College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, 15588, South Korea.
School of Public Health, China Medical University, Shenyang, 110122, China.
Food Chem Toxicol. 2023 Sep;179:113985. doi: 10.1016/j.fct.2023.113985. Epub 2023 Aug 11.
Phthalates in contaminated foods and personal care products are one of the most frequently exposed chemicals with a public health concern. Phthalate exposure is related to cardiovascular diseases, including diabetic vascular complications and cerebrovascular diseases, yet the mechanism is still unclear. The blood-brain barrier (BBB) integrity disruption is strongly associated with cardiovascular and neurological disease exacerbation. We investigated BBB damage by di-(2-ethylhexyl) phthalate (DEHP) or its metabolite mono-(2-ethylhexyl) phthalate (MEHP) using brain endothelial cells and rat models. BBB damage by the subthreshold level of MEHP, but not a DEHP, significantly increased by the presence of methylglyoxal (MG), a reactive dicarbonyl compound whose levels increase in the blood in hyperglycemic conditions in diabetic patients. Significant potentiation in apoptosis and autophagy activation, mitochondria-derived reactive oxygen species (ROS) production, and mitochondrial metabolic disturbance were observed in brain ECs by co-exposure to MG and MEHP. N-acetyl cysteine (NAC) restored autophagy activation as well as tight junction protein impairment induced by co-exposure to MG and MEHP. Intraperitoneal administration of MG and MEHP significantly altered mitochondrial membrane potential and tight junction integrity in rat brain endothelium. This study may provide novel insights into enhancing phthalate toxicity in susceptible populations, such as diabetic patients.
受污染食物和个人护理产品中的邻苯二甲酸酯是最常暴露于人体且备受公众关注的化学物质之一。邻苯二甲酸酯暴露与心血管疾病有关，包括糖尿病血管并发症和脑血管疾病，但具体机制尚不清楚。血脑屏障（BBB）完整性的破坏与心血管和神经系统疾病的恶化密切相关。我们使用脑内皮细胞和大鼠模型研究了邻苯二甲酸二（2-乙基己基）酯（DEHP）或其代谢物单（2-乙基己基）邻苯二甲酸酯（MEHP）对 BBB 的损害。亚阈值水平的 MEHP 与存在甲基乙二醛（MG）（一种在糖尿病患者高血糖条件下血液中水平升高的反应性二羰基化合物）一起，会显著增加 BBB 的损害。在脑 ECs 中，MG 和 MEHP 共同暴露会导致细胞凋亡和自噬激活、线粒体来源的活性氧（ROS）产生以及线粒体代谢紊乱显著增强。N-乙酰半胱氨酸（NAC）可恢复由 MG 和 MEHP 共同暴露引起的自噬激活和紧密连接蛋白损伤。腹腔内给予 MG 和 MEHP 可显著改变大鼠脑内皮细胞中线粒体膜电位和紧密连接的完整性。这项研究可能为增强易感人群（如糖尿病患者）中邻苯二甲酸酯的毒性提供新的见解。
