Ochratoxin A exerts neurotoxicity in human astrocytes through mitochondria-dependent apoptosis and intracellular calcium overload. (1st October 2019)

• Record Type: Journal Article
• Authors: Park, Sunwoo; Lim, Whasun; You, Seungkwon; Song, Gwonhwa
• Is Part Of: Toxicology letters. Volume 313(2019)
• Page Start: 42
• Page End: 49
• Publication Date: 2019-10-01
• Subjects: Ochratoxin A -- Astrocyte -- Proliferation -- Apoptosis -- Toxicity; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.05.021
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: The illustration of overall hypothetic working mechanism of ochratoxin A on human astrocyte cells. Highlights: Ochratoxin A inhibits cell proliferation with cell cycle arrest of human astrocytes. Ochratoxin A induces apoptosis of astrocytes through mitochondrial dysfunction. Ochratoxin A disrupts the calcium homeostasis necessary for astrocyte reactivation. Ochratoxin A may exert neurotoxic effects on human astrocyte cells. Abstract: Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53 . In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.