Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring

Abstract

Increasing evidence from human epidemiological studies suggests that poor growth before birth is associated with postnatal growth retardation and the development of cardiovascular disease in adulthood. We have shown previously that nutritional deprivation in the pregnant rat leads to intrauterine growth retardation (IUGR), postnatal growth failure, changes in the endocrine parameters of the somatotrophic axis, and to increased blood pressure in later life. In the present study, we investigated whether administration of insulin-like growth factor-I (IGF-I) or bovine growth hormone (GH) during pregnancy could prevent IUGR and/or alter long-term outcome. Dams from day 1 of pregnancy throughout gestation received a diet of ad libitum available food or a restricted dietary intake of 30% of ad libitum fed dams. From day 10 of gestation, dams were treated for 10 days with three times daily subcutaneous injections of saline (100 microl), IGF-I (2 micrograms/g body weight) or GH (2 micrograms/g body weight). Maternal weight gain was significantly increased (P<0.001) in ad libitum fed dams treated with GH, (98.9+/-4.73 g) compared with the IGF-I (80.5+/-2.17 g) and saline-treated (70.7+/-2.65 g) groups. There was a small increase in maternal weight gain (P<0.06) in 30% ad libitum fed dams following GH (16.3+/-2.47 g) and IGF-I (15.8+/-1.97 g) treatment compared with saline (9.2+/-1.96 g). Whole spleen, kidney and carcass weights were significantly (P<0.05) increased in ad libitum fed and 30% ad libitum fed dams with GH treatment. Circulating IGF-I was significantly increased (P<0.001) in ad libitum fed dams with both IGF-I (369.6+/-32.33 ng/ml) and GH (457.9+/-33.32 ng/ml) compared with saline treatment (211.7+/-14.02 ng/ml), and with GH (223.4+/-23.72 ng/ml) compared with saline treatment (112.0+/-7.33 ng/ml) in 30% ad libitum fed dams. Circulating GH binding protein (GHBP) levels were significantly reduced (P<0.05) in GH-treated (299.1+/-51.54 ng/ml) compared with saline-treated (503.9+/-62.43 ng/ml) ad libitum fed dams, but were not altered in 30% ad libitum fed dams. There was no significant effect of either IGF-I or GH treatment on fetal weight, placental weight, fetal organ weights or circulating IGF-I levels in both ad libitum fed and 30% ad libitum fed fetuses. Offspring of 30% ad libitum fed dams remained significantly growth retarded postnatally and showed elevated blood pressure in later life. The increased maternal weight gain following IGF-I or GH administration, without an effect on fetal and placental weights, suggests a modification in the mode of maternal nutrient repartitioning during mid to late pregnancy at the expense of the fetus.