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Abstract-Preeclampsia is pregnancy-specific, affecting 2% to 7% of women, and is a leading cause of perinatal and maternal morbidity and mortality. Preeclampsia may also predispose the fetus to increased risks of adult cardiovascular disease. Selenium, acting through the selenoprotein glutathione peroxidases, has critical roles in regulating antioxidant status. Recent reports implicate poor maternal selenium status as a nutritional factor predisposing the mother to preeclampsia but the fetus and placenta have not been studied in tandem. Measurement of selenium concentrations, expression, and activity levels of glutathione peroxidase and markers of oxidative stress were performed on maternal and umbilical venous blood samples or the placenta from 27 normal pregnant, 25 preeclamptic, and 22 healthy age-matched nonpregnant women. The results of this study revealed highly significant reductions in serum selenium concentrations and plasma glutathione peroxidase activity in pregnancy per se compared to nonpregnant controls. Moreover, these levels were further decreased in the preeclamptic mothers and babies compared to normal pregnancies. Umbilical venous selenium was particularly low (42.1Ϯ11.8 and 29.0Ϯ9.9 g/L; meanϮSD; PϽ0.05). Both mother and baby had significantly increased levels of markers for oxidative stress in the preeclamptic group. The placental glutathione peroxidase activity and immunohistochemical staining were also reduced in the preeclampsia placentae.Oxidative stress associated with preeclampsia may be a consequence of reduced antioxidant defense pathways specifically involving glutathione peroxidases, perhaps linked to reduced selenium availability. Reduced glutathione peroxidases could be associated with increased generation of toxic lipid peroxides contributing to the endothelial dysfunction and hypertension of preeclampsia. Key Words: pregnancy Ⅲ human Ⅲ preeclampsia Ⅲ hypertension Ⅲ oxidative stress Ⅲ selenium Ⅲ glutathione peroxidase Ⅲ placenta P reeclampsia is estimated to occur in 2% to 7% of all pregnancies and is a leading cause of maternal and perinatal mortality and morbidity in the Western world. 1,2 The effects of the disease are not restricted to pregnancy, as it also predisposes both the mother and baby to adult cardiovascular disease. 3 Preeclampsia is now commonly regarded as being a state of oxidative stress (see: 4 ). It is thought that excessive production of reactive oxygen species (ROS), secondary to reduced placental perfusion, results in oxidative stress, playing a critical role as a possible mediator of endothelial cell dysfunction, 5 hypertension, and thus clinical manifestations of preeclampsia. 6 The trace element selenium is an essential component of the antioxidant selenoproteins, including glutathione peroxidases (GPx). These remove the products of attack by hydroperoxides and oxidized lipoproteins, 7 and so limit adverse effects on the endothelium. 8 Various forms of GPx are found in vertebrates: the cellular and cytosolic GPx (GPx1), the cytosolic gastrointestinal GP...

Abstract-An adverse environment around conception and implantation influences later fetal growth and development to term in humans and sheep. Indeed, preimplantation undernutrition of rats elevated the systolic blood pressure of the resultant adult offspring. In this study, adult cardiovascular function is examined in a slower growing, non-litter-bearing species after peri-implantation undernutrition. Eight ewes were fed to 50% equivalent food intake of 12 control ewes from 1 to 30 days (term Ϸ147 days) only. Following consumption of an adequate diet to term, natural lambing, and then weaning, resting cardiovascular status and baroreflex function were examined in the resultant young adult offspring. Birth weight and postnatal growth to 1 year of age were unaffected by early undernutrition; however, nutrient-restricted sheep had increased pulse pressure, a reduced rate pressure product, and a leftward shift in their baroreflex function curve. Baroreflex sensitivity during angiotensin II infusion was also blunted in early nutrient-restricted sheep but the tachycardia following a reduction in central blood pressure appeared potentiated, relative to controls. The data suggest that peri-implantation undernutrition may program long-term cardiovascular dysfunction that ultimately increases the risk of hypertension later in life. An increase in regional angiotensin II activity during this critical early phase of development is a likely candidate mechanism for the effects observed. The data have broad implications for the health outcome of those offspring from mothers who were poorly nourished during early, often unknown pregnancy and for embryos artificially manipulated because of infertility treatment. Key Words: sheep Ⅲ angiotensin II Ⅲ blood pressure Ⅲ baroreflex H ypertension is a major risk factor associated with coronary heart disease and represents a common cause of death in the population more than 50 years old. 1 Hypertension and coronary heart disease are both multifactorial in their etiology but epidemiological studies in a number of different human populations have shown that the prenatal environment has an important role in determining the incidence of these diseases. 2 Consequently, there has been renewed interest in the effect of poor gestational nutrition on pre-and postnatal growth after the early studies of McCance and Widdowson. 3,4 These original hypotheses have been advanced to include changes in physiological function leading to adult pathology-the "developmental origins of adult disease hypothesis." 5,6 The methodologies and inferences of the hypothesis have been criticized 7,8 but meta-analyses have illustrated the strength of the epidemiological findings. 1,9 Work from the many animal models that now exist strongly supports the hypothesis and suggests that programming of disease risk is both biologically plausible and of major importance in terms of public health. 5,10

The prenatal nutritional environment influences the subsequent risk of hypertension in adulthood. Animal studies have used, generally, the rat as a model species to illustrate the association between maternal nutrient intake and blood pressure in the resulting adult offspring. No study to date has shown programming of adult cardiovascular function in the sheep through maternal dietary intervention. We therefore fed pregnant sheep to either 100% recommended intake from day 0 of gestation to term [ approximately 147 days gestational age (dGA); controls n = 8] or to 50% recommended intake from day 0 to 95 dGA and thereafter to 100% intake (NR; n = 9). Sheep lambed naturally, offspring were weaned at 16 wk, and the male offspring were reared on pasture until 3 yr of age. At this time, cardiovascular catheters were inserted under halothane anesthesia and sheep were allowed 2-4 days recovery. Basal cardiovascular status and pressor responses to infusion of norepinephrine, angiotensin II, and captopril were then assessed alongside basal plasma concentrations of glucose, cortisol, and leptin. NR sheep were of similar birth weight to controls but at 3 yr of age had higher blood pressure before, but not after, feeding. Peripheral sensitivity to vasoconstrictor infusion was similar between dietary groups, although a reflex bradycardia was not apparent in NR sheep during norepinephrine infusion. Circulating leptin correlated well with fat mass and increased more after vasoconstrictor infusion in NR sheep. In conclusion, early NR has been shown to program aspects of cardiovascular control and adipocyte function in adult sheep.