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Abnormalities in ureter and kidney development in mice given acetazolamide-amiloride or dimethadione (DMO) during
1Children's Hospital Research Foundation, Cincinnati, Ohio.
Abstract:
These experiments more accurately define the effects of the combination acetazolamide-amiloride or a single dose of dimethadione (DMO), the active metabolite of trimethadione, on the development of the ureter. When acetazolamide-amiloride was administered in C57BL/6NCrlBR mice on day 9, 9.5, or 10 of gestation (plug = day 0) a second ureter was formed, anterior to the original ureter, inducing a second kidney. The second ureter then fails to make a connection with the developing bladder and remains attached to the mesonephric duct. The mesonephric duct becomes the vas deferens in the male and deteriorates completely in the female leading to either a restricted ureter or a blocked ureter depending on the sex of the fetus. Administration of a single dose of DMO between gestational day 9 and 10.3 produced both renal agenesis and ureters of varying lengths. Some ureters were of normal length with a tuft of one or two nephrons at their tip, while others were one half or one quarter of their normal length. In some instances the ureter was completely absent. The reason for this strong effect on the ureter is unknown.
Insights
Acetazolamide-amiloride combination therapy in mice induced a second ureter and kidney, potentially causing blocked ureters. Dimethadione (DMO) caused varying ureter lengths and renal agenesis.
Area of Science:
- Developmental biology
- Toxicology
- Urology
Background:
- Ureter development is crucial for kidney function.
- Teratogens can disrupt normal embryonic development, leading to congenital anomalies.
- Acetazolamide and dimethadione (DMO) are known to affect embryonic development.
Purpose of the Study:
- To precisely define the teratogenic effects of acetazolamide-amiloride and dimethadione (DMO) on ureter development.
- To investigate the impact of these agents on kidney and ureter formation in mice.
Main Methods:
- Administration of acetazolamide-amiloride or DMO to pregnant C57BL/6NCrlBR mice during critical gestational periods (days 9-10.3).
- Detailed examination of fetal development, focusing on kidney and ureter morphology.
- Sex-specific analysis of ureter anomalies.
Main Results:
- Acetazolamide-amiloride induced a supernumerary ureter and kidney, with the secondary ureter failing to connect to the bladder.
- Sex-specific outcomes were observed: males developed a restricted ureter, while females experienced a blocked ureter.
- DMO administration resulted in renal agenesis and ureters of abnormal lengths, including complete absence in some cases.
Conclusions:
- Acetazolamide-amiloride and DMO are potent teratogens affecting ureter and kidney development.
- The precise mechanisms underlying these teratogenic effects on ureterogenesis remain to be elucidated.
- These findings highlight the sensitivity of early embryonic development to specific drug exposures.