Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 -85,Gray -al vlnore@n-osazd;wbsite www.umwelttoxikologie.uni-konstanz.de Konstanz, web 25, [email protected]; Str. E-mail: Germany. Jacob-Burckhardt D-78457, Konstanz, of University cology, niomna oiooy nvriyo osaz Germany Konstanz, of Dietrich University Toxicology, Environmental R. Daniel and O’Brien Evelyn Enigma Continuing The A: Ochratoxin Copyright Toxicology, in Reviews Critical inmr rgntn rmteacetGek“ Greek “ ancient partial gus) the a is from name originating the misnomer, Even characterized. adequately been have BACKGROUND O:10.1080/10408440590905948 DOI: online 1547-6898 / print 1040-8444 ISSN: h as fdsae nbt uasadanimals. and humans both in diseases being of as well cause con- as the with products agricultural conjunction unsafe thus in and losses taminated financial been large have mycotoxins for be, responsible may case the Whichever candidates. uret n pc n h eeaino aoal germina- favorable of spores fungal generation for the conditions tion and for sugges- space microorganisms the other and with production, nutrients competition their facilitated for of reasons tions proposed many the the of members including molds, P of number a by w nclim uaim Claviceps, Fusarium, enicillium, cm.Teesbtne r eodr eaoie produced metabolites secondary are substances These .com). ftemra fcretykonmctxn nyahandful a only mycotoxins known currently of myriad the Of drs orsodnet vlnOBin niomna Toxi- Environmental O’Brien, Evelyn to correspondence Address τ o c ζικ T yo n rni Inc. Francis and aylor o υ ” (arrow-poison) K relevance discuss their and on collate focus to particular is with review toxicity OTA-mediated fo this the on in of data vital intention available be currently The to appears the data. systems experimental model vitro relevant in of and toxicity. OTA-mediated vivo generation in of re- appropriate investigation by of structure–activity the characterized use strict in the and apparently crucial Furthermore, to be an subject could as is nature. considerations well OTA These epigenetic as of lationship. an differences, toxicity or sex-specific the genotoxic and that a species- is of however, large clear, is mechanism is predominant that adducts. mi- the aspect DNA of if One of unclear disruption generation still apoptosis, the is of via it indeed, induction suggested or, Thus, via cytoskeleton, been effects the has toxic and/or Ochratoxin respiration its tochondrial out. mediate to carried researchers animal be various in must by and studies foods, epidemiological processed and in mechanistic coffee), con- and OTA for wine, limits meat, legal f grain, safe (e.g., define foodstuffs result, to in a attempting centration As currently humans. are in agencies tumors urothelial international Nephropathy, and several be Endemic CIN) to Nephropathy, (Balkan thought Interstitial nephropathies Chronic being of and as development BEN in the well in as states agent im- animals, disease causal teratogenic, domestic probable several carcinogenic, and the nephrotoxic, of laboratory as in genesis described hepatotoxic the been and has to munotoxic, It linked humans. been and has animals (OTA) both A ochratoxin mycotoxin The fohaoi A. ochratoxin of de.I re oaheeti ol nacrt ikassmn fOAtxct including toxicity OTA of assessment risk accurate an goal, this achieve to order In odder. r eywords 53–0 2005 35:33–60, h nvv iuto,adas osgetpsil uuesrtge o nokn h secrets the unlocking for strategies future possible suggest to also and situation, vivo in the 1 2 iny ehns,Nprpty crtxnA Ochratoxin Nephropathy, Mechanism, Kidney, , 3 freyooysewww.m- see etymology (for and r rubytems likely most the arguably are Alternaria µυκηδ f Aspergillus, mle.Of amilies. ” (fun- 33 psil ua acngn yteIARC. carcinogen the 2B by class carcinogen) a human as (possible classified been (de- has populations OTA later), human scribed in animal studies on Based epidemiological humans. and and animals studies both in few, a but name to toxicity, renal immunotoxicity, including and neurotoxicity, teratogenicity, mutagenicity, effects, toxicological of range diverse a aual e oawat frsac en are u into out carried being research of wealth a to led naturally has hence and action of mechanisms a the foodstuffs, of animal elucidation and the human making of contamination particular, ochratoxin in and, by mycotoxins by posed risks health potential the n osmrmagazines consumer and aeb eea onre nldn h ntdStates United the including countries several de- by under bate currently are respectively, products, 3 cereal and processed 5 of concentrations OTA sible nitrainltaeae oee,mkn gemn difficult. agreement making however, are, to trade etc.) respect international wine, in beer, with coffee, (e.g., conflicts products and commodity for data standards available the of terpretation ebrsae fteErpa Union. European the of states member oerlal ikassmn imperative. assessment risk reliable more n ftee crtxnA(T) a enipiae na in implicated been has (OTA), A ochratoxin these, of One h iest ftxcatosascae ihochratoxins with associated actions toxic of diversity The eea esae reports newspaper Several 12 − 15 9 − aerie ulcaaeesof awareness public raised have 11 n rilsi oua science popular in articles and µ 6 − /gi a eel and cereals raw in g/kg 8 ifiute ntein- the in Difficulties 4 aiu permis- Maximum 5 n the and Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 crtxn sntteitnino hstx,abifoeve is overview aspects available. these brief are with a dealing text, reviews and this papers of Several provided. intention the not is ochratoxins Properties and Production research. new ochratoxin indicate future for possibly strategies and and toxicity information OTA-mediated available goal on currently the opinions the therefore collate to ochratoxin- is review It of this another. of aspect in and one those such perspective with in of maintain toxicity observed mediated face to effects the task the In reconcile arduous to health. an human is to it family ochratoxin difficulties, risk the potential of their members of and action to as of exist mechanism still arguments the and discrepancies many yet topic, this 34 rOBi h ua ooyecl ieTHP-1. line cell monocyte human the in OTB or OT eaue(21–28 perature by produced are which ticular 1), Figure the (see of molds C several and B, A, members, aeds seblw yafco f20, of factor a by below) virtually (see recommended dose the safe surpass to shown been has wines red pce,rsetvl)adhmdt ( humidity and respectively) species, aiat faia odradhmnpoiin sdvreas diverse wine. as and provisions coffee, human muesli, con- and as fodder regularly animal found of are taminants ochratoxins fungi, producing the of ioadi ir.Frhrsrcua leain il ochratoxin yield alterations C( structural in Further both vitro. toxic B in less and 20-fold) a ochratoxin vivo to for yields (10– significantly chloride moiety is of isocumarin which (OTB), Substitution the three. in the atom detected of hydrogen commonly toxic most most with the the both potentials, and being toxic (OTA) respective A their ochratoxin differences on these effects however, other; marked each have l- from slightly to very bond differ toxins only peptide three the a Structurally, 1). by Figure (see joined phenylalanine moiety dihydroisocumarin a of impossible. practically is consumption ochratoxin oi potential. toxic aigadratn euetetxncnetb ee20%, mere a effect. by no content has toxin boiling of the while effect reduce stable; carryover roasting heat a relatively and are via baking Ochratoxins and pork. products particular in grain meat, and grain maize of of example, for and of, contamination storage and field to lead rvd h e oulcigtesceso hseimtcfamily enigmatic this mycotoxins. indeed of of secrets could the OTC unlocking and to key OTB OTA, the clear provide of the effects of the exploitation in that differences forgotten on be however, focussed not, has should most research the much as members, role OT family its to the Due of toxicity. toxic ochratoxin of relationships feature structure–activity a strict are that therefore, effect. appears, specific cell-type It a be may this data, published previously hl opeerve ftepouto n hmsr of chemistry and production the of review complete a While hmcly crtxn r ekogncaisconsisting acids organic weak are ochratoxins Chemically, .Ti eiwas ocnrtspiaiyo hsapc.It aspect. this on primarily concentrates also review This A. Ct O C,wihi eeal ecie shvn iteo no or little having as perceived generally is which TC), o seglu ochraceus Aspergillus oss a rae oi oeta hnete OTA either than potential toxic greater far a possess 1 , 16 25 ◦ − − C 18 27 n 25–28 and h aiyo crtxn ossso three of consists ochratoxins of family The Aspergillus oee,arcn ulcto a reported has publication recent a However, 24 ned h osmto fcertain of consumption the Indeed, 22 ) ◦ , C ne utbecniin ftem- of conditions suitable under 23 and for u oteuiutu nature ubiquitous the to Due P P enicillium a enicillium w 9 > n oa viac of avoidance total and 0 . 7) and .OBINADD .DIETRICH R. D. AND O’BRIEN E. . pce i par- (in species 19 28 − 21 Aspergillus nlgtof light In hscan This Tbe1.Oa LD Oral sensitivity in 1). differences (Table species large by characterized and low Toxicity Acute Carcinogenesis Renal and Nephropathy, Chronic Toxicity, Acute gn nnprptisosre nsvrlseiso agricul- of species pigs, in several particularly animals, in tural observed nephropathies in agent OT from silo. wheat storage in the present be to chromatography) (thin-layer mined eeldauetblrncoi,adatog h ain’ blood patient’s wa the although and necrosis, tubular acute revealed following burning w retrosternal and distress, respiratory tension, asadmc,rsetvl,t .– gk . npg,cats, pigs, in b.w mg/kg dogs. 0.2–1 and to rabbits, respectively, in (b.w.) mice, weight and body mg/kg rats 46–58 and 20 approximately from nalseisexamined. species apparent all also in were atrophy villious tissues, coincident lymphoid with and enteritis kidney, liver and liver, the brain, in spleen, necrosis Nephrosis, the heart. in and thrombi fibrin and ma- organs all jor almost in haemorrhaging multifocal included poisoning ct T oiiyi uashsbe eotdi southern in reported been has humans Italy, in toxicity OTA acute led enrvee nMrurtadFrohlich and Marquardt in have reviewed effects These been industry. food already the in and agriculture in losses aknedmcnprpty(E)aduohla uos(UT). tumors urothelial and (BEN) nephropathy endemic Balkan OT later). (discussed areas research these for in incentive increased an in resulted has OTA of teratogenic effects and agriculture hepatotoxic, immunotoxic, the the for through losses industry potential recent the Indeed, an of factors. have awareness socioeconomic heightened may on prominent, impact less large while equally OTA, teratogenic to and attributed hepatotoxic, effects immunotoxic, The therein. ences rigi rnr hthdbe lsdfr2yas biopsy A years. 2 for closed been had that granary a in orking os 85 0hs2,34 29, 32 30, 31 30, 29 hrs hrs 55–120 40 60 hrs 72–120 days 20–30 48–58 21 days 35.5 1.0–6.0 n.d. Mouse n.d. Rat Pig Monkey b.w.) (mg/kg Human Species .. odt available data no n.d., s A ohteauetxct n aflf fOAaerelatively are OTA of half-life and toxicity acute the Both ti,hwvr ahrtesbhoi n hoi fet of effects chronic and subchronic the A rather however, is, It OT eetdLD Selected o nlzdfrtepeec fOA h oi a deter- was toxin the OTA, of presence the for analyzed not oe t Note. 36 n ua Disease Human and htaeo raetcnen T scniee h causal the considered is OTA concern. greatest of are that A hr n niiulpeetdwt rnioyepigastric transitory with presented individual one where a lobe soitdwt w ua ies states: disease human two with associated been also has 1 / 2 pce olwn rladministration oral following species V re osdrbywt h ot fadministration; of route the with considerably aries rlLD Oral 50 29 v 50 − le n aflvso T nrelevant in OTA of half-lives and alues 34 v le aebe eosrtdt range to demonstrated been have alues nteesuistesmtm facute of symptoms the studies these In 35 50 T A BE1 ABLE igeaedtlcs fprobable of case anecdotal single 37 t , 1 38 / 2 eutn nhg financial huge in resulting p)References (po) 39 n refer- and Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 iia.Ytteesih leain lyalrerl nterltv oiiyo h niiulsbtne.A satm a been has aspartame As substances. individual the comparison. of for included toxicity also relative is the structure in its toxicity, role OTA-mediated extremely large reduce structurally competitively a are family to play ochratoxin suggested the alterations of members slight The metabolites. these major Yet and ochratoxins similar. of structures Chemical 1. FIG. CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN 35 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 ies nPigs in Disease in Sava river the along areas the of Croatia. neighboring regions in lowland and the basin in populations Danube for al- ago described years first 50 disease, most kidney progressive chronic a is BEN 36 ibtcnprptyrpeet ny7%). comparison, only (for represents Yugoslavia nephropathy former diabetic the in diagnosed diseases h nta ieo tak ipaigads-adtime-dependent are and dose- tubules a proximal displaying attack, The of animals. site exposed initial occur the of which kidneys changes, pathological the These the in reduced. in markedly reflected also are are deficits gravity specific rates clearance urinary creatinine and BEN, for protein case and the cholesterol is serum As concentration. in decrease a with coupled ferase oe rtis ecn mnppiae and aminopeptidase, glu- leucine of proteins, concentrations urinary cose, increased include to shown been consumption. human for unfit as animals contaminated from meat of condemnation Scan- the in to dinavia, particularly countries, humans, certain in in UT leads OTA and ani- of BEN detection with the association by the gain on based weight but, reduced mals hence and intake food reduced yepatcatroah,adedsaernlfailure. renal end-stage and arteriopathy, hyperplastic in- cysts, cortical e and to fibrosis, leading periglomerular nephropathy, atrophy, tubular tubulointerstitial progressive by ized inb uglseis aeas niae ikbtendi- urothelial between and renal link of tumors. a development the indicated and OTA also of intake have produc- etary OTA species, promote fungal products by subopti- grain tion and and/or grain conditions of climatic storage mal where France, hu- and Tunisia, including in Egypt countries several tumors in out urothelial carried and Studies mans. nephropathy of incidence higher and BEN/UT a between link direct a OT Although females. dis- the in of ease incidence higher slightly very a indicated have studies ise rgesn oatvto n rlfrto fvascular of cells. proliferation adventitial and and endothelial activation to progressing connective fibroblastic tissue, of proliferation with coupled atrophy lar chronic by caused be- lesions OT The has attention. OTA much of of focus the activity Bulgarian) come nephrotoxic probably the (and nephropathy, Danish porcine in factor causative probable h ainn uoso h pe rnr rc htotnac- often that nature tract in aggressive urinary extremely reduced. are upper BEN markedly the company are of tumors gravity malignant specific The urinary clear- and Creatinine rates concentration. ance protein and cholesterol serum aminopep- and leucine tidase, proteins, glucose, increased include of episode, concentrations acute dis- urinary an the without of begins stages which early ease, the in deficits functional accompanying ial rgesn odgnrtv n ertcrnlepithelia, renal necrotic and degenerative to progressing vitably oeaeices nsrmOAlvl ihasignificantly a with levels OTA serum in increase moderate ic t eosrto yKohadcoworkers and Krogh by demonstration its Since ucinldfiisi isrsligfo T xouehave exposure OTA from resulting pigs in deficits Functional A Ae ean ob salse,eieilgcldt correlates data epidemiological established, be to remains psr npg r hrceie yporsietubu- progressive by characterized are pigs in xposure 41 40 , , 45–50 41 γ urnl,BNrpeet 1 falpiayrenal primary all of 11% represents BEN Currently, guay rnfrs,culdwt eraein decrease a with coupled transferase, -glutamyl 51 o nyde hsrsl in result this does only Not 42 E scharacter- is BEN γ guay trans- -glutamyl .OBINADD .DIETRICH R. D. AND O’BRIEN E. 43 , 44 n some and 37 41 , 43 sthe as The ilclsculdwt oa eiuua boi n thickening membrane. and basement fibrosis the peritubular of focal with coupled epithe- cells the lial of degeneration focal and desquamation irreversible ntersos fmc oOAepsr eedmntae by demonstrated colleagues, were and exposure OTA Bendele to mice of differences response starker the Even in un- conditions. pathology experimental P3 same milder much the displayed a der and rats incidence tumor female 6% Remarkably, a only bilateral. of- and were multiple which to carcinomas, ten progressed and adenomas lesions cell Hyperplastic renal 2). malignant Figure noted (see commonly rats those aging from in distinct were renal which and cysts, nuclei, cortical karyomegalic casts, outer protein the as and well cortex as renal medulla, the of epithelium tubular the degen- of with eration presented this animals in exposed of reported cortex were renal UTs the no study, Although OTA. to expo- rats of male months of 9 sure following pars apparent became the which of (P3), pathology recta distinct a with coupled (RCC), carcinoma l xrt T i h ilayrue hra ea excretion renal humans. whereas route, in billiary dominates the via OTA primar- excrete Rodents dose. ily this of calculation the in renal omitted were however human considerations important Two for ng/kg/day. 0.2 (VSD) the of risk dose generate cancer to safe used virtually were accepted coworkers currently respective their and dele differences. sensitivity these of origin clues the with provide to possibly vary could below) can (see age molecules and/or sex, transporter species, com- anion the organic that of observations The plement date. to differences unsuccessful sex been these explain have to attempts However, risk. at are more humans female the that with studies contrast epidemiological higher in from clearly The suggestion is rats. studies these F344 than in males OTA with of sensitivity study of Boorman’s concentration in higher employed 20-fold that a despite to refractive, exposed totally being being females and tumors renal oping ih3. as sapoiaey1 ie ogrta hti the in that than longer times rat. humans, 14 in approximately which is 1), days, (Table 35.3 date with to tested OTA species of various half-life the observed in the is in critical those than more higher Arguably far rodents. probably are kidney human the reaching et.A2ya acngnsssuycridotb Boorman by out carried coworkers study and carcinogenesis 2-year A dents. OT Pathologies Renal Rodent disease. human in OTA human of role in the causative into noted investigations numerous those in resulted and have cases pigs BEN/UT in observed deficits and functional are changes tumori- pigs pathological the which of between at parallels period age The slaughtered. young latent relatively long the relatively with coupled the genesis to This due exposure. inci- OTA probably following tumor pigs is increased in observed no been later), has (discussed dence rats in and humans h frmnindsuiscridotb ora n Ben- and Boorman by out carried studies aforementioned The Ae A 27 , la astv eainhphsbe salse between established been has relationship causative clear 59 psr n h eeomn frnlptooisi ro- in pathologies renal of development the and xposure , 60 54 eosrtda6%icdneo renal-cell of incidence 60% a demonstrated 56 − 55 58 ihol 8 fml iedevel- mice male of 28% only with 37 hs h ocnrtoso OTA of concentrations the Thus, , 52 , 53 ncnrs otefidnsin findings the to contrast In Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 I.2 A eaoyi–oi-tie inyscino aert rae ih1m/gohaoi o as demonstrating days, 7 for A ochratoxin mg/kg 1 with treated rat, male a of section a kidney Hematoxylin–eosin-stained (A) 2. FIG. netgtosit h culmcaimo cinwsclearly was Hult, action and Hagelbert of by shown mechanism actual for the also hence into and investigations differences species-related and sex- obvious eosrtn xoitdclsseigyudron ppoi erss( necrosis apoptotic undergoing seemingly cells exfoliated demonstrating magnification ntesrmbodo h nml ttriaino h ex- the of termination at coworkers animals experi- and the Stoev of of periment. range serum/blood present a OTA the of in concentration in OTA the assessed of have species effects mental pathological the mine Levels Serum more allowing proteins, plasma later). for (discussed elimination be affinity rapid to lesser appears a This monkey). to and related rat, mouse, quail, (fish, tested af lrsuycridotb utiadcolleagues and Curtui n by con- (66.8–616 out varied carried ng/ml study concentrations 249 ilar and serum 27 en- and between in tissue, siderably 1 farms renal of from in average pigs An found Bulgaria. in of OTA areas of demic concentrations tissue nal e odtoso rical otmntdfde,toeresults those fodder, contaminated artificially of conditions der to up a of over concentrations OTA 1582 pigs serum in to resulted fodder period 6-month contaminated highly experimentally of eetsuyb te tal. n et (33 Stoev ng/ml by 13.4 study of recent concentrations n with (6 concentra- sented ng/ml OTA 2.43 serum of average tion an determined pigs slaughter .Shatr n ..Dietrich. D.R. and Schlatter, J. ( −→ ihnme fncoi ( necrotic of number high rsotrhl-ieta t oetxcaao nalspecies all in analog toxic more its than half-life shorter ar htti setcudb infiatfrteudrtnigthe understanding the for significant be could aspect this That notntl,rltvl e tde are u odeter- to out carried studies few relatively Unfortunately, ) ± ihgatnce a eosre ihntesm fetdtbl apo.magnification (approx. tubule affected same the within observed be can nuclei giant with 0n/l(3.9 ng/ml 40 × 0) B eaoyi–oi-tie inyscino aert rae ih1m/gohaoi o days, 7 for A ochratoxin mg/kg 1 with treated rat, male a of section kidney Hematoxylin–eosin-stained (B) 400). ± 0.1 M ,atog niiulaiaspre- animals individual although ), µ
) steelte eut rs un- arose results latter these As M). 62 29 53 )e h eosrtdOBt have to OTB demonstrated who 51 eosrtdta h feeding the that demonstrated flae rrgnrtv ( regenerative or xfoliated nlzdtesrmadre- and serum the analyzed CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN . 32 ± 61 1 . nRomanian in M 5n/ was ng/g 25 M .Amore A ). .Asim- A ). → ) pteiltblsclsi h ne ato h otx(approx. cortex the of part inner the in cells tubules epithelial osvrlfcos nldn oieooi n/rehi-or ethnic- considerations. and/or due dietary socioeconomic be tradition-based including to suggested factors, been several has to BEN/UT- variation deter- in This and values patients. individuals healthy The affected in areas. both hugely endemic vary affected mined in in cohorts as well nonaffected concen- as toxin areas, and nonendemic the and of endemic analysis in the tration on concentrated far thus have concentrations. serum represen- actual more of probably tative are OTA of levels nanomolar showing ntersuycridoti ooc.Priae al. et individuals Peraica healthy Morocco. in in out than carried patients study CIN their in in higher 16- be 36-fold to to concentrations OTA reported coworkers and Abid and nesiilnprpty(I)ptet nTunisia. in patients (CIN) nephropathy interstitial 0 of concentrations high remarkably of ocnrtosblwti au.Atog oesuishave studies some OTA Although showed value. cohorts this control below Healthy concentrations areas. endemic in BEN niae ocnrtosi h o aooa eini the in region patients. nanomolar BEN low of the serum in concentrations indicated ainete oternlsau ftednr rt hi origins In their study. coworkers to and this Nikolov or in contrast, donors attempted the was corre- of regions) status no (endemic/nonendemic renal Unfortunately, the n Croatia. to 39.4 of either lation to population the up of of survey levels OTA serum individual usd nei ein a ensont eblw1n 1 below be to shown The been BEN. has regions or to endemic within identical outside either not individuals healthy if for similar concentrations highly observed be to appears state tepst eemn la ikbtenBNU n OTA and BEN/UT between link clear a determine to Attempts ≥ 5n/ ocreaewl ihteicdneo Tand UT of incidence the with well correlate to ng/L 15
.Rgnrtv pteilcls( cells epithelial Regenerative ). 63 , 64 × oee,oesuyhsreported has study one However, 0) erne rmT R´ T. from Reprinted 800). 67 eosrtdconcentrations demonstrated . 11 60 ± eea eot have reports Several 0 → . 04 )a M µ 65 s M ela cells as well nageneral a in hsdisease This 66 nchronic in reported M asonyi, , 64 37 , 65 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 neoeai iclto loapast eafco nteki- the coworkers in and factor Sreemannarayana OTA. a be of to netics appears also circulation Enterohepatic concentration a against even place take absorption gradient, Indeed, can mice. jejunum and the rats in from intestine stom- small the the from both and OTA rapidly ach reader. absorbed be the to to determined recommended been has are therein cited authors and with and/or foodstuffs a produced con- locally the in with detected concentration centrations OTA serum correlate to attempted 38 in h uaino diitain n loo species-specific on also f and administration, of duration administra- the of route tion, dose, including factors of de- number a metabolites on its pends and toxin the Following of later). concentration the (discussed OTA absorption, transport to capacity the with fseisicuigrodents including species of n te armlclsi h blood. the in macromolecules other albumin serum and for affinity high extremely deter- an have have studies to OTA Several mined damage. renal suscepti- to the species hence that and of bility species given any in OTA of half-life the Kinetics and Binding Protein account. into considerations such take OTA must of UT role and the BEN defining in at aimed studies fu- epidemiological Any smoking. ture and consumption alcohol/medication factors as confounding such possible for controlled that out carried been ulndhr.Mr ealdrvescridotb Marquardt are by points out al. salient carried et reviews the detailed text, More this here. of outlined intention and scope the yond vitro. in and action, the vivo of in for mechanism both the characteristic on this data experimental of of importance interpretation the also arguably ochratoxins con- of and half-life the of biological in the importance for than the binding rats demonstrate serum/protein deficient observations albumin These of cohort. urine trol and OTA bile of the concentrations higher in 70-fold to 20- demonstrated also opeoiatyyedtennoi ognrochratoxin- congener nontoxic the yield predominantly to lui-ecetta nnra rats. in normal shorter in much than be albumin-deficient cowork- to OTA of and half-life Kumagai the by demonstrated who presented ers, body. was the thesis from this OTA for of Support elimination time the of retard periods furthermore, extended and over bioavailable rendered hence and of generation the in result a to suggested been has albumin serum aebe aeb te uhr nrt n mice. and rats in authors other by made been have re- OTA biliary of superimposition a c to due be to this and suggested administration OTA oral following OTA calves serum in of concentrations analysis their in peak secondary protracted single ebopino T ytekde a lobe rpsdto rodents. proposed in been toxicity also has kidney f the by OTA of reabsorption cossc shl-ieadtedge fsrmbinding. serum of degree the and half-life as such actors cltt h eiulpritneo h oi n ec h renal the hence and toxin the of persistence residual the acilitate cigo h vrl lmnto rcs.Smlrobservations Similar process. elimination overall the on ycling oiersroro crtxn hc a esol released slowly be can which ochratoxin, of reservoir mobile aslrl nrnldisease, renal in role causal rti idn spoal h eiiefco ndetermining in factor decisive the probably is binding Protein lhuhacmlt eiwo h ieiso T sbe- is OTA of kinetics the of review complete a Although 39 n h on xetCmiteo odAdditives Food on Committee Expert Joint the and 71 ugsigtepeec fogncaintransporters anion organic of presence the suggesting 76 , 77 nvv eaoimo T nanumber a in OTA of metabolism vivo In 78 65 n ruminants and , 67 ocmrhniesuyhas study comprehensive no 70 oevr hs authors these Moreover, 30 , 68 , 79 69 a enshown been has hsbn with bond This .OBINADD .DIETRICH R. D. AND O’BRIEN E. 73 58 bevda observed , 74 , 75 α , 29 The that , 72 35 n opudhsbe bevdi ihrkde rliver. or par- kidney the either of in conversion observed a been little be has as to compound tract, appears ent intestinal cleavage the bond of peptide function metabolic This (Fig- 1). group phenylalanine ure the lacking moiety isocumarin the is, lowt h oiiyrnigfreprmna nml nvivo. in animals coworkers experimental and for Il’ichev ranking toxicity the with also (human authors other by determined determining in role V a play renal could of OT species complements different protein from in binding variations cells example, and/or For OTA. transporter governed of be the handling to renal suggested specific been have by ochratoxin to species ous T the include metabolites detected Other ecie.Tegnrtdbnigcpct akn fhuman rat of ranking previously binding-capacity belong later) generated (discussed The not described. transporters au- does anionic the component organic competition, the binding to binding this protein that suggested of thors pattern the on Based systems microsomal rat epimers and human these 4 in of example dominating for with each species-dependent, be of to appears prevalence The 4-hydroxy-OTA. tosi aflvsadtxct.Huse n colleagues and Heussner toxicity. and half-lives in ations a idn ie.Tecmiaino h eut bevdb these by observed results the of combination binding The this sites. these of binding from OTA integrity displace not the could for aspartame Interestingly, critical site. be I domain to and determined IIB were be subdomain however, to HSA; determined of was IIA site subdomain one binding accommodate affinity can least highest which The at of dianion. has each HSA sites, that binding concluded unique two authors recombinant the Using HSA, (HSA). of albumin fractions serum human to dianions ul eotdt ersosbefrtetasoto OTA. of transport the for responsible previ- be transporters to steroid anion reported for organic affinity ously various have to for known and/or substances receptors of range a by for nnl aetcmon secee n h rmr ot of route primary the and excreted e is compound predom- monkeys), parent (vervet inantly primates nonhuman and humans in h oeadterueo administration. of on route dependent the be and also dose may the this although predominating, route in- are routes v renal to and microsomes biliary rabbit Both 10-hydroxy-OTA. reported produce also al. et Størmer microsomes. 4 uhr ecie h rsneo tlatoehomogeneous for capacity one high but least affinity at of presence OT the sexes. described both these assay, of authors receptor-binding classical human a of and modification cortical a rat, Using renal mouse, in pig, present from proteins bind- homogenates to OTA the of in characteristics differences ing species-dependent stark reported also ceini i h kidney. the via is xcretion le nteeceino T yrt n ie ihtebiliary the with mice, and rats by OTA of excretion the in olved asotProteins ransport S dn n Bruinink and edani oeldpedrcpo hnOBcudhl oepanvari- explain to help could OTB than pseudoreceptor modelled O ain en oecmol rdcdb i liver pig by produced commonly more being variant -OH A vari- of sensitivities relative the in differences blatant The -idn opnn.Ti opnn perdt aelow have to appeared component This component. A-binding > pig cuuaini estv el.Ide,tefidnsof findings the Indeed, cells. sensitive in accumulation ≥ os orltswl ihtebooia half-lives biological the with well correlates mouse 84 87 htOAbns2-odmr togyto strongly more 27-fold binds OTA that ecie ihafiiybnigo OTA of binding high-affinity described 60 3 , 83 -T,wihcudb competed be could which H-OTA, > rat R 27 ≥ , 72 and pig , 81 , 82 > S os)and mouse) ncontrast, In pmr of epimers R 78 O pre- -OH n the and 85 have 33 , > 80 86 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 I.3 ceai oe fogncaintasotr nkde rxmltbl.Utk fogncain (OA anions organic of Uptake tubule. proximal kidney in transporters anion organic of model Schematic 3. FIG. rnpr.Teogncaintasotn oyetd AP,tekde pcfi A-1 n h upsdioom OAT-K2 isoforms supposed the OA and OAT-K1, facilitated specific mediate kidney may the Oat4 OATP1, and polypeptide anion-transporting organic The transport. n coworkers, and ( n eelcscretyi rgessol ipiymtes A matters. simplify should progress in currently locus species gene denoting and symbols gene standardized of human use the denoting to change authors some with v proteins, pro- nomen- these human The of the letters. uppercase of clature with equivalents designated rodent are which the teins, are include kid- which family transporter Oats, including the the of systems, members organ Other brain. other and ney numerous since in have found members individual been extremely and an specificity, has substrate liver, wide in demonstrated initially family, porter n rvn oc r nnw.OT a eapsil addt.Terl ftemlirgrssac rnpre,MP,as MRP6, transporter, resistance various multidrug contains the membrane (luminal) of OA apical role of The efflux The unclear. still for candidate. is systems possible interstitium, transport a the to be mechanism may extrusion OAT3 ATP-dependent unknown. putative are force driving and otasotr(DT) eodNa second A (SDCT2). co-transporter aoaea ebaei eitdb h lsi Na classic the by mediated is membrane basolateral hrceie fteei h A1fml,md po orsplice four of v up made family, OAT1 the best is these The of (Oatp). characterized proteins transporter anion organic of family the toward humans OT for sensitivity higher even an Il’ichev suggest could and al.) al, et et Heussner Bruinink, and (Vedani investigators α rat ihalwraehpex scmlctd oee,the however, complicated; is prefix, h lowercase a with ariants rat rmtesm ee(A11 2 3 -4). -3, -2, (OAT1-1, gene same the from ariants -KG2 te uhr aeas niae T ob usrt for substrate a be to OTA indicated also have authors Other acknowledged. previously than toxicity A-mediated − )/OA − 88 e ihpermission. with cag i h rai no rnpre,OT,adNa and OAT1, transporter, anion organic the via xchange − notelmn h utdu eitnepoen R2adMP eit rmr active primary mediate MRP4 and MRP2 proteins resistance multidrug The lumen. the into − + idpnetutk ytmfrblyOA bulky for system uptake -independent fu,btte ol lob novdi ebopino etdlk rg.Fo Russel From drugs. peptidelike of reabsorption in involved be also could they but efflux, CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN 88 hstrans- This + dpnetogncaintasotsse,wihincludes which system, transport anion organic -dependent umr ftetasotrpoen huh ob novdin involved be to thought proteins OT transporter the of summary sotie nFgr .Ecletdtie eiw fteor- the of function reviews their detailed available, of Excellent are model transporters 3. anion schematic ganic Figure a in and outlined 2, is Table in given is n el n coworkers, and Gekle and f srpre yGoe n colleagues and Groves or by respectively, reported cells, as kidney if, opossum and vesicles membrane ess hcee stecs,clua cuuainprobably accumulation cellular case, the is pro- Whichever carrier-mediated cesses. and passive binding of nonspecific combination and/or a diffusion via occurs accumulation tubules, mal ytePHtasotptwya ugse ySo tal. et Skol by suggested as pathway transport PAH the by and (http://rgnc.gen.gu.se). (RGNC) Genome Committee Rat Nomenclature the (http:// pages and (HUGO) Internet Committee www.gene.ucl.ac.uk/nomenclature) the Nomenclature Gene from Human obtained the be of can nomenclature on tion A otoes xssa owehrOAi rnpre solely transported is OTA whether to as exists Controversy cuuain oehrwt hi prvdgn symbols, gene approved their with together accumulation, + ktguaaetasotvateNa the via transport -ketoglutarate − a enietfid u t oeua identity molecular its but identified, been has 91 w rigi abtrenal-basolateral rabbit in orking 88 , 92 89 nrbi ea proxi- renal rabbit in n ute informa- further and + α /dicarboxylate -ketoglutarate − ) costhe across 39 90 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 40

TABLE 2 Molecular characteristics of selected renal organic anion transporters

Gene Gene Nephron Membrane Transport symbol product Species distribution localization mechanism Substrates Inhibitors References

SLC22A6 OAT1-1 Human PT BLM OA/dicarboxylate PAH; PMEA; cidofovir; Probenicid; furosemide; 208–210 antiport PMEG; PMEDAP indomethacin; urate; α-KG; glutarate; betamipron; cilastatin OAT1-2 PT BLM ? OAT1-3 PT BLM OAT1-4 ? ? ? 211 Slc22a6 Oat1 Mouse/rat PT (S2) BLM OA/dicarboxylate PAH; salicylate; MTX; Probenicid; naproxen; 86, 208, 212–217 antiport cAMP; acetylsalicylate; ibuprofen; salicylurate; indomethicin; folate; piroxicam; salycilate; cGMP; PGE2; urate; acetylsalicylate; α-KG; ochratoxin A; phenaticin; paracetamol; cephaloridine; benzylpenicillin; benzylpenicillin; AZT; carbenicillin; cephalothin; acyclovir; cidofovir; cefazolin; cephalexin; PMEA; Zalcitabine; furosemide; indomethacin; lamivudine; stauvidine; urate; furosamide; trifluridine; PMEG; indomethacin; α-KG; PMEDAP glutarate; PGE2; cAMP; cGMP SLC22A7 OAT2 Human ? ? ? PAH; MTX; cAMP; α-KG; 218 Slc22a7 Oat2 Rat ? PAH; MTX; PGE2; α-KG; BSP; ketoprofen; rifampicin; 219 salicylate; acetylsalicylate bumetanide; enalapril; cefoperazone; cholate Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007

SLC22A8 OAT3 Human BLM BLM ? PAH; MTX; cimetidine; Probenecid; cholate; BSP; 220, 221 estrone-sulfate; E217BG; betamipron; cilastatin; glutarate; PGE2; diclofenac; ibuprofen; ochratoxin A; cAMP; indomethacin; bumetanide; salicylate; urate furosemide; benzylpenicillin; corticosterone; quinidine; tetraethylammonium Slc22a8 Oat3 Mouse/rat PT BLM Dicarboxylate PAH; ochratoxin A; Probenicid; BSP; 222, 223 exchange estrone-sulfate; cimetidine indocyanine green; bumetanide; piroxicam; furosemide; AZT; DIDS; melatonin n.a. OAT4 Human ? ? PAH; ochratoxin A; DHEA Probenecid; BSP; 224 sulfate; estrone sulfate indomethacin; ibuprofen; diclofenac; furosmide; bumentanide; corticosterone Note.Adapted from Russel et al. (2002).88 Human variants are denoted with upper case letters and rodent variants are represented by lower case letters. The gene symbol beginning with SLC (Slc) denotes the function of the gene products: gene family of solute carriers. n.a.: gene symbol not yet approved. Abbreviations: AZT, azidothymidine; BLM, basolateral   membrane; BSP, bromosulfuphthalein; DIDS, 4,4 -diisothiocyanostilbene-2,2 -disulfonic acid; E217BG, Estradiol-17β-d-glucuronide; α-KG, α-ketoglutarate; MTX, methotrexate; OA,organic anion; PAH, p-aminohippopurate; PGE2, prostaglandin E2; PMEA/PMEG/PMEDAP, 9-(2-phosphonylmethoxyethyl)adenine/-guanine/-diaminopurine; PT, proximal tubule. Only differences between rat/mouse orthologs and human are indicated. Substrates and inhibitors indicated do not represent an exhaustive listing. 41 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 ly nipratrl nOAmdae yooiiy O’Brien colleagues cytotoxicity. OTA-mediated and in role important an plays 42 diint utrso ea el rmmc xrsigthe expressing mice from (OAT1, hOAT1 SLC22A6 cells transporters anion renal organic human of multispecific cultures to addition with rapidly, extremely other a occur by to confirmed demonstrated been and has researchers OTA of accumulation tracellular ua n ocn rgnt ail cuuae1-t 15-fold to 10- accumulate rapidly more to origin porcine and human u o9 )adcudb eosrtdt ene h elcycle cell the toxin. reenter the to of removal demonstrated following be proliferate could and and h) 96 to (up 5 fec eltp uvvdepsr oee xrml high extremely even approximately to exposure ( Interestingly, survived type OTB. cell each of of 15% effect weaker ten-fold expo- n hour 1 48 after to apparent (signifi- sure was donors numbers antipro- female cell in from the reduction for cells cant to of tendency sensitivity sensitive slight higher most a even type an with OTA, cell of the effects be liferative/cytotoxic to origin man otnoseihla ellnsfo a NK5E n pig and as (NRK-52E) well rat al. as et from O’Brien cells tested lines (LLC-PK1), epithelial that cell study renal epithelial a porcine continuous In and groups. human research primary em- various ranges the concentration by ployed and sys- conditions, cell endpoints, experimental numerous tems, the con- of of because matter least a not still troversy, is effects antiproliferative and/or death cell EFFECTS? ITS MEDIATE OTA DOES HOW of treatment and prevention the intoxications. for could strategies furthermore, determine and, OTA help for assessment risk a reliable generate help more could specificity substrate and species expression including and levels proteins these of analysis closer a then tem, and/or accumulation family OTA protein intracellular e If this dependent. of age members be some to of levels expression the eut orsodt hs bandi iia td carried study rats. similar in authors a same the in by obtained out those to correspond results ifrne nmN xrsinlvl eeosre o Oat2 for observed ( were levels expression sex-specific mRNA study, in a this differences In of transporters. levels anion organic expression of the number in variations species-dependent and mltbl el tbytasetdwt hOAT4. with transfected stably cells tubule imal eetsuyb us n Klaassen and Buist by study recent hi pteilcutrat,NK5E iia bevtosof OT observations Similar NRK-52E. counterparts, epithelial their be to of OT shown effects was antiproliferative/cytotoxic the line to cell insensitive relatively fibroblast renal NRK-49F the same study, the In cells. of subpopulation apoptotic-defective, possibly v ≥ Slc22a7 ceini nedafnto fteogncaintasotsys- transport anion organic the of function a indeed is xcretion tosrieteqeto fteeitneo nOTA-resistant, an of existence the of question the raise ations lta hs curn ihnoet w iue fOTA of minutes two to one within occurring phase plateau 100 h oeua ehns ywihOAatal mediates actually OTA which by mechanism molecular The A A ept cuuaigOAcnetain oprbewith comparable concentrations OTA accumulating despite eitnehv enmd o rmr ua fibroblasts human primary for made been have resistance 3 µ -T hntercniuu elln oneprs In- counterparts. line cell continuous their than H-OTA M ) ) n a3( Oat3 and M n OT (OAT3, hOAT3 and ) ocnrtoso T vretne ieperiods time extended over OTA of concentrations OT 93 ) hssuyas eotda approximately an reported also study This A). eosrtdpiayrnleihla el of cells epithelial renal primary demonstrated Slc22a8 93 )b eosrtdpiayclso hu- of cells primary demonstrated 97 SLC22A8 tntfrOt ( Oat1 for not ut h uhr lodemonstrated also authors The 96 eosrtdlresex- large demonstrated ) 94 n nmueprox- mouse in and 93 Slc22a6 , .OBINADD .DIETRICH R. D. AND O’BRIEN E. 98 95 hs obser- These oevr a Moreover, .These ). hsmdlpooe yOBinadcwresi lutae in illustrated is 4. coworkers Figure and fibroblasts. O’Brien by with proposed tissue model This functional healthy, of replacement sive progres- in resulting proliferation, fibroblast a continued with through pled arise could BEN c for characteristic fibrosis pro- the gressive that indicates This communication). personal (O’Brien, mutagenic h eeaino ecieoye species, oxygen reactive of generation the hs eut eeotie sn ocnrtoso T that OTA of concentrations using obtained were results these a entetdwt T nvivo. in OTA which with hamsters, treated Chinese from been cells hep- had ovary primary in in SCE synthesis nor DNA atocytes unscheduled p induce not 60 could between ranging concentrations thermore, a ypoye olwn xouet 10–25 to exposure following lymphocytes man yDne-lutsadcoworkers. investigated and was Donmez-Altuntas frequency by micronucleus in increase an induce agn rm1t 4h. 24 to periods 1 for OTA from human- to the ranging exposure following of HepG2 cultures line in cell cells derived mononuclear Ehrlich in of increase situation. percentage time-dependent “real-life” the and dose- the a reported represent coworkers not and re- may yield can that aforementioned sults the of any of choice Inappropriate systems. model and regimens, are exposure substances, concentrations, relevant carcinogenic to respect with particularly nation, cell of number a in serum researchers. several of by absence models the in cytotoxic acutely 25 action Moreover, OTA. genotoxic specific of a than rather cytotoxicity of indicative concentra- high 25 of extremely tion the to exposure following however, a and primary frequency of micronucleus in cultures increase in An lymphocytes. micronuclei human of frequency the on effect no OT hoai xhne(SCE), for- exchange sister be chromatid including not mechanisms potential should other Several testing here. toxicity gotten mammalian for systems test- microbial ing of failings accepted the although systems, testing tcnetain agn ewe 0 p 100 OTA between to ranging exposed concentrations cells at bladder urinary porcine cultured in SCE in Genotoxic? Metabolites) Its of One (or OTA Is ppoi nsniiecl populations cell sensitive in apoptosis yDgnadco-workers and obtained al- were Degen results proteins by Similar serum questionable. for is OTA described, of ready affinity known the considering ev eia eilsadSra ase mro,rsetvl.In respectively. coworkers and embryos, Cooray hamster contrast, Syrian and vesicles seminal ttxcctsai feto T nrnleihla el,cou- cells, epithelial renal in OTA of effect ytotoxic/cytostatic eraei h ubro iulae el eeapparent, were cells binucleated of number the in decrease r hssuywscridoti eu-ervdcls which, cells, serum-deprived in out carried was study this er, OT ute motn osdrtosi oeo-cindetermi- mode-of-action in considerations important Further p 100 from ranging concentrations at A, F¨ lmn n ookr eotdads-eedn increase dose-dependent a reported coworkers and ollmann A n/rismtbltshv enrpre ob both be to reported been have metabolites its and/or µ 99 M n nonmutagenic and . hscicdn euto nbncetdclsis cells binucleated in reduction coincident This µ 111 M 106 h uhr tesd oee,that however, stressed, authors The 101 OT n yDp tal. et Dopp by and nceue N synthesis, DNA unscheduled 108 A 4 , 72 a endmntae obe to demonstrated been has eotdalc fSEi hu- in SCE of lack a reported , 100 109 110 104 narneo microbial of range a in , M 105 hs uhr reported authors These h blt fOAto OTA of ability The 103 n 0 n 100 and M aebe proposed. been have n h nuto of induction the and o10 to µ M M µ 107 M n m 1 and M OTA. . 101 novine in ,tohave How- Fur- 102 M Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 enfudi ua eu odate. to serum human in found (5–50 been higher 100-fold to 50- were granulocyte- GM-CSF, transforming Abbreviations: TGF, release factor; factor. fibrosis. ensuing growth necrosis The platelet-derived self-perpetuating tumor PDGF, system. TNF, chronic, interleukin; immune factor; OTA-mediated IL, a the growth interferon; of to in IFN, cells sensitive resulting factor; activated colony-stimulating other more situation, macrophage and are the macrophages exacerbates which of recruitment cytokines cells, the of epithelial to leads of debris death resulting The the fibrosis. OTA-mediated for c model Proposed 4. FIG. hepatocytes, etbet oi nutta hi rnfre otnoscell reported continuous also transformed group This their counterparts. than line insult toxic to ceptible -5 34 A n C uesms,adi a n human and rat in and Supersomes), cytochrome 2C9 human and in 1A2 mice, (3A4, and P-450 rats from microsomes liver in a omcooa ag,fudn vdneo eciiybe- reactivity of evidence no found tween range, micromolar to lar concentrations.” exposure “realistic more under was repeated be It should action. experiments these of that mode suggested furthermore genotoxic) and (epigenetic to OTA mixed suggested a have authors these chromosome disruption, either spindle from or result breakage can cells mononuclear of dence ned ersne ny36 ftettlOAadd Simi- added. OTA coworkers total and the Zepnik of larly, 3–6% only and, represented DNA with indeed, react to demonstrated of be could None metabolites incubation. these eight-hours following of hepatocytes supernatant the rat human this in determined by in were hepatocytes metabolites produced six rat be and study, primary to by reported generated were been microsomes previously had that lites metabo- OTA Three hepatocytes. primary by metabolized poorly ttxct,alw ride a tmlt h rlfrto ffirbat,wihaerltvl T-nestv.Cl et and death Cell OTA-insensitive. relatively are which fibroblasts, of proliferation the stimulate may indeed or allows ytotoxicity, rs-timyradcwres okn ntenanomo- the in working coworkers, and Gross-Steinmeyer 3 -T n h N fete a rhmnprimary human or rat either of DNA the and H-OTA 114 lhuhpiayclsaenral oesus- more normally are cells primary although 115 eotdlwmtbls rates metabolism low reported µ 112 /l hntoeta have that those than g/ml) , 113 CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN sa nrae inci- increased an As 3 -T ob very be to H-OTA ba peroxidase. abean semipuri- glutathione, and glutathione NADPH fied with fortified fractions S9 n rats. and mtl 2 ffml aspeetdwt N dut,some adducts, DNA with presented rats female of approx- 42% although imately Indeed species. this adenocar- in karyomegaly of or frequency cinoma observed inci- the the and between adducts DNA drawn of be dence can OTA correlation no of However, carcinogenicity rats. in sex-dependent known the and adducts This females. in that than higher wa be to rats male in adducts DNA ae iharneo ua n a nyesystems. enzyme rat and human of range a incu- with coworkers was OTA bated and when rates Gautier metabolism Likewise, low be extremely DNA. described to to unlikely binding are formed of are capable that intermediates intermedi- those reactive highly and of ates, is production the and in rates result low to extremely unlikely at occurs OTA of biotransformation yteprn opudhsbe eotdi eea tde em- studies the several in ploying reported been has compound parent the by by not metabolites. and its compound of parent the one the that by assumption mediated is the OTA to of support toxicity further lend studies latter the s h eeaino N dut yratv eaoie and metabolites reactive by adducts DNA of generation The ugsieo orlto ewe h niec fDNA of incidence the between correlation a of suggestive 120 atgaoadclege eemndtelvl of levels the determined colleagues and Castegnaro 32 -otaeln ehdcridoti mice in out carried method P-postlabelling S taseae osrds eoiae n soy- and peroxidase, horseradish -transferase, 115 hs uhr ocue htteoxidative the that concluded authors These 116 117–119 Thus, 43 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 32 Dirheimer and Obrecht- evident. Pflumio neither were rats, tumors male epithelial exposed renal in nor as karyomegaly levels same the at were which of 44 eiiy utemr,telc fDAratvt of reactivity DNA carcino- of in OTA-mediated lack relative for the known rats Furthermore, and the genicity. mice with of pre- sharply sensitivities that contrasts vivo than Agouti This higher dark rats. and much Sprague-Dawley, (DA) be Lewis, to for reported spots inci- viously of the number found authors and these dence groups, research Castegnaro and h aegop htas eotdOAt xr t fet by cowork- effects and its Creppy exert mechanism. genotoxic to OTA directly a reported of by also means suggested that been groups have same synthetase, such the t-RNA these, of of inhibition the some epigenetic Curiously, as proposed. potential been Several have pathway. predom- pathways epigenetic the is an likely of More inance mechanism. genotoxic speak purely not a do for toxicity OTA with associated species-differences vitro. in confirmed or vivo be in to either remain occurring potential deoxyguanosine, as a of indicating generation certainly the while for results, These sequence suggested events. the of of scheme detailed a for studies cited to the directed is reader The formation. radical OTA-mediated of ory olwn xouet T eotdb rs-timyrand Gross-Steinmeyer by coworkers, reported OTA levels to glutathione exposure hepatocyte re- human following and the rat Indeed, primary glutathione. in with duction product reported conjugation was a species form quinone to physiological the study, under same levels the low In relatively conditions. at formed authors deriva- only quinone is The the tive that adducts. remark DNA the with dam- 8-oxoG however, this, DNA of qualified oxidative production the in and resulting age species, formation oxygen the reactive cause thus of can adducts. OTA that dG suggested form authors and/or These stress oxidative cause and cycling dox ol ecrooae sn PCM rLC-MS. or HPLC-MS using corroborated be adducts DNA could reported genotoxic the nor neither purely changes, oxidative Furthermore, of a presence questioned. the be representing must action as ob- of method results mechanism of this interpretation using the tained moreover, and, adducts DNA N n exgaoie3 deoxyguanosine and DNA ino unn pce eutn rmtedclrnto of dechlorination the from resulting species forma- OTA. quinone the syn- a described previously of have group C8-deoxyguanosine tion and same resulting The radical, adduct. the phenolic (dG) characterized a via and DNA thesized with react deed ul nuae ihmuemcooe.Uigteidentical the previ- Using been microsomes. had mouse that with OTA incubated to ously exposure following DNA testes asdb h rdcso xdtv tesadcttxct,the cytotoxicity, and stress oxidative v of products the those by and caused itself chemical the by caused adducts between tinguish dutfrain sthe As formation. adduct timyradcolleagues and Steinmeyer rismtbltsrpre yGuire al. et Gautier by reported metabolites its or ldt fuigthe using of alidity -otaeigmto sdb h rpy Pfohl-Leszkowicz, Creppy, the by used method P-postlabeling a n coworkers and Dai tsol lontb ogte httemre e-and sex- marked the that forgotten be not also should It 124 , 125 114 hsqioeseiscudptnilyudrore- undergo potentially could species quinone This rvdssm icmtnileiec o h the- the for evidence circumstantial some provides 32 123 121 -otaeigmto o determining for method P-postlabeling 32 eetyrpre htOAcnin- can OTA that reported recently lorpre h eeaino both of generation the reported also 114  -otaeigmto antdis- cannot method P-postlabeling mnpopaeadcsi salmon in adducts -monophosphate sntidctv fOTA–DNA of indicative not is 116 .OBINADD .DIETRICH R. D. AND O’BRIEN E. n yGross- by and 115 , 116 3 H-OTA , 122 r eotda niiino -N ytaeb T n its and OTA by synthase cells hepatoma t-RNA cultured of in metabolites inhibition an reported ers oi,spotn oeo xdtv tesi h rcs.In process. the in stress coworkers oxidative and of Gautier contrast, role mela- a of coadministration supporting by tonin, prevented liver, be serum, could effects the (250 OTA These with in treated GR) rats of and kidneys and free-radical GSPx, in GSH, involved enzymes (SOD, de- several scavenging of a levels with the in coupled crease formation, malondialdehyde and peroxidation lipid products of production increased an demonstrated also rldsn ihu o2m/gOA oee,a2%decrease 22% a However, OTA. plasma mg/kg 2 in to up with dosing oral ywihlpdprxdto sfclttdb T hlto of chelation OTA by facilitated is Fe peroxidation mechanism lipid a which suggested authors by These ions. iron and reductase, P450 NADPH-cytochrome phospholipid, microsomal of sisting eoiain smaue yicesdmlnileyefor- reported been malondialdehyde also has increased mation, by measured tox- as renal peroxidation, OTA-mediated n of (500 OTA-mediated stages similar early A observed very icity. the effects re- in the role of that a impairment indicates play probably time an and This with dose function. associated be nal not to found were were but effects oxida- dependent these of of indicative All are stress. which tive of all superoxide activity, reduced (SOD) dismutase and concentration, (LPO) in accom- peroxidase increase lipid an was formation, apoptosis malondialdehyde This increased by assay. panied TUNEL the low the using to detected exposed rats 120 of of kidneys dose the in cells apoptotic which aodadhd ocnrto rtefraino 8-oxo-7,8- of dihydro-2 formation the or concentration malondialdehyde usqetDAdmg rt h ntaino ppoi pro- apoptotic colleagues of and initiation Petrik the to cesses. or indicated damage have DNA vitro, subsequent in and vivo in including OT both events, reports, of In- several factors. number growth deed and a cytokines, radicals, necrosis, by free stress, for induced oxidative characteristic be is Al- may employed. damage apoptosis dose/concentration membrane the cell on way though small investigated no system in experimental and and factors, substance many the on dependent including is predominates process which and Radicals Free for and Role Stress A Oxidative Pro-Cytotoxic?: or Pro-Apoptotic OTA Is to close mice. fact and in rats are in and dose lethal situation acutely vivo the in the for studies prob- irrelevant are from ably that OTA arisen of however, concentrations high have, extremely cytotoxi- reports employing OTA-mediated these in of event Most initial city. the as promoted been ol ervre yadto fpeyaaiet h culture the to peroxidation lipid phenylalanine ascorbate-dependent or NADPH of of addition Enhancement medium. by reversed be could 3 At apoptotic, or necrotic either as categorized be can death Cell + ihsbeun euto oFe to reduction subsequent with o nueoiaiesrs,wihmyte edete to either lead then may which stress, oxidative induce  doyunsn ntekdeso as2 following h 24 rats of kidneys the in -deoxyguanosine α tcpeo eesadafieodices nrenal in increase fivefold a and levels -tocopherol 103 µ gO , 128 , T 129 /gbd egtfru o6 aswere days 60 to up for weight body A/kg n yokltlchanges cytoskeletal and 131 132 122 eetypbihdasuyin study a published recently narcntttdsse con- system reconstituted a in on oices neither in increase no found M 126 2 + . OT n nyeast, in and eiadHussein and Meki µ )ices nlipid in increase A) /gdy weeks). 4 g/kg/day, 130 aealso have 127 which 133 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 eesmlri ir n nvv,idctn httei vitro in the vivo that in the indicating represent vivo, adequately indeed in may used and expression system model vitro gene in in similar changes were The S). cathepsin (alpha-2-macroglobulin, ceruloplasmin, reactions 1, inflammatory factor (hypoxia-inducible and stress catalase) oxidative 45, to GADD V) 153, annexin (GADD and re- apoptosis the and in damage involved DNA be to to sponse tran- known genes the several alter of to OTA levels technique scription determined the authors Using these vitro. arrays, in DNA cells of tubule of proximal vivo study renal in in recent kidney and rat their in in changes observations transcriptional treatment-specific various these linking of ieaincnetainadpeec/bec fsrm Luhe con- serum. colleagues into of and presence/absence take and which concentration procedures, sideration experimental planned executed carefully by and determined be The only earlier. can outlined in events of as resulting sequence apoptosis radicals, and/or free DNA of to damage production direct the func- in mitochondrial result normal could of tion disruption a Conversely, tions. et nioae iohnrahv enrpre yseveral by reported been have ef- investigators, mitochondria such isolated Indeed, on respiration. fects mitochondrial cellular on impact investigation. niaigarl o eea ifrn pce fratv oxy- reactive al. et of Hoehler species contrast, different In species. several gen with for not role but a viability, indicating cell of loss any prevented antioxidant the conse- with a preincubation than by ap- blocked rather be became could cause effects the a viability Furthermore, cytotoxicity. be of cell quence to in former the loss indicating any parent, before occurred LLC-PK1 ROS increase in the in Interestingly, 8-oxyguanine cells. intracel- tubule of proximal of rat production depletion primary and the a ROS, and of GSH, production lular the in increase an h eeaino rerdcl n aodadhd forma- malondialdehyde and radicals in free tion of generation the OT Eb ohi ioadi vitro, in hepatotoxicity and and vivo neural, in in- by both renal, the OTA reported reduce in been to E groups have vitamin several antioxidants of Indeed, inclusion effects mixture. the These cubation potencies. by vitro ameliorated correlates in be which and OTA, could vivo for in observed relative that their the than with the Interestingly, less in far analogs. production was radical its tem free of on OTB several of and impact OTA to posure rerdclgnrto a efudi h nvtoobserva- vitro in the in co-workers, and found Schaaf be of tions can generation radical free in radicals free and ROS of pro- general. involvement cited the studies for dosage the evidence different of vide all the Nevertheless, by employed. explained regimens studies be vivo probably in the can in mentioned differences oxida- The of apparent. markers were are stress, tive which of both activity, hemoxygenase-1 h eeaino rerdcl ol aual lohv an have also naturally could radicals free of generation The Ai ute upr o h novmn foiaiesrs and/or stress oxidative of involvement the for support Further tntvtmnCt mloaetepoxdtv fet of effects prooxidative the ameliorate to C vitamin not ut n ailsbrevis Bacillus h hc oe.Tesm ru lodemonstrated also group same The model. chick the 137 146 , 141–145 eetyrpre h rtse nteprocess the in step first the reported recently 136 lhuha eyhg T concentra- OTA high very at although 138–140 n nhepatocytes in and nelnn h edfrfurther for need the underlining 134 h eotdOAt cause to OTA reported who 135 N aeycsen,which -acetylcysteine, CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN eosrtdvitamin demonstrated 137 olwn ex- following α .brevis B. -tocopherol, sys- eitdcttxct tdeayrlvn (n dietary-relevant at cytotoxicity mediated parts), gained. information vitro the in refine perhaps and would vivo parameters in (both study a this were dosage in OTA of employed comparable concentrations also using high authors very however, cor- other As, vivo regimens. of in those observed with changes related pathological the and situation, el tal., et Gekle 25 n 1 from ranging concentrations at OTA to exposed epithelia renal primary porcine or human in nor Kobras, communication), (Kristin personal of cells NRK-52E induction with or LLC-PK1 the working either 5% for in authors, apoptosis evidence in Other no found vitro. apoptosis medium, in serum-replete induced cells kidney only hamster exposure of OTA that reported onigo natnce tie ihcytlviolet. crystal with and stained uptake, nuclei red intact neutral of reduction, counting MTT of analysis standard of the methods using medium serum-replete con- in OTA dietary-relevant of to centrations exposed cells kidney human primary in 5 between re- concentrations OTA cells, to mononuclear exposure Following blood spectively. peripheral human and LLC-PK1 bandb el n colleagues, and Gekle by obtained OT f nrosefc ntetp frsos one yacl to cell a potential. by an protein-binding mounted have response to known of is type ag serum the of on absence effect the enormous Finally, cell. the machinery of protein-synthetic with cycle entire cell the the suppresses of phase hydroxyurea G1 the in counter- synchronization nontransformed and cul- their toxic parts, than the to manner in respond different a to serum in known calf insults are fetal cells Transformed of medium. absence ture with the pretreatment in via or synchronized transformed been hydroxyurea, the had previously that as in cells either results, in out cells, these carried of been interpretation have the studies in taken be however colleagues ain tde yGnaiadcoworkers and Gennari by conden- Studies chromatin and sation. concen- fragmentation DNA higher scavengers in to resulted radical Exposure trations of chelators. n use calcium 10 the intracellular by to or abrogated exposure be following not cells could which IHKE in 3 caspase human and observed a coworkers cells, and Schwerdt cells. (IHKE) (SB3) epithelial kidney kidney human MDCK-C7 immortalized dedifferentiated cells, in apoptosis induce to OTA strated el ol erssatt T-eitdcttxct and/or cytotoxicity OTA-mediated to resistant be could these that returned cells possible and thus collected is It if medium. cycle serum-replete OTA-free, cell to the reenter to and reattach substrate medium to the culture ability the the demonstrated in exposure floating OTA cells following of number large a estingly, actor- lgtbtsgicn nraei h ciiyo h pro-apoptotic the of activity the in increase significant but slight ogtr,lwds td netgtn h aeo similar or same the investigating study low-dose long-term, µ µ iv eety eea eot aebe ulse nOTA- on published been have reports several Recently, At ncnrs,asuycridotb egr n coworkers and Seegers by out carried study a contrast, In M ntxn atclrywe h oi nqeto possesses question in toxin the when particularly toxin, en M o α n 50 and . 98 oetaetepoaottcato ftmrnecrosis tumor of action pro-apoptotic the potentiate nMC-7adoosmkde el.Cr should Care cells. kidney opossum and MDCK-C7 in , 151 149 147 yooi fet ol,hwvr edemonstrated be however, could, effects Cytotoxic eetyrpre h nuto faotssin apoptosis of induction the reported recently µ cwrte al., et Schwerdt M nsrmfe eim iia eut were results similar medium, serum-free in 104 n ovt tal. et Horvath and 147 h nadto showed addition in who M 148 ) concentrations. n sa and Assaf and 93 105 , 152 M demon- Inter- OTA, M 150 45 to Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 nldn nices nitaellrp i disruption a via pH conductance, intracellular anion in membrane in increase an including Mechanisms Proposed Other R´ of findings vivo in the colleagues, by generation supported tumor is for theory epithelium. transitional This basis the the into invasion form and transformation could via cells Such vivo. cells OTA-resistant of in equivalent vitro in the represent could concentrations, low and such at occurs apoptosis indeed if apoptosis, 46 omncto nhmnkde n a ie epithelial liver rat and kidney Horvath human by cells. proposed in intercellular that gap-junctional disrupt communication with to OTA observed agreement who al., in et also is This processes. theory adhesion lamina cell-basal and tertiary communication even or secondary expo- a OTA be ev following to 2) apoptosis Figure suggested and (see sure rats in tubules affected of n colleagues and system. immune humoral the of involve- without ment immunity cell-mediated of depression a in sults as nices nttlluoyenme,t euerelative reduce to number, leukocyte total in increase an cause induction, eei)wr bandb h aegopi ir sn porcine using vitro in group lymphocytes. same the by obtained were lymphoblasto- genesis) PHA-stimulated and production IL-2 (sup- of results pression Similar production. (IL)-2 concanavalin interleukin decreased A-mediated and activity, macrophage lymphoblastogen- reduced was for esis, index This stimulation fodder). reduced a in with mg/kg coupled (2.5 in exposure respectively, OTA following protein, pigs tuberculin and (PHA) tohemaglutinin phy- to (DTH) hypersensitivity type delayed and (CBH) basophil ra transport, drial odtc h fet edons.Teeefcs ulndi this 3. in Table outlined in used effects, summarized methods are These the section, (endpoints). least, effects means the no detect by to and, tested, dose the of tion, number a dependent be f im- to the immune appears of of type experienced The suppression suppression date. a to tested in species every results in OTA system mune area. car- being this studies into OTA- early out of to ried number a exposure to following led animals fodder contaminated domestic of species ous Investigations Vivo In IMMUNOTOXICITY of role earlier. postulated outlined investi- the as intensively with transporters more anion correlate organic be well the must could these they of as any gated, or each of role cos nldn h pce novd h ot fadministra- of route the involved, species the including actors, n nOAtxct,rsligfo irpin nintercellular in disruptions from resulting toxicity, OTA in ent eea te oeta ehnsshv enproposed, been have mechanisms potential other Several nafrhrsre feprmnsuigwae is M¨ pigs, weaner using experiments of series further a In avyadcoworkers and Harvey vari- in infection to susceptibility increased an of Reports 105 155 153 n niiino iohnra respiration. mitochondrial of inhibition and 157 h on paetyaottcclsi h lumen the in cells apoptotic apparently found who 158 141 h uhr ocue htOAepsr re- exposure OTA that concluded authors The eosrtdOA(20–50 OTA demonstrated , 142 rvnino etsokpoen70 protein heat-shock of prevention 156 ecie euto ncutaneous in reduction a described 154 niiino mitochon- of inhibition µ /gbw,s)to sc) b.w., g/kg .OBINADD .DIETRICH R. D. AND O’BRIEN E. sniand asonyi 143 uller The aua-adTkle el a eosrtdi isb Harvey by pigs of in al. activity demonstrated et was phagocytic cells the T-killer in and natural- reduction apoptotic ability in similar increase phagocytic A observed the in phagocytes. by explained reduction be part this in that could significant. suggest statistically always authors not was The but study, this in parent neu- FITC-labeled polymorphonuclear phagocytose A of to counts. ability trophils reduced neutrophil a relative toward raise tendency to and counts, lymphocyte h fet fOAo h uieimn ytm M¨ system, immune murine the coworkers on OTA of effects the ege nvitro in leagues eead na ale os study, mouse earlier an in and, here to anti- response of IgM in suppression the production a body and of spleen the suppression in significant cells producing a antibody coworkers, pigs for and reported Stoev system immune by humoral the on agreement the effect In the of reported. with also some was OTA, for to attributed responsible effects be other could which leukocytes, blood monocytes and neutrophils wa of activity un- phagocytic remained the mice. population changed, lymphocyte in actual eosinophilia the although and Also, neutrophilia, lymphopenia, demon- the authors strated these to earlier, Similarly outlined b.w. OTA/kg pigs in mg made 3 observations of dose high exposure relatively following the although to investigated, parameters the of all npau-omn el a eotdb nte ru,after group, another by 1 of reported administration was cells plaque-forming expo- in following 0.005 mice just in to sure cells antibody-producing of number u igeds,cudcnevbyalwfracranadap- suggested certain been has a as for exposure, toxin ver- allow repeated to conceivably repeated response could is, tive dose, that regimens, single or of employed dosage sus use assays in the the differences by in indeed explained Variations be strains. can mouse different magnitude this of crepancies abortus ntehmrlimn ytmapa,hwvr ob subject be to variations. however, huge appear, to system OTA immune of stronger humoral effects a the The OTA. on produce pure not than effect did suppressive extract immune culture raw of ministration fet fOArsl rmasprsino ypoyeblasto- production. lymphocyte IL-2 of and suppression genesis a from result OTA immune-modulating of the effects that suggestion the to im- led humoral pigs on in effects bone munity overt of by lack A mediated nodes. response lymph and immune marrow the on effects differential have to OTA concluded the thus in authors The increase population. an lymphocyte with com- coupled which granulocytes count, in decrease cell a blood prised white total in reduction overall an aeas enrpre nrabbits. in reported been also have ta.cudntfidayeiec o h upeso flympho- of suppression the for c evidence any find not could al. et t rlfrto nvitro. in proliferation yte s noeo h otcmrhniesuiscridotinto out carried studies comprehensive most the of one In abc n coworkers and Haubeck ifrnilefcso T ntewiebodcl population cell blood white the on OTA of effects Differential 156 eue.A nrae rdcino xgnrdcl by radicals oxygen of production increased An reduced. .I ncnrs oterslsotie yHlbr n col- and Holmberg by obtained results the to contrast In n 160 otat ntesuyb M¨ by study the in contrast, eosrtdagnrlzddpeso falmost of depression generalized a demonstrated 157 n avyadcwresi vivo, in coworkers and Harvey and µ µ gO /gb.w. g/kg T /gbw,weesa9%reduction 90% a whereas b.w., A/kg 162 156 bevda5%dces nthe in decrease 50% a observed P 163 , 157 asturella tapasulkl htdis- that unlikely appears It 159 161 P hs uhr described authors These le n ookr,ad- coworkers, and uller nrsos to response in asteurella nieswr evident were antigens wa 156 s le and uller Brucella loap- also M¨ uller Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 o citrinin, for fpr oi,dsiehvn oprbelvl fOTA. of levels comparable having administration despite following toxin, observed pure of those than overt more were de- exposure OTA M¨ by following scribed phagocytes slight apoptotic the in of exception increase the with Interestingly, systems. from test same extract crude of effects responses. observed the in differences the explain could procedures, experimental different with my- together other of This, presence cotoxins. the for extracts the effects. analyzed immune-modulating study Neither with mycotoxins other with nated the and chromatography via OT purified and isolated although ies, e P wa tat from xtracts enicillium s eea fteaoeetoe tde loivsiae the investigated also studies abovementioned the of Several A rbbya euto h rsneo te substances other of presence the of result a as probably otn usqetymaue,myhv encontami- been have may measured, subsequently content 164 pce.Mr iey oee,i htteculture the that is however, likely, More species. le n ookr,teefcso h rd extract crude the of effects the coworkers, and uller seglu niger Aspergillus nte yooi rdcdby produced mycotoxin another hc 130–799 Chick 1 Mouse 0.005 Mouse af320–500 4 Calf Chick 2 Chick neutrophilia; Lymphopenia; b.w. mg/kg 3 Mouse 1–3 Pig 20–50 Pig pce oeEfcsReferences Effects Dose days 35 fodder, mg/kg 2.5 Pig Species p nrprtna neto;I,itreknpouto;PN oyopoula el;s,subcutaneous control. with sc, compared cells; as measured polymorphonuclear parameter in PMN, cells; production; blood white interleukin WBC, injection; IL, injection; intraperitoneal ip, Note. T,dlydtp yesniiiyrato;CH uaeu aohlhprestvt response; hypersensitivity basophil cutaneous CBH, reaction; hypersensitivity delayed-type DTH, µ µ µ –0days 7–10 /gbw igeds ip dose single b.w. g/kg /gfde,2 days 20 fodder, g/kg days 42 fodder, g/kg µ .ochraceus A. /gfde,1–1days 14–21 fodder, g/kg µ RL37 sdi hs stud- these in used 3174 NRRL µ nvv fet fOAo h muesse fvrosspecies various of system immune the on OTA of effects vivo In /g igeds ip dose single g/kg, /gbw c 83 days 28–35 sc, b.w. g/kg µ µ /gfodder, g/kg /gfde 7dy oefc natbd rdcin170 production antibody on effect No days 87 fodder g/kg CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN utrsuigthe using cultures Aspergillus ↑ , nraei aaee esrda oprdwt control; with compared as measured parameter in increase 158 This and T ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↓ BE2 ABLE ubro lqefrigcells plaque-forming of Number cells producing antibody of Number g,IM n g rdcin169 production IgA and IgM, IgG, against efficiency Immunization weights; organ lymphoid T B on ( count WBC CBH; (90%) (50%) ecsl disease Newcastle disease Newcastle ↓ ↑ ↓ to response monocytes; and neutrophils of ↓ number; eosinophilia; ↓ infections; secondary of nodes; lymph mesenteric and splenic in changes degenerative ↓ tlluoyecut ( count; leucocyte otal muiainefiinyto efficiency immunization infections; secondary L cells PMN of activity Phagocytic muiainefficiency immunization production IL-2 mhodcl counts; cell ymphooid Immunotoxicity OTA-Mediated of Considerations Practical an in act studies. these or also in analyzed identified may not however, which were but extract, manner crude immunosuppressive the in (mycotoxins) penadmsnei yp oe fbt xouegroups. exposure both of nodes the of lymph follicles mesenteric lymph and De- the spleen cells. in blood apparent white were in changes generative increase observed the salmonellosis, developed for rapidly accounting fodder ex- OTA/kg animals a mg The 3 OTA. and to mg/kg to posed 3 cells exposure and blood 1 following with white population contaminated fodder of lymphocyte number the the in decrease in re- increase authors an These susceptibility. ported with disease pigs subsequent in to suppression respect immune OTA-mediated of effects the ↓ namr eetsuy te n coworkers and Stoev study, recent more a In DTH; ↑ etohlnumber); neutrophil P ↓ asteurella ↓ ↓ ypoyecount); lymphocyte arpaeactivity; macrophage hgctcactivity phagocytic ↓ lymphocyte ↑ number ↓ IgM ↓ , decrease 163 162 160 140 166 158 161 156 165 investigated 47 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 ini oetcanimals. domestic in sion progres- and susceptibility disease microbial and parasitic of tion farming farming. intensive the of for climate current risk the large in pop- a particularly industry, cell represent may immune activity the and in ulations changes sug- OTA-induced and the pigs that in report gested activity first humoral the in was decrease OTA-mediated This of immunisation. following con- animals with compared trol when cells plaque-forming increase of number reduced the a in by evidenced as immuni- salmonellosis against of sation efficiency the reduced exposure animals. OTA-exposed OTA in Furthermore, apparent also were cohort, control the to this odysentriae attributed with Infections authors infections. the bacterial and secondary the group, exposure apparent higher only the were follicles in lymph the in changes Hyperplastic 48 edn nteseisivsiae swl sds n ot of route and dose coworkers as and well Dwivedi administration. de- as investigated be to species appear the system on immune pendent humoral the on OTA of effects dysfunction. symp- kidney clinical /or by and liver also with partly associated and liver toms and kidney histopathological the by in accompanied effects were system immune the on ppm 2 to (2 exposed chicks in disease Newcastle against efficiency euto fimngoui I)G g,adIMconcen- IgM and IgA, G, (Ig) immunoglobulin of reduction nasmlrstudy, similar a complemented in and confirmed fol- were susceptibility results the duodenum These coccidiosis. increase and to further jejenum could the exposure OTA in lowing epithelium degeneration mucosal that the indicated further of Stoev by study second cytotoxic- A OTA-mediated ity. on effect ameliorating any other have (nanomolar) to by OTA not of demonstrated concentrations lower been with has working groups phenylalanine excess addi- of earlier, tion mentioned as in Furthermore, and/or OTA cells. become of serum-deprived concentrations to micromolar only higher appeared at coworkers relevant synthase and tRNA Creppy phenylalanine by of described inhibition the as likely, more gi alyflkscnaiae iha xrc of extract an with ochraceus contaminated flakes barley in kg chicks in patches Peyer’s e and of spleen follicles thymus, the Fabricii, in present bursa cells the lymphoid of number the as in organs as lymphoid the well of weight relative the in decrease a ported i,a ugse ypeiu researchers. previous by synthe- suggested protein as sis, in of reduction OTA-mediated differentiation a an to and or activation either lymphocytes, proliferation, to attributed the be in can reduction This test. inhibition haemag- glutination via measured as here. disease vaccination Newcastle to reduced cause response a immune probable displayed the also was chicks as OTA-exposed 790 cells The infections and blood secondary 305 white cite to of authors exposed number chicks and the in thymus in apparent the increase of centers An germinal spleen. the in changes generative psdt T ocnrtosrnigfo 3 o790 to 130 from ranging concentrations OTA to xposed µ ute tde aecnre oefrOAi h exacerba- the in OTA for role a confirmed have studies Further h ihyvral n fe otaitr eot fthe of reports contradictory often and variable highly The /g T nfe.I l ftemnindsuis h effects the studies, mentioned the of all In feed. in OTA g/kg) . lsrhsoahlgcleaiainrvae de- revealed examination histopathological Closer and aplbce coli Campylobacter 140 hc eosrtdrdcdvaccination reduced demonstrated which 140 , 166 , 167 te n coworkers and Stoev , hc eentpeetin present not were which 169 168 bevdasignificant a observed h omrappears former The µ /gOA The OTA. g/kg .OBINADD .DIETRICH R. D. AND O’BRIEN E. epln hy- Serpulina Aspergillus 166 µ re- g/ tr T a oefc nimngoui eesi calves. in levels di- immunoglobulin on whereas effect no grain had OTA-contaminated OTA etary fed chickens in trations h uhr eotdOAt eue[ reduce to OTA reported authors The yeti setuigi ir ehius h eut fthese of results and coworkers Charoenpornsook The 4. Table techniques. in vitro summarised ana- are in investigations to using begin aspect least at this to lyze attempted however have action. OTA’s immune-modulatory authors of Some mechanism the to as ture Studies Vitro In guinea and mice in responses pigs. antibody suppress to has shown exposure been dietary not but injection intraperitoneal Similarly, eaeirtdb odiitaino hnllnn IMre- cells) (IgM blood red phenylalanine sheep to of sponse coadministration could by effects observed ameliorated the be of Some administration. respec- of the route following tive reached concentrations peak the to related la el BM sn ordfeetbosas [ mononu- bioassays: different blood four using peripheral (BPM) cells bovine clear in proliferation stimulated invaiiya sesdb tnadMTrdcinasywas assay reduction MTT standard by assessed as tion/viability epnet ecsl ies inoculation), disease Newcastle to response e PM-tmltdBMwt IC mito- with pokeweed BPM and (PWM)-stimulated PHA-, A)-, gen (Con A concanavalin into tion ncniuu ea ellines. and cell primary renal in continuous authors in other by described been also has OTA for apparent wa became effects significant statistically concentration first the the sug- which Unfortunately, no at occurs. offered this how but OTA to as of gestions effect antiproliferative the are an studies of several concluded result in authors observed The effects immunotoxic testing. the toxicity range), that acute nanomolar (low in relevance justifiable dietary are of still those while than used, higher concentrations the and medium, serum-replete 0.15 el,MTrdcin n rpnbu xlso.O these, Of exclusion. blue trypan and [ intact reduction, of MTT content cells, (LDH) dehydrogenase lactate incorporation, te ihmctxn,cudntb demonstrated. be not could capabil- mycotoxins, ion-exchange with and ities capacity adsorbent high have aluminosilicates, which of coadministration of effect protective con- a In trast, exposure. risk OTA the with reduce associated can immuno-suppression excretion of faster that indicating latter the result synthetase and tRNA may phenylalanine of mediated inhibition competitive suppression a from immune the that suggesting ntepeec fOTA. of presence proliferation the and in viability (PMA)-stimulated cellular cor- with 13-acetate cytokines to of attempted 12-myristate production colleagues phorbol and Marin the cells, relate T for model a as a n con- 1 at as detected low be as could centrations control to compared as reductions numbers cell significant in statistically first range, micromolar the in 3 eaedonor. female ]hmdn noprto rvdt etems sensitive. most the be to proved incorporation H]thymidine s notntl,teei erho nomto ntelitera- the in information of dearth a is there Unfortunately, nasuyuigE- hoacls(TCnme TIB181) number (ATCC cells thyoma EL-4 using study a In o etoe yteeatos natpoieaieaction antiproliferative An authors. these by mentioned not 161 µ /l epciey hs xeiet eecridotin out carried were experiments These respectively. g/ml, , 171 173 , 172 netgtdteaiiyo T ordc mitogen- reduce to OTA of ability the investigated h esn o hsaeucer u ti probably is it but unclear, are this for reasons The M 174 npiayhmnkde el from cells kidney human primary in 93 A 162 ee lhuhIC although Here, euto nclua prolifera- cellular in reduction ratcoeetat(antibody extract artichoke or 50 3 ]hmdn incorpora- H]thymidine v le f01 .,and 0.2, 0.1, of alues 166 ihteformer the with 50 3 140 H]thymidine v le were alues 170 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 ardfloigOAexposure. OTA receptor following paired IL-2 and production In IL-2 used. e reported was al. toxin et crude Lea when contrast, parameters same the on stronger reported effects also authors These line. cell pro- EL-4 the IL-6 in enhance duction and IL-4 reduce to OTA demonstrated further Ca cytoso- lic in increase an namely, systems, messenger two second in major active be may OTA that indicates production IL-2 in produc- crease IL-5 12.5 in of decrease concentrations a at and tion IL-2 in increase an with 25 coupled of concentration high relatively the at apparent s fet navreyo aaeesicuigmetabolic including parameters great- and of counting), the (Coulter variety have proliferation reduction), to a (MTT extract activity on crude effects the est and OTC reported thors ltos iia eut ulse yHle n coworkers and Heller by published pop- results -2 and Similar cell-1 helper ulations. ef- T the opposing on these effects differential that reflect fects suggested authors The activation. gene OT 4), aspect. this Figure into (see research nephropathies further justifying porcine hence as- and fibrosis BEN renal progressive with and sociated could chronic production the cytokine to contribute in also alterations that assume to seems logical it However, established. be to species- remains differences represent specific response in variations subpop- these or Whether ulation. cell population in lymphocyte processes of irrespective essential metabolism, with immunosup- interference its OTA. via mediate to effect to pressive OTA exposure suggested following thus polyclonal inhibited authors to These was B-lymphocytes vitro purified in highly activators of Furthermore, response OTA. of the effect inhibitory the prevented OTB with 1. ochratoxin- of and peso fatvtdhmnTlmhctst esvrl im- severely be to T-lymphocytes human activated of xpression 28 M¨ C ncnrs otegnrlyacpe pno,teeau- these opinion, accepted generally the to contrast In le n olausivsiae h fet fOA OTB, OTA, of effects the investigated colleagues and uller n ait ffatosfo utr of culture a from fractions of variety a and 2 + n rti iaeC(K)atvto ihassociated with activation (PKC) C kinase protein and ua ypoye oSE10–25 References Concentration effect and Parameter SCE No lymphocytes Human cells THP-1 B-lymphocytes Human thymocytes Human cells thyoma EL-4 BPM System -l-,-ihnlerzlu rmd] I rpdu iodide; control; propidium PI, bromide]; 2-yl)-2,5-diphenyltetrazolium Note. ↓ P,bvn eihrlbodmnncercls L nelui rdcin T,[3-(4,5-dimethylthiazol- MTT, production; interleukin IL, cells; mononuclear blood peripheral bovine BPM, α , eraei aaee esrda oprdwt control. with compared as measured parameter in decrease ntehmnmnct elln THP- line cell monocyte human the in µ M 176 n bv.Teosre in- observed The above. and neetnl,preincubation Interestingly, ↓ ↓ ↓ ↓ ↓ No ↑ nvtoefcso T nclso h muesystem immune the of cells on OTA of effects vitro In T euto n 50 reduction, MTT activators polyclonal to Response production, IL-2 reduction, MTT reduction MTT irnce occurence, Micronuclei Apoptosis production) (cytokine iulae cells binucleated ↑ CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN nmcouliocrne10p 100 occurence micronuclei in µ .ochraceus A. M . hswas This ↓ ↑ ↓ Iexclusion, PI IL-2, L2rcpo xrsin12.5–50 expression receptor IL-2 T 175 BE3 ABLE ↓ ↑ IL-5, ubrof number inycl line, cell kidney Schw¨ by reported was OTA of protec- effects antiproliferative of the against lack l-phenylalanine similar by action A tive effects. observed the of any ameliorate however, not is could l-phenylalanine increase of minimal addition Interestingly, this questionable. of of significance rate The basal 8%. ng/ to a 5% from 1000 annexin, against of antibody concentration FITC-labeled via cellu- a in at decrease OTA ( a and ml caused production, also NO extract lar OTA culture Both crude the exclusion). and iodide (propidium integrity membrane OT Defects Developmental Specific Causes OTA TOXICITY DEVELOPMENTAL obtained. results the of in- the for crucial The is v endpoints elucidated. and systems be model relevant to of remain use which phagocytic mechanism(s), moderating by of possibly activity production and the cytokines, rates, and influenc- death antibodies system, and/or immune the proliferation in cellular levels ing of number to a appears OTA at summary, active In be presented. be to remains proof convinc- however, ing mechanism; genotoxic potential a suggested tde,cridotb ae n colleagues, and Hayes by out carried studies, et nhatyhmnlmhctsb 5n 15 by de- lymphocytes similar human of healthy induction in the fects as well as patients, BEN of lym- phocytes in aberrations been chromosomal have of observation studies The out. mechanistic carried actual fewer Far OTA. of effects v hc cells. chick siaino hs ehnssadteprietinterpretation pertinent the and mechanisms these of estigation lpeto utbemdlssest td h immunotoxic the study to systems model suitable of elopment ↑ h rtrprso eeomna oiiyrsligfrom resulting toxicity developmental of Ae reports first The h tde utdsrbdrpeettefis tp ntede- the in steps first the represent described just studies The ↓ ∼ ↑ , IL-4, nraei aaee esrda oprdwith compared as measured parameter in increase 25 (?) psr perdi h al 90.I n ftefirst the of one In 1970s. early the in appeared xposure µ ↑ M 178 IL-6 )w 177 srpre oices ppoi,a measured as apoptosis, increase to reported as n yBunn ta.i rmr embryonic primary in al. et Bruinink by and 25 12.5–25 ≥ M 25 µ µ − M M µ M M µ µ ble l nteLCP1porcine LLC-PK1 the in al. et obel –10 M M µ µ M M µ M 28 176 175 174, 173 108 176 110 M OT 180 Ai a n igeip single vitro, 179 49 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 n thalidomide. and GD sensitive most the studies with subsequent group, in same hamsters the v and by rats out for carried true GD the hold on also determined dependent to and be confirmed were to results appear These administration. not of did mortality GD in with crease dams, gestation the to the terato- administered on 8 was the OTA dependent the of be which incidence on to day and observed injection severity were following effects the group genic Both median a mg/kg. in extreme 3 noted with were an effects severe of less Se- presence pups. the the f in and tail and microphthalmy, digits, face, eye, increased v an the in of mal- resulted and formations be- exencephaly 12 particular mice in and malformations, pregnant 7 of incidence to (GD) b.w.) days mg/kg gestation tween (5 OTA of administration 50 ee oefloigasnl cijcino h aso D12 GD on adminis- dams OTA. the b.w. the mg/kg of of 2.5 injection with 0.07% sc single exceed developing a following not the dose does tered in OTA accumulate fetal total can OTA fetus, although that strated nmc olwn igeamnsrto f8m/gbw OTA b.w. mg/kg gavage, 8 stomach of administration via single reported a were following results Similar mice nature. in slower in far a processes of repair are the brain the whereas studies, these in have effects masked organs these suggested, authors a and the kidney as as such However, organs spleen. target expected the alterations in no observed Interestingly, were fetuses. mouse exposed of eyes brains and the in cells neuroectodermal necrotic of incidence creased h uieueiewl ihu ann cest h developing the to fetuses. access gaining in without remain wall to uterine 17 murine or the 10 GD on administered OTA, majority radiolabelled the of demonstrated who de- Arora, was and latter Appelgren the by for livered Support stages. gestation barrier later placental in the reduced crossing or is toxin tissues, of target amount the the to that toxin secondly, the of stage this access at prevents complete gestation, is of which pore, neural this: the for of ex- closure explanations the plausible to that two fetuses are There of 9. here. insensitivity GD noted an after posure were described embryos authors generalized exposed these a of of and All skin size facial the bone of facial edema and previous skull by described reduced ip effects of authors, the instead to oral addition by In caused administration. de- concentration natural peak the reaching to in due lay study—possibly this in sensitive most the eeeiu fet ntedams. the in effects deleterious coincident without embryos multiple rat cause developing to in b.w. effects mg/kg teratogenic 1.75 of also dose have metabo- single colleagues a fetal demonstrated and of Mayura evidence Furthermore, no found. and was study, lites this in postdosing h 48 etlpoess nldn apocacid, valproic develop- including for specific with processes, made interfere mental been that have teratogens, windows classical other sensitivity of observations ilar ca lf,wr paeti h -gk ru.Smlrbut Similar group. 5-mg/kg the in apparent were cleft, acial rigbten7ad1,dpnigo species. on depending 10, and 7 between arying r ailcailefcs nldn xnehl,anopthalmy, exencephaly, including effects, facial/cranial ere eaieyhg aaiyfrrgnrto,wihcudhave could which regeneration, for capacity high relatively en h otsniie ncnrs,teosre lgtin- slight observed the contrast, In sensitive. most the being 56 A iia td yBligradcwresdemon- coworkers and Ballinger by study similar 186 odadcwresas eotda in- an reported also coworkers and Hood 187 lhuhG a eotda being as reported was 9 GD although 32 aiu ea eeswr reached were levels fetal Maximum 188 hs tapasta h terato- the that appears it Thus, 184 eiocacid, retinoic .OBINADD .DIETRICH R. D. AND O’BRIEN E. 181 − 183 Sim- 185 fAoaadcoworkers and observations The of Arora fetus. action of developing direct the a on by compound parent caused the are OTA by mediated effects genic h eosrtdOAt euenuieotrwhi cultured in outgrowth neurite reduce to OTA demonstrated who ein fdvlpn os mro sn iebu sulfate exposure. blue OTA Nile maternal following using staining embryos histological mouse developing of regions Studies Mechanistic Vivo In in that covered not possible study. was is this transfer it placental that for indicating window sensitivity tissue, the fetal could OTA in and detected 28 and be 21 not GD between out carried only was sure ugse hst earsl fpo edii rwhi h de- the in growth dendritic poor of result v a They be synapses. fewer to num- by forming this increased neuron suggested an death each of with cell presence utero, neurons the of of in to ber reports OTA due be the to to exposed to authors, several contrary mice reported, of they brains which the in ratio neuron oeta npigs. out teratogenic in carried no potential have study to OTA these a indicated coworkers to species, and Shreeve contrast several by In in OTA. teratogenesis to of exposed reports of rats absence in or fetuses reduction overall abnormal an in resulted transpla- flow, reduce blood to cental shown been and have which diethylstilbestrol of of both zearalenone, administration simultaneous as tions, n h mato n rerdcl eeae olwn OTA reduc- following thus generated radicals antioxidant, free an any as e of impact acted the have ing simply also may u oasiuaoyefc flmtinn nteezmsin- enzymes the on be l-methionine to of this v effect suggested stimulatory and a rats to in due OTA ameliorate of effects who to teratogenic colleagues, l-methionine the and of Abdel-Wahhab by coadministration by provided demonstrated out was carried theory study this the for for Support mechanisms investigation. candidate and/or as future generation synthesis protein radical of free inhibition devel-the suggested subsequent and directing regions, in stages embryonal involved opmental be specific may in which death of some cell excessive to posure ftenua ueadi rna set ftepiiiestreak. primitive the regions of aspects ventral cranial the in We in and tube apparent neural was the death of cell majority The observed notochord. the the in caudal of not region but tube somite neural last-formed the the to in death cell extensive and OTA-exposed in chicks number Sulik. somite and in Wei using reduction a by obtained described also authors system, were model results as de- Similar embryos chick abnormalities authors. craniofacial other apparent, by the also scribed with was well prominence correlates frontonasal which the extreme An of pore. advanced neural narrowing posterior more the of slightly periphery developmentally the embryos, in plate, anterior and, the neural of folds, the periphery neural the of cells, crest half neural medial premigratory the the included regions affected xposure. le nDAadpoensynthesis. protein and DNA in olved lpn ri.Spotfrti a rvddb oge al., et Hong by provided was this for Support brain. eloping We uu n colleagues and Fukui i n ui trbtdteanraiiscue yOAex- OTA by caused abnormalities the attributed Sulik and i n ui eosrtdecsiecl et nseveral in death cell excessive demonstrated Sulik and 190 tms emnind oee,ta expo- that however, mentioned, be must It 189 194 emt orbrt hs observa- these corroborate to seem bevddfiisi h synapse-to- the in deficits observed 193 oee,l-methionine However, 191 192 The The 195 Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 ri,nua eia n eigsdslydsmlrresponses similar concentrations. displayed nanomolar to meninges and retina, neural brain, possess not does OTA that a concluded al. et Bruinink of cells. nature those dopaminergic/nondopaminergic the on based not least possesses OTA indeed if a that concluded authors the Thus tested. v bevdt eue[ reduce to midbrain observed embryonic was OTA (nondopaminergic). rat cells bud cultured limb and in (dopaminergic) differentiation cell and ity etatrto fete aa r1-ex PGJ 15-deoxy or basal either of alteration PPAR- rect the of ment ie hs fet ol o eargtdb h diinof addition the by abrogated sensi- be more not e minimally could cell only effects both being These in tive. cells levels midbrain glutathione with and types, viability, cell content, tein ino PPAR- of tion P1adNF- demonstrated and coworkers AP-1 and Hong OT cells, midbrain bryonic neu- OTA-mediated in dismissed. be generation can radical rotoxicity free for role a before ct nmdri cells, midbrain in icity cytotox- OTA-mediated prevent not could certain catalase and Although muthase, dis- systems. superoxide indol-3-carbinol, as model such scavengers suitable free-radical extensive in requires research and further controversial remains neurotoxicity its l-phenylalanine. of addition by OT OT fet r faselective a of are effects ftemcoehl bevdfloigi tr xoue In- co-workers exposure. and utero Monnet-Tschudi in cause deed, following the observed be to microcephaly purported the and of reported been have vitro in origin Studies Vitro In 1.1 olausdmntae T n T ouin ob tbeat stable be 36.5 to solutions and OTB Bruinink and OTA as can demonstrated compound, effects colleagues parent vitro the in to These attributed OTA. be of probably effects the to fetal sensitive of were more periods cultures developmental earlier cell from cells aggregating telencephalon, rat man- employing study, time-dependent this a In in ner. concentrations, nanomolar at occur idotb ogadcwresatmtdt drs oeof some address to attempted issues. coworkers these and Hong by out ried J cnwegdefcso PPAR- of effects acknowledged PPAR- a mroi ibanclswt IC with cells midbrain embryonic rat 2 oeosguahoe odfeec a paeti h IC the in apparent was difference No glutathione. xogenous le eemndfrtetocl ye o n fteparameters the of any for types cell two the for determined alues pcfi ertxcato,a elclue febyncchick embryonic of cultures cell as action, neurotoxic specific eetv oiiyfrpriua erntps hnti sat is this then types, neuron particular for toxicity selective nasbeun td,as are u nclue a em- rat cultured in At out carried also study, subsequent a In sfralo h oi cin fOA h ehns of mechanism the OTA, of actions toxic the of all for As Ai la yooi fet fOAi utrdclso neuronal of cells cultured in OTA of effects cytotoxic Clear Bw 1-ex PGJ (15-deoxy µ ◦ C M n o γ sosre ob prxmtl 0fl estxcthan toxic less 10-fold approximately be to observed as ove . hssuy n h fet fOAcudntb reversed be not could OTA of effects the and study, this nraeteatvto ftetasrpinfactors transcription the of activation the increase ciiyb T ol o edmntae.The demonstrated. be not could OTA by activity ra 195 t γ κ es days. 7 least h uhr sesdOAmdae cytotoxic- OTA-mediated assessed authors The B. ciainb 15-deoxy- by activation 200 2 γ .Atog hssget h involve- the suggests this Although ). 3 199 ]hmdn noprto,clua pro- cellular incorporation, H]thymidine aha ntetxct fOA di- a OTA, of toxicity the in pathway hscudb rvne i stimula- via prevented be could This 197 aymr nixdnsms etested be must antioxidants more many 178 rgnrlnature. general or 178 ti urnl o la fthese if clear not currently is It iial opeiu findings, previous to Similarly γ 50 nmcohg activa- macrophage on 196 v le fapproximately of alues CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN

eosrtdti to this demonstrated 12 , 198 14 -prostaglandin A 2 -stimulated td car- study 50 eea rti ytei nads-eedn anrwt IC with and manner proteoglycans dose-dependent a cartilage in of synthesis protein accumulation general the inhibit ochratox- to demonstrated Stormer ins and Wiger buds, limb embryo chick from cells have mesenchymal the effects prechondrogenic and Using systems, starkest skeleton. neural related the and brain where the namely, areas noted, been two the have OTA on of concentrated action of mechanism teratogenic the investigating AP-1 the of antagonism investigation. via production NF- and cytokine and tion v fisidvda opnnsfrtepeec fsvrlo the of several of presence the for components individual several its and feed of complete the analyzed also investigators These n riesadcridotafeigeprmn ihOTA- with experiment goslings, grain. OTA-free feeding with geese, and OTA) a in ng/g out (110–930 study contaminated carried case and a broilers and such on expanded however, poultry nature in f occurring in ochratoxicoses of descriptive studies case purely with deal are and reports ter- Most or effects. immunotoxic, nephrotoxic, atogenic with dealing those than much rarer are OTA of potential promoting carcinoma hepatocellular n h hrceitcanraiy(EC to abnormality sensitive characteristic other be be- narrowing the all to craniofacial ing with demonstrated for OTA, of been described effects teratogenic date, effects the to the tested ( studies. with frog species mechanistic useful agreement clawed for a in African samples provides South have, the of it of generation as Embryos the possibility, for such tool one present could mechanistic for systems model appropriate research. of use the the for more once need underlines This incubations. OTA of on effect outcome moderating the no had OTB with cultures micromass the of ioai mice, in cinoma HEPATOTOXICITY future for highly considered be two should the investigations. and between analogs rapid differentiate structural and can similar simple system this assay Thus, h) (O’Brien preparation). OTA (96 in for manuscript observed al., that et than approx- the higher were and fourfold malformation OTB, imately induce to to exposure em- required following incom- in concentrations evident by decrease was follow- significant accompanied length apparent no bryo were Furthermore, those coiling. which to gut OTB, contrast plete to in nature exposure specific ing to controls. a appeared with of exposure compared OTA be following when effects inhibition craniofacial growth The 20% to ( concentrations up higher to exposed bryos nprpea ypoye ytesm group, obtained same results the by the lymphocytes to T peripheral contrast ef- in In the substances. attributed parent authors the to the fects detected, be could metabolites no rsweetefe a asvl otmntd n study, One contaminated. massively was feed the where arms le f19ad6.2 and 1.9 of alues h aoiyo ehnsi rmdlbsdsuis ie at aimed studies, model-based or mechanistic of majority The h rgeby eaoeiiyassay teratogenicity embryo frog The lhuhOAhsbe eotdt as eaoellrcar- hepatocellular cause to reported been has OTA Although κ B ahasmk hs nig otyo further of worthy findings these make pathways 55 eot eln ihtehpttxcadthe and hepatotoxic the with dealing reports µ M o T n T,respectively. OTB, and OTA for 50 > = 0 n 200 Xenopus 176 0n 60 eou laevis Xenopus preincubation M M ) displayed ). (FETAX) 202 201 Em- As 203 51 50 ) Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 te td are u ntecikmdl hr h primary the where model, chick nephrosis. the was in pathology an- out in reported carried those study to other contrast complete in symptoms. were intoxication results overall These the re- to with contribution importance their lesser to of spect be to broilers; deemed in of were observed these some were however, nephropathies in Slight seen birds. ob- older also the be the was with could Amyloidosis concurrent This hepatotoxicity. suppression sites. served immune necrotic an the of at indicative dis- in colonies also diffuse geese bacterial Several more goslings. played in was extensive more which and necrosis, broilers presented hepatic species Both multifocal samples. with the (250). in detected verrucarin was and OTA Only (250), roridin zearalenone (50), toxin (100), deoxynivalenol HT-2 neosolaniol (50), (50), (50), toxin T-2 diacetoxyscirpenol OTA (10), (50), included aflatoxin parentheses) (100), in citrinin ng/g This (20), pathology. as observed limits the (detection for screen responsible be my- could which cotoxin determine to attempt an in mycotoxins common most 52 iiyo eea nye omnyue ssniiemarkers humans. sensitive in as necrosis hepatocellular used of commonly enzymes several ac- the of on tivity toxicity OTA acute of effects the examined coworkers ng/g 410 sample. to same ng/g the 20 of than de- subsamples OTA less in from of ranged concentrations values the These in tected. one variation when huge myco- however, unknown the apparent yet considers become as problems other one Serious least the toxin. at to hepatotoxicity and OTA the of attributed presence paper the former found, the be could of mycotoxin authors known other no where samples, h ie,i isfloigepsr ofde otiig3 OT containing or fodder to kidney exposure following the pigs either in liver, in the changes could degenerative which with activities, associated AlkPh be and ALD, ALAT, ASAT, serum ol ecreae ihicesdurinary increased with correlated be could ht oi copne yseln fbt h ailr en- capillary the cells. both Kupffer’s of and swelling dothelium by accompanied foci, white direction. this in research future could point selenium and indeed E vitamin established. of be effects protective not the However, could changes radicals this pathological free of subsequent in generation and out the between carried link direct was a that measurement so study, radical free of nor examinations livers the pathological neither Unfortunately, actu- controls. selenium lower and a E displayed vitamin and ally AP, with ac- in pretreated ALAT increase animals or OTA-associated ASAT indeed, the in prevent increase did observed but the selenium tivity, and on E effect vitamin no with ALAThad pretreatment in contrast, increase In any AP. prevented and indeed observed and ASAT the in reduced increase gastric tamoxifen via b.w. mg/kg with 2.5 Pretreatment of dose intubation. single a given rats of l- livers the not but (AP) alkaline phosphatase and (ALAT), aminotransferase alanine (ASAT), trans- ferase amino aspartate of activity increased significantly a strated namr eetadbte otoldsuy toh and Atroshi study, controlled better and recent more a In .Hwvr ept ecitv eot fOTA-mediated of reports descriptive despite However, A. te ta.dsrbdmdrt ie eeeainwt gray- with degeneration liver moderate described al. et Stoev γ G ciiyta hi corresponding their than activity -GT 204 ae nteraayi ftegrain the of analysis their on Based γ guay rnfrs ( transferase -glutamyl 165 iceial,teeeffects these Biochemically, 205 hs uhr demon- authors These γ G ciiyand activity -GT .OBINADD .DIETRICH R. D. AND O’BRIEN E. γ G)in -GT) µ g/kg swl si h kidney, the in liver as the well in accumulate as can OTA that evidence and hepatoxicity es sdsrbdi hsrve,ms lob osdrdin considered be also must review, this sys- in experimental these described in as serum of tems, absence or presence concentrations of dose/exposure and risk of issues human trustworthy crucial a The achieve assessment. DNA to order using in example, technologies, for chip investigated, renal be of markers must Suitable, possible carcinogenesis area. earliest of this the effects on in the exposure and OTA made generated chronic be be must to systems is model cell progress reliable if crucial is sign of characteristic differences in OT species-dependent variations and large the type- of cell indicative be to appear mechanism(s) to leading chain the in fibrosis. event renal initial and the carcinogenesis with identifying experiments of vitro goal in the and com- vivo a in of well-designed use of the toxin bination through intangible achieved be this only of can action This imperative. of ochratox- mechanism of the the make effects of which elucidation The implications, socioeconomic established. massive be have ins to endemic remain tu- Balkan urothelial also characteristic to the mors of link etiology the causal action and definitive nephropathy of A mechanism elusive. animals the laboratory remains documented, and extensively domestic been in have ochratoxins of effects the YEGSI FET IHOHRMYCOTOXINS OTHER WITH EFFECTS SYNERGISTIC results. contradictory highly often and inconclusive and few relatively fa been have hepatotoxicity OTA-mediated of fteefcsosre ohi ioadi ir,a a been has as vitro, in and vivo B in fumonisin for both achived observed effects the of PERSPECTIVES FUTURE AND STATUS CURRENT manuscript (Heussner, toxic actions more individual submitted). be their of to sum combinations the certain than indicated mycotoxins have nephrotoxic vitro known of in range a cyto- with initial studies Indeed toxicity substance. single a conse- to severe exposure more than quences have this could clarify substances to to exposure nephrotoxic that order several assume in to logical out appears carried it However, be question. mycotox- must other studies more Further or ob- ins. two of those combination and a alone following served exposure OTA from by resulting produced pathologies also are which cillium citrinin, and acid including mycotoxins penicillic nephrotoxic different of exposure combination from a result to may effects authors renal these observed pigs, the that 12-month-old suggest to 3- in experiments nephropathy. porcine on of Based patholog- cases the Bulgarian of cause in sole observed effects the as ical OTA of role the on doubt some r -eitdtxct.Teotmzto feprmna de- experimental of optimization The toxicity. A-mediated reported the in differences and contradictions obvious The A n rpsdmcaimo cinsol i oepanall explain to aim should action of mechanism proposed Any ewe,adtoeta aebe are u aeyielded have out carried been have that those and between, eetpbiainb te n coworkers and Stoev by publication recent pce.Teatosdsrbddfeecsi h renal the in differences described authors The species. 1 206 n fltxnA ept h atthat fact the Despite A. aflatoxin and tepst en h mechanism the define to attempts 62 ata least at cast P eni- Downloaded By: [Universitaet Konstanz] At: 08:25 8 March 2007 evtosmd yBitadcolleagues and Buist by made servations ento fteiiileeti T-eitdtxct,b that the be is toxicity, OTA-mediated aim one’s in so event when initial and Thus, the specific assessment. of sex risk definition and/or for species crucial be be to to likely more review this much in ki- are outlined observed considerations the dose-response also sub- and and per- specific netics events of avoid upstream toxicity to early the order These of stances. in investigation the made between in be biases interaction must sonal direct DNA, a and substance from the result of necessarily damage view DNA not that broader must accepts the which genotoxicity, an to of from return definition the result A cytotoxicity. may “simple” these initial even of although the loss to exchange, etc., chromatid example, heterozygosity, sister for adducts, effect leads, DNA direct interaction of a direct generation has This question DNA. in the ac- substance on widely the incor- more that moreover namely, and another, restrictive rect: have very Unfortu- is to DNA. which come definition, to cepted has damage term causing this of still nately, capable is those there are made, icals been has progress a although and decades, A NAME? IN WHAT’S NONGENOTOXIC: OR GENOTOXIC mechanistic study. any in considered the be to must OTB, response analogue in differences structural marked the as well as trans- cells, mention primary formed to and not fibroblasts, NRK-49F and cells and epithelial renal NRK-52E human example, for types, OTA-mediatedcell to type cell particular c a of sensitivity the define accumulate to ability their with OT correlated this have cells should primary and this complement particular protein in transporter in their research for and characterized extensive be systems should for model need cell the Thus, to area. in support least at lend age, rat, with the considerably vary OATs certain of patterns ct ncide,wihhsbe ugse nrpr published report in coworkers suggested and Wolff been by has relevance which tox- OTA particular children, of in of risk icity increased is possible This determining to action. respect effects of with toxic mode of the diversity the hence, for and reasons the determining in ical crit- prove could accumulation OTA intracellular for responsible More- understood. better necessity, be a may ove is kinetics cellular toxicity OTA the for that relevance such their to respect with area. this be in research further to detailed support proven to more reasonable have and appears it origin in far, so porcine sensitive models As most and effects. the these vivo human in for of and look cells vitro in primary to compare logical to and is species relevant it toxicity, in dif- species-specific ferences and sex- the on Based investigations. future ttxct,tedfeecsi h epneo ait frelated of variety a of response the in differences the ytotoxicity, ogwyt ot nlyfidtease.Gntxcchem- Genotoxic answer. the find finally to go to way long hsqeto a ethnrd frsacesa okfor work at researchers of hundreds kept has question This to insufficient is alone accumulation OTA intracellular As A. otnigrsac nteae fogncaintransporters anion organic of area the in research Continuing r, h eemnto fwih fay fteepoen is proteins these of any, if which, of determination the 207 ob ihrta naut.Teob- The adults. in than higher be to 96 CRTXNA H OTNIGENIGMA CONTINUING THE A: OCHRATOXIN , 97 htteexpression the that REFERENCES OTA-mediated of mechanism the for toxicity. more search prove the may in effects rewarding nongenotoxic delineation strict and a likely genotoxic of highly thinking between current is the from it distancing Furthermore, a that analyzed. relevant be the must developmental, parameters or immunological, hepatic, renal, 6 aqad,RR,adFolc,A 19) crtxna nim- An a: Ochratoxin (1990). th- A. 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