Oxidative stress and reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O(2)), which is detoxified by catalase, are implicated in fetal death and birth defects. However, embryonic levels of catalase are only ∼ 5% of adult activity, and its protective role is not understood completely. Herein, we used mutant catalase-deficient mice [acatalasemic (aCat)] and transgenic mice expressing human catalase (hCat), which, respectively, exhibited 40-50% reductions and 2-fold elevations in the activities of embryonic and fetal brain catalase, to show that embryonic catalase protects the embryo from both physiological oxidative stress and the ROS-initiating antiepileptic drug phenytoin. Compared to wild-type (WT) catalase-normal controls, both untreated and phenytoin-exposed aCat mice exhibited a 30% increase in embryonic DNA oxidation and a >2-fold increase in embryopathies, both of which were completely blocked by protein therapy with exogenous catalase. Conversely, compared to WT controls, untreated and, to a lesser extent, phenytoin-exposed hCat mice were protected, with untreated hCat embryos exhibiting a 40% decrease in embryonic DNA oxidation and up to a 67% decrease in embryopathies. Embryonic catalase accordingly plays an important protective role, and both physiological and phenytoin-enhanced oxidative stress can be embryopathic.

Reactive oxygen species (ROS) are implicated in spontaneous and xenobiotic-enhanced embryopathies, and protein therapy with exogenous catalase suggests an embryoprotective role, although embryonic catalase activity is only about 5% of adult activity. Using mutant catalase-deficient (acatalasemic, aCat) mice and transgenic mice expressing human catalase (hCat, enhanced catalase activity) compared with a confirmed outbred CD-1 mouse model, we investigated the protective importance of constitutive embryonic catalase against endogenous ROS and the ROS-initiating teratogen phenytoin in embryo culture. Vehicle-exposed aCat and hCat embryos, respectively, exhibited reduced and enhanced catalase activity compared with wild-type (WT) controls, with conversely enhanced and reduced spontaneous embryopathies. Phenytoin was embryopathic in all strains without altering catalase activity but less so in the WT embryos for the aCat and hCat strains, which exhibited about half the catalase activity of CD-1 embryos. Phenytoin, respectively, enhanced and reduced embryopathies in aCat and hCat embryos. Among aCat embryos exposed to phenytoin, embryopathies increased with decreasing catalase activity and were completely blocked by addition of exogenous catalase, which increased embryonic catalase activity to WT levels. These results provide the first direct evidence that (1) the low level of constitutive embryonic catalase protects the conceptus from developmental and xenobiotic-enhanced oxidative stress and (2) embryonic variations in activity of this enzyme affect development.

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