In spite of the large use of salicylates, introduced into clinical practice more than 100 years ago, their anti-inflammatory and cancer preventive mechanisms are still under study. Teratogenic effects of salicylates have been reported in experimental animals since 1959 but the pathogenic pathways and the mechanisms of action were never described until now. The aim of this work is to verify if the inhibition of embryonic histone deacetylase (HDAC) enzymes and the consequent tissue hyperacetylation could be the mechanism responsible for axial skeletal defects described after the exposure of pregnant rodents to sodium salicylate (SAL). E8 pregnant CD-1 mice were intraperitoneally treated with SAL 0-150-300-450 mg/kg and sacrificed at 1, 3, 5 hrs after treatment or at term of gestation (E18). E8 embryos were processed for Western blotting and immunostaining analyses, while skeletons of E18 fetuses were double stained for bone and cartilage. A group of control E8 embryos were used to prepare embryonic nuclear extract for the HDAC enzyme assay. A significant SAL dose-related HDAC inhibition activity, compatible with a mixed type partial inhibition mechanism, was detected. A clear dose-related hyperacetylation of histones was observed in embryos exposed in utero to SAL, with a peak at 3 hrs after treatment of dams. The most hyperacetylated organs were somites and the heart. Histone hyperacetylation is suggested to be the mechanism accounting for SAL-related axial skeletal and cardiovascular defects and is proposed as the mechanism responsible for other biological effects of salicylates.
The inhibition of embryonic histone deacetylases as the possible mechanism accounting for axial skeletal malformations induced by Sodium Salicylate / F. Di Renzo, G. Cappelletti, M.L. Broccia, E. Giavini, E. Menegola. - In: TOXICOLOGICAL SCIENCES. - ISSN 1096-6080. - 104:2(2008), pp. 397-404.
|Titolo:||The inhibition of embryonic histone deacetylases as the possible mechanism accounting for axial skeletal malformations induced by Sodium Salicylate|
|Parole Chiave:||Enzymatic activity; HDAC; Histone; Hyperacetylation; Mouse; Somite|
|Settore Scientifico Disciplinare:||Settore BIO/06 - Anatomia Comparata e Citologia|
|Data di pubblicazione:||2008|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/toxsci/kfn094|
|Appare nelle tipologie:||01 - Articolo su periodico|