Alshamrani Ali A, Alshehri Samiyah, Alqarni Sana S, Ahmad Sheikh F, Alghibiwi Hanan, Al-Harbi Naif O, Alqarni Saleh A, Al-Ayadhi Laila Y, Attia Sabry M, Alfardan Ali S, Bakheet Saleh A, Nadeem Ahmed
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Medical Laboratory Science, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia.
Metabolites. 2023 Mar 22;13(3):458. doi: 10.3390/metabo13030458.
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.
自闭症谱系障碍（ASD）是一种多维度疾病，环境、免疫和遗传因素共同发挥关键作用。ASD的特征是社交互动/沟通障碍和刻板行为模式。已知表观遗传修饰通过多种机制调节基因表达。其中一种机制是DNA甲基化，它由DNA甲基转移酶（DNMTs）调节。DNMT将甲基基团转移到胞嘧啶核苷酸的第五个碳原子上，从而在DNA的启动子区域将其转化为5-甲基胞嘧啶（5mC）。DNA甲基化模式的破坏通常与基因表达的调节有关。据报道，环境污染物如增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）会影响表观遗传机制；然而，此前尚未研究DEHP是否会调节ASD患者中性粒细胞中的DNMT1表达、DNA甲基化和炎症介质。因此，本研究聚焦于DNMT1和整体DNA甲基化在ASD儿童和发育正常的健康儿童（TDC）中性粒细胞中与炎症介质（CCR2、MCP-1）的关系。此外，还探讨了DEHP对中性粒细胞中整体DNA甲基化、DNMT1、CCR2和MCP-1的影响。我们的结果表明，ASD患者的中性粒细胞中DNMT1表达减少，这与DNA低甲基化以及CCR2和MCP-1等炎症介质增加有关。DEHP进一步导致ASD患者中性粒细胞中DNMT1表达下调，可能是通过氧化炎症，因为抗氧化治疗导致DEHP诱导的DNMT1减少得到逆转。这些数据突出了环境污染物DEHP在修饰ASD患者中性粒细胞中DNA甲基化等表观遗传机制方面的重要性。
