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Evaluation of hepatotoxicity of chemicals using hepatic progenitor and hepatocyte-like cells derived from mouse embryonic stem cells : Effect of chemicals on ESC-derived hepatocyte differentiation

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Evaluation of hepatotoxicity of chemicals using hepatic progenitor and hepatocyte-like cells derived from mouse embryonic stem cells : Effect of chemicals on ESC-derived hepatocyte differentiation

Content Provider	Springer Nature Link
Author	Kang, Seok Jin Jeong, Sang Hee Kim, Eun Joo Cho, Joon Hyoung Park, Young Il Park, Sung Won Shin, Hyo Sook Son, Seong Wan Kang, Hwan Goo
Copyright Year	2012
Abstract	Embryonic stem cell testing is an alternative model system to assess drug and chemical toxicities because of its similar developmental characteristics with in vivo embryogenesis and organogenesis. This study evaluated the toxicity of chemicals at specific developmental stages of mouse embryonic stem cell (ESC)-derived hepatic differentiation; hepatic progenitor cells (HPCs), and hepatocyte-like cells (HCs). The toxic effects of carbon tetrachloride (CCl4), 5-fluorouracil (5-FU), and arsanilic acid (Ars) were evaluated by measuring the expressions of Cytokeratin (CK18) and GATA binding protein 4 (GATA-4) and the activities of aspartate transaminase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) during the hepatic differentiation process. Non-toxic doses of three chemicals at a range of 25 to 500 μM for CCl4, 12.5 to 800 nM for 5-FU and 6.25 to 400 mM for Ars were treated. In the CCl4-treated group, significant decreases (P < 0.05) of the marker expression were observed by more than 300 μM from day 10 in CK18 and by more than 400 μM of CCl4 from day 22 in GATA-4, respectively. However, both markers were decreased (P < 0.01) by treatments of all doses at day 40. In the 5-FU-treated group, the expressions of two proteins were not affected by any of the doses at day 10 and 22, whereas the GATA-4 expression was decreased (P < 0.05) by more than 400 nM of 5-FU at days 28 and 40. In the Ars-treated group, the CK18 expression was inhibited (P < 0.05) by more than 100 mM of Ars at day 22 but showed a tendency to recover. Although the GATA-4 was inhibited by all doses at day 22, the inhibition of GATA-4 recovered at days 28 and 40. ALP activities of three chemicals were significantly increased (P < 0.05) by a dose-dependent manner. The activities of AST and LDH were prone to be increased by more than 300 μM of CCl4, but not affected by all doses of 5-FU except for 800 nM of 5-FU in AST activities. In the Ars, the enzyme activities were significantly increased (P < 0.05) by more than 50 μM of Ars in AST and more than 6.25 μM of Ars in LDH. The present results indicate that CCl4 has a more toxic effect on HCs, whereas Ars is more toxic to HPCs. Additionally, in vitro alternative testing using ESC-derived HPCs and HCs could provide useful information on chemical toxicity during the hepatic differentiation process and could be a useful model system for assessing chemical hepatotoxicity.
Starting Page	1
Ending Page	11
Page Count	11
File Format	PDF
ISSN	07422091
Journal	Cell Biology and Toxicology
Volume Number	29
Issue Number	1
e-ISSN	15736822
Language	English
Publisher	Springer Netherlands
Publisher Date	2012-10-30
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	5-fluorouracil Arsanilic acid Carbon tetrachloride Embryonic stem cell Hepatic progenitor cell Hepatocyte-like cell Toxicity Cell Biology Pharmacology/Toxicology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Health, Toxicology and Mutagenesis Toxicology

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