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Developmental abnormalities of the otic capsule and inner ear following application of prolyl-hydroxylase inhibitors in chick embryos

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1194-1204
Number of pages11
JournalBirth Defects Research
Volume110
Issue number15
Early online date6 Aug 2018
DOIs
DateAccepted/In press - 9 Jul 2018
DateE-pub ahead of print - 6 Aug 2018
DatePublished (current) - 1 Sep 2018

Abstract

Background
Naturally hypoxic conditions in amniote embryos play important roles in normal development. We previously showed that a hypoxic condition is required to produce a sufficient amount of neural crest cells (NCCs) during embryogenesis and that promoting a hypoxic response by prolyl-hydroxylase (PHD) inhibitors increases NCCs. Given that PHD inhibitors are considered as a potential treatment for anaemia and ischemic diseases, we investigated the phenotypic effect of PHD inhibitors on embryonic development.

Methods
Chick embryos were administered with PHD inhibitors prior to the induction of NCCs on day 1.5. Three main events relating to hypoxia, NCCs induction, vasculogenesis and chondrogenesis, were examined.

Results
PHD inhibitors caused an increase of Sox10-positive NCCs in vivo. Vasculogenesis was promoted temporarily, although rapid vasculogenesis diminished the effect by day 5 in cephalic and pharyngeal regions. Studies on chondrogenesis at day 7 showed advanced development of the otic capsule, a cartilaginous structure encapsulating the inner ear. Analysis by X-ray micro-computed-tomography (µCT) revealed smaller otic capsule, suggesting premature differentiation. This in turn deformed the developing semicircular canals within it. Other skeletal structures such as the palate and jaw were unaffected. The localised effect on the otic capsule was considered a result of the multiple effects from the hypoxic responses, increased NCCs and promoted chondrogenesis.

Conclusion
Given the wide range of clinical applications being considered for PHD inhibitors, this study provides crucial information to caution and guide use of PHD inhibitors when treating women of childbearing age.

    Research areas

  • chick embryos, hypoxia, inner ear, otic capsule, prolyl-hydroxylase inhibitors, semicircular canals, μCT

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Wiley at https://onlinelibrary.wiley.com/doi/full/10.1002/bdr2.1375 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 414 KB, PDF document

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