Re: Tremorgenic mycotoxins from Aspergillus fumigatus as a possible occupational hea

[Guest guest]

Thanks KC, this may prove out to be a main culprit for me. at the

second home with tremmors, ect., ect. and green cat@@/scratch that,

green pupils.was thinking that I had read that some type of

aspergillius caused tremmors but couldn't remember.

>

> Tremorgenic mycotoxins from Aspergillus fumigatus as a possible

> occupational health problem in sawmills.

> Authors:

>

> Land CJ

>

> Hult K

>

> Fuchs R

>

> Hagelberg S

>

> Lundström H

>

> Source: Appl Environ Microbiol. 1987, Apr; 53(4):787-90. [Applied

> and environmental microbiology]

>

> http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~vUnAFq:468

>

> Abstract:

>

> Wood-trimmers' disease, generally called extrinsic allergic

> alveolitis, which affects workers in sawmills, is thought to be

> caused by fungal diaspores. The importance of Aspergillus fumigatus

> on the surface of wood dried in kilns is accentuated by its ability

> to produce tremorgenic mycotoxins. Eight strains of A. fumigatus

> from five different sawmills were isolated and cultivated on liquid

> media, and one of the strains was also cultivated on wood blocks.

> Extracts were prepared, and the tremorgenic reactions were induced

> by oral administration of extracts to rats. Extracts of the strain

> grown in liquid medium and on wood blocks induced very strong

> tremorgenic reactions when administered orally to rats. Four other

> strains induced mild tremorgenic reactions. High-performance liquid

> chromatography analysis revealed two tremorgenic mycotoxins,

> verruculogen and fumitremorgen C, in the five toxic strains. One

> nontoxic strain produced detectable levels of verruculogen. These

> results, coupled with the known resemblance of the acutely toxic

> phase of wood-trimmers' disease to the symptoms produced by these

> tremorgens, imply that wood-trimmers' disease and similar

> occupational diseases are, at least in part, mycotoxicoses.

>

> Medical Subject Headings (MeSH):

>

> Air Microbiology

>

> Alveolitis, Extrinsic Allergic/*etiology

>

> Animals

>

> Aspergillus fumigatus/*pathogenicity

>

> Female

>

> Humans

>

> Mycotoxins/analysis/*toxicity

>

> Occupational Diseases/*etiology

>

> Rats

>

> Rats, Inbred Strains

>

> CAS Registry Numbers:

>

> Mycotoxins (0)

>

> Language: English

>

>

> International Standard Serial Number: 0099-2240 (Print)

>

>

> Publication Types:

>

> Journal Article

>

> Research Support, Non-U.S. Gov't

>

> Entry Month: September, 1987

>

>

> Title Abbreviation: Appl Environ Microbiol

>

>

> Year of Publication: 1987

>

>

> Last Revision Date: June 9, 1987

>

>

> Medline Citation: NLM

>

>

> Country: UNITED STATES

>

>

> Citation Subset: IM

>

>

> Medline Title Abbreviation: Applied and environmental microbiology

>

>

> Stat: MEDLINE

>

>

> Document Number: medline/3555338

>

[Guest guest]

Jeanine,

Ochratoxin A is neurotoxic in a way similar to MPTP -i.e. excitotoxic

to dopamine receptor cells in the substantia nigra.

In a paper which I found thanks to you, Jeanine, I found that it was

neurotoxic in a way that can cause Parkinsons disease. which is known

for tremor-like symptoms.

Also, I think that several *penicillium* species are especially known

for producing tremerogenic mycotoxins.

Here are some abstracts on ochratoxin a...

J Neurol Sci. 2006 Nov 1;249(1):68-75. Epub 2006 Jul 14.

Can low level exposure to ochratoxin-A cause parkinsonism?

Sava V,

Reunova O,

Velasquez A,

-Ramos J.

University of South Florida, Tampa, FL 33612, USA.

Mycotoxins are fungal metabolites with pharmacological activities that

have been utilized in the production of antibiotics, growth promoters,

and other classes of drugs. Some mycotoxins have been developed as

biological and chemical warfare agents. Bombs and ballistic missiles

loaded with aflatoxin were stockpiled and may have been deployed by

Iraq during the first Gulf War. In light of the excess incidence of

amyotrophic lateral sclerosis (ALS) in veterans from Operation Desert

Storm, the potential for delayed neurotoxic effects of low doses of

mycotoxins should not be overlooked. Ochratoxin-A (OTA) is a common

mycotoxin with complex mechanisms of action, similar to that of the

aflatoxins. Acute administration of OTA at non-lethal doses (10% of

the LD(50)) have been shown to increase oxidative DNA damage in brain

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

caudate/putamen (CP) and hippocampus (HP). Levels of dopamine (DA) and

its metabolites in the striatum (e.g., CP) were shown to be decreased

in a dose-dependent manner. The present study focused on the effects

of chronic low dose OTA exposure on regional brain oxidative stress

and striatal DA metabolism. Continuous administration of low doses of

OTA with implanted subcutaneous Alzet minipumps caused a small but

significant decrease in striatal DA levels and an upregulation of

anti-oxidative systems and DNA repair. It is possible that low dose

exposure to OTA will result in an earlier onset of parkinsonism when

normal age-dependent decline in striatal DA levels are superimposed on

the mycotoxin-induced lesion.

PMID: 16844142 [PubMed - indexed for MEDLINE]

Neurotoxicology. 2006 Jan;27(1):82-92. Epub 2005 Sep 2.

Acute neurotoxic effects of the fungal metabolite ochratoxin-A.

Sava V, Reunova O, Velasquez A, Harbison R, -Ramos J.

University of South Florida, Department of Neurology (MDC 55), 12901

Bruce B. Downs Blvd., Tampa, FL 33612, USA.

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 72 h, with peak effects

noted at 24 h in midbrain (MB), CP (caudate/putamen) and HP

(hippocampus). Oxidative DNA repair activity (oxyguanosine glycosylase

or OGG1) was inhibited in all regions at 6 h, but recovered to control

levels in cerebellum (CB) by 72 h, 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 (0-6 mg/kg i.p.) to mice resulted in a

dose-dependent decrease in striatal DA content and turnover with an

ED50 of 3.2 mg/kg. A single dose of 3.5 mg/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.

Toxicol Sci. 2003 Jun;73(2):315-28. Epub 2003 Apr 15. s

A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity:

expression profiling in vivo and in vitro employing cDNA microarrays.

Luhe A, Hildebrand H, Bach U, Dingermann T, Ahr HJ.

Department of Molecular and Genetic Toxicology, Bayer AG, Aprather Weg

18a, 42096 Wuppertal, Germany. anke.luehe.al@...

Ochratoxin A (OTA) is a mycotoxin often found in cereals as a

contaminant, and it is known to cause severe nephrotoxicity in animals

and humans. There have been several investigations studying the mode

of action of this toxicant, suggesting inhibition of protein

synthesis, formation of DNA adducts, and provocation of DNA

single-strand breaks as a result of oxidative stress, but little is

known about the transcriptional alterations underlying OTA-derived

nephrotoxicity so far. We carried out DNA microarray analyses to

assess OTA-specific expression profiles in vivo and in vitro. Cultures

of primary rat proximal tubular cells and male Wistar rats were

treated with a low dose (5 microM and 1 mg/kg, respectively) or a high

dose (12.5 microM and 10 mg/kg, respectively) of OTA for 24 or 72 h.

Microarray experiments were carried out after dual fluorescent

labeling of sample cDNA, and data analysis was performed utilizing

different statistical methods. Validity of selected microarray data

was confirmed by quantitative real-time PCR. We were able to

demonstrate that microarray data derived from our proximal tubule cell

(PTC) culture model were highly comparable to the in vivo situation.

Marked treatment-specific transcriptional changes were detected for

genes involved in DNA damage response and apoptosis (upregulation of

GADD 153, GADD 45, annexin V), response to oxidative stress

(differential expression of hypoxia-inducible factor 1 and catalase),

and inflammatory reactions (upregulation of alpha 2 macroglobulin,

ceruloplasmin, and cathepsin S). We conclude that our results provide

a molecular basis for interpretation of OTA-induced nephrotoxicity.

PMID: 12700408 [PubMed - indexed for MEDLINE] ________________________________

Free Radic Biol Med. 2001 May 15;30(10):1089-98.

Oxidative damage and stress response from ochratoxin a exposure in rats.

Gautier JC, Holzhaeuser D, Markovic J, Gremaud E, Schilter B, Turesky RJ.

Nestle Research Center, Nestec Ltd., Lausanne, Switzerland.

Ochratoxin A (OTA) is a mycotoxin found in some cereal and grain

products.It is a potent renal carcinogen in male rats, although its

mode of carcinogenic action is not known. Oxidative stress may play a

role in OTA-induced toxicity and carcinogenicity.In this study, we

measured several chemical and biological markers that are associated

with oxidative stress response to determine if this process is

involved in OTA-mediated toxicity in rats. Treatment of male rats with

OTA (up to 2 mg/ 24 h exposure) did not increase the formation of

biomarkers of oxidative damage such as the lipid peroxidation marker

malondialdehyde in rat plasma, kidney, and liver, or the DNA damage

marker 8-oxo-7,8-dihydro-2' deoxyguanosine in kidney DNA. However, OTA

treatment (1 mg/kg) did result in a 22% decrease in alpha-tocopherol

plasma levels and a 5-fold increase in the expression of the oxidative

stress responsive protein haem oxygenase-1, specifically in the

kidney. The selective alteration of these latter two markers indicates

that OTA does evoke oxidative stress, which may contribute at least in

part to OTA renal toxicity and carcinogenicity in rats during

long-term exposure.

PMID: 11369498 [PubMed - indexed for MEDLINE]

Biochim Biophys Acta. 2002 Nov 20;1588(2):149-58.

The role of oxidative stress in the ochratoxin A-mediated toxicity

in proximal tubular cells.

Schaaf GJ, Nijmeijer SM, Maas RF, Roestenberg P, de Groene EM,

Fink-Gremmels J.

Department of Veterinary Pharmacology, Pharmacy and Toxicology

(VFFT) Faculty of Veterinary Medicine, Utrecht University, P.O. Box

80152, NL 3508 TD Utrecht, The Netherlands.

Balkan endemic nephropathy (BEN), a disease characterized by

progressive renal fibrosis in human patients, has been associated with

exposure to ochratoxin A (OTA). This mycotoxin is a frequent

contaminant of human and animal food products, and is toxic to all

animal species tested. OTA predominantly affects the kidney and is

known to accumulate in the proximal tubule (PT). The induction of

oxidative stress is implicated in the toxicity of this mycotoxin.In

the present study, primary rat PT cells and LLC-PK(1) cells, which

express characteristics of the PT, were used to investigate the

OTA-mediated oxidative stress response. OTA exposure of these cells

resulted in a concentration-dependent elevation of reactive oxygen

species (ROS) levels, depletion of cellular glutathione (GSH) levels

and an increase in the formation of 8-oxoguanine.The OTA-induced ROS

response was significantly reduced following treatment with

alpha-tocopherol (TOCO). However, this chain-braking anti-oxidant did

not reduce the cytotoxicity of OTA and was unable to prevent the

depletion of total GSH levels in OTA-exposed cells. In contrast,

pre-incubation of the cell with N-acetyl-L-cysteine (NAC) completely

prevented the OTA-induced increase in ROS levels as well as the

formation of 8-oxoguanine and completely protected against the

cytotoxicity of OTA. In addition, NAC treatment also limited the GSH

depletion in OTA-exposed PT- and LLC-PK(1) cells.From these data, we

conclude that oxidative stress contributes to the tubular toxicity of

OTA. Subsequently, cellular GSH levels play a pivotal role in limiting

the short-term toxicity of this mycotoxin in renal tubular cells.

Publication Types:

* Comparative Study

* Research Support, Non-U.S. Gov't

PMID: 12385779 [PubMed - indexed for MEDLINE]

Toxicology. 2005 Jan 31;206(3):413-25.

Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity

and apoptosis in mammalian cell lines and primary cells.

Kamp HG, Eisenbrand G, Schlatter J, Wurth K, Janzowski C.

Department of Chemistry, Division of Food Chemistry and

Environmental Toxicology, University of Kaiserslautern, Erwin

Schroedinger Strasse 52, D-67663 Kaiserslautern, Germany.

Ochratoxin A (OTA) is a nephrotoxic/-carcinogenic mycotoxin,

produced by several Aspergillus- and Penicillium-strains. Humans are

exposed to OTA via food contamination, a causal relationship of OTA to

human endemic Balkan nephropathy is still under debate. Since

DNA-adducts of OTA or its metabolites could not be identified

unambiguously, its carcinogenic effectiveness might be related to

secondary effects, such as oxidative cell damage or cell

proliferation. In this study, OTA mediated induction of (oxidative)

DNA damage, cytotoxicity (necrosis, growth inhibition, apoptosis) and

modulation of glutathione were investigated in cell lines (V79, CV-1)

and primary rat kidney cells. After 24 h incubation, viability of V79

cells was strongly decreased by OTA concentrations >2.5 micromol/L,

whereas CV-1 cells were clearly less sensitive. Strong growth

inhibition occurred in both cell lines (IC(50) approximately 2

micromol/L). Apoptosis, detected with an immunochemical test and with

flow cytometry, was induced by >1 micromol/L OTA. Oxidative DNA

damage, detected by comet assay after additional treatment with repair

enzymes, was induced in all cell systems already at five-fold lower

concentrations. Glutathione in CV-1 cells was depleted after 1 h

incubation (>100 micromol/L). In contrast, an increase was measured

after 24 h incubation (>0.5 micromol/L). In conclusion, OTA induces

oxidative DNA damage at low, not yet cytotoxic concentrations.

Oxidative DNA damage might initiate cell transformation eventually in

connection with proliferative response following cytotoxic cell death.

Both events might represent pivotal factors in the chain of cellular

events leading into nephro-carcinogenicity of OTA.

Publication Types:

* Research Support, Non-U.S. Gov't

PMID: 15588931 [PubMed - indexed for MEDLINE]

Arch Toxicol. 2003 Dec;77(12):685-93. Epub 2003 Sep 10.

Apoptosis and oxidative stress induced by ochratoxin A in rat kidney.

Petrik J, Zanic-Grubisic T, Barisic K, Pepeljnjak S, Radic B,

Ferencic Z, Cepelak I.

Department of Medical Biochemistry and Haematology, Faculty of

Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, PO

Box 156, 10000 Zagreb, Croatia, jpetrik@...

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.

Publication Types:

* In Vitro

* Research Support, Non-U.S. Gov't

PMID: 13680094 [PubMed - indexed for MEDLINE]

[Guest guest]

Thank you Live,I only have tremmor symptoms now with some MCS

siezures,they happen from the waist down but the overall effect

leaves me drained and mighty sore all over. hey,if you come across

any human case studys on fungal neurotoxicity,mycotoxicity,ect.

please post them.

>

> Jeanine,

>

> Ochratoxin A is neurotoxic in a way similar to MPTP -i.e.

excitotoxic

> to dopamine receptor cells in the substantia nigra.

>

> In a paper which I found thanks to you, Jeanine, I found that it was

> neurotoxic in a way that can cause Parkinsons disease. which is

known

> for tremor-like symptoms.

>

> Also, I think that several *penicillium* species are especially

known

> for producing tremerogenic mycotoxins.

>

> Here are some abstracts on ochratoxin a...

>

>

>

> J Neurol Sci. 2006 Nov 1;249(1):68-75. Epub 2006 Jul 14.

>

> Can low level exposure to ochratoxin-A cause parkinsonism?

>

> Sava V,

> Reunova O,

> Velasquez A,

> -Ramos J.

>

> University of South Florida, Tampa, FL 33612, USA.

>

> Mycotoxins are fungal metabolites with pharmacological activities

that

> have been utilized in the production of antibiotics, growth

promoters,

> and other classes of drugs. Some mycotoxins have been developed as

> biological and chemical warfare agents. Bombs and ballistic missiles

> loaded with aflatoxin were stockpiled and may have been deployed by

> Iraq during the first Gulf War. In light of the excess incidence of

> amyotrophic lateral sclerosis (ALS) in veterans from Operation

Desert

> Storm, the potential for delayed neurotoxic effects of low doses of

> mycotoxins should not be overlooked. Ochratoxin-A (OTA) is a common

> mycotoxin with complex mechanisms of action, similar to that of the

> aflatoxins. Acute administration of OTA at non-lethal doses (10% of

> the LD(50)) have been shown to increase oxidative DNA damage in

brain

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

> caudate/putamen (CP) and hippocampus (HP). Levels of dopamine (DA)

and

> its metabolites in the striatum (e.g., CP) were shown to be

decreased

> in a dose-dependent manner. The present study focused on the effects

> of chronic low dose OTA exposure on regional brain oxidative stress

> and striatal DA metabolism. Continuous administration of low doses

of

> OTA with implanted subcutaneous Alzet minipumps caused a small but

> significant decrease in striatal DA levels and an upregulation of

> anti-oxidative systems and DNA repair. It is possible that low dose

> exposure to OTA will result in an earlier onset of parkinsonism when

> normal age-dependent decline in striatal DA levels are superimposed

on

> the mycotoxin-induced lesion.

>

> PMID: 16844142 [PubMed - indexed for MEDLINE]

>

>

>

>

>

> Neurotoxicology. 2006 Jan;27(1):82-92. Epub 2005 Sep 2.

>

>

> Acute neurotoxic effects of the fungal metabolite ochratoxin-A.

>

> Sava V, Reunova O, Velasquez A, Harbison R, -Ramos J.

>

> University of South Florida, Department of Neurology (MDC 55), 12901

> Bruce B. Downs Blvd., Tampa, FL 33612, USA.

>

> 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 72 h, with peak effects

> noted at 24 h in midbrain (MB), CP (caudate/putamen) and HP

> (hippocampus). Oxidative DNA repair activity (oxyguanosine

glycosylase

> or OGG1) was inhibited in all regions at 6 h, but recovered to

control

> levels in cerebellum (CB) by 72 h, 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 (0-6 mg/kg i.p.) to mice resulted in a

> dose-dependent decrease in striatal DA content and turnover with an

> ED50 of 3.2 mg/kg. A single dose of 3.5 mg/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.

>

> Toxicol Sci. 2003 Jun;73(2):315-28. Epub 2003 Apr 15. s

> A new approach to studying ochratoxin A (OTA)-induced

nephrotoxicity:

> expression profiling in vivo and in vitro employing cDNA

microarrays.

>

> Luhe A, Hildebrand H, Bach U, Dingermann T, Ahr HJ.

>

> Department of Molecular and Genetic Toxicology, Bayer AG, Aprather

Weg

> 18a, 42096 Wuppertal, Germany. anke.luehe.al@...

>

> Ochratoxin A (OTA) is a mycotoxin often found in cereals as a

> contaminant, and it is known to cause severe nephrotoxicity in

animals

> and humans. There have been several investigations studying the mode

> of action of this toxicant, suggesting inhibition of protein

> synthesis, formation of DNA adducts, and provocation of DNA

> single-strand breaks as a result of oxidative stress, but little is

> known about the transcriptional alterations underlying OTA-derived

> nephrotoxicity so far. We carried out DNA microarray analyses to

> assess OTA-specific expression profiles in vivo and in vitro.

Cultures

> of primary rat proximal tubular cells and male Wistar rats were

> treated with a low dose (5 microM and 1 mg/kg, respectively) or a

high

> dose (12.5 microM and 10 mg/kg, respectively) of OTA for 24 or 72 h.

> Microarray experiments were carried out after dual fluorescent

> labeling of sample cDNA, and data analysis was performed utilizing

> different statistical methods. Validity of selected microarray data

> was confirmed by quantitative real-time PCR. We were able to

> demonstrate that microarray data derived from our proximal tubule

cell

> (PTC) culture model were highly comparable to the in vivo situation.

> Marked treatment-specific transcriptional changes were detected for

> genes involved in DNA damage response and apoptosis (upregulation of

> GADD 153, GADD 45, annexin V), response to oxidative stress

> (differential expression of hypoxia-inducible factor 1 and

catalase),

> and inflammatory reactions (upregulation of alpha 2 macroglobulin,

> ceruloplasmin, and cathepsin S). We conclude that our results

provide

> a molecular basis for interpretation of OTA-induced nephrotoxicity.

>

> PMID: 12700408 [PubMed - indexed for MEDLINE]

________________________________

>

> Free Radic Biol Med. 2001 May 15;30(10):1089-98.

>

> Oxidative damage and stress response from ochratoxin a exposure in

rats.

>

> Gautier JC, Holzhaeuser D, Markovic J, Gremaud E, Schilter B,

Turesky RJ.

>

> Nestle Research Center, Nestec Ltd., Lausanne, Switzerland.

>

> Ochratoxin A (OTA) is a mycotoxin found in some cereal and grain

> products.It is a potent renal carcinogen in male rats, although its

> mode of carcinogenic action is not known. Oxidative stress may play

a

> role in OTA-induced toxicity and carcinogenicity.In this study, we

> measured several chemical and biological markers that are associated

> with oxidative stress response to determine if this process is

> involved in OTA-mediated toxicity in rats. Treatment of male rats

with

> OTA (up to 2 mg/ 24 h exposure) did not increase the formation of

> biomarkers of oxidative damage such as the lipid peroxidation marker

> malondialdehyde in rat plasma, kidney, and liver, or the DNA damage

> marker 8-oxo-7,8-dihydro-2' deoxyguanosine in kidney DNA. However,

OTA

> treatment (1 mg/kg) did result in a 22% decrease in alpha-tocopherol

> plasma levels and a 5-fold increase in the expression of the

oxidative

> stress responsive protein haem oxygenase-1, specifically in the

> kidney. The selective alteration of these latter two markers

indicates

> that OTA does evoke oxidative stress, which may contribute at least

in

> part to OTA renal toxicity and carcinogenicity in rats during

> long-term exposure.

>

> PMID: 11369498 [PubMed - indexed for MEDLINE]

>

> Biochim Biophys Acta. 2002 Nov 20;1588(2):149-58.

>

> The role of oxidative stress in the ochratoxin A-mediated

toxicity

> in proximal tubular cells.

>

> Schaaf GJ, Nijmeijer SM, Maas RF, Roestenberg P, de Groene EM,

> Fink-Gremmels J.

>

> Department of Veterinary Pharmacology, Pharmacy and Toxicology

> (VFFT) Faculty of Veterinary Medicine, Utrecht University, P.O. Box

> 80152, NL 3508 TD Utrecht, The Netherlands.

>

> Balkan endemic nephropathy (BEN), a disease characterized by

> progressive renal fibrosis in human patients, has been associated

with

> exposure to ochratoxin A (OTA). This mycotoxin is a frequent

> contaminant of human and animal food products, and is toxic to all

> animal species tested. OTA predominantly affects the kidney and is

> known to accumulate in the proximal tubule (PT). The induction of

> oxidative stress is implicated in the toxicity of this mycotoxin.In

> the present study, primary rat PT cells and LLC-PK(1) cells, which

> express characteristics of the PT, were used to investigate the

> OTA-mediated oxidative stress response. OTA exposure of these cells

> resulted in a concentration-dependent elevation of reactive oxygen

> species (ROS) levels, depletion of cellular glutathione (GSH) levels

> and an increase in the formation of 8-oxoguanine.The OTA-induced ROS

> response was significantly reduced following treatment with

> alpha-tocopherol (TOCO). However, this chain-braking anti-oxidant

did

> not reduce the cytotoxicity of OTA and was unable to prevent the

> depletion of total GSH levels in OTA-exposed cells. In contrast,

> pre-incubation of the cell with N-acetyl-L-cysteine (NAC) completely

> prevented the OTA-induced increase in ROS levels as well as the

> formation of 8-oxoguanine and completely protected against the

> cytotoxicity of OTA. In addition, NAC treatment also limited the GSH

> depletion in OTA-exposed PT- and LLC-PK(1) cells.From these data, we

> conclude that oxidative stress contributes to the tubular toxicity

of

> OTA. Subsequently, cellular GSH levels play a pivotal role in

limiting

> the short-term toxicity of this mycotoxin in renal tubular cells.

>

> Publication Types:

>

> * Comparative Study

> * Research Support, Non-U.S. Gov't

>

>

> PMID: 12385779 [PubMed - indexed for MEDLINE]

>

> Toxicology. 2005 Jan 31;206(3):413-25.

>

> Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity

> and apoptosis in mammalian cell lines and primary cells.

>

> Kamp HG, Eisenbrand G, Schlatter J, Wurth K, Janzowski C.

>

> Department of Chemistry, Division of Food Chemistry and

> Environmental Toxicology, University of Kaiserslautern, Erwin

> Schroedinger Strasse 52, D-67663 Kaiserslautern, Germany.

>

> Ochratoxin A (OTA) is a nephrotoxic/-carcinogenic mycotoxin,

> produced by several Aspergillus- and Penicillium-strains. Humans are

> exposed to OTA via food contamination, a causal relationship of OTA

to

> human endemic Balkan nephropathy is still under debate. Since

> DNA-adducts of OTA or its metabolites could not be identified

> unambiguously, its carcinogenic effectiveness might be related to

> secondary effects, such as oxidative cell damage or cell

> proliferation. In this study, OTA mediated induction of (oxidative)

> DNA damage, cytotoxicity (necrosis, growth inhibition, apoptosis)

and

> modulation of glutathione were investigated in cell lines (V79, CV-

1)

> and primary rat kidney cells. After 24 h incubation, viability of

V79

> cells was strongly decreased by OTA concentrations >2.5 micromol/L,

> whereas CV-1 cells were clearly less sensitive. Strong growth

> inhibition occurred in both cell lines (IC(50) approximately 2

> micromol/L). Apoptosis, detected with an immunochemical test and

with

> flow cytometry, was induced by >1 micromol/L OTA. Oxidative DNA

> damage, detected by comet assay after additional treatment with

repair

> enzymes, was induced in all cell systems already at five-fold lower

> concentrations. Glutathione in CV-1 cells was depleted after 1 h

> incubation (>100 micromol/L). In contrast, an increase was measured

> after 24 h incubation (>0.5 micromol/L). In conclusion, OTA induces

> oxidative DNA damage at low, not yet cytotoxic concentrations.

> Oxidative DNA damage might initiate cell transformation eventually

in

> connection with proliferative response following cytotoxic cell

death.

> Both events might represent pivotal factors in the chain of cellular

> events leading into nephro-carcinogenicity of OTA.

>

> Publication Types:

>

> * Research Support, Non-U.S. Gov't

>

>

> PMID: 15588931 [PubMed - indexed for MEDLINE]

>

> Arch Toxicol. 2003 Dec;77(12):685-93. Epub 2003 Sep 10.

>

> Apoptosis and oxidative stress induced by ochratoxin A in rat

kidney.

>

> Petrik J, Zanic-Grubisic T, Barisic K, Pepeljnjak S, Radic B,

> Ferencic Z, Cepelak I.

>

> Department of Medical Biochemistry and Haematology, Faculty of

> Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, PO

> Box 156, 10000 Zagreb, Croatia, jpetrik@...

>

> 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.

>

> Publication Types:

>

> * In Vitro

> * Research Support, Non-U.S. Gov't

>

>

> PMID: 13680094 [PubMed - indexed for MEDLINE]

>