The inhibition of embryonic histone deacetylases as the possible mechanism accounting for axial skeletal malformations induced by sodium salicylate.
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 h 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 h 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.
Di Renzo
Francesca
F
Department of Biology, University of Milan, 20133 Milan, Italy.
Cappelletti
Graziella
G
Broccia
Maria Luisa
ML
Giavini
Erminio
E
Menegola
Elena
E
D000014:Abnormalities, Drug-Induced / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D000107:Acetylation; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D007274:Injections, Intraperitoneal; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D012980:Sodium Salicylate / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*
D016861:Cyclooxygenase Inhibitors; D006657:Histones; D013723:Teratogens; D051548:Histone Acetyltransferases; D012980:Sodium Salicylate