Development of an in vitro blood–brain barrier model—cytotoxicity of mercury and aluminum

Toimela, Tarja; Mäenpää, Hanna; Mannerström, Marika; Tähti, Hanna

doi:10.1016/j.taap.2003.11.002

Cited by 62 publications

(45 citation statements)

References 68 publications

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“…In previous studies (McAmis et al 2003;Wolf & Baynes 2006), we found that the anticancer quinones depleted ATP and caused a barrier dysfunction. In other studies, mercury caused ATP depletion along with barrier dysfunction (Toimela et al 2004) and cadmium caused ATP depletion and increased permeability in renal epithelial cells (Stinson et al 2003). These changes may have just been simultaneous occurrences, but the sulfhydryl reagent, iodoacetate, depletes ATP prior to the appearance of a barrier dysfunction in EC (Wilson et al 1990).…”

Section: Discussionmentioning

confidence: 94%

“…Effects of heavy metals on endothelial barrier function have been noted previously. Mercury, at 10lM concentration, caused a significant increase in low molecular weight fluorescein leakage in a blood-brain barrier model using transformed EC (Toimela et al 2004). A review (Nolan & Shaikh 1986) summarized earlier studies and suggested that the vascular endothelium was a primary target for cadmium and that the result was an increase in vascular permeability in a number of tissues.…”

Section: Discussionmentioning

confidence: 99%

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Cadmium and mercury cause an oxidative stress-induced endothelial dysfunction

Wolf

Baynes

2006

Biometals

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We investigated the ability of cadmium and mercury ions to cause endothelial dysfunction in bovine pulmonary artery endothelial cell monolayers. Exposure of monolayers for 48 h to metal concentrations greater than 3-5 microM produced profound cytotoxicity (increased lactate dehydrogenase leakage), a permeability barrier failure, depletion of glutathione and ATP and almost complete inhibition of the activity of key thiol enzymes, glucose-6-phosphate dehydrogenase (G6PDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In contrast, metal concentrations less than 1-2 microM induced increases in glutathione and thiol-enzyme activities with minimal changes in LDH leakage, barrier function and ATP content. At shorter incubation times (24 h or less), high concentrations of cadmium caused glutathione induction rather than depletion. Thus, oxidative stress and cytotoxicity induced by lower concentrations of the metal ions stimulate compensatory responses, including increased synthesis of glutathione, which presumably preserved the activity of key thiol enzymes, however these responses were not sustainable at higher metal ion concentrations. We conclude, while high concentrations of heavy metals are cytotoxic, lower concentration induce a compensatory protective response, which may explain threshold effects in metal-ion toxicity.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Cadmium and mercury cause an oxidative stress-induced endothelial dysfunction

Wolf

Baynes

2006

Biometals

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“…Our results indicate that the studied hESC-RPE cells have electrical impedance properties that are near to in vitro cultured human RPE [7,13,18] (Table 2). In previous studies, hESC-RPE cells had greater TER [27,31] than ARPE-19 cells [6,14,26]. We used ARPE-19 cells as controls to model immature epithelia.…”

Section: Discussionmentioning

confidence: 99%

“…In general, TER measurements have some drawbacks: Firstly, TER is often measured with simple handheld devices [2,5,9,16,18,26,27]. Thus, the geometry between the electrodes and the cell culture inserts vary from measurement to measurement and produces inaccuracy in the results.…”

Section: Introductionmentioning

confidence: 99%

Electric impedance of human embryonic stem cell-derived retinal pigment epithelium

Onnela

Savolainen

Juuti‐Uusitalo³

et al. 2011

Med Biol Eng Comput

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The barrier properties of epithelium are conventionally defined by transepithelial resistance (TER). TER provides information about the tightness of the epithelium. Electrical impedance spectroscopy (EIS) provides additional information regarding cell membrane properties, such as changes in electric capacitance and possible parallel or serial pathways that may correlate with the morphology of the cell layer. This study presents EIS of retinal pigment epithelial (RPE) cell model of the putative RPE differentiated from human embryonic stem cells (hESC-RPE). The generally utilized RPE cell model, ARPE-19, was used as immature control. The measured EIS was analyzed by fitting an equivalent electrical circuit model describing the resistive and capacitive properties of the RPE. Our results indicated that TER of hESC-RPE cells was close to the values of human RPE presented in the literature. This provides evidence that the stem cell-derived RPE in vitro can reach high-barrier function. Furthermore, hESC-RPE cells produced impedance spectra that can be modeled by the equivalent circuit of one time constant. ARPE-19 cells produced low-barrier properties, that is, an impedance spectra that suggested poor maturation of ARPE-19 cells. To conclude, EIS could give us means for non-invasively estimating the functionality and maturation of differentiated-RPE cells.

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“…Mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining/associated with autistic disorders, and these similarities extend to neuroanatomy, neurotransmitters, and biochemistry (Stringari et al 2008;Toimela et al 2004;Waly et al 2004;Blaylock 2008;Blaylock and Struneka 2009;Danscher et al 1990;Fonfria et al 2005;Huang et al 2008;Olanow and Arendash 1994). Furthermore, a review of molecular mechanisms indicates that Hg exposure can induce death, disorganization and/or damage to selected neurons in the brain similar to that seen in recent brain pathology studies of patients diagnosed with an ASD, and this alteration may likely produce the symptoms by which ASDs are diagnosed (Lopez-Hertado and Prieto 2008;Kern 2003;Kern and Jones 2006).…”

Section: Introductionmentioning

confidence: 99%

A biomarker of mercury body-burden correlated with diagnostic domain specific clinical symptoms of autism spectrum disorder

Kern

Geier²,

Adams

et al. 2010

Biometals

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The study purpose was to compare the quantitative results from tests for urinary porphyrins, where some of these porphyrins are known biomarkers of heavy metal toxicity, to the independent assessments from a recognized quantitative measurement, the Autism Treatment Evaluation Checklist (ATEC), of specific domains of autistic disorders symptoms (Speech/Language, Sociability, Sensory/Cognitive Awareness, and Health/Physical/Behavior) in a group of children having a clinical diagnosis of autism spectrum disorder (ASD). After a Childhood Autism Rating Scale (CARS) evaluation to assess the development of each child in this study and aid in confirming their classification, and an ATEC was completed by a parent, a urinary porphyrin profile sample was collected and sent out for blinded analysis. Urinary porphyrins from twenty-four children, 2-13 years of age, diagnosed with autism or PDD-NOS were compared to their ATEC scores as well as their scores in the specific domains (Speech/Language, Sociability, Sensory/Cognitive Awareness, and Health/Physical/Behavior) assessed by ATEC. Their urinary porphyrin samples were evaluated at Laboratoire Philippe Auguste (which is an ISO-approved clinical laboratory). The results of the study indicated that the participants' overall ATEC scores and their scores on each of the ATEC subscales (Speech/Language, Sociability, Sensory/Cognitive Awareness, and Health/Physical/Behavior) were linearly related to urinary porphyrins associated with mercury toxicity. The results show an association between the apparent level of mercury toxicity as measured by recognized urinary porphyrin biomarkers of mercury toxicity and the magnitude of the specific hallmark features of autism as assessed by ATEC.

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Development of an in vitro blood–brain barrier model—cytotoxicity of mercury and aluminum

Cited by 62 publications

References 68 publications

Cadmium and mercury cause an oxidative stress-induced endothelial dysfunction

Cadmium and mercury cause an oxidative stress-induced endothelial dysfunction

Electric impedance of human embryonic stem cell-derived retinal pigment epithelium

A biomarker of mercury body-burden correlated with diagnostic domain specific clinical symptoms of autism spectrum disorder

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