Ochratoxin A mediates MAPK activation, modulates <i>IL-2</i> and <i>TNF-α</i> mRNA expression and induces apoptosis by mitochondria-dependent and mitochondria-independent pathways in human H9 T cells

Abstract

-Ochratoxin A (OTA) is a natural fungal secondary metabolite that contaminates food and animal feed. Human exposure and involvement of this mycotoxin in several pathologies have been demonstrated worldwide. We investigated OTA immunotoxicity on H9 cells, a human cutaneous CD4+ T lymphoma cell line. Cells were treated with 0, 1, 5, 10, and 20 μM OTA for up to 24 hr. Western blotting revealed increased phosphorylation of all three major mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun amino-terminal kinase, p38). OTA triggered mitochondrial transmembrane potential loss and caspase-3 activation. The 24-hr OTA treatment caused marked changes in cell morphology and DNA fragmentation, suggesting the occurrence of apoptotic events that involved a mitochondriadependent pathway. Moreover, OTA triggered significant modulation of survivin, interleukin 2 (IL-2) and tumor necrosis factor α (TNF-α): mRNA expression of survivin and IL-2 were decreased, while TNF-α was increased. OTA also caused caspase-8 activation in a time-dependent manner, which evokes the death receptor pathway activation; we suspect that this occurred via the autocrine pro-apoptotic effect of TNF-α on H9 cells.

Assessment of Toxic Effects of Ochratoxin A in Human Embryonic Stem Cells

“…Further studies need to be performed in order to clarify whether the same mechanisms of oxidative stress are triggered in hESC by OTA. Our results are in line with previous studies, which have reported OTA as a trigger for the caspase-9 and caspase-3 activation with potential mitochondrial membrane loss in different human primary cells [49,50,51]. To our knowledge, the present study is the first one describing the effects of OTA in a prenatal human cellular model, demonstrating the importance of assessing toxicity in early stages of development.…”

Effects of ochratoxin A on ER stress, MAPK signaling pathway and autophagy of kidney and spleen in pigs

“…The data obtained from this study indicated that OTA decreased total antioxidant capacity and increased GRP78 mRNA and protein expression in kidney and spleen of pigs, consistent with the previous study that OTA induced GRP78 expression in rat glomerular mesangial cells in vitro. 15 In addition, dietary supplementation of OTA at 400 lg and 800 lg/kg increased p38 and ERK1/2 phosphorylation in kidney and spleen of pigs in this study, consistent with previous study that OTA could activate ERK1/2 and p38 MAPKs pathways in human proximal tubule HK-2 cells 17 and H9 T cells 41 and in rat liver cells. 42 Autophagy is an intracellular process of homeostatic degradation, and proper autophagy promotes cell survival under various stressors.…”

Transcriptome Analysis of Ochratoxin A-Induced Apoptosis in Differentiated Caco-2 Cells

“…Liang et al [55] pointed out that OTA suppresses the cell cycle, particularly DNA replication, leading to cell cycle arrest and apoptosis. OTA has been shown to regulate apoptosis, the cell cycle, and cell fate following DNA damage by stimulating MAPK signaling pathways, such as p38 MAPK, ERK1/2, and JNK [56][57][58]. Apoptosis of liver and/or kidney cells has also been shown to be influenced by activation of certain signal transduction pathways, such as MAPK, ERK, p38, and JNK [56,59,60].…”