17β-Estradiol inhibits chondrogenesis in the skull development of zebrafish embryos

Fushimi, Shigeko; Wada, Naoki; Nohno, Tsutomu; Tomita, Masafumi; Saijoh, Kiyofumi; Sunami, Shigeo; Katsuyama, Hironobu

doi:10.1016/j.aquatox.2009.03.004

Cited by 38 publications

(45 citation statements)

References 55 publications

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“…The screening approach and execution appears to have been independently validated by a recent report examining the effect of exogenous 17-β-estradiol exposure on chondrocranial development in the zebrafish (Fushimi et al, 2009). The authors demonstrated that exposure above 5 μM caused craniofacial dysmorphia grossly mimicking that of both shh- mutant and cyclopamine-exposed zebrafish (Wada et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening

Lipinski

Bushman

2010

Toxicology in Vitro

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In animal models, chemical disruption of the Hedgehog (Hh) signaling pathway during embryonic development causes severe birth defects including holoprosencephaly and cleft lip and palate. The exact etiological basis of correlate human birth defects remains uncertain but is likely multifactorial, involving the interaction of genetic and environmental or chemical influences. The Hh transduction mechanism relies upon endogenous small molecule regulation; conferring remarkable pathway sensitivity to inhibition by a structurally diverse set of exogenous small molecules. Here, we employed small molecule screening to identify human exposure-relevant Hh signaling inhibitors. From of a library of 4,240 compounds -including pharmaceuticals, natural products, and pesticides, three putative Hh pathway inhibitors were identified: tolnaftate, an antifungal agent; ipriflavone, a dietary supplement; and 17-β-estradiol, a human hormone and pharmaceutical agent. Each compound inhibited Hh signaling in both mouse and human cells. Dose-response assays determined the three compounds to be 8-to-30 fold less potent than the index Hh pathway inhibitor cyclopamine. Despite current limitations in chemical library availability, which narrowed the scope of this study to only a small fraction of all human exposure-relevant small molecules, three structurally diverse environmental Hh signaling inhibitors were identified, highlighting an inherent pathway vulnerability to teratogenic influences.

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Section: Discussionmentioning

confidence: 99%

Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening

Lipinski

Bushman

2010

Toxicology in Vitro

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“…21 The severity of the craniofacial anomaly is dependent on the dose of estradiol and the time window of treatment. At higher doses, estradiol can generate severe disruption of both the ethmoid plate and the mandible.…”

Section: Analysis Of Cncc Migration After Estradiol Treatmentmentioning

confidence: 99%

“…20 Loss of the median ethmoid plate also results from inhibition of shh signaling, which can be phenocopied with estradiol chemical treatment. 1,2,21 Construction of developmental fate maps has been a powerful tool for studying the migration of CNCCs. 22 The transgenic line sox10:egfp, in which a fluorescent protein is driven by a promoter for sox10, a marker of premigratory neural crest, has been used for tracking movements of neural crest cells in the zebrafish embryo.…”

Section: What Is This Box?mentioning

confidence: 99%

Embryonic Fate Map of First Pharyngeal Arch Structures in the sox10

Dougherty

Kamel

Shubinets

et al. 2012

Journal of Craniofacial Surgery

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Cranial neural crest cells follow stereotypic patterns of migration to form craniofacial structures. The zebrafish is a powerful vertebrate genetic model where transgenics with reporter proteins under the transcriptional regulation of lineage-specific promoters can be generated. Numerous studies demonstrate that the zebrafish ethmoid plate is embryologically analogous to the mammalian palate. A fate map correlating embryonic cranial neural crest to defined jaw structures would provide a useful context for the morphogenetic analysis of craniofacial development. To that end, the sox10:kaede transgenic was generated, where sox10 provides lineage restriction to the neural crest. Specific regions of neural crest were labeled at the 10-somite stage by photoconversion of the kaede reporter protein. Lineage analysis was carried out during pharyngeal development in wild-type animals, after miR140 injection, and after estradiol treatment. At the 10-somite stage, cranial neural crest cells anterior of the eye contributed to the median ethmoid plate, whereas cells medial to the eye formed the lateral ethmoid plate and trabeculae and a posterior population formed the mandible. miR-140 overexpression and estradiol inhibition of Hedgehog signaling resulted in cleft development, with failed migration of the anterior cell population to form the median ethmoid plate. The sox10:kaede transgenic line provides a useful tool for neural crest lineage analysis. These studies illustrate the advantages of the zebrafish model for application in morphogenetic studies of vertebrate craniofacial development.

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“…The majority of fish toxicology studies to date have focused on acute toxicity to chemicals, pesticides, and pharmaceuticals. 46 Examples include testing of the antirheumatic drug diclofena, 50 endocrine disrupters such as estrogens and the antiarrhythmic agent Amiodarone, 51,52 as well as ethanol and acetaldehyde. [53][54][55] In all cases, zebrafish larvae exhibited similar xenobiotic, genetic, and physiological responses as documented in mammalian systems.…”

Section: Toxicology Studiesmentioning

confidence: 99%

The Zebrafish: A Powerful Platform forIn Vivo, HTS Drug Discovery

Delvecchio

Tiefenbach

Krause

2011

ASSAY and Drug Development Technologies

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The zebrafish (Danio rerio) is an emerging vertebrate model for drug discovery that permits whole animal drug screens with excellent throughput, combined with ease of use and low cost. This review will begin with a discussion on the background, suitability, and advantages of this vertebrate model system and then, citing specific examples, will describe the utility of zebrafish at specific stages in the drug development pipeline. We will end with a synopsis of recent drug screens based on morphological disruptions, genetic disease models, fluorescent markers, behavioral changes, and specific targets. The numerous advantages of this whole animal approach provide new promise for the discovery of safe, specific, and powerful new drugs.

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17β-Estradiol inhibits chondrogenesis in the skull development of zebrafish embryos

Cited by 38 publications

References 55 publications

Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening

Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening

Embryonic Fate Map of First Pharyngeal Arch Structures in the sox10

The Zebrafish: A Powerful Platform forIn Vivo, HTS Drug Discovery

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