effects of don and aflatoxin g1 onapoptosis of human blood

[Guest guest]

<http://www.caspases.org/showabstract.php?pmid=11938994>

study of fusariu mycotoxins on apoptosis of cells

<http://www.caspases.org/showabstract.php?pmid=12725071>

molecular biology of multiple organ dysfunction syndrome;

injury,adaption, and apoptosis

<http://www.caspases.org/showabstract.php?pmid=12594891>

[Guest guest]

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

Penicillium species..

*1: *J Neurol Sci. 2006 Jul 13; [Epub ahead of print]

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_Abstract & db=pubmed & c\

md=Display & dopt=pubmed_pubmed & from_uid=16844142 & itool=ExternalSearch>

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

*Sava

V*<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Search & itool=pubm\

ed_Abstract & term=%22Sava+V%22%5BAuthor%5D>,

*Reunova

O*<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Search & itool=pubm\

ed_Abstract & term=%22Reunova+O%22%5BAuthor%5D>,

*Velasquez

A*<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Search & itool=pubm\

ed_Abstract & term=%22Velasquez+A%22%5BAuthor%5D>,

*-Ramos

J*<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Search & itool=pubm\

ed_Abstract & term=%22%2DRamos+J%22%5BAuthor%5D>

..

University of South Florida, Tampa, FL, USA; Haley VA Hospital, Tampa,

FL, 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 - as supplied by publisher]

Neurotoxicology. 2006 Jan ;27:82-92

[Pubmed]<http://lib.bioinfo.pl/pmid:16140385>

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[show] *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.

Latest similar papers:

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

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[show] *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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[show] *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.