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Acetazolamide exposure during early gestation causes postaxial forelimb deformities in mouse embryos. This developmental issue arises from mesenchyme tissue deficiency, not cell death or impaired cartilage precursor aggregation.
Area of Science:
- Developmental biology
- Teratology
- Pharmacology
Background:
- Acetazolamide is a carbonic anhydrase inhibitor used medically.
- Drug-induced developmental abnormalities are a significant concern in prenatal health.
- Understanding the mechanisms of teratogenesis is crucial for drug safety.
Purpose of the Study:
- To investigate the effects of acetazolamide on embryonic limb development.
- To identify the timing and nature of acetazolamide-induced limb malformations.
- To elucidate the cellular mechanisms underlying these deformities.
Main Methods:
- Histological examination of mouse embryonic forelimbs.
- Timed pregnancies in C57Bl/6J mice exposed to acetazolamide.
- Analysis of limb development at various embryonic stages post-exposure.
Main Results:
- Postaxial forelimb mesenchyme deficiency was observed in embryos.
- Deformities were evident by embryonic day 10.9, 36 hours after a second acetazolamide dose.
- The observed defect occurred prior to mesenchyme cell aggregation and chondrogenesis.
- Cellular organization in adjacent mesenchyme was normal, suggesting acetazolamide's effect is not on initial precartilage aggregate formation.
Conclusions:
- Acetazolamide induces postaxial limb developmental defects in mice.
- The primary mechanism involves mesenchyme tissue deficiency, not cell necrosis.
- The drug's teratogenic effect appears to target early limb development processes beyond initial mesenchymal condensation.
Abstract:
Histologic sections were made of the forelimbs of day 10 to 12.5 embryos removed 3, 16, 30, 36, 42, 45, 63 and 75 hours after the intraperitoneal injection of acetazolamide into C57Bl/6J pregnant females. A postaxial deformity was first visible in the right forelimb of day 10.9 embryos 36 hours after the second dose of acetazolamide 1,000 mg/kg on day 9 of gestation. The deformity was a postaxial deficiency of mesenchyme tissue without any evidence of cell necrosis. The deformity was present before aggregation of mesenchyme cells occurs as the first step in chrondrogenesis. The pattern of cell orientation in the adjacent mesenchyme aggregate of a deformed day 12.5 forelimb was normal. This means that the primary effect of acetazolamide is not on the formation of precartilage aggregates in the postaxial region, but involves other aspects of early limb development.