A Comparative Study of Ochratoxin A-Induced Apoptosis in Hamster Kidney and HeLa Cells

Seegers, J.C.; Bohmer, L.H.; Krüger, Marcus; Lottering, Mona-Liza; Dekock, M.

doi:10.1006/taap.1994.1222

Cited by 60 publications

(29 citation statements)

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“…1 and 2), corroborating histopathological changes observed previously in the proxima of rats following chronic treatment with OTA (Mantle et al, 1991). Similar pathological changes were reported by Heussner et al (1998) in primary rat cortex and distal kidney cells as well as in LLC-PK1 cells and by Seegers and coworkers (Seegers et al, 1994) in hamster kidney cells exposed to moderate to high OTA concentrations (10 − 7 -5× 10 − 5 M) in vitro. The above findings thus indicate that comparable pathological changes can be observed at high and low doses of OTA in an acute and chronic exposure setting, respectively.…”

Section: Cell Replicationsupporting

confidence: 90%

“…All efforts aimed at demonstrating DNA laddering using DNA extracts from the renal cortex of OTA treated rats failed (data not shown), most likely to the low number of cells affected in proportion to the 'normal' cells present. This interpretation is corroborated by Seegers and coworkers (Seegers et al, 1994) who found a maximum of 5% of hamster kidney cells exposed to OTA in vitro to undergo apoptotic necrosis. In contrast to the findings presented here, the latter authors were able to demonstrate DNA laddering, however, only after synchronizing the hamster kidney cells and then analyzing the detached cells in the supernatant of the exposure dish.…”

Section: Cell Replicationsupporting

confidence: 64%

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The role of α2u-globulin in ochratoxin A induced renal toxicity and tumors in F344 rats

1999

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The mycotoxin ochratoxin A (OTA) was shown to be a potent kidney carcinogen in rats demonstrating a marked sex difference in the response. Compared to female rats, male rats had a 10-fold higher incidence of kidney carcinomas. The objective of this study was to investigate whether this sex difference in tumor response is due to an exacerbation of effect resulting from the interaction of the male rat specific urinary protein h2u-globulin (h2u) with OTA. Male and female rats were treated by oral gavage with OTA (1 mg/kg per day), D-limonene (dL; 1650 mg/kg per day) as a positive control or corn oil for 7 consecutive days. OTA induced severe renal lesions predominantly in the P 3 region of the proximal tubules. The lesions consisted of necrotic cells and cell exfoliations. No hyaline droplets were found in the P 2 segment following OTA treatment, whereas dL induced the expected accumulation of droplets. The results suggest that OTA induced kidney lesions are in all characteristic points different from the known h2u-nephropathy induced by dL. Based on these experiments the male rat specific protein h2u does not seem to be involved in the mechanism(s) leading to the high tumor incidence observed in OTA exposed male rats.

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Section: Cell Replicationsupporting

confidence: 90%

Section: Cell Replicationsupporting

confidence: 64%

The role of α2u-globulin in ochratoxin A induced renal toxicity and tumors in F344 rats

1999

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“…In contrast, a study carried out by Seegers and coworkers 150 reported that OTA exposure only induced apoptosis in 5% of hamster kidney cells in vitro. Other authors, working with serum-replete medium, found no evidence for the induction of apoptosis in either LLC-PK1 or NRK-52E cells (Kristin Kobras, personal communication), nor in human or porcine primary renal epithelia exposed to OTA at concentrations ranging from 1 nM to 25 µM.…”

Section: Is Ota Pro-apoptotic or Pro-cytotoxic?: A Role For Oxidativementioning

confidence: 81%

Ochratoxin A: The Continuing Enigma

O'Brien

Dietrich

2005

Critical Reviews in Toxicology

357

212

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The mycotoxin ochratoxin A (OTA) has been linked to the genesis of several disease states in both animals and humans. It has been described as nephrotoxic, carcinogenic, teratogenic, immunotoxic, and hepatotoxic in laboratory and domestic animals, as well as being thought to be the probable causal agent in the development of nephropathies (Balkan Endemic Nephropathy, BEN and Chronic Interstitial Nephropathy, CIN) and urothelial tumors in humans. As a result, several international agencies are currently attempting to define safe legal limits for OTA concentration in foodstuffs (e.g., grain, meat, wine, and coffee), in processed foods, and in animal fodder. In order to achieve this goal, an accurate risk assessment of OTA toxicity including mechanistic and epidemiological studies must be carried out. Ochratoxin has been suggested by various researchers to mediate its toxic effects via induction of apoptosis, disruption of mitochondrial respiration and/or the cytoskeleton, or, indeed, via the generation of DNA adducts. Thus, it is still unclear if the predominant mechanism is of a genotoxic or an epigenetic nature. One aspect that is clear, however, is that the toxicity of OTA is subject to and characterized by large species-and sex-specific differences, as well as an apparently strict structure-activity relationship. These considerations could be crucial in the investigation of OTA-mediated toxicity. Furthermore, the use of appropriate in vivo and in vitro model systems appears to be vital in the generation of relevant experimental data. The intention of this review is to collate and discuss the currently available data on OTA-mediated toxicity with particular focus on their relevance for the in vivo situation, and also to suggest possible future strategies for unlocking the secrets of ochratoxin A.

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“…Cells were incubated for 24 h at 37 o C, fixed in Bouin's fixative for 60 min and stained by standard haematoxylin and eosin staining procedures. 24 In order to obtain quantitative data from the morphological study, mitotic indices were determined on the stained slides by counting 1000 cells on every coverslip and expressing it as the percentage of cells in mitosis.…”

Section: Morphology Studymentioning

confidence: 99%

In vitro effects of 2‐methoxyestradiol on MCF‐12A and MCF‐7 cell growth, morphology and mitotic spindle formation

Zijl

Lottering

Steffens

et al. 2008

Cell Biochemistry & Function

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The influence of 2-methoxyestradiol (2ME) was investigated on cell growth, morphology and spindle formation in a tumorigenic (MCF-7) and non-tumorigenic (MCF-12A) epithelial breast cell line. Inhibition of cell growth was more pronounced in the MCF-7 cells compared to the MCF-12A cells following 2ME treatment. Dose-dependent studies (10 -5 -10 -9 M) revealed that 10 -6 M 2ME inhibited cell growth by 44% in MCF-12A cells and by 84% in MCF-7 cells (P-value < 0.05). 2ME-treated MCF-7 cells showed abnormal metaphase cells, membrane blebbing, apoptotic cells and disrupted spindle formation. These observations were either absent, or less prominent in MCF-12A cells. 2ME had no effect on the length of the cell cycle between S-phase and the time a mitotic peak was reached in either cell line but MCF-7 cells were blocked in mitosis with no statistically significant alterations in the phosphorylation status of Cdc25C.Nevertheless, Cdc2 activity was significantly increased in MCF-7 cells compared to MCF-12A cells (P-value < 0.05). The results indicate that 2ME disrupts mitotic spindle formation and enhances Cdc2 kinase activity, leading to persistence of the spindle checkpoint and thus prolonged metaphase arrest that may result in the induction of apoptosis. The tumorigenic MCF-7 cells were especially sensitive to 2ME treatment compared to the normal MCF-12A cells.Therefore, differential mechanism(s) of growth inhibition are evident between the normal and tumorigenic cells.

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A Comparative Study of Ochratoxin A-Induced Apoptosis in Hamster Kidney and HeLa Cells

Cited by 60 publications

References 0 publications

The role of α2u-globulin in ochratoxin A induced renal toxicity and tumors in F344 rats

The role of α2u-globulin in ochratoxin A induced renal toxicity and tumors in F344 rats

Ochratoxin A: The Continuing Enigma

In vitro effects of 2‐methoxyestradiol on MCF‐12A and MCF‐7 cell growth, morphology and mitotic spindle formation

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