Placental transfer of ochratoxin A and its cytotoxic effect on the mouse embryonic brain

Fukui, Yoshihiro; Hoshino, Kiyoshi; Kameyama, Yoshiro; Yasui, Teruyo; Toda, Chitose; Nagano, Hideo

doi:10.1016/0278-6915(87)90302-4

Cited by 57 publications

(25 citation statements)

References 13 publications

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“…administration, respectively (Hagelberg et al 1989). The long elimination half-lives stand in contrast to the considerably shorter half-lives of OTA of 40 h in mice (Fukui et al 1987;Hagelberg et al 1989), 55±120 h in rats, (Ballinger et al 1986;Galtier et al 1979;Hagelberg et al 1989) and 72±120 h in pigs (Galtier et al 1981;Mortensen et al 1983). Species di erences in OTA uptake from the gastrointestinal tract, distribution (speci®c plasma proteins and thus binding capacities of OTA) and metabolism may be the physiological factors limiting OTA elimination (Fuchs 1988;Hagelberg et al 1989).…”

Section: Discussionmentioning

confidence: 94%

Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans

Studer-Rohr

Schlatter

Dietrich

2000

Archives of Toxicology

222

139

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The mycotoxin ochratoxin A (OTA) is a rodent carcinogen produced by species of the ubiquitous fungal genera Aspergillus and Penicillium. OTA is found in a variety of food items and as a consequence is also found in human plasma (average concentrations found in this study: 0.1±1 ng OTA/ml plasma). To improve the scienti®c basis for cancer risk assessment the toxicokinetic pro®le of OTA was studied in one human volunteer following ingestion of 395 ng 3 H-labeled OTA (3.8 lCi). A two-compartment open model consisting of a central compartment was found to best describe the in vivo data. This two-compartment model consisted of a fast elimination and distribution phase (T 1/2 about 20 h) followed by a slow elimination phase (renal clearance about 0.11 ml/min.) and a calculated plasma half-life of 35.55 days. This half-life was approximately eight times longer than that determined previously in rats. In addition, the intraindividual¯uctuation of OTA plasma levels was investigated in eight individuals over a period of 2 months. The concentrations determined ranged between 0.2 and 0.9 ng OTA/ml plasma. The plasma levels in some individuals remained nearly constant over time, while others varied considerably (e.g. increase of 0.4 ng/ml within 3 days, decrease of 0.3 ng/ml within 5 days) during the observation period. This intraindividual¯uctuation in OTA plasma levels, which may represent di erences in OTA exposure and/or metabolism, as well as the large di erence in plasma half-life in humans compared to rats must be taken into consideration when the results of rat cancer study data are extrapolated to humans for risk assessment purposes.

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Section: Discussionmentioning

confidence: 94%

Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans

Studer-Rohr

Schlatter

Dietrich

2000

Archives of Toxicology

222

139

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“…OTA has also been shown to cause immunotoxic, genotoxic, and carcinogenic effects (Bendele et al, 1985;Lea et al, 1989;Creppy et al, 1985). OTA induces maternal toxicosis in pregnant females and crosses the placenta to produce teratogenicity and/ or embryotoxicity in animals (Brown et al, 1976;Gilani et al, 1978;Fukui et al, 1987;Poppe et al, 1983;Wei & Sulik, 1993.…”

Section: Effects Of Ochratoxin a On Cytotoxicity And Cell Differentiamentioning

confidence: 96%

“…Necrotic and/or cytotoxic effects (formation of pyknotic cells) in embryonic brain were proposed as an underlying mechanism responsible for microcephaly in animals and in vitro whole embryo cultures treated with OTA (Fukui et al, 1987;Wei & Sulik, 1993. Regional selective distribution and toxicity was found in the brain following intracerebral injection of OTA (Belmadani et al, 1998).…”

Section: Effects Of Ochratoxin a On Cytotoxicity And Cell Differentiamentioning

confidence: 97%

Effects of Ochratoxin a on Cytotoxicity and Cell Differentiation in Cultured Rat Embryonic Cells

Hong

Park

Han

et al. 2000

Journal of Toxicology and Environmental Health, Part A

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In the present study, the effects of ochratoxin A (OTA) on cytotoxicity, cell differentiation, and other cell functions in the embryonic midbrain cells, which are dopaminergic, were compared to those in the limb bud cells, which are nondopaminergic, to assess the selectivity of OTA central action. Twelve-day rat embryo midbrain and limb bud cells were cultured in Dulbecco's modified Eagle's medium nutrient and Ham's F12 (1:1) mix ture containing 10% Nuserum for 96 h in the presence of various concentrations of OTA. OTA signicfiantly reduced the levels of protein, DNA and glutathione, and [H]thymidine incorporation into DNA in both embryonic midbrain and limb bud cells in a similar concentration-dependent manner. The IC50 values for cytotoxicity measured by neutral red uptake were 1.10 microM in the midbrain cells and 1.05 microM in the limb bud cells. The IC50 values of cell differentiation were 1.10 microM in the midbrain cells and 1.0 microM in the limb bud cells. The addition of exogenous glutathione (32.5 microM) did not change the OTA-induced fall in protein and DNA levels, or the IC50 values of cytotoxicity and differentiation in the midbrain and limb bud cells. Data show that OTA does not appear to exert a selective toxic dopaminergic cell action and that OTA-induced cytotoxicity and inhibition of cell differentiation were not prevented by exogenous glutathione.

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“…OTA induced cytostasis or enhanced apoptosis, cell dedifferentiation may be of greater importance (O'BRIEN et al 2001). The fact that the elimination half-life of OTA in humans, with approximately 36 days (STUDER-ROHR et al 2000), is considerably longer than noted in other mammalian species (mice (40 h) (FUKUI et al 1987;HAGELBERG et al 1989), rats (55-120 h) (BALLINGER et al 1986;GALTIER et al 1979;HAGELBERG et al 1989), pigs (72-120h) (GALTIER et al 1981;MORTENSEN et al 1983) or monkeys (820 h) (KUIPER-GOODMAN and SCOTT 1989), that tissue homogenates from the human renal cortex display a higher binding affinity and capacity for [ 3 H]-OTA than the respective tissue homogenates from rat, mouse or pig [abstract, DIETRICH et al, Toxicological Sciences 54: 170, 2000], as well as the data presented here, suggest that OTA may constitute a higher risk in humans than previously considered.…”

Section: Characterization Of Cell Culturesmentioning

confidence: 99%

Species- and sex-specific renal cytotoxicity of Ochratoxin A and B in vitro

Dietrich

O'Brien

Stack

et al. 2001

Experimental and Toxicologic Pathology

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SummaryFour different cell models were chosen for comparison of OTA and OTB toxicity: primary porcine (PKC), rat (RPTC) and human renal proximal epithelial cells (HKC) from both sexes and a porcine renal cell line: LLC-PK1. Culture conditions were tested and optimized for each respective cell type (species/sex and origin). All cell types were characterized for epithelial origin and growth patterns and following optimization of dosing strategies and assay procedures, a strict study design was implemented to avoid systemic variations. Due to possible sensitivity differences, three simple endpoints were chosen to provide basic data for interspecies comparison: neutral red uptake, MTT reduction and cell number. Of the endpoints tested neutral red appeared the most sensitive, although all three parameters yielded comparable EC 50 's. Sex-differences were observed between male and female HKC cells following 96 h exposure to OTA, with HKC(m) being more sensitive than HKC(f). No sex-difference was observed in PKC cells, however, the PKC were approximately 3 and 10 times more sensitive than HKC(m) and HKC(f), respectively, to OTA and OTB. Interestingly, the CI 95 of the EC 50 values obtained for OTA (15.5-16.5 µM) and OTB (17.0-21.0 µM) were comparable in the PKC cells. In contrast, OTB had lower cytotoxicity than OTA in HKC and LLC-PK1 (approx. 2-fold) and no effects in RPTC. Overall, HKC(m) were nearly as sensitive as PKC towards OTA, followed by RPTC, LLC-PK1 and HKC(f), thus suggesting a sex specific sensitivity in humans towards OTA induced cytotoxicity.

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Placental transfer of ochratoxin A and its cytotoxic effect on the mouse embryonic brain

Cited by 57 publications

References 13 publications

Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans

Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans

Effects of Ochratoxin a on Cytotoxicity and Cell Differentiation in Cultured Rat Embryonic Cells

Species- and sex-specific renal cytotoxicity of Ochratoxin A and B in vitro

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