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The Effects of Class-Specific Histone Deacetylase Inhibitors on the Development of Limbs During Organogenesis.
- Source :
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2015 Nov; Vol. 148 (1), pp. 220-8. Date of Electronic Publication: 2015 Aug 06. - Publication Year :
- 2015
-
Abstract
- Histone deacetylases (HDACs) play a major role in chromatin remodeling, gene regulation, and cellular signaling. While the role of each class of HDAC during normal development is unclear, several HDAC inhibitors are embryotoxic; the mechanisms leading to the teratogenicity of HDAC inhibitors are not known. Here, we investigated the effects of class-specific HDAC inhibitors on the development of organogenesis-stage murine limbs. Timed-pregnant COL2A1-ECFP, COL10A1-mCherry, and COL1A1-YFP CD1 reporter mice were euthanized on gestation day 12; embryonic forelimbs were excised and cultured in vitro for 1, 3, and 6 days in the presence or absence of MS275 (a class I HDAC inhibitor), MC1568 (a class III HDAC inhibitor), Sirtinol (a class II HDAC inhibitor), or valproic acid, our positive control. Fluorescently tagged COL2A1, COL10A1, and COL1A1 served as markers of the differentiation of proliferative chondrocytes, hypertrophic chondrocytes, and osteoblasts, respectively. MS275 and valproic acid caused a reduction in expression of all three markers, suggesting effects on both chondrogenesis and osteogenesis. MC1568 had no effect on chondrocyte markers and mildly inhibited COL1A1 expression at 6 days. Sirtinol had no effect on COL2A1 expression or chondrocyte differentiation 1 day following exposure; however, it caused a drastic regression in limb cartilage and reduced the expression of all three differentiation markers to nearly undetectable levels at 6 days. MS275 and Sirtinol caused a 2.2- and 2.7-fold increase, respectively, in cleaved-caspase 3, a marker of apoptosis, suggesting embryotoxicity. These data demonstrate that inhibition of class I or III HDACs causes severe developmental toxicity and is highly teratogenic.<br /> (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Animals
Benzamides classification
Benzamides toxicity
Biomarkers metabolism
Cells, Cultured
Collagen Type I genetics
Collagen Type I metabolism
Collagen Type I, alpha 1 Chain
Collagen Type II genetics
Collagen Type II metabolism
Collagen Type X genetics
Collagen Type X metabolism
Embryo, Mammalian cytology
Embryo, Mammalian metabolism
Embryo, Mammalian pathology
Female
Forelimb
Genes, Reporter drug effects
Histone Deacetylase Inhibitors classification
Hydroxamic Acids classification
Hydroxamic Acids toxicity
Luminescent Proteins genetics
Luminescent Proteins metabolism
Mice, Transgenic
Naphthols classification
Naphthols toxicity
Pregnancy
Pyridines classification
Pyridines toxicity
Pyrroles classification
Pyrroles toxicity
Recombinant Fusion Proteins metabolism
Teratogens classification
Apoptosis drug effects
Chondrogenesis drug effects
Embryo, Mammalian drug effects
Gene Expression Regulation, Developmental drug effects
Histone Deacetylase Inhibitors toxicity
Osteogenesis drug effects
Teratogens toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0929
- Volume :
- 148
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 26251326
- Full Text :
- https://doi.org/10.1093/toxsci/kfv174