2,3,7,8-Tetrachlorodibenzo-p-dioxin Inhibits Zebrafish Caudal Fin Regeneration

Zodrow, Jeanmarie; Tanguay, Robert L.

doi:10.1093/toxsci/kfg205

Cited by 69 publications

(50 citation statements)

References 61 publications

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“…We have reported previously that aryl hydrocarbon receptor ligands block regeneration at both early and late stages in adult and larval zebrafish (15,36). To define the regenerative stage that is most responsive to GR activation, beclomethasone (1 M) was added beginning at a number of distinct time windows postamputation.…”

Section: Gr Activation Is Required For Beclomethasone To Inhibitmentioning

confidence: 99%

Unraveling Tissue Regeneration Pathways Using Chemical Genetics

Mathew

Sengupta

Kawakami

et al. 2007

Journal of Biological Chemistry

162

168

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Identifying the molecular pathways that are required for regeneration remains one of the great challenges of regenerative medicine. Although genetic mutations have been useful for identifying some molecular pathways, small molecule probes of regenerative pathways might offer some advantages, including the ability to disrupt pathway function with precise temporal control. However, a vertebrate regeneration model amenable to rapid throughput small molecule screening is not currently available. We report here the development of a zebrafish early life stage fin regeneration model and its use in screening for small molecules that modulate tissue regeneration. By screening 2000 biologically active small molecules, we identified 17 that specifically inhibited regeneration. These compounds include a cluster of glucocorticoids, and we demonstrate that transient activation of the glucocorticoid receptor is sufficient to block regeneration, but only if activation occurs during wound healing/blastema formation. In addition, knockdown of the glucocorticoid receptor restores regenerative capability to nonregenerative, glucocorticoid-exposed zebrafish. To test whether the classical anti-inflammatory action of glucocorticoids is responsible for blocking regeneration, we prevented acute inflammation following amputation by antisense repression of the Pu.1 gene. Although loss of Pu.1 prevents the inflammatory response, regeneration is not affected. Collectively, these results indicate that signaling from exogenous glucocorticoids impairs blastema formation and limits regenerative capacity through an acute inflammation-independent mechanism. These studies also demonstrate the feasibility of exploiting chemical genetics to define the pathways that govern vertebrate regeneration.

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Section: Gr Activation Is Required For Beclomethasone To Inhibitmentioning

confidence: 99%

Unraveling Tissue Regeneration Pathways Using Chemical Genetics

Mathew

Sengupta

Kawakami

et al. 2007

Journal of Biological Chemistry

162

168

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“…The development of in vivo models to explore the complexity of AHR signal transduction is essential. Adult zebrafish have the remarkable capacity to regenerate their caudal fins completely within 14 days after amputation (Geraudie et al, 1995), and it was previously demonstrated that TCDD inhibits this complex process (Zodrow and Tanguay, 2003). Recently, it was reported that the caudal fin primordia of zebrafish larvae are also capable of tissue regeneration in a process remarkably similar to that observed in adults (Kawakami et al, 2004).…”

mentioning

confidence: 93%

Aryl Hydrocarbon Receptor Activation Inhibits Regenerative Growth

2005

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There is considerable literature supporting the conclusion that inappropriate activation of the aryl hydrocarbon receptor (AHR) alters cellular signaling. We have established previously that fin regeneration is specifically inhibited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in adult zebrafish and have used this in vivo endpoint to evaluate interactions between AHR and growth-controlling pathways. Because there are experimental limitations in studying regeneration in adult animals, we have developed a larval model to evaluate the effect of AHR activation on tissue regeneration. Two-day-old zebrafish regenerate their amputated caudal fins within 3 days. Here, we demonstrate that TCDD specifically blocks regenerative growth in larvae. The AHR pathway in zebrafish is considerably more complex than in mammals, with at least three zebrafish AHR genes (zfAHR1a, zfAHR1b, and zfAHR2) and two ARNT genes (zfARNT1 and zfARNT2). Although it was presumed that the block in regeneration was mediated by AHR activation, it had not been experimentally demonstrated. Using antisense morpholinos and mutant fish lines, we report that zfAHR2 and zfARNT1 are the in vivo dimerization partners that are required for inhibition of regeneration by TCDD. Several pathways including fibroblast growth factor (FGF) signaling are essential for fin regeneration. Even though impaired FGF signaling and TCDD exposure both inhibit fin regeneration, their morphometric response is distinct, suggesting that the mechanisms of impairment are different. With the plethora of molecular and genetic techniques that can be applied to larval-stage embryos, this in vivo regeneration system can be further exploited to understand cross-talk between AHR and other signaling pathways.

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“…The drug may also have inhibited the cells responsible for collagen synthesis, as has been reported for the lipolytic drug SU5402 and the substance 2,3,7,8-tetrachlorodibenzop-dioxin (Zodrow and Tanguay, 2003). Moreover, it may have inhibited collagen-producing cells through the inhibition of the translation of mRNA for type II collagen, as reported by Kawashima et al (2003) in cultures cells.…”

Section: Discussionmentioning

confidence: 75%

Dexamethasone action on caudal fin regeneration of carp Cyprinus carpio (Linnaeus, 1758)

2015

Braz. J. Biol.

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Studies have demonstrated that the prolonged use of corticoids can delay the healing process, affecting re-epithelialization, neovascularization and collagen synthesis. As the fins of teleost fish contain a large amount of collagen, the aim of the present study was to investigate the effect of dexamethasone (anti-inflammatory and glucocorticoid steroid widely used in the treatment of rheumatic diseases) during the regeneration process in the caudal fin of specimens of carp (Cyprinus carpio). For such, two glass aquaria were used -one for a group of fish treated with dexamethasone (Henrifarma) in a 20 mg/L concentration and the other for the control group. The caudal fins were amputated transversally and fish remained in their respective aquaria until regeneration occurred. Samples of regenerating fins were collected on days 1, 2, 4, 6, 8 and 10 after amputation. The fins in the control group regenerated normally and grew within the expected in time course. The fins in the group treated with dexamethasone were significantly smaller in comparison to the control group at every evaluation time. Thus, it was possible to verify that, at this concentration of dexamethasone, the regeneration of the caudal fins was delayed, but not completely inhibited. The results show that the caudal fin is a good model for histological studies on regeneration and the action of drug toxicity, but it's also of great importance the interaction with further studies for a better knowledge and understanding of all the changes in all the phases.Keywords: dexamethasone, caudal fin, tissue regeneration, collagen, fish. Estudo da ação da dexametasona na regeneração da nadadeira caudal deCyprinus carpio (carpa) (Linnaeus, 1758) ResumoEstudos mostram que corticóides usados por longos períodos podem atrasar o processo de cicatrização, influenciando na reepitelização, na neovascularização e na síntese do colágeno. Os constituintes das nadadeiras dos peixes teleósteos contêm grande quantidade de colágeno e assim o objetivo do presente trabalho foi estudar o efeito da dexametasona (um antiinflamatório e glicocorticóide esteróide bastante utilizado no tratamento de doenças reumáticas) durante o processo regenerativo das nadadeiras caudais das carpas (Cyprinus carpio). Para isso, foram montados dois aquários de vidro, um para o grupo controle e outro para o grupo tratado com a dexametasona (Henrifarma) na concentração de 20mg/L. Os peixes distribuídos nesses aquários tiveram suas nadadeiras caudais amputadas transversalmente e permaneceram nos respectivos aquários para que ocorresse a regeneração. Foram feitas coletas das nadadeiras em regeneração em intervalos de 1, 2, 4, 6, 8 e 10 dias após a amputação. Foi observado que nos peixes do grupo controle, as nadadeiras regeneraram normalmente e cresceram o esperado em cada intervalo de tempo. No entanto, foi verificado que nos peixes do grupo tratado com dexametasona, em cada intervalo analisado, as nadadeiras regeneradas dos peixes expostos à droga eram menores que a medida das nadadeiras dos pei...

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2,3,7,8-Tetrachlorodibenzo-p-dioxin Inhibits Zebrafish Caudal Fin Regeneration

Cited by 69 publications

References 61 publications

Unraveling Tissue Regeneration Pathways Using Chemical Genetics

Unraveling Tissue Regeneration Pathways Using Chemical Genetics

Aryl Hydrocarbon Receptor Activation Inhibits Regenerative Growth

Dexamethasone action on caudal fin regeneration of carp Cyprinus carpio (Linnaeus, 1758)

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