Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats

Kamp, Hennicke; Eisenbrand, Gerhard; Janzowski, C.; Kiossev, Jetchko; Latendresse, John R.; Schlatter, Josef Rudolf; Turesky, Robert J.

doi:10.1002/mnfr.200500124

Cited by 103 publications

(75 citation statements)

References 52 publications

(76 reference statements)

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“…In vitro and in vivo data suggest an involvement of oxidative stress in OTA-mediated cytotoxicity [1,4,16,17,23,30]. In fact, we observed in kidney tubulus cells a significant increase in reactive oxygen species production after OTA treatment already at relatively low OTA concentrations (0.5-2.5 lmol/L) [5] which were similar to those concentrations we used in the present study in neurons.…”

Section: Discussionsupporting

confidence: 88%

Ochratoxin A induces apoptosis in neuronal cells

et al. 2009

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The mycotoxin ochratoxin A (OTA), which is produced by Aspergillus and Penicillium subspecies, is a frequently present contaminant of food and feedstuffs. OTA exhibits a wide range of toxic activities including nephro-and hepatotoxicity. However, little is known regarding potential neurotoxic effects of OTA. In the present study primary neurons as well as SH-SY5Y neuronal cells were incubated with increasing concentrations of OTA (0.1-2.5 lmol/L). OTA treatment resulted in a dose-dependent increase in cytotoxicity in both neuronal cell types. Caspase-9 and caspase-3 were activated in response to OTA treatment. Furthermore, caspase inhibitors were effective in partly counteracting OTA induced neurocytotoxicity. OTA induced apoptosis was accompanied by a loss of mitochondria membrane potential. Overall, present data indicated that OTA is neurotoxic at relatively low concentrations. OTA induced neurotoxicity seems to be, at least party, mediated by apoptosis. OTA may contribute to the pathogenesis of neurodegenerative diseases (e.g. Alzheimer's and Parkinson's disease) in which apoptotic processes are centrally involved.

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Section: Discussionsupporting

confidence: 88%

Ochratoxin A induces apoptosis in neuronal cells

et al. 2009

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“…In addition, the differences of the serum biochemical indexes at 13 weeks were higher in high-dose (compared to control) livers than medium-dose (compared to control) livers. Medial-dose OTA does not have impact on the serum chemical or histopathological indexes, which is consistent with OTA studies [4][5][6] . Nonetheless, the derivatives found in the liver indicates that OTA must be metabolized in order to act as a carcinogen 26 .…”

Section: Discussionsupporting

confidence: 88%

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Yang

Chen

et al. 2014

Sci Rep

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The mycotoxin ochratoxin A (OTA) is found widely in agricultural commodities. OTA can induce various toxicities. In this study, rats were gavaged with OTA for different weeks. Then, the expression of microRNAs, mRNAs and proteins were measured in the rat livers treated with OTA for 13 weeks. Our sequencing data suggests that the medial and the high doses of OTA exert different effects on livers. Five distinctive pathways were induced after OTA treatment as collectively demonstrated at miRNA, mRNA and protein levels. Two (primary bile acid biosynthesis, and metabolism of xenobiotics by cytochrome P450) are directly associated with liver damage, whereas the remaining pathways (arginine and proline metabolism, cysteine and methionine metabolism, and PPAR signaling pathway) cause metabolic disease. This study reveals OTA-induced early hepatotoxicity for the first time by combining multi-omics methods. The novel metabolic pathways may contribute to the pathogenesis of metabolic diseases later in life.O chratoxin A (OTA) is a low molecular weight mycotoxin produced by certain strains of filamentous fungi of the Aspergillus and Penicillium genera and has been detected in a large variety of agricultural commodities. OTA carries potential health-associated risks and has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer 1 . OTA has previously been found to induce various toxic effects including nephrotoxicity, hepatotoxicity, immunotoxicity, genotoxicity, carcinogenicity, teratogenicity, neurotoxicity and mutagenicity.The liver is one of the major target organs of OTA biotransformation. Although, some early hepatotoxicity studies employed relative high concentrations of OTA and found remarkable liver lesion 2,3 , lower doses of OTA did not provoke significant pathological changes 4-6 . Most of the previous studies have been extensively focused on OTA-induced kidney damage, less on liver. However, it is still unknown how OTA affects the liver which is the largest detoxification organ of body. Therefore, the identification of early hepatotoxicity can be helpful to understand the mechanism of some diseases that may be developed and progressed by OTA in later stage, and to prevent these diseases in early stage to improve human health.Omics approaches, such as transcriptome and proteome, are promising to detect the pathological changes of liver at a molecular level. Till date, omics technology has been employed only in a few studies to understand the mechanism of OTA hepatotoxicity. Moreover, a high-throughput microarray profiling study on HepG2 liver cell transcriptome demonstrated that multiple hepatic metabolism genes are modulated by OTA exposure 7 . In addition, proteomic approaches have helped identify key proteins in the livers of pigs treated with OTA 8 . These omics approaches have widened our view about OTA hepatotoxicity, however the mechanism of OTA actions remains largely unknown.Recently, microRNAs (miRNAs) in animals and plants are shown to play an impor...

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“…3). However, in both strains, up-regulation of CYP4A12 and down-regulation of other phase I and II genes could provide for increased generation of reactive oxygen species and enhanced oxidative DNA damage (19,20), which could lead to cellular damage and regenerative cell proliferation. Indeed, enhanced proximal tubular damage and cell regeneration/proliferation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the mycotoxin OTA increased the incidence of renal adenoma and carcinoma in rats when exposed for up to 2 years to dietary OTA (18) or 210 Ag OTA/kg body weight/day via gavage (10). However, as OTA has not been convincingly shown to covalently interact with DNA, a nongenotoxic mechanism of action is assumed (19,20).…”

Section: Introductionmentioning

confidence: 99%

Carcinogen-Specific Gene Expression Profiles in Short-term Treated Eker and Wild-type Rats Indicative of Pathways Involved in Renal Tumorigenesis

et al. 2007

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Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogeninduced changes in gene expression. Male Eker and wild-type rats were gavaged daily with AA (10 mg/kg body weight) or OTA (210 Mg/kg body weight). After 1, 3, 7, and 14 days of exposure, renal histopathology, tubular cell proliferation, and Affymetrix gene expression profiles from renal cortex/outer medulla were analyzed. AA-treated Eker and wild-type rats were qualitatively comparable in all variables assessed, suggesting a Tsc2-independent mechanism of action. OTA treatment resulted in slightly increased cortical pathology and significantly elevated cell proliferation in both strains, although Eker rats were more sensitive. Deregulated genes involved in the phosphatidylinositol 3-kinase-AKT-Tsc2-mammalian target of rapamycin signaling, among other important genes prominent in tumorigenesis, in conjunction with the enhanced cell proliferation and presence of preneoplastic lesions suggested involvement of Tsc2 in OTA-mediated toxicity and carcinogenicity, especially as deregulation of genes involved in this pathway was more prominent in the Tsc2 mutant Eker rat. [Cancer Res 2007;67(9):4052-68]

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Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats

Cited by 103 publications

References 52 publications

Ochratoxin A induces apoptosis in neuronal cells

Ochratoxin A induces apoptosis in neuronal cells

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Carcinogen-Specific Gene Expression Profiles in Short-term Treated Eker and Wild-type Rats Indicative of Pathways Involved in Renal Tumorigenesis

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