Tubulotoxic Mechanisms of Ochratoxin A

Gekle, Michael; Sauvant, Christoph; Schwerdt, Gerald; Silbernagl, Stefan

doi:10.1159/000025877

Cited by 29 publications

(17 citation statements)

References 25 publications

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“…Since OTA is a multi-organ carcinogen to experimental animals (Kanisawa and Suzuki, 1978;Bendele et al, 1985;National Toxicology Program, 1989), the International Agency for Research on Cancer (IARC) has classified OTA as a possible human carcinogen (group 2B) in 1993 (IARC, 1993). Due to its extreme stability and almost ubiquitous incidence as a food contaminant, it is impossible to achieve a complete avoidance of dietary intake of OTA (Gekle et al, 1998). Thus, consumption of OTAcontaminated food might be involved in esophageal carcinogenesis in Cixian County.…”

Section: Introductionmentioning

confidence: 99%

Ochratoxin A induces DNA damage and G2 phase arrest in human esophageal epithelium Het-1A cells <i>in vitro </i>

et al. 2015

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-Ochratoxin A (OTA), a toxin produced by several species of Aspergillus and Penicillium, is one of the most abundant food-contaminating mycotoxins. The International Agency for Research on Cancer (IARC) has classified OTA as a possible human carcinogen. Our previous study showed that there were high levels of OTA contaminations in wheat in the areas with high incidence of esophageal cancer in north China. This finding suggests that exposure to low levels of OTA may be a critical etiological factor for esophageal cancer in these areas. However, up to now, the potential biological effects of OTA on human esophageal epithelial cells have not been fully elucidated. In the present study, we explored the cytotoxicity of OTA in human esophageal epithelium immortalized cells (Het-1A). We found that OTA could induce DNA strand breaks and chromosome aberrations in Het-1A cells. OTA-induced DNA damage was followed by G2 cell cycle arrest, and down-regulation of Cdc2 and cyclinB1 contributed to the OTA-induced G2 arrest in Het-1A cells. Additionally, OTA induced apoptosis in Het-1A cells by activating caspase-3. In conclusion, our results indicated that OTA could induce DNA damage, G2 arrest and apoptosis in Het-1A cells, which may be involved in the esophageal toxicity of OTA.

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Section: Introductionmentioning

confidence: 99%

Ochratoxin A induces DNA damage and G2 phase arrest in human esophageal epithelium Het-1A cells <i>in vitro </i>

et al. 2015

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“…OTA enters the food chain by cereals and its products, coffee, beer, wine, poultry and pork. Due to its extreme stability and its almost ubiquitous incidence as food contaminant, complete avoidance of dietary intake of OTA is impossible [3].…”

Section: Introductionmentioning

confidence: 99%

The Nephrotoxin Ochratoxin A Induces Key Parameters of Chronic Interstitial Nephropathy in Renal Proximal Tubular Cells

Sauvant

Holzinger

Gekle³

2005

Cell Physiol Biochem

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Ochratoxin A (OTA) is a nephrotoxic and cancerogenic mycotoxin. There is epidemiological evidence that OTA exposition leads to cortical interstitial nephropathies in humans. However, virtually no data are available investigating the effect of OTA on renal cortical cells with respect to induction of nephropathy. Thus, we investigated whether OTA is able to induce changes of cellular properties potentially leading to interstitial nephropathy, using proximal tubular cell lines (OK, NRK-52E). OTA decreased cell number and cell protein time and dose dependently. Accordingly we investigated the effect of 100 nM or 1000 nM OTA. The decline of cell number after OTA exposure is due to necrosis and apoptosis, as measured by LDH release or DNA ladder formation and caspase-3 activation, respectively. OTA incubation of proximal tubular cells also resulted in a loss of epithelial tightness as determined by diffusion of FITC labeled inulin. Inflammation, fibrosis and epithelial-to-mesenchymal transition are described in chronic interstitial renal disease. Therefore, we also investigated the effect of OTA on NFκB activity, collagen secretion and generation of α smooth muscle actin. OTA alone was sufficient to induce the latter parameters in proximal tubular cells. Finally, OTA is a nephrotoxcic substance and elevated activity of mitogen activated protein kinases (MAPK) is described in nephropathies. As we investigated the effect of OTA on activity of ERK, JNK and p38 by ELISA, we found that OTA activates the MAPK measured dose dependently. In summary, OTA induced phenomena typical for chronic interstitial nephropathy, like loss of cells and epithelial tightness, necrosis and apoptosis as well as markers of inflammation, fibrosis and epithelial-to-mesenchymal transition in proximal tubular cells. Thus, we could show for the first time that OTA is able to induce key parameters of nephropathy in proximal tubular cells in culture. Moreover OTA interacts with MAPK and thus may exert its specific toxic actions.

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“…The toxin acts on different sites of nephron function, including renal blood flow, glomerular function and tubular epithelia (Krogh 1980;Gekle and Silbernagl 1993;Gekle et al 1998). Exposure to relatively low concentrations of OTA for several years has resulted in accumulation of toxin in various tissues, with maximal accumulation in proximal tubule cells.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis and oxidative stress induced by ochratoxin A in rat kidney

et al. 2003

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Ochratoxin A (OTA) is a widespread mycotoxin produced by several species of fungi. OTA induces a tubular-interstitial nephropathy in humans and in animals. It has been implicated as one of the aetiological agents involved in the development of endemic nephropathy. OTA-induced oxidative stress and apoptosis may play key roles in the development of chronic tubulointerstitial nephritis connected to the long-term exposure to this food contaminant. We studied the effects of low doses of OTA on kidney cells. Wistar rats were treated with 120 microg OTA/kg bodyweight daily, for 10, 30 or 60 days. Toxin concentration in kidney was proportional to the time of exposure, and amounted to 547.2, 752.5 and 930.3 ng OTA/g kidney tissue after 10, 30 and 60 days, respectively. OTA treatment caused an increased number of cells undergoing apoptosis in both proximal and distal epithelial kidney cells. The apoptotic cells were visualised using the TUNEL assay and staining with haematoxylin and eosin in situ. The number of apoptotic cells in rats treated for 10, 30 and 60 days increased by 5-, 6.4- and 12.7-fold, respectively, compared with the control cells. However, DNA electrophoresis did not show characteristic fragmentation (DNA laddering). The oxidative stress was evident via increased malondialdehyde formation. The concentration of lipid peroxides showed an increase (36%), but the activity of superoxide dismutase decreased (26%) in 60-day treated rats. In spite of the observed biochemical and morphological changes in the kidney cells, renal functional status was preserved to the end of experiment. This study demonstrates that a combination of morphologic and biochemical markers can be used to monitor early cell death in OTA-induced renal injury. We have shown that the exposure to the relatively low OTA concentrations has activated apoptotic processes and oxidative damage in kidney cells.

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Tubulotoxic Mechanisms of Ochratoxin A

Cited by 29 publications

References 25 publications

Ochratoxin A induces DNA damage and G2 phase arrest in human esophageal epithelium Het-1A cells <i>in vitro </i>

Ochratoxin A induces DNA damage and G2 phase arrest in human esophageal epithelium Het-1A cells <i>in vitro </i>

The Nephrotoxin Ochratoxin A Induces Key Parameters of Chronic Interstitial Nephropathy in Renal Proximal Tubular Cells

Apoptosis and oxidative stress induced by ochratoxin A in rat kidney

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