Di(2-ethylhexyl) phthalate exposure aggravates hypoxia/reoxygenation injury in cerebral endothelial cells by downregulating epithelial cadherin expression.

IF 2.2 4区 医学 Q3 TOXICOLOGY Toxicology Research Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI:10.1093/toxres/tfae163
Jin Hee Kim, Jae Hoon Lee, Zhengyu Nan, Ja Woo Choi, Jong Wook Song
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Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that has adverse health effects. Most phthalates exhibit reproductive toxicity and are associated with diseases such as cardiovascular disorders. However, the effect of DEHP exposure on acute hypoxia/reperfusion injury remains unknown. Therefore, we assessed whether hypoxia/reperfusion injury is aggravated by exposure to DEHP and investigated plausible underlying mechanisms, including oxidative stress and expression of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and endothelial junctional proteins. bEnd.3 cells were exposed to DEHP and subsequently subjected to oxygen-glucose deprivation (OGD). Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) proliferation assay. The effect of DEHP/OGD/reoxygenation (R) was evaluated by assessing the levels of NO, reactive oxygen species (ROS), and PGE2. The expression of COX-2, cleaved caspase-3, cleaved PARP, inducible nitric oxide synthase (iNOS), and the endothelial tight junction proteins claudin-5 and ZO-1 was evaluated using quantitative polymerase chain reaction and western blotting. OGD/R decreased cell viability, and DEHP exposure before OGD/R further aggravated cell viability. DEHP/OGD/R significantly increased NO, PGE2, and ROS production following OGD/R. In the DEHP/OGD/R group, iNOS, COX-2, cleaved caspase-3, and cleaved PARP expression increased, and claudin-5 and ZO-1 levels decreased compared with those in the OGD/R group. E-Cadherin expression decreased significantly after DEHP/OGD/R exposure compared with that after OGD/R; this decrease in expression was recovered by treatment with the COX-2 inhibitor indomethacin and antioxidant N-acetylcysteine. Exposure to DEHP exacerbated hypoxia-reoxygenation injury. The enhanced damage upon DEHP exposure was associated with increased oxidative stress and COX-2 expression, leading to E-cadherin downregulation and increased apoptosis.

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接触邻苯二甲酸二(2-乙基己酯)会通过下调上皮粘连蛋白的表达加重脑内皮细胞的缺氧/复氧损伤。
邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种广泛使用的增塑剂,对健康有不良影响。大多数邻苯二甲酸盐具有生殖毒性,并与心血管疾病等疾病有关。然而,DEHP 暴露对急性缺氧/再灌注损伤的影响仍然未知。因此,我们评估了暴露于 DEHP 是否会加重缺氧/再灌注损伤,并研究了可能的潜在机制,包括氧化应激和环氧化酶-2(COX-2)/前列腺素 E2(PGE2)及内皮连接蛋白的表达。bEnd.3 细胞暴露于 DEHP,随后进行氧-葡萄糖剥夺(OGD)。使用 3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺酸苯基)-2H-四唑鎓(MTS)增殖试验分析细胞活力。通过评估 NO、活性氧(ROS)和 PGE2 的水平来评估 DEHP/OGD/ 复氧(R)的效果。使用定量聚合酶链式反应和 Western 印迹法评估了 COX-2、裂解的 Caspase-3、裂解的 PARP、诱导型一氧化氮合酶(iNOS)以及内皮紧密连接蛋白 claudin-5 和 ZO-1 的表达。OGD/R 降低了细胞存活率,而在 OGD/R 之前暴露于 DEHP 会进一步恶化细胞存活率。OGD/R后,DEHP/OGD/R明显增加了NO、PGE2和ROS的产生。与 OGD/R 组相比,DEHP/OGD/R 组 iNOS、COX-2、裂解的 Caspase-3 和裂解的 PARP 表达增加,Claudin-5 和 ZO-1 水平降低。与OGD/R组相比,暴露于DEHP/OGD/R组后E-Cadherin的表达量明显下降;经COX-2抑制剂吲哚美辛和抗氧化剂N-乙酰半胱氨酸处理后,表达量的下降得以恢复。暴露于 DEHP 会加剧缺氧-复氧损伤。暴露于DEHP时损伤的加剧与氧化应激和COX-2表达的增加有关,导致E-cadherin下调和细胞凋亡增加。
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来源期刊
Toxicology Research
Toxicology Research TOXICOLOGY-
CiteScore
3.60
自引率
0.00%
发文量
82
期刊介绍: A multi-disciplinary journal covering the best research in both fundamental and applied aspects of toxicology
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