Interaction of dietary zinc, genetic strain, and acetazolamide in teratogenesis in mice

Abstract

The effect of dietary zinc and genetic strain on acetazolamide-induced malformations was assessed. CBA (sensitive) and SWV (resistant) mice were fed purified diets containing five different levels of zinc throughout gestation and were given acetazolamide orally for a limited period during organogenesis. Controls received either no treatment or the drug vehicle. Litters were assessed for resorptions and malformations at term. The significance for influencing litter outcome was tested for the three main treatments: strain, dietary zinc level, and acetazolamide dose, plus their interactions. The magnitude of the litter response was strongly influenced by strain. The incidence of forelimb ectrodactyly, a characteristic malformation caused by acetazolamide, was much greater in CBA than in SWV fetuses. SWV fetuses had no ectrodactyly when dams were fed at least 9 micrograms/g zinc, but 5-8% showed ectrodactyly when dams received a zinc-deficient (0.4 or 4.5 micrograms/g) diet. The incidence of ectrodactyly in the CBA strain decreased as dietary zinc increased, but was still present when dams were fed a high (1,000 micrograms/g) zinc diet. The incidence of resorptions and total abnormal sites from litters of dams receiving acetazolamide decreased as dietary zinc increased, with the magnitude of the response being influenced by the strain. A significant (dietary zinc X acetazolamide) and (strain X acetazolamide) interaction was found for the ectrodactyly response. The results demonstrate the importance of considering interactions among genetic strain, diet, and drugs, as well as single factors as determinants of fetal risk.

Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development

“…While the concept that APR-induced changes in maternal-fetal zinc metabolism might represent a common mechanism contributing to the teratogenicity of a wide variety of toxicants and environmental insults has received considerable support, it still must be viewed as a hypothesis. Regardless, it is exciting to consider the possibility that this concept could help to explain the observation that the teratogenicity of diverse agents ranging from thalidomide (Jackson and Schumacher, 1979), acetazolamide (Hackman and Hurley, 1983), alcohol (Carey et al, 2003b;Miller et al, 1983), salicylate (Hackman and Hurley, 1984), and 6-MP (Amemiya et al, 1986) to alpha-hederin Duffy et al, 1997), can be modulated by the mother's intake of dietary zinc. From a larger perspective, this might provide one explanation for why women who consume ''poor diets'' have an elevated risk for pregnancy complications, as it would suggest that such women would have an increased sensitivity to teratogenic insults that trigger an APR.…”

Microarray analysis of murine limb bud ectoderm and mesoderm after exposure to cadmium or acetazolamide

“…Interestingly, acetazolamide‐induced postaxial forelimb ectrodactyly is heavily dependent on zinc status. Lowering dietary zinc increases the frequency of offspring with postaxial forelimb ectrodactyly at a constant dose of acetazolamide (Hackman and Hurley, 1983). Acetazolamide is a sulfonamide that acts pharmacologically through inhibition of carbonic anhydrase, a zinc metalloenzyme.…”

Effects of oyster extract on the reproductive function of zinc-deficient mice: Bioavailability of zinc contained in oyster extract

“…However, the incidence of malformations in the oyster-supplemented group was identical to the zinc-supplemented group (20 pprn Zn). With marginal zinc deficiency (4.5-10 pprn zinc), previous studies have shown low incidences of external malformations in mice (Hackman and Hurley, 1983;Sato et al, 1985). These findings suggest that zinc from the oyster extract may also have been absorbed effectively.…”