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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. Copyright © 2023 Elsevier Ltd. All rights reserved.


Donghyun Kim, Eujin Oh, Haram Kim, Seung Mi Baek, Junho Cho, Eun-Hye Kim, Sungbin Choi, Yiying Bian, Wondong Kim, Ok-Nam Bae. Mono-(2-ethylhexyl)-phthalate potentiates methylglyoxal-induced blood-brain barrier damage via mitochondria-derived oxidative stress and bioenergetic perturbation. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2023 Sep;179:113985

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PMID: 37572985

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