism Spectrum Disorder*/chemically induced
Autistic Disorder*/chemically induced
Animals ; Carrier Proteins ; Case-Control Studies ; Child ; Humans ; Protein Serine-Threonine Kinases ; Rats ; Tumor Suppressor Protein p53/genetics
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Contributed Indexing:
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Keywords: Arsenic; Autism; Biomarker; HIPK2 and p53; Translational study
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Substance Nomenclature:
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0 (Carrier Proteins)
0 (Tumor Suppressor Protein p53)
EC 2.7.1.- (HIPK2 protein, human)
EC 2.7.11.1 (HIPK2 protein, rat)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
N712M78A8G (Arsenic)
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Entry Date(s):
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Date Created: 20201201 Date Completed: 20201204 Latest Revision: 20211204
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Update Code:
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20240105
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DOI:
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10.1016/j.envpol.2020.115568
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PMID:
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33254717
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Previous studies have associated the risk of autism spectrum disorder (ASD) with increased exposures to metals and metalloids such as arsenic. In this study, we used an animal-to-human translational strategy to identify key molecular changes that potentially mediated the effects of arsenic exposures on ASD development. In a previously established rat model, we have induced autistic behaviors in rat pups with gestational arsenic exposures (10 and 45 μg/L As 2 O 3 in drinking water). Neuronal apoptosis and the associated epigenetic dysregulations in frontal cortex were assayed to screen potential mediating pathways, which were subsequently validated with qPCR, western blotting, and immunohistochemistry analyses. Furthermore, the identified pathway, along with serum levels of 26 elements including arsenic, were characterized in a case-control study with 21 ASD children and 21 age-matched healthy controls. In animals, we found that arsenic exposures caused difficulties of social interaction and increased stereotypic behaviors in a dose-dependent manner, accompanied by increased neuronal apoptosis and upregulation of Hipk2-p53 pathway in the frontal cortex. In humans, we found that serum levels of Hipk2 and p53 were 24.7 (95%CI: 8.5 to 43.4) % and 23.7 (95%CI: 10.5 to 38.5) % higher in ASD children than in healthy controls. ASD children had significantly higher serum levels of 15 elements, among which arsenic, silicon, strontium, and vanadium were positively associated with both Hipk2 and p53. Results from both the rat arsenic exposure and human case-control studies suggest a likely role of Hipk2-p53 pathway in ASD development induced by exposures to environmental pollutants such as arsenic.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
