Compromised fetal growth has been associated with an increased risk of morbidity and mortality at birth and in later life. The placenta is an important determinant of fetal growth mediating substrate delivery to the fetus. The ovine placenta is cotyledonary where fetomaternal exchange predominates at the placentomes. Placental 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2 regulate the transfer of maternal glucocorticoids to the fetus catalysing the interconversion of cortisol to hormonally inactive cortisone. Overexposure of the fetus to excess glucocorticoids can retard fetal growth. To elucidate the mechanisms by which maternal undernutrition may compromise fetal growth, the effects of maternal undernutrition on placental 11β-HSD type 1 and type 2 activity were investigated.
Welsh Mountain ewes (n = 18) of body condition score 2.5 were fed 70 % (undernourished, U) or 100 % (controls, C) of their daily maintenance requirements from day 22 of gestation. Ewes carrying singleton pregnancies were humanely killed by captive bolt on day 90 (C, n = 4; U, n = 5) or day 135 (C, n = 4; U, n = 5) of gestation (term = ~150 days) and their uteri removed. Fetuses were recovered and killed by intracardiac administration of sodium pentabarbitone (10 ml) before fetal parameters, including organ weights, were measured. All procedures accorded with UK legislation. Placentomes were dissected and placental 11β-HSD type 1 and 2 activities determined over 60 min using a standard radiometric conversion assay. Values are expressed as pmol cortisol oxidised to cortisone per mg protein in 1 h. Data (means ± S.E.M.) were analysed by one-way ANOVA.
On day 90 the fetal brain and thymus weight were lighter in U than C ewes whilst the weight of the fetal ovaries were heavier (P < 0.05). On day 135 the fetal heart, pancreas, thymus, gut and kidney weights were lighter in U than C ewes (P < 0.05). When expressed as a percentage of fetal body weight, significance was retained in the thymus and ovaries on day 90 (P < 0.05) and heart, pancreas and thymus on day 135 (P < 0.05). Placental 11β-HSD type 2 activity was reduced in U ewes on day 90 (C, n = 3, 151.6 ± 5.7 vs. U, n = 5, 72.3 ± 5.5; P < 0.001) and day 135 (C, n = 4, 143.7 ± 3.7 vs. U, n = 5, 78.4 ± 8.4; P < 0.001) whilst type 1 activity was lower than type 2 (P < 0.05) and unaltered by maternal diet (day 90: C, n = 3, 24.2 ± 3.6, U, n = 5, 23.2 ± 3.3; day 135: C, n = 4, 32.2 ± 1.2, U, n = 5, 37.5 ± 3.5).
In conclusion reduced placental 11β-HSD type 2 activity may contribute to the retarded fetal growth observed in undernourished ewes, possibly due to fetal cortisol levels becoming raised.
This work was funded by The Wellcome Trust, BBSRC and SERAD.