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ToxSci Advance Access originally published online on May 21, 2007
Toxicological Sciences 2007 98(2):582-588; doi:10.1093/toxsci/kfm115
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Relationship between Embryonic Histonic Hyperacetylation and Axial Skeletal Defects in Mouse Exposed to the Three HDAC Inhibitors Apicidin, MS-275, and Sodium Butyrate

Francesca Di Renzo, Maria Luisa Broccia, Erminio Giavini and Elena Menegola1

Department of Biology, University of Milan, via Celoria, 26, 20133 Milan, Italy

1 To whom correspondence should be addressed. Fax: +39-02-50314802. E-mail: elena.menegola{at}unimi.it.

Received March 7, 2007; accepted May 3, 2007


  Abstract

Some histone deacetylase inhibitors (HDACi) have recently been related to teratogenic effects in rodents. Skeletal defects have been directly associated with embryonic hyperacetylation of somitic nuclei after valproic acid or trichostatin A exposure in vivo. Albeit the antitumoral activity of HDACi has been classically related to chromatin condensation due to histonic lysine hyperacetylation, nonhistonic proteins have also been suggested as an HDACi target. The aim of this work was the study of the effects of three HDACi (apicidin, API; MS-275; sodium butyrate, BUT) on mouse development and their activity on embryonic histonic and nonhistonic proteins. Pregnant mice were ip treated with 10 mg/kg body weight API, 25 mg/kg MS-275, 2000 mg/kg BUT or with the vehicle alone on day 8 post coitum. Embryos were extracted 1, 2, or 3 h after treatment and Western blotting (using antibodies antihyperacetylated histone H4, antiacetylated lysine, or antitubulin) and immunohistochemistry (using the antibody antihyperacetylated histone H4) were performed. Fetuses, explanted at term of gestation, were double stained for bone and cartilage to detect skeletal abnormalities. The studied HDACi were teratogenic. The specific axial skeletal malformations were fusions or homeotic respecifications. These molecules induced hyperacetylation restricted to somitic histones. The hyperacetylation index of histone H4 as well as immunohistochemical and skeletal analyses indicated BUT as the less active molecule. These new data on effects of API, MS-275, and BUT on development suggest histonic hyperacetylation as the mechanism for the induction of the observed skeletal abnormalities.

Key Words: HDACi; teratogenesis; embryo; immunohistochemistry; Western blot; somite.


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F. Di Renzo, G. Cappelletti, M. L. Broccia, E. Giavini, and E. Menegola
The Inhibition of Embryonic Histone Deacetylases as the Possible Mechanism Accounting for Axial Skeletal Malformations Induced by Sodium Salicylate
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[Abstract] [Full Text] [PDF]


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