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Genetic control of the teratogenic response to acetazolamide in mice Biddle, Frederick Gordon


Acetazolamide is a potent carbonic anhydrase inhibitor and a known teratogen. In mice, it Induces a specific postaxial ectrodactyly of the right forelimb; occasionally the left forelimb is also affected. No other malformations are produced by this drug except fetal death with high doses. The SWV strain of mice was found to be resistant to any teratogenic or embryotoxic action of acetazolamide. Very high doses resulted in death of the SWV dam. The teratogenic action and dose-response relationship of acetazolamide were documented for the sensitive CBA/J strain. Mid-day 10 was found to be the embryo sensitive stage for the induction of forelimb ectrodactyly. With an appropriate acetazolamide dosage regime of two injections on day 10 of pregnancy, a genetic analysis was made of the teratogenic sensitivity of the CBA/J strain and resistance of the SWV strain. Reciprocal crosses between the two demonstrated that resistance was dominant to sensitivity. No affected SWV.CBA F₁ hybrids were found in SWV dams but a low frequency of ectrodactyly was found among CBA.SWV F₁ hybrids in CBA/J dams. This disparity may be due to small sample size of the treated SWV.CBA F₁ hybrids and was not considered to be a differential influence of the dams. A backcross program was set up using the CBA/J dam throughout. Both a biometrlcal analysis and an examination of the mean frequencies of ectrodactyly in each generation suggested that three independently segregating loci controlled the trait of embryonic sensitivity to the teratogenic action of acetazolamlde. From this model, the predicted BC₃ generation mean frequency of ectrodactyly was achieved in a further breeding program. Also, the CBA/J inbred strain frequency of ectrodactyly was recovered with two BG₂ sires and this suggested that the CBA/J genotype had been recovered. It was found that induction of ectrodactyly and fetal death were two separate actions of acetazolamlde. The embryo transfer technique was used in a preliminary investigation of the CBA/J and SWV strain responses to acetazolamlde. It was demonstrated that the teratogenic environment does exist in the SWV dam after acetazolamide administration and that resistance of this strain is a property of the embryo. The sensitivity and resistance of the CBA/J and SWV strains remained with dlchlorphenamide, another ectrodactyly inducing carbonic anhydrase Inhibitor. It is suggested that SWV may have a general resistance to this .class of teratogens. The results of this study are discussed in the light of other investigations of the mechanism of acetazolamide teratogenesls as well as in the context of other studies of genetic variation in teratogenic responses.

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