Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels

Abstract

Fetal intrauterine growth restriction (IUGR) is a frequently occurring and serious complication of pregnancy. Infants exposed to IUGR are at risk for numerous perinatal morbidities, including hypoglycemia in the neonatal period, as well as increased risk of later physical and/or mental impairments, cardiovascular disease and non-insulin-dependent diabetes mellitus. Fetal growth restriction most often results from uteroplacental dysfunction during the later stage of pregnancy. As glucose, which is the most abundant nutrient crossing the placenta, fulfills a large portion of the fetal energy requirements during gestational development, and since impaired placental glucose transport is thought to result in growth restriction, we investigated the effects of maternal 50% food restriction (FR50) during the last week of gestation on rat placental expression of glucose transporters, GLUT1, GLUT3 and GLUT4, and on plasma glucose content in both maternal and fetal compartments. Moreover, as maternal FR50 induces fetal overexposure to glucocorticoids and since these hormones are potent regulators of placental glucose transporter expression, we investigated whether putative alterations in placental GLUT expression correlate with changes in maternal and/or fetal corticosterone levels.At term (day 21 of pregnancy), plasma glucose content was significantly reduced (P<0·05) in mothers subjected to FR50, but was not affected in fetuses. Food restriction reduced maternal body weight (P<0·001) but did not affect placental weight. Plasma corticosterone concentration, at term, was increased (P<0·05) in FR50 mothers. Fetuses from FR50 mothers showed reduced body weight (P<0·001) but higher plasma corticosterone levels (P<0·05). Adrenalectomy (ADX) followed by corticosterone supplementation of the mother prevented the FR50-induced rise in maternal plasma corticosterone at term. Food restriction performed on either sham-ADX or ADX mothers induced a similar reduction in the body weight of the pups at term (P<0·01). Moreover, plasma corticosterone levels were increased in pups from sham-ADX FR50 mothers (P<0·01) and in pups from ADX control mothers (P<0·01). Western blot analysis of placental GLUT proteins showed that maternal FR50 decreased placental GLUT3 protein levels in all experimental groups at term (P<0·05 and P<0·01), but did not affect either GLUT1 or GLUT4 protein levels. Northern blot analysis of placental GLUT expression showed that both GLUT1 and GLUT3 mRNA were not affected by the maternal feeding regimen or surgery.We concluded that prolonged maternal malnutrition during late gestation decreases maternal plasma glucose content and placental GLUT3 glucose transporter expression, but does not obviously affect fetal plasma glucose concentration. Moreover, the present results are not compatible with a role of maternal corticosterone in the development of growth-restricted rat fetuses.

Expression discordance of monozygotic twins at birth: Effect of intrauterine environment and a possible mechanism for fetal programming

“…75,76 Impaired function of SLC2A3/ GLUT3 (solute carrier family 2A3/glucose transporter 3), which is involved in fetoplacental growth and metabolism, has been linked with intrauterine growth restriction and adiposity in animal models. [77][78][79] Although twin numbers are relatively small, the associations we found do support the hypothesis that epigenetic factors accumulated in utero can contribute to low birthweight and predisposition to complex diseases in later life. Further studies are needed to reveal more about these links.…”

Prenatal Programming of Hypertension

“…Some investigators have proposed that the key is increased fetal exposure to glucocorticoids (9,76), caused by elevated maternal glucocorticoid levels (as a result of stress), by increased passage of glucocorticoids to the fetus, or by activation of the fetal hypothalamic-pituitary-adrenal axis (HPA). Fetal corticosterone levels have been reported to be increased by maternal food restriction (77,78) but not by maternal protein restriction (79). Administration of dexamethasone, a synthetic glucocorticoid that is not inactivated by the placenta (see below), to pregnant rats or sheep on normal diet leads to hypertension in the offspring (9,11,21,48), supporting the hypothesis.…”

The Effects of Glucocorticoids on Fetal and Placental Development

“…At day 21 of pregnancy plasma corticosterone levels were increased. Correspondingly, placental GLUT3 protein was decreased, GLUT1 and GLUT4 protein levels were not affected by maternal feeding regimen and therefore enhanced corticosterone level [148].…”