Monoisoamyl dimercaptosuccinic acid abrogates arsenic-induced developmental toxicity in human embryonic stem cell-derived embryoid bodies: comparison with in vivo studies.
The ability of human embryonic stem (ES) cells to differentiate into the three germ layers has proposed its application in studying human developmental toxicity in vitro. In the current study we investigated if the prompted application could be utilized to evaluate the efficacy of a newly developed arsenic antidote, monoisoamyl dimercaptosuccinic acid (MiADMSA) against arsenic (III) and if the results obtained in vitro were in concordance with the animal model for studying developmental toxicity. On the basis of real time PCR (qRT-PCR) and cytotoxicity analysis of human embryoid bodies (EBs), we observed that arsenic (III) caused a significant down regulation of gene expression in all the three germ layers, which could be correlated with high mortality, visceral and skeletal defects in pups. Reversal of arsenic-induced dysfunctioning could be observed with concomitant treatment of MiADMSA in vitro and in vivo, indicating ES-EB model could provide toxicity information similar to in vivo model. IR spectroscopy further suggested that MiADMSA bind to arsenic to form adduct, which prevents arsenic from exerting its toxic effect in both models. To our knowledge this study provides first experimental evidence suggesting human ES cells could be utilized in studying the efficacy of drugs in a comparable manner with animal models. We conclude that the ES-EB model seems to be an effective, faster, cost effective method for predicting efficacy of a drug.
Flora
S J S
SJ
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 001, India. sjsflora@hotmail.com
Mehta
Ashish
A
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D000013:Congenital Abnormalities / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D047108:Embryonic Development / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000187:drug effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005855:Germ Layers / Q000187:drug effects; D006801:Humans; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D017670:Sodium Compounds / Q000633:toxicity*; D004113:Succimer / Q000031:analogs & derivatives* / Q000494:pharmacology; D018675:Toxicity Tests / Q000379:methods
D018053:Arsenites; D002614:Chelating Agents; D004785:Environmental Pollutants; D017670:Sodium Compounds; C017947:sodium arsenite; C091888:monoisoamyl-2,3-dimercaptosuccinate; D004113:Succimer