DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate
Autism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction/communication impairments and stereotypical behavioral patterns. Epigenetic modifications are known to r...
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MDPI AG
2023-03-01
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| author | Ali A. Alshamrani Samiyah Alshehri Sana S. Alqarni Sheikh F. Ahmad Hanan Alghibiwi Naif O. Al-Harbi Saleh A. Alqarni Laila Y. Al-Ayadhi Sabry M. Attia Ali S. Alfardan Saleh A. Bakheet Ahmed Nadeem |
| author_facet | Ali A. Alshamrani Samiyah Alshehri Sana S. Alqarni Sheikh F. Ahmad Hanan Alghibiwi Naif O. Al-Harbi Saleh A. Alqarni Laila Y. Al-Ayadhi Sabry M. Attia Ali S. Alfardan Saleh A. Bakheet Ahmed Nadeem |
| author_sort | Ali A. Alshamrani |
| collection | DOAJ |
| description | Autism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction/communication impairments and stereotypical behavioral patterns. Epigenetic modifications are known to regulate genetic expression through various mechanisms. One such mechanism is DNA methylation, which is regulated by DNA methyltransferases (DNMTs). DNMT transfers methyl groups onto the fifth carbon atom of the cytosine nucleotide, thus converting it into 5-methylcytosine (5mC) in the promoter region of the DNA. Disruptions in methylation patterns of DNA are usually associated with modulation of genetic expression. Environmental pollutants such as the plasticizer Di(2-ethylhexyl) phthalate (DEHP) have been reported to affect epigenetic mechanisms; however, whether DEHP modulates DNMT1 expression, DNA methylation, and inflammatory mediators in the neutrophils of ASD subjects has not previously been investigated. Hence, this investigation focused on the role of DNMT1 and overall DNA methylation in relation to inflammatory mediators (CCR2, MCP-1) in the neutrophils of children with ASD and typically developing healthy children (TDC). Further, the effect of DEHP on overall DNA methylation, DNMT1, CCR2, and MCP-1 in the neutrophils was explored. Our results show that the neutrophils of ASD subjects have diminished DNMT1 expression, which is associated with hypomethylation of DNA and increased inflammatory mediators such as CCR2 and MCP-1. DEHP further causes downregulation of DNMT1 expression in the neutrophils of ASD subjects, probably through oxidative inflammation, as antioxidant treatment led to reversal of a DEHP-induced reduction in DNMT1. These data highlight the importance of the environmental pollutant DEHP in the modification of epigenetic machinery such as DNA methylation in the neutrophils of ASD subjects. |
| first_indexed | 2024-03-11T06:11:54Z |
| format | Article |
| id | doaj.art-fbb35eb03af245fb9cd5eaac1f1f52d3 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-11T06:11:54Z |
| publishDate | 2023-03-01 |
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| series | Metabolites |
| spelling | doaj.art-fbb35eb03af245fb9cd5eaac1f1f52d32023-11-17T12:37:45ZengMDPI AGMetabolites2218-19892023-03-0113345810.3390/metabo13030458DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) PhthalateAli A. Alshamrani0Samiyah Alshehri1Sana S. Alqarni2Sheikh F. Ahmad3Hanan Alghibiwi4Naif O. Al-Harbi5Saleh A. Alqarni6Laila Y. Al-Ayadhi7Sabry M. Attia8Ali S. Alfardan9Saleh A. Bakheet10Ahmed Nadeem11Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Medical Laboratory Science, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Physiology, College of Medicine, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaAutism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction/communication impairments and stereotypical behavioral patterns. Epigenetic modifications are known to regulate genetic expression through various mechanisms. One such mechanism is DNA methylation, which is regulated by DNA methyltransferases (DNMTs). DNMT transfers methyl groups onto the fifth carbon atom of the cytosine nucleotide, thus converting it into 5-methylcytosine (5mC) in the promoter region of the DNA. Disruptions in methylation patterns of DNA are usually associated with modulation of genetic expression. Environmental pollutants such as the plasticizer Di(2-ethylhexyl) phthalate (DEHP) have been reported to affect epigenetic mechanisms; however, whether DEHP modulates DNMT1 expression, DNA methylation, and inflammatory mediators in the neutrophils of ASD subjects has not previously been investigated. Hence, this investigation focused on the role of DNMT1 and overall DNA methylation in relation to inflammatory mediators (CCR2, MCP-1) in the neutrophils of children with ASD and typically developing healthy children (TDC). Further, the effect of DEHP on overall DNA methylation, DNMT1, CCR2, and MCP-1 in the neutrophils was explored. Our results show that the neutrophils of ASD subjects have diminished DNMT1 expression, which is associated with hypomethylation of DNA and increased inflammatory mediators such as CCR2 and MCP-1. DEHP further causes downregulation of DNMT1 expression in the neutrophils of ASD subjects, probably through oxidative inflammation, as antioxidant treatment led to reversal of a DEHP-induced reduction in DNMT1. These data highlight the importance of the environmental pollutant DEHP in the modification of epigenetic machinery such as DNA methylation in the neutrophils of ASD subjects.https://www.mdpi.com/2218-1989/13/3/458ASDenvironmental pollutantneutrophilsDNMT1DNA methylation |
| spellingShingle | Ali A. Alshamrani Samiyah Alshehri Sana S. Alqarni Sheikh F. Ahmad Hanan Alghibiwi Naif O. Al-Harbi Saleh A. Alqarni Laila Y. Al-Ayadhi Sabry M. Attia Ali S. Alfardan Saleh A. Bakheet Ahmed Nadeem DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate Metabolites ASD environmental pollutant neutrophils DNMT1 DNA methylation |
| title | DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate |
| title_full | DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate |
| title_fullStr | DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate |
| title_full_unstemmed | DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate |
| title_short | DNA Hypomethylation Is Associated with Increased Inflammation in Peripheral Blood Neutrophils of Children with Autism Spectrum Disorder: Understanding the Role of Ubiquitous Pollutant Di(2-ethylhexyl) Phthalate |
| title_sort | dna hypomethylation is associated with increased inflammation in peripheral blood neutrophils of children with autism spectrum disorder understanding the role of ubiquitous pollutant di 2 ethylhexyl phthalate |
| topic | ASD environmental pollutant neutrophils DNMT1 DNA methylation |
| url | https://www.mdpi.com/2218-1989/13/3/458 |
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