Experimental modeling of hypoxia in pregnancy and early postnatal life

Abstract

The important role of equilibrium of environmental factors during the embryo-fetal period is undisputable. Women of reproductive age are increasingly exposed to various environmental risk factors such as hypoxia, prenatal viral infections, use of drugs, smoking, complications of birth or stressful life events. These early hazards represent an important risk for structural and/or functional maldevelopment of the fetus and neonates. Impairment of oxygen/energy supply during the pre- and perinatal period may affect neuronal functions and induce cell death. Thus when death of the newborn is not occurring following intrauterine hypoxia, various neurological deficits, including hyperactivity, learning disabilities, mental retardation, epilepsy, cerebral palsy, dystonia etc., may develop both in humans and in experimental animals. In our animal studies we used several approaches for modeling hypoxia in rats during pregnancy and shortly after delivery, i.e. chronic intrauterine hypoxia induced by the antiepileptic drug phenytoin, neonatal anoxia by decreased oxygen saturation in 2-day-old pups. Using these models we were able to test potential protective properties of natural (vitamin E, melatonin) and synthetic (stobadine) compounds. Based on our results, stobadine was also able to reduce hypoxia-induced hyperactivity and the antioxidant capacity of stobadine exceeded that of vitamin E and melatonin, and contrary to vitamin E, stobadine had no adverse effects on developing fetus and offspring.

Keywords: animal models; antioxidants; behavior; hypoxia; pregnancy.

Figure 1

Teratogenic mechanisms of PHT. I. Hypoxia–reoxygenation as the cause of PHT teratogenicity, which is induced by embryonic bradycardia and arrhythmias and free radical damage during reoxygenation. Hemodynamic alterations may contribute to embryonic hypoxia (Danielsson et al., 1997). II. Bioactivation of PHT by cytochrome P450 (Cyp450), prostaglandin H-syntase (PHS) and lipoperoxidase (LPO) to reactive toxic intermediates (Wells and Winn, 1996).

Figure 2

Increase of pups mortality dependent on age and duration of anoxic insult. (n=40–80 pups/group).