Nadeem Ahmed, Ahmad Sheikh F, Al-Harbi Naif O, Al-Ayadhi Laila Y, Alanazi Mohammed M, Alfardan Ali S, Attia Sabry M, Algahtani Mohammad, Bakheet Saleh A
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Int Immunopharmacol. 2022 May;106:108619. doi: 10.1016/j.intimp.2022.108619. Epub 2022 Feb 16.
Autism spectrum disorder (ASD) is characterized by constellation of impaired behaviors that include deficits in social interaction/communication and the presence of restricted/repetitive behavioral patterns. Both genetic component and environmental factors are thought to play a key role in the initiation and progression of ASD. Several environmental factors such as heavy metals and plasticizers are known to affect the progression of ASD. One of the most common pollutants in the environment today is di-2-ethylhexyl phthalate (DEHP). DEHP is utilized as a plasticizer in several household and office materials which range from medical devices to plastic toys. Children usually get exposed to DEHP at an early age through use of plastic toys and other plastic materials. Nuclear factor erythroid 2 (NFE2)-relatedfactor-2 (Nrf2) is a master redox regulator as it controls transcription of several antioxidant genes. DEHP has been reported to cause dysregulation in Nrf2 signaling in vitro/in vivo and ASD subjects also exhibit oxidant-antioxidant imbalance.Therefore, this study attempted to delineate the effect of DEHP on Nrf2 signaling in neutrophils of ASD and typically developing healthy children (TDC) in vitro. Our data display that neutrophils of ASD subjects have dysregulated Nrf2 and hemeoxygenase-1 (HO-1) expression as compared to TDC subjects. DEHP treatment leads to elevation of oxidant stress in neutrophils of both ASD and TDC subjects, however TDC neutrophils have better antioxidant response to mitigate oxidative stress. This is depicted by enhancement of Nrf2/HO-1 signaling in TDC neutrophils in response to DEHP whereas ASD neutrophils fail to do so. These results suggest that plasticizer, DEHP may cause further dysregulation in Nrf2 signaling which may promote progression of ASD.
自闭症谱系障碍（ASD）的特征是一系列行为受损，包括社交互动/沟通缺陷以及存在受限/重复的行为模式。遗传因素和环境因素都被认为在ASD的发生和发展中起关键作用。已知几种环境因素，如重金属和增塑剂，会影响ASD的发展。当今环境中最常见的污染物之一是邻苯二甲酸二（2-乙基己基）酯（DEHP）。DEHP在从医疗设备到塑料玩具等多种家用和办公材料中用作增塑剂。儿童通常在幼年时通过使用塑料玩具和其他塑料材料接触DEHP。核因子红细胞2（NFE2）相关因子2（Nrf2）是一种主要的氧化还原调节剂，因为它控制多种抗氧化基因的转录。据报道，DEHP在体外/体内会导致Nrf2信号失调，ASD患者也表现出氧化-抗氧化失衡。因此，本研究试图在体外描绘DEHP对ASD儿童和发育正常的健康儿童（TDC）中性粒细胞中Nrf2信号的影响。我们的数据显示，与TDC儿童相比，ASD儿童的中性粒细胞中Nrf2和血红素加氧酶-1（HO-1）的表达失调。DEHP处理导致ASD和TDC儿童中性粒细胞中的氧化应激升高，然而TDC中性粒细胞对减轻氧化应激具有更好的抗氧化反应。这表现为TDC中性粒细胞中Nrf2/HO-1信号因DEHP而增强，而ASD中性粒细胞则不然。这些结果表明，增塑剂DEHP可能会导致Nrf2信号进一步失调，从而可能促进ASD的发展。
