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Teratogen screening using transcriptome profiling of differentiating human embryonic stem cells.

Mayshar Y, Yanuka O, Benvenisty N - J. Cell. Mol. Med. (2010)

Bottom Line: Our results point to the potency of specific teratogens and their affected tissues and pathways.Specifically, we could show that ethanol caused dramatic increase in endodermal differentiation, RA caused misregulation of neural development and thalidomide affected both these processes.We thus propose this method as a valuable addition to currently available animal screening approaches.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.

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Related in: MedlinePlus

(A) Anterior homeobox genes are up-regulated by RA. Shown is a schematic representation of the homeobox gene clusters and fold induction by RA relative to control, in both HESC and HiPSC EBs. Red boxes indicate significance of P < 0.05 in HESC as judged by two-tailed Student’s t-test. (B) Early hepatic markers are specifically up-regulated following ethanol treatment. Shown are the expression levels of the AFP and transthyretin genes as well as genes from the apolipoprotein and fibrinogen gene families that have been found to be significantly (P < 0.05) up-regulated by high ethanol (1.5% and 2%) using two-tailed Student’s t-test, error bars represent S.D.
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fig03: (A) Anterior homeobox genes are up-regulated by RA. Shown is a schematic representation of the homeobox gene clusters and fold induction by RA relative to control, in both HESC and HiPSC EBs. Red boxes indicate significance of P < 0.05 in HESC as judged by two-tailed Student’s t-test. (B) Early hepatic markers are specifically up-regulated following ethanol treatment. Shown are the expression levels of the AFP and transthyretin genes as well as genes from the apolipoprotein and fibrinogen gene families that have been found to be significantly (P < 0.05) up-regulated by high ethanol (1.5% and 2%) using two-tailed Student’s t-test, error bars represent S.D.

Mentions: To further characterize the molecular events induced by ethanol, RA and thalidomide, Gene Ontology based functional annotation was performed [23] (Fig. 2). Of the categories enriched in genes up-regulated by RA are the homeobox protein genes (14.1-fold above expected frequency). Hox genes of the Homeobox gene family are key regulators of many developmental processes and are known to be directly regulated by RA signalling [24]. Hox genes have been shown to be expressed in vertebrates along the dorsal axis in a spatially and temporally regulated manner, such that the 3′ located genes are expressed earlier and in the anterior regions, while the 5′ located genes are expressed later on and in the posterior parts of the embryo. In our analysis we show that the anterior HoxA and HoxB genes are specifically up-regulated by RA treatment both in HESC and HiPSC EBs (Fig. 3A). In the ethanol treated EBs the most significantly up-regulated functional group were liver protein genes (9.3-fold) (Fig. 2). These include several apolipoprotein and fibrinogen genes (Fig. 3B) as well as the early hepatic markers AFP and transthyretin. Later adult hepatic markers such as albumin and the alcohol dehydrogenase genes were not up-regulated. Thalidomide caused significant up-regulation of genes responsible for metabolism of xenobiotics (11.5-fold) and down-regulation of oxidative stress response genes (15.8-fold). This observation fits with previous reports connecting thalidomide activity with reactive oxygen species induced DNA damage. Additionally affected were several developmental related gene groups such as nervous system development genes (2.5-fold) and transforming growth factor β genes (29.6-fold) (Fig. 2).


Teratogen screening using transcriptome profiling of differentiating human embryonic stem cells.

Mayshar Y, Yanuka O, Benvenisty N - J. Cell. Mol. Med. (2010)

(A) Anterior homeobox genes are up-regulated by RA. Shown is a schematic representation of the homeobox gene clusters and fold induction by RA relative to control, in both HESC and HiPSC EBs. Red boxes indicate significance of P < 0.05 in HESC as judged by two-tailed Student’s t-test. (B) Early hepatic markers are specifically up-regulated following ethanol treatment. Shown are the expression levels of the AFP and transthyretin genes as well as genes from the apolipoprotein and fibrinogen gene families that have been found to be significantly (P < 0.05) up-regulated by high ethanol (1.5% and 2%) using two-tailed Student’s t-test, error bars represent S.D.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4373338&req=5

fig03: (A) Anterior homeobox genes are up-regulated by RA. Shown is a schematic representation of the homeobox gene clusters and fold induction by RA relative to control, in both HESC and HiPSC EBs. Red boxes indicate significance of P < 0.05 in HESC as judged by two-tailed Student’s t-test. (B) Early hepatic markers are specifically up-regulated following ethanol treatment. Shown are the expression levels of the AFP and transthyretin genes as well as genes from the apolipoprotein and fibrinogen gene families that have been found to be significantly (P < 0.05) up-regulated by high ethanol (1.5% and 2%) using two-tailed Student’s t-test, error bars represent S.D.
Mentions: To further characterize the molecular events induced by ethanol, RA and thalidomide, Gene Ontology based functional annotation was performed [23] (Fig. 2). Of the categories enriched in genes up-regulated by RA are the homeobox protein genes (14.1-fold above expected frequency). Hox genes of the Homeobox gene family are key regulators of many developmental processes and are known to be directly regulated by RA signalling [24]. Hox genes have been shown to be expressed in vertebrates along the dorsal axis in a spatially and temporally regulated manner, such that the 3′ located genes are expressed earlier and in the anterior regions, while the 5′ located genes are expressed later on and in the posterior parts of the embryo. In our analysis we show that the anterior HoxA and HoxB genes are specifically up-regulated by RA treatment both in HESC and HiPSC EBs (Fig. 3A). In the ethanol treated EBs the most significantly up-regulated functional group were liver protein genes (9.3-fold) (Fig. 2). These include several apolipoprotein and fibrinogen genes (Fig. 3B) as well as the early hepatic markers AFP and transthyretin. Later adult hepatic markers such as albumin and the alcohol dehydrogenase genes were not up-regulated. Thalidomide caused significant up-regulation of genes responsible for metabolism of xenobiotics (11.5-fold) and down-regulation of oxidative stress response genes (15.8-fold). This observation fits with previous reports connecting thalidomide activity with reactive oxygen species induced DNA damage. Additionally affected were several developmental related gene groups such as nervous system development genes (2.5-fold) and transforming growth factor β genes (29.6-fold) (Fig. 2).

Bottom Line: Our results point to the potency of specific teratogens and their affected tissues and pathways.Specifically, we could show that ethanol caused dramatic increase in endodermal differentiation, RA caused misregulation of neural development and thalidomide affected both these processes.We thus propose this method as a valuable addition to currently available animal screening approaches.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.

Show MeSH
Related in: MedlinePlus