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 µl), IGF-I (2 µg/g body weight) or GH (2 µg/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.

Dietary restriction in pregnant rats causes gender‐related hypertension and vascular dysfunction in offspring

“…These have uniformally been raised (Langley & Jackson, 1994;LangleyEvans et al 1996b,c;Woodall et al 1996Woodall et al , 1999Gardner et al 1997). Direct comparisons with the present study are hindered by differences in baseline pressures.…”

“…Other studies using the tail-cuff method have not observed gender differences and may reflect the lower sensitivity of the method used; Langley-Evans et al (1996c) have shown no difference in blood pressure of male and female 4-week-old offspring of proteinrestricted dams and Woodall et al (1999) considered male and female offspring together as no gender differences were apparent in offspring of control or restricted groups. Studies in 60-day-old oophorectomised offspring of the nutritionally restricted dams are planned to determine if female sex hormones offer protection against the rise in blood pressure observed in the males.…”

“…Whilst most of these associations are based on retrospective population studies, prospective investigations in animals are now providing substantial experimental evidence to support the hypothesis of 'fetal programming'. In relation to hypertension, studies in pregnant rats have reported that a 50% reduction of dietary protein intake (Langley & Jackson, 1994;LangleyEvans et al 1996a,b;Gardner et al 1997) or severe calorie restriction (Woodall et al 1996(Woodall et al , 1999 leads to elevated blood pressure in adult offspring. Mechanisms implicated have included alteration of the offspring's reninangiotensin system Sherman & Langley-Evans, 1998) and stress-induced stimulation of the hypothalamic pituitary adrenal (HPA) axis (Gardner et al 1997).…”

Global undernutrition during gestation influences learning during adult life

“…A possible alternative explanation of these differences could be the (necessary) cross-fostering of the IUGR pups (but not the control pups) onto normal dams to generate a transition from a nutritionally deprived environment before birth to a nutritionally adequate environment after birth. We chose to use the exact experimental approach employed in a number of earlier studies where considerable data are available about the IUGR phenotype Krechowec, Vickers, Gertler, & Breier, 2006;Vickers et al, 2000;Vickers et al, 2001;Woodall et al, 1999;Woodall et al, 1996) so that direct physiological comparisons could be made. Thus, it is possible (though we believe it unlikely) that the learning differences we have documented here arose fully, or partially, from crossfostering.…”

“…Thus, IUGR offspring were provided with the same nutrient-rich environment after birth as were control offspring, and IUGR pups were cross-fostered onto control dams that had their offspring removed after birth. This experimental approach generates IUGR offspring of significantly reduced birth weight without affecting litter size (Vickers et al, 2000;Woodall et al, 1999;Woodall et al, 1996). For the present study, we used conditions identical to those reported by our laboratory for physiological, metabolic, and endocrine studies investigating the impact of maternal undernutrition during gestation on the biological phenotype of offspring.…”