Biomedical Engineering Reference
In-Depth Information
Table 11.3 Concentrations Used to Assess Organ Toxicity
Compound
Concentrations (mM)
17-DMAG
10, 50, 100, 500, 1000, 1500
HDAC inhibitor X
10, 50, 100, 200, 300, 400
Paclitaxel
a
0.01, 0.05, 0.1, 0.5, 1.0, 2.0
SMA-838
300, 600, 900, 1250, 1500, 2000
Zebularine
Not tested per Study Sponsor's instructions
a
Since 2 mM was the highest soluble paclitaxel concentration, higher concentrations were not tested.
untreated, carrier-treated, and positive compound-treated zebrafish were assessed
concurrently. Results for assessing toxic effects on heart, CNS, liver, and kidney are
shown in Fig. 11.2.
In order to reduce repetition, images of control-treated zebrafish are shown
separately (Fig. 11.1). No difference was observed for untreated zebrafish (fish
water), used as assay control, and 0.4% DMSO-treated zebrafish, used as carrier
control, indicating 0.4% DMSO did not cause adverse effects. Celebrex (30
M), a
positive control for cardiotoxicity, caused slow heart rate, arrhythmia, and peri-
cardial edema. 7.5 and 10
m
M brefeldin A were used as positive controls for
assessing CNS and liver toxicity, respectively. Treatment with brefeldin A caused
CNS and liver discoloration, indicating tissue degeneration. Ethanol (3%), which
was used as a positive control for assessing kidney toxicity, caused trunk edema,
indicating potential dysfunction.
Organ toxicity results are shown in Fig. 11.2. 17-DMAG caused toxicity in all
four organs: heart, CNS, liver, and kidney. Reduced heart rate and pericardial edema
were also observed. Tissue discoloration was observed in brain, indicating degen-
eration. Small, discolored liver and hemorrhage were observed. Trunk edema
indicating potential defective kidney function was observed. HDAC inhibitor X
caused slowheart rate, slowcirculation, and pericardial edema. However, toxicitywas
not observed in the other three organs. At concentrations up to 2
m
M, the highest
soluble concentration, paclitaxel did not cause visible organ toxicity. SMA-838
caused liver toxicity, including small size and discoloration.
Results for visual assessment of organ toxicity in live zebrafish after treatment for
24 h are summarized in Table 11.4.
m
11.3.3 Cell Death Assessed After 24h Compound
Treatment
Using the same treatment conditions for visually assessing organ toxicity, we next
assessed cell death. Two or four dpf zebrafish were treated with each drug for 24 h
and cell death in heart, CNS, liver, and kidney was assessed. Compound-induced
celldeathineachorganwasassessedvisuallybystainingwithfluorescentacridine
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