Exposure to the plasticizer, Di-(2-ethylhexyl) phthalate during juvenile period exacerbates autism-like behavior in adult BTBR T + tf/J mice due to DNA hypomethylation and enhanced inflammation in brain and systemic immune cells

Nadeem, Ahmed; Al-Harbi, Naif O.; Ahmad, Sheikh F.; Alhazzani, Khalid; Attia, Sabry M.; Alsanea, Sary; Alhoshani, Ali; Mahmood, Hafiz Majid; Alfardan, Ali S.; Bakheet, Saleh A.

doi:10.1016/j.pnpbp.2021.110249

Cited by 31 publications

(17 citation statements)

References 63 publications

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“…Peripheral upregulated inflammation (IL-6, IL-1β, etc.) could worsen autistic symptoms in mice (84). These proinflammatory cytokines cross the blood-brain barrier and activate microglia.…”

Section: Discussionmentioning

confidence: 99%

Association of Peripheral Blood Levels of Cytokines With Autism Spectrum Disorder: A Meta-Analysis

Zhao

Zhang

Liu³

et al. 2021

Front. Psychiatry

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Background: Although increasing evidence suggests an association between alterations in peripheral cytokines and autism spectrum disorder (ASD), a consensus is lacking. To determine whether abnormal cytokine profiles in peripheral blood were associated with ASD, we performed this systemic review and meta-analysis.Methods: A systematic literature search was conducted through the Embase, PubMed, Web of Knowledge, PsycINFO, and Cochrane databases up to 4 June 2020. Clinical studies exploring the aberration of peripheral cytokines of autistic patients and controls were included in our meta-analysis. We pooled extracted data using fixed- or random-effects models based on heterogeneity tests with Comprehensive Meta-analysis software. We converted standardized mean differences to Hedges' g statistic to obtain the effect sizes adjusted for sample size. Subgroup analyses, sensitivity analyses, meta-regression, and publication bias tests were also carried out.Results: Sixty-one articles (326 studies) were included to assess the association between 76 cytokines and ASD. We conducted our meta-analysis based on 37 cytokines with 289 studies. Since there were fewer than three studies on any of the other 39 cytokines, we only provided basic information for them. The levels of peripheral IL-6, IL-1β, IL-12p70, macrophage migration inhibitory factor (MIF), eotaxin-1, monocyte chemotactic protein-1 (MCP-1), IL-8, IL-7, IL-2, IL-12, tumor necrosis factor-α (TNF-α), IL-17, and IL-4 were defined as abnormal cytokines in the peripheral blood of ASD patients compared with controls. The other 24 cytokines did not obviously change in ASD patients compared with the controls.Conclusions: The findings of our meta-analysis strengthen the evidence for an abnormal cytokine profile in ASD. These abnormal cytokines may be potential biomarkers for the diagnosis and treatment of ASD in the future.

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“…Peripheral upregulated inflammation (IL-6, IL-1β, etc.) could worsen autistic symptoms in mice (84). These proinflammatory cytokines cross the blood-brain barrier and activate microglia.…”

Section: Discussionmentioning

confidence: 99%

Association of Peripheral Blood Levels of Cytokines With Autism Spectrum Disorder: A Meta-Analysis

Zhao

Zhang

Liu³

et al. 2021

Front. Psychiatry

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“…The cerebral cortex was isolated in RNAlater and kept at −20 °C for a month before being used for the isolation of RNA. Total RNA was extracted from these samples utilizing RNeasy mini kit (Qiagen, Germantown, MD, USA), followed by transformation of 0.5 μg RNA into cDNA through reverse transcription technique (High-Capacity cDNA archive kit, Applied Biosystems, Grand Island, NY, USA), according to the directions of the manufacturer [ 26 , 27 ]. mRNA expression of IL-17A, IL-1β, and iNOS was evaluated by real-time PCR on ABI PRISM 7500 sequence detection system (Applied Biosystems), as stated before [ 26 , 27 ].…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted from these samples utilizing RNeasy mini kit (Qiagen, Germantown, MD, USA), followed by transformation of 0.5 μg RNA into cDNA through reverse transcription technique (High-Capacity cDNA archive kit, Applied Biosystems, Grand Island, NY, USA), according to the directions of the manufacturer [ 26 , 27 ]. mRNA expression of IL-17A, IL-1β, and iNOS was evaluated by real-time PCR on ABI PRISM 7500 sequence detection system (Applied Biosystems), as stated before [ 26 , 27 ]. Fold change in mRNA expression of different markers was analyzed by a well-known method of relative gene expression analysis, as described before [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

“…Spleens were isolated from different groups and crushed by a 2 mL syringe plunger on a 100 µm sieve, followed by sieving on a 70 µm strainer to obtain a single cell suspension in RPMI-1640, as stated before [ 26 , 27 , 29 ]. After lysis of RBCs, splenocytes were immunostained for cell surface markers such as CD4/GR-1 (BioLegend, San Diego, CA, USA) using monoclonal antibodies fluorescently coupled to FITC/PE-Dazzle/APC-Cy7/APC.…”

Section: Methodsmentioning

confidence: 99%

“…After the normal procedure of fixation and permeabilization of splenic leukocytes (Miltenyi Biotech, Bergisch Gladbach, North Rhine-Westphalia, Germany), cells were then immunolabeled for intracellular proteins such as p-STAT3, IL-17A, IL-23R, IL-1β, iNOS, and nitrotyrosine (Santacruz Biotech, Dallas, Texas, USA; BioLegend, San Diego, CA, USA; R&D Systems, Minneapolis, MN, USA) using monoclonal antibodies fluorescently coupled to FITC/PE/APC. Splenic leukocytes immunostained with cell surface and intracellular proteins were then acquired on a flow cytometer (Beckman Coulter, Indianapolis, IN, USA), followed by an evaluation of the 10,000 events (cells) according to the fluorescent characteristics ( Supplementary Figure S1 ) using Cytomics FC 500 software, as stated earlier [ 26 , 27 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

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Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing–Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice

et al. 2021

Self Cite

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Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing–remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1β), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1β/MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE. Therefore, pharmacological inhibition of STAT3 in RRMS could be a potential therapeutic strategy.

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Role of melatonin in autism spectrum disorders in a male murine transgenic model: Study in the prefrontal cortex

Borsani

Bonomini

Bonini

et al. 2022

J of Neuroscience Research

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Autism spectrum disorders (ASDs) are a group of clinically heterogeneous neurodevelopmental disorders sharing common features related to impaired social and communication abilities in addition to stereotyped behaviors. ASD patients present encephalic morphological, physiological, and biomolecular alterations with low levels of melatonin due to alterations in its pathways. Therefore, even if ASDs have traditionally been framed as behavioral disorders, several lines of evidence are accumulating that ASDs are characterized by certain anatomical and physiological abnormalities, including oxidative stress and inflammation in peripheral biomarkers, but likewise present in human brain tissue also characterized by alterations in synaptic remodeling and neuromodulation. Melatonin has also protective and antioxidant properties, so we can therefore hypothesize that alterations in melatonin's pathways may be one of the causes of the symptomatology of autism. The aim of the present study was to analyze the beneficial effect induced by melatonin administration and its possible mechanism of action in a transgenic mouse model of autism, immediately after weaning. The male mice were daily treated per os with melatonin (10 mg/Kg/day) or vehicle for 8 weeks starting from the sixth week of life. The antioxidant modulation, the GABAergic/glutamatergic impairment, and the synaptic remodeling in the prefrontal cortex have been evaluated. Social and repetitive behaviors were also evaluated. The behavioral results showed no statistical evidences, instead the immunohistochemical results indicated the ability of melatonin to promote the activity of antioxidant system, the GABAergic/glutamatergic equilibrium, and the synaptic remodeling. The results show that melatonin may be a possible adjuvant therapeutic strategy in ASDs.

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Exposure to the plasticizer, Di-(2-ethylhexyl) phthalate during juvenile period exacerbates autism-like behavior in adult BTBR T + tf/J mice due to DNA hypomethylation and enhanced inflammation in brain and systemic immune cells

Cited by 31 publications

References 63 publications

Association of Peripheral Blood Levels of Cytokines With Autism Spectrum Disorder: A Meta-Analysis

Association of Peripheral Blood Levels of Cytokines With Autism Spectrum Disorder: A Meta-Analysis

Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing–Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice

Role of melatonin in autism spectrum disorders in a male murine transgenic model: Study in the prefrontal cortex

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