Pathogenesis of bromodeoxyuridine-induced polydactyly

Area of Science:

• Developmental biology
• Teratology
• Molecular biology

Background:

• Limb development involves precise cell death (necrosis) patterns.
• Preaxial polydactyly is a limb malformation affecting digit development.
• Bromodeoxyuridine (BUdR) is a thymidine analog used in cell proliferation studies.

Purpose of the Study:

• To investigate the mechanism of BUdR-induced preaxial polydactyly in rat hindlimbs.
• To determine if drug-induced or physiological necrosis is involved in BUdR teratogenesis.
• To explore the role of programmed cell death in limb malformation.

Main Methods:

• Intraperitoneal injection of BUdR into pregnant rats on gestational days 11 or 12.
• Embryonic examination to assess limb morphology and identify malformations.
• Histological analysis to evaluate patterns of mesenchymal and apical ectodermal ridge (AER) necrosis.
• Administration of thymidine concurrently with BUdR to assess protective effects.

Main Results:

• BUdR injection resulted in preaxial polydactyly of the hindlimb.
• The development of this polydactyly did not require drug-induced mesenchymal necrosis.
• Altered patterns of physiological necrosis in the apical ectodermal ridge (AER) were not observed.
• A specific zone of physiological necrosis in the preaxial mesoderm, crucial for digit formation, was abolished.
• Concomitant thymidine administration protected against BUdR-induced polydactyly, suggesting BUdR incorporation is key.

Conclusions:

• BUdR induces preaxial polydactyly by interfering with programmed cell death in the developing limb mesoderm.
• The mechanism differs from other polydactyly-inducing agents that rely on mesenchymal necrosis.
• Preventing the incorporation of BUdR into cells can prevent the malformation, highlighting the role of BUdR uptake in prospective necrotic cells.