Putative models of ochratoxin A neurotoxicity?

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Ochratoxin A is a mycotoxin that is produced by numerous Aspergillus and

Penicillium species..

Neurotoxicology. 2006 Jan ;27:82-92

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*Acute neurotoxic effects of the fungal metabolite

ochratoxin-A.*<http://lib.bioinfo.pl/pmid:16140385>

* * V Sava, <http://lib.bioinfo.pl/auth:Sava,V> O Reunova,

<http://lib.bioinfo.pl/auth:Reunova,O> A Velasquez,

<http://lib.bioinfo.pl/auth:Velasquez,A> R Harbison,

<http://lib.bioinfo.pl/auth:Harbison,R> J Sánchez-Ramos

<http://lib.bioinfo.pl/auth:S%C3%A1nchez-Ramos,J> Ochratoxin-A (OTA) is a

fungal metabolite with potential toxic effects on the central nervous system

that have not yet been fully characterized. OTA has complex mechanisms of

action that include evocation of oxidative stress, bioenergetic compromise,

inhibition of protein synthesis, production of DNA single-strand breaks and

formation of OTA-DNA adducts. The time course of acute effects of OTA were

investigated in the context of DNA damage, DNA repair and global oxidative

stress across six brain regions. Oxidative DNA damage, as measured with the

" comet assay " , was significantly increased in the six brain regions at all

time points up to 72h, with peak effects noted at 24h in midbrain (MB), CP

(caudate/putamen) and HP (hippocampus). Oxidative DNA repair activity

(oxyguanosine glycosylase or OGG1) was inhibited in all regions at 6h, but

recovered to control levels in cerebellum (CB) by 72h, and showed a trend to

recovery in other regions of brain. Other indices of oxidative stress were

also elevated. Lipid peroxidation and superoxide dismutase (SOD) increased

over time throughout the brain. In light of the known vulnerability of the

nigro-striatal dopaminergic neurons to oxidative stress, levels of striatal

dopamine (DA) and its metabolites were also measured. Administration of OTA

(0-6mg/kg i.p.) to mice resulted in a dose-dependent decrease in striatal DA

content and turnover with an ED50 of 3.2mg/kg. A single dose of 3.5mg/kg

decreased the intensity of tyrosine hydroxylase immunoreactivity (TH+) in

fibers of striatum, TH+ cells in substantia nigra (SN) and TH+ cells of the

locus ceruleus. TUNEL staining did not reveal apoptotic profiles in MB, CP

or in other brain regions and did not alter DARPP32 immunoreactivity in

striatum. In conclusion, OTA caused acute depletion of striatal DA on a

background of globally increased oxidative stress and transient inhibition

of oxidative DNA repair.

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Chem Res Toxicol. 2006 Sep 18;19:1241-1247

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*Genotoxicity of the Hydroquinone Metabolite of Ochratoxin A:

Structure-Activity Relationships for Covalent DNA

Adduction.*<http://lib.bioinfo.pl/pmid:16978030>

* * na Tozlovanu, <http://lib.bioinfo.pl/auth:Tozlovanu,M> Virginie

Faucet-Marquis, <http://lib.bioinfo.pl/auth:Faucet-Marquis,V> Annie

Pfohl-Leszkowicz, <http://lib.bioinfo.pl/auth:Pfohl-Leszkowicz,A>

Manderville <http://lib.bioinfo.pl/auth:Manderville,R> Ochratoxin A (OTA)

is a mycotoxin that shows potent nephrotoxicity and renal carcinogenicity in

rodents. One hypothesis for OTA-induced tumor formation is based on its

genotoxic properties that are promoted by oxidative metabolism. Like other

chlorinated phenols, OTA undergoes an oxidative dechlorination process to

generate a quinone (OTQ)/hydroquinone (OTHQ) redox couple that may play a

role in OTA-mediated genotoxicity. To determine whether the OTQ/OTHQ redox

couple of OTA contributes to genotoxicity, the DNA adduction properties, as

evidenced by the (32)P-postlabeling technique, of the hydroquinone analogue

(OTHQ) have been compared to OTA in the absence and presence of metabolic

activation (pig kidney microsomes) and within human bronchial epithelial

(WI26) and human kidney (HK2) cells. Our experiments show that OTHQ

generates DNA adduct spots in the absence of metabolic activation. These

adducts are ascribed to covalent DNA adduction by OTQ generated through

autoxidation of the hydroquinone precursor, OTHQ. Although OTA does not

interact with DNA in the absence of metabolism, the OTQ-mediated DNA adduct

spots noted with OTHQ are also observed with OTA following treatment with

pig kidney microsomes and NADPH, suggesting that OTA undergoes oxidative

activation to OTQ by cytochrome P450 or enzymes with peroxidase activity.

Comparison of DNA adduction by OTHQ and OTA in human cell lines shows that

OTQ-mediated adduct spots form in a dose- and time-dependent manner. The

adduct spots form at a faster rate with OTHQ, which is consistent with more

facile generation of OTQ from its hydroquinone precursor. These results

establish structure-activity relationships for OTA-mediated DNA adduction

and provide new evidence for the potential role of the OTQ/OTHQ redox couple

in OTA-induced genotoxicity.

Toxicology. 2006 Jun 10;: [Pubmed] <http://lib.bioinfo.pl/pmid:16140385>

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*Early cytotoxic effects of ochratoxin A in rat liver: A morphological,

biochemical and molecular study.*

<http://lib.bioinfo.pl/pmid:16857307> * * tta

Gagliano, <http://lib.bioinfo.pl/auth:Gagliano,N> Isabella Dalle Donne,

<http://lib.bioinfo.pl/auth:Donne,ID> Carlo Torri,

<http://lib.bioinfo.pl/auth:Torri,C> Massimiliano Migliori,

<http://lib.bioinfo.pl/auth:Migliori,M> Fabio Grizzi,

<http://lib.bioinfo.pl/auth:Grizzi,F> Aldo Milzani,

<http://lib.bioinfo.pl/auth:Milzani,A> Cristina Filippi,

<http://lib.bioinfo.pl/auth:Filippi,C> Giorgio Annoni,

<http://lib.bioinfo.pl/auth:Annoni,G> Piergiuseppe Colombo,

<http://lib.bioinfo.pl/auth:Colombo,P> Francesco Costa,

<http://lib.bioinfo.pl/auth:Costa,F> Giorgia Ceva-Grimaldi,

<http://lib.bioinfo.pl/auth:Ceva-Grimaldi,G> Alberto A E Bertelli,

<http://lib.bioinfo.pl/auth:Bertelli,AAE> Luca Giovannini,

<http://lib.bioinfo.pl/auth:Giovannini,L> Magda Gioia

<http://lib.bioinfo.pl/auth:Gioia,M> We characterized the overall early

effect of chronic ochratoxin A (OTA) treatment on rat liver, analyzing

different aspects related to: (i) fibrosis, by measuring collagen content

and turnover, and alpha-smooth muscle actin (alphaSMA); (ii) oxidative

stress and stress response, by analyzing protein carbonylation, superoxide

dismutase (SOD) and heat shock protein (HSP70) gene expression; (iii) the

possible tumor promoter effect, evaluating cadherin and connexin (CX) mRNA

levels. Light microscopy analysis showed no histological differences in

OTA-treated and control (CT) rats. Collagen content, determined by computer

analysis of Sirius red-stained liver sections, was similar in both groups.

In liver homogenates COL-I, COL-III, TIMP-1 and TGF-beta1 mRNA levels and

alphaSMA were unaffected by OTA. Matrix metalloproteinase (MMP)-1, MMP-2 and

MMP-9 protein levels were also similar in the two groups. Protein

carbonylation, a marker of severe oxidative stress, was not evident in the

homogenates of OTA-treated livers; superoxide dismutase (SOD) mRNA tended to

be lower and HSP70 was strongly down-regulated. OTA reduced E-cadherin and

DSC-2 transcription, and down-regulated liver CX26, CX32 and CX43. In

conclusion, these in vivo results show that OTA-induced liver injury

involves a reduction in the ability to counterbalance oxidative stress,

maybe leading to altered gap junction intercellular communication and loss

of cell adhesion and polarity. This suggests that mild oxidative damage

might be a key factor, in combination with other cytotoxic effects, in

triggering the promotion of liver tumors after exposure to OTA.

Neurotoxicology. 2006 Jun 9;: [Pubmed]<http://lib.bioinfo.pl/pmid:16140385>

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*Neuroanatomical mapping of DNA repair and antioxidative responses in mouse

brain: Effects of a single dose of MPTP.*<http://lib.bioinfo.pl/pmid:16831462>

* * V Sava, <http://lib.bioinfo.pl/auth:Sava,V> O Reunova,

<http://lib.bioinfo.pl/auth:Reunova,O> A Velasquez,

<http://lib.bioinfo.pl/auth:Velasquez,A> S Song,

<http://lib.bioinfo.pl/auth:Song,S> J -Ramos

<http://lib.bioinfo.pl/auth:-Ramos,J> The primary objective of this

study was to map the normal distribution of the base excision enzyme

oxyguanosine glycosylase (OGG1) across mouse-brain regions as a prelude to

assessing the effects of various neurotoxicants, ranging from highly

selective molecules like MPTP to more global toxic agents. This research is

based on the hypothesis that regional brain vulnerability to a toxicant is

determined, in part, by variation in the intrinsic capacity of cellular

populations to successfully repair oxidative DNA damage. After mapping the

normal distributions of OGG1 and superoxide dismutase (SOD) across 44 loci

dissected from mouse brain, MPTP, a mitochondrial toxicant with selective

dopamine (DA) neuron cytotoxicity was used to elicit focal oxidative stress

and DNA repair responses. A single dose of MPTP (20mg/kg, i.p.) elicited

time- and region-dependent changes in both SOD and OGG1, with early

increases in DNA repair and anti-oxidant activities throughout all regions

of brain. In some sampled loci, notably the substantia nigra (SN) and

hippocampus, the heightened DNA repair and antioxidant responses were not

maintained beyond 48h. Other loci from cerebellum, cerebral cortex and pons

maintained high levels of activity up to 72h. Levels of dopamine (DA) were

decreased significantly at all time points and remained below control levels

in nigro-striatal and mesolimbic systems (ventral tegmental area and nucleus

accumbens). Assessment of apoptosis by TUNEL staining revealed a significant

increase in number of apoptotic nuclei in the substantia nigra at 72h and

not in other loci. The marked degree of apoptosis that became evident in SN

at 72h was associated with large decreases in SOD and DNA repair activity at

that locus. In conclusion, MPTP elicited global effects on DNA repair and

antioxidant activity in all regions of brain, but the most vulnerable loci

were unable to maintain elevated DNA repair and antioxidant responses.

Synapse. 2006 May 31;60:185-193 [Pubmed]<http://lib.bioinfo.pl/pmid:16140385>

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*Single or multiple injections of methamphetamine increased dopamine

turnover but did not decrease tyrosine hydroxylase levels or cleave

caspase-3 in caudate-putamen.* <http://lib.bioinfo.pl/pmid:16739116> *

* Frederico

Costa Pereira, <http://lib.bioinfo.pl/auth:Pereira,FC> Elita Santos

Lourenço, <http://lib.bioinfo.pl/auth:Louren%C3%A7o,ES> Fernanda Borges,

<http://lib.bioinfo.pl/auth:Borges,F> Morgadinho,

<http://lib.bioinfo.pl/auth:Morgadinho,T> Fontes Ribeiro,

<http://lib.bioinfo.pl/auth:Ribeiro,CF> Tice Reis Macedo,

<http://lib.bioinfo.pl/auth:Macedo,TR> Syed F Ali

<http://lib.bioinfo.pl/auth:Ali,SF> Methamphetamine (METH), leading to

striatal dopamine (DA) nerve terminal toxicity in mammals, is also thought

to induce apoptosis of striatal neurons in rodents. We investigated the

acute effects induced by multiple injections of METH (4 x 5 mg/kg, i.p.) at

2-h intervals or a single injection of METH (20 mg/kg, i.p.) on terminal

dopaminergic toxicity markers, including DA levels, DA turnover, and

tyrosine hydroxylase (TH) immunoreactivity in rat caudate-putamen (CPu). We

further investigated whether both treatment paradigms would change Bax and

activate caspase-3 expression, thus triggering striatal apoptotic

mitochondria-dependent biochemical cascades. The first injection of METH (5

mg/kg, i.p.) produced a significant release of DA that peaked 30 min and

stayed above control levels up to 1.5 h within CPu. In another set of

experiments, rats were killed 1 and 24 h following the last injection, for

tissue DA and metabolite content measurement and Western blot analysis (24

h). Multiple doses induced DA depletion and increased turnover at both

endpoints. Single-dose METH reproduced these effects at 24 h; however,

turnover was significantly higher than that evoked by the multiple doses at

24 h. Although both paradigms evoked similar DA depletion, however, none of

the dosing regimens induced changes in TH expression at 24 h. The former

paradigm produced an increase in Bax expression in CPu not sufficient to

induce cleavage of caspase-3 proenzyme at 24 h. This study suggests that

both paradigm induced changes in striatal dopaminergic markers that are

independent of terminal degeneration and striatal apoptotic

mitochondria-dependent caspase-3 driven cascade within 24 h. Synapse

60:185-193, 2006. Published 2006 Wiley-Liss, Inc.

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*Expression of COX-2 and hsp72 in peritoneal macrophages after an acute

ochratoxin A treatment in mice.* <http://lib.bioinfo.pl/pmid:16643956>

* *

Carmela Ferrante, <http://lib.bioinfo.pl/auth:Ferrante,MC> Marcella

Bilancione, <http://lib.bioinfo.pl/auth:Bilancione,M> Giuseppina Mattace

Raso, <http://lib.bioinfo.pl/auth:Raso,GM> Emanuela Esposito,

<http://lib.bioinfo.pl/auth:Esposito,E> Iacono,

<http://lib.bioinfo.pl/auth:Iacono,A> lisa Zaccaroni,

<http://lib.bioinfo.pl/auth:Zaccaroni,A> ria Meli

<http://lib.bioinfo.pl/auth:Meli,R> Ochratoxin A (OTA) is a secondary

fungal metabolite produced by Aspergillus and Penicillium strains that

elicits a broad spectrum of toxicological effects in animals and man. A

single oral OTA administration (10 mg/kg) in mice induced after 24 h

oxidative damage and polymorphonuclear leukocyte (PMN) infiltration in

parenchymal organs. In fact, OTA treatment increased lipid peroxidation (via

malondialdehyde formation) in kidney and liver and PMN accumulation in

duodenum, as shown by myeloperoxidase activity. Following in vivo OTA

treatment an increase of cyclooxygenase-2 and of heat shock protein 72

expression was evidenced in peritoneal macrophage lysates by Western blot.

That OTA modulates these proteins involved in the inflammatory process

indicates that the mycotoxin is able to activate immune cells. This study

suggests that the oxidative stress, the neutrophil accumulation in

parenchymal tissues and the modulation of inflammatory parameters in

peritoneal macrophages induced by OTA are involved in its toxicity, and

represent early events related to several aspects of OTA mycotoxicosis.

Toxicology. 2006 Feb 21;: [Pubmed] <http://lib.bioinfo.pl/pmid:16140385>

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*Standard and Fpg-modified comet assay in kidney cells of ochratoxin A- and

fumonisin B(1)-treated rats.* <http://lib.bioinfo.pl/pmid:16497426> *

* Ana-Marija

Domijan, <http://lib.bioinfo.pl/auth:Domijan,A> Davor Zelje¾iæ,

<http://lib.bioinfo.pl/auth:Zelje%C5%BEi%C4%87,D> Nevenka Kopjar,

<http://lib.bioinfo.pl/auth:Kopjar,N> Maja Peraica

<http://lib.bioinfo.pl/auth:Peraica,M> The effect of ochratoxin A (OTA),

fumonisin B(1) (FB(1)), and their combinations on DNA damage was studied

using the standard alkaline comet assay and the Fpg-modified comet assay.

Rats were orally receiving OTA (5ng/kg b.w., 0.05mg/kg b.w., and 0.5mg/kg

b.w., respectively) for 15 days, FB(1) (200ng/kg b.w., 0.05mg/kg b.w., and

0.5mg/kg b.w., respectively) for 5 days, and the combinations of two lower

OTA and FB(1) doses. The tail length, tail intensity, and Olive tail moment

(OTM) obtained with the standard comet assay and Fpg-modified comet assay

were significantly higher in treated animals than in controls, even at the

lowest dose of OTA or FB(1) (p<0.01). The Fpg-modified comet assay showed

significantly greater tail length, tail intensity, and OTM in all treated

animal than did the standard comet assay (p<0.05), which suggests that

oxidative stress is likely to be responsible for DNA damage. DNA damage

detected by the standard comet assay at all OTA or FB(1) doses indicates

that some other mechanism is also involved. Combined OTA+FB(1) treatment

measured either by the standard comet or the Fpg-modified comet assay showed

a synergistic increase in the tail intensity and OTM in kidney cells, even

at doses that correspond to the daily human exposure in Europe.

Arh Hig Rada Toksikol. 2005 Dec ;56:311-5

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*The effect of ochratoxin A on the concentration of protein carbonyls in

rats.* <http://lib.bioinfo.pl/pmid:16370513> * * Ana-Marija Domijan,

<http://lib.bioinfo.pl/auth:Domijan,A> Kamilo Rudes,

<http://lib.bioinfo.pl/auth:Rudes,K> Maja Peraica

<http://lib.bioinfo.pl/auth:Peraica,M> The mechanism of ochratoxin A (OTA)

toxicity has been found to involve the production of free radicals and

consequent oxidative stress. Until now, the only studied pathway of

OTA-caused oxidative damage was peroxidation of lipids. The aim of this

study was to check whether OTA induced the production of protein carbonyls,

markers of protein oxidation. Exposed rats (5 per group) were given daily

OTA (0.5 mg kg(-1) b. w., i. p.) for 7 days, 14 days, or 21 days, and

control rats solvent only (TRIS). All animals were killed 24 hours after the

last treatment. The levels of OTA in plasma, kidney and liver homogenates

increased gradually during the whole length of the experiment. The levels of

protein carbonyls in kidney homogenates of OTA-treated rats was

significantly higher after days 14 and 21 than in controls (P < 0.05). The

levels of protein carbonyls in the liver was significantly higher in

OTA-treated animals only after day 21 (P < 0.05). These results confirm that

oxidative stress is involved in the mechanism of OTA toxicity, and that it

causes the oxidation of proteins.

Food Addit Contam. 2005 ;22 Suppl 1:88-93

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*Ochratoxin A: Potential epigenetic mechanisms of toxicity and

carcinogenicity.* <http://lib.bioinfo.pl/pmid:16332626> * * Benoît Schilter,

<http://lib.bioinfo.pl/auth:Schilter,B> Maricel Marin-Kuan,

<http://lib.bioinfo.pl/auth:Marin-Kuan,M> Thierry Delatour,

<http://lib.bioinfo.pl/auth:Delatour,T> Nestler,

<http://lib.bioinfo.pl/auth:Nestler,S> Mantle,

<http://lib.bioinfo.pl/auth:Mantle,P> Christophe Cavin

<http://lib.bioinfo.pl/auth:Cavin,C> Assessment of the significance to

human health of ochratoxin A (OTA) in food is limited by a lack of human

toxicity data. Therefore, OTA risk evaluation relies mainly on the use of

animal data, with renal carcinogenicity in rat being considered as the

pivotal effect. The elucidation of the mechanism of action would improve the

use of the carcinogenicity data for risk assessment. Direct genotoxicity

versus epigenetic mechanisms appears to be a key question. In this

presentation, new biochemical and toxicogenomic results obtained in a recent

European project (EU-Grant # QLK1-CT-2001-011614) will be summarized in the

context of previously reported mechanisms of action including inhibition of

protein synthesis, production of oxidative stress and alteration of cell

signalling. Amongst others, the new data indicate that chronic

administration of a carcinogenic dose of OTA affected cell-signalling

pathways resulting in a significantly reduced renal antioxidant defence and

increased oxidative DNA damage. These data confirm previous hypotheses

involving oxidative stress as a possible key epigenetic mechanism of OTA

toxicity and carcinogenicity.

Mol Nutr Food Res. 2005 Dec ;49:1160-7

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*Ochratoxin A induces oxidative DNA damage in liver and kidney after oral

dosing to rats.* <http://lib.bioinfo.pl/pmid:16302199> * * Hennicke G Kamp,

<http://lib.bioinfo.pl/auth:Kamp,HG> Gerhard Eisenbrand,

<http://lib.bioinfo.pl/auth:Eisenbrand,G> Janzowski,

<http://lib.bioinfo.pl/auth:Janzowski,C> Jetchko Kiossev,

<http://lib.bioinfo.pl/auth:Kiossev,J> R Latendresse,

<http://lib.bioinfo.pl/auth:Latendresse,JR> f Schlatter,

<http://lib.bioinfo.pl/auth:Schlatter,J> J Turesky

<http://lib.bioinfo.pl/auth:Turesky,RJ> The nephrotoxic/carcinogenic

mycotoxin ochratoxin A (OTA) occurs as a contaminant in food and feed and

may be linked to human endemic Balkan nephropathy. The mechanism of

OTA-derived carcinogenicity is still under debate, since reactive

metabolites of OTA and DNA adducts have not been unambiguously identified.

Oxidative DNA damage, however, has been observed in vitro after incubation

of mammalian cells with OTA. In this study, we investigated whether OTA

induces oxidative DNA damage in vivo as well. Male F344 rats were dosed with

0, 0.03, 0.1, 0.3 mg/kg bw per day OTA for 4 wk (gavage, 7 days/wk, five

animals per dose group). Subsequently, oxidative DNA damage was determined

in liver and kidney by the comet assay (single cell gel electrophoresis)

with/without use of the repair enzyme formamido-pyrimidine-DNA-glycosylase

(FPG). The administration of OTA had no effect on basic DNA damage

(determined without FPG); however, OTA-mediated oxidative damage was

detected with FPG treatment in kidney and liver DNA of all dose groups.

Since the doses were in a range that had caused kidney tumors in a 2-year

carcinogenicity study with rats, the oxidative DNA damage induced by OTA may

help to explain its mechanism of carcinogenicity. For the selective

induction of tumors in the kidney, increased oxidative stress in connection

with severe cytotoxicity and increased cell proliferation might represent

driving factors.

Toxicol Sci. 2005 Oct 26;: [Pubmed] <http://lib.bioinfo.pl/pmid:16140385>

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*A Toxicogenomics Approach to Identify New Plausible Epigenetic Mechanisms

of Ochratoxin A Carcinogenicity in Rat.*<http://lib.bioinfo.pl/pmid:16251485>

* * M Marin-Kuan, <http://lib.bioinfo.pl/auth:Marin-Kuan,M> S Nestler,

<http://lib.bioinfo.pl/auth:Nestler,S> C Verguet,

<http://lib.bioinfo.pl/auth:Verguet,C> C Bezençon,

<http://lib.bioinfo.pl/auth:Bezen%C3%A7on,C> D Piguet,

<http://lib.bioinfo.pl/auth:Piguet,D> R Mansourian,

<http://lib.bioinfo.pl/auth:Mansourian,R> J Holzwarth,

<http://lib.bioinfo.pl/auth:Holzwarth,J> M Grigorov,

<http://lib.bioinfo.pl/auth:Grigorov,M> T Delatour,

<http://lib.bioinfo.pl/auth:Delatour,T> P Mantle,

<http://lib.bioinfo.pl/auth:Mantle,P> C Cavin,

<http://lib.bioinfo.pl/auth:Cavin,C> B Schilter

<http://lib.bioinfo.pl/auth:Schilter,B> Ochratoxin A (OTA) is a mycotoxin

occurring naturally in a wide range of food commodities. In animals, it has

been shown to cause a variety of adverse effects, nephrocarcinogenicity

being the most prominent. Because of its high toxic potency and the

continuous exposure of the human population, OTA has raised public health

concerns. There is significant debate on how to use the rat carcinogenicity

data to assess the potential risk to humans. In this context, the question

of the mechanism of action of OTA appears of key importance and was studied

through the application of a toxicogenomics approach. Male Fischer rats were

fed OTA for up to two years. Renal tumours were discovered during the last

six months of the study. The total tumour incidence reached 25% at the end

of the study. Gene expression profile was analysed in groups of animals

taken in intervals from 7 days to 12 months. Tissue-specific responses were

observed in kidney vs liver. For selected genes, microarray data were

confirmed at both mRNA and protein levels. In kidney, several genes known as

markers of kidney injury and cell regeneration were significantly modulated

by OTA. The expression of genes known to be involved in DNA synthesis and

repair, or genes induced as a result of DNA damage, were only marginally

modulated. Very little or no effect was found amongst genes associated with

apoptosis. Alterations of gene expression indicating effects on calcium

homeostasis and a disruption of pathways regulated by the transcription

factors hepatocyte nuclear factor 4 alpha (HNF4alpha) and nuclear

factor-erythroid 2-related factor 2 (Nrf2) were observed in the kidney but

not in the liver. Previous data have suggested that a reduction in HNF4alpha

may be associated with nephrocarcinogenicity. Many Nrf2-regulated genes are

involved in chemical detoxication and antioxidant defence. The depletion of

these genes is likely to impair the defence potential of the cells resulting

in chronic elevation of oxidative stress in the kidney. The inhibition of

defence mechanism appears as a highly plausible new mechanism, which could

contribute to OTA carcinogenicity.