A model of intrauterine growth retardation caused by chronic maternal undernutrition in the rat: effects on the somatotrophic axis and postnatal growth

Abstract While it is well established that severe maternal undernutrition during pregnancy causes intrauterine growth retardation (IUGR), there has been relatively little study of the endocrine consequences and postnatal development of growth-retarded offspring. We have developed a model in the rat of IUGR by nutritional restriction of the mother throughout gestation and have examined the effects of fetal growth retardation on the endocrine and metabolic status during the perinatal period. Timed matings were performed in Wistar rats and dams were randomly assigned to one of two dietary treatment groups. Food was available ad libitum throughout pregnancy to a control group (ad libitum group) and a restricted group was fed 30% of the ad libitum intake (restricted fed group). After birth, food was available ad libitum in both groups and litter size was adjusted to eight pups per litter. Dams lost a significant amount of body weight throughout gestation due to undernutrition but were able to catch up to the ad libitum group by day 10 postnatally. Litter size was not affected by maternal undernutrition. Maternal plasma IGF-I levels were significantly reduced in the restricted fed group throughout gestation (P<0·001) but were not different postnatally. Maternal plasma IGF-binding proteins (IGFBPs)-1, -2 and -3 were significantly (P<0·05) increased in the restricted fed dams. The mean body weights of fetuses in late gestation from the restricted fed dams were significantly lower (P<0·001) in comparison with fetuses from control dams. Placental weights were also significantly (P<0·01) reduced in the restricted fed compared with control dams. Body weights were significantly lower in the offspring of restricted fed dams than control dams from birth (P<0·01) until 90 days of age (P<0·05). Nose–rump length was reduced in the fetuses of the restricted fed group at day 22 of gestation (P<0·001) until weaning (P<0·05). Plasma IGF-I levels were significantly reduced in the pups of restricted fed dams from day 22 of gestation (P<0·01) until postnatal day 9 (P<0·05) but were not significantly different at the later time-points. Plasma insulin levels were significantly reduced in the pups of restricted fed dams at birth (P<0·05) but not at later time-points. Plasma IGFBP-1 and -2 levels were significantly increased in the offspring from restricted fed dams at day 22 of gestation, at birth and at day 9 postnatally (P<0·05). 125I-Bovine GH specific binding to liver membranes was significantly lower (P<0·05) in offspring from restricted fed dams at 21 days of age but not at 90 days of age. These data demonstrate that nutritional deprivation in the pregnant rat leads to IUGR and postnatal growth failure and to changes in allometric growth patterns and endocrine parameters of the somatotrophic axis postnatally. Journal of Endocrinology (1996) 150, 231–242

Download Full-text

Nutritional programming and the reproductive function of the offspring

Animal Production Science ◽

10.1071/an14470 ◽

2014 ◽

Vol 54 (9) ◽

pp. 1166 ◽

Cited By ~ 9

Author(s):

P. Chavatte-Palmer ◽

C. Dupont ◽

N. Debus ◽

S. Camous

Keyword(s):

Growth Retardation ◽

Intrauterine Growth Retardation ◽

Maternal Nutrition ◽

Reproductive Function ◽

Fetal Life ◽

Ample Evidence ◽

Primordial Follicles ◽

Intrauterine Growth ◽

Maternal Undernutrition ◽

Males And Females

There is ample evidence on the importance of maternal nutrition during pregnancy on fetal and offspring development. In ruminant females, the pool of oocytes is complete and definitive before birth, based on the resting reserve of primordial follicles established during fetal life, which represent the lifespan supply for the female’s fertilisable oocytes, whereas in males, although the production of spermatozoa is a continuous process throughout post-pubertal life. Sertoli cells, which play a central role in the development of a functional testis, proliferate during pre- and post-natal life, coordinating testicular development. Both male and female fertility may, therefore, be affected by the maternal environment, but studies on the effects of developmental nutritional conditions on reproductive function and fertility, both in males and females, are relatively scarce. In humans, intrauterine growth retardation has been associated with abnormal ovarian development, characterised by a decreased volume of primordial follicles in the ovarian cortical tissue in girls, and a higher incidence of cryptorchidism in boys, with subsequent low sperm counts in adulthood. Age at puberty and gonadotropin and inhibin B plasma concentrations are also affected. Animal studies suggest both in males and females that maternal undernutrition during pregnancy may affect pituitary response to GnRH and gonadal development and function, depending on the timing and magnitude of the undernutrition. Excess nutrition, which is often associated with intrauterine growth retardation in domestic species, induces effects on the onset of puberty and both testicular and ovarian function, maybe through the observed reduction in fetal growth. This review addresses the influence of maternal nutrition on offspring reproductive function using examples in humans and animals, with particular focus on ruminants.

Download Full-text

Mutation at Cleavage Site of Insulin-Like Growth Factor Receptor in a Short-Stature Child Born with Intrauterine Growth Retardation

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1947 ◽

2005 ◽

Vol 90 (8) ◽

pp. 4679-4687 ◽

Cited By ~ 84

Author(s):

Yuki Kawashima ◽

Susumu Kanzaki ◽

Fan Yang ◽

Tomoe Kinoshita ◽

Keiichi Hanaki ◽

...

Keyword(s):

Short Stature ◽

Growth Retardation ◽

Cleavage Site ◽

Intrauterine Growth Retardation ◽

Growth Factor Receptor ◽

Heterozygous Mutation ◽

Β Subunit ◽

Direct Dna Sequencing ◽

Intrauterine Growth ◽

Igf I

Context: Mouse knockout models have clearly demonstrated the critical importance of IGF-I and IGF receptor type 1 (IGF-IR) for embryonic growth as well as postnatal growth. Objective: We hypothesized that mutations of IGF-IR gene might predispose to short stature in children born with intrauterine growth retardation (IUGR). Patients: Twenty-four children with unexplained IUGR (birth weight < −1.5 sd) and short stature (<−2.0 sd) were screened for abnormalities of the IGF-IR gene. Methods: Direct DNA sequencing was used to identify IGF-IR gene mutations. Unprocessed IGF-IR proreceptor in fibroblasts was detected by immunoblot analysis. Functions of mutated IGF-IR in fibroblasts were evaluated by IGF-I binding, and IGF-I-stimulated DNA synthesis and β-subunit autophosphorylation. Results: We found the following results: 1) a heterozygous mutation (R709Q) changing the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg was identified in a 6-yr-old Japanese girl (case 1) and her mother who also had IUGR with short stature (case 2); 2) fibroblasts from case 2 contained more IGF-IR proreceptor protein (189 ± 26% of normal) and less mature β-subunit protein (63 ± 12%); 3) [125I]IGF-I binding to fibroblasts from case 2 was reduced, compared with normal control (0.61 ± 0.16 × 106vs. 1.14 ± 0.12 × 106 sites per cell; P < 0.05); and 4) both IGF-I-stimulated [3H]thymidine incorporation and IGF-IR β-subunit autophosphorylation were low in fibroblasts from case 2, compared with those of control (P < 0.05). Conclusions: These findings strongly suggest that this mutation leads to failure of processing of the IGF-IR proreceptor to mature IGF-IR and causes short stature and IUGR.

Download Full-text

PRENATAL AND POSTNATAL DEVELOPMENTAL CONSEQUENCES OF MATERNAL PHENYLKETONURIA

PEDIATRICS ◽

10.1542/peds.37.6.979 ◽

1966 ◽

Vol 37 (6) ◽

pp. 979-986

Author(s):

Robert O. Fisch ◽

William A. Walker ◽

John A. Anderson

Keyword(s):

Growth Retardation ◽

Intrauterine Growth Retardation ◽

Detrimental Effect ◽

Postnatal Growth ◽

Maternal Phenylketonuria ◽

Phenylalanine Level ◽

Postnatal Growth Retardation ◽

Intrauterine Growth ◽

Prenatal Growth ◽

Abnormal Metabolism

Two children, one homozygous and the other heterozygous for phenylketonuria, born of an untreated phenylketonuric mother were found to exhibit intrauterine growth retardation and persistent postnatal growth retardation. Microcephaly was present in both children at birth. Microcephaly, mental retardation, and growth retardation were present in the heterozygous child at 5 years of age and in the untreated homozygous child at 2 years of age. The possibility that the comparatively high phenylalanine level in the mother's blood and the concomitant abnormal metabolism had a detrimental effect on the child's prenatal growth and predetermined the rate of their postnatal physical as well as mental development, was discussed.

Download Full-text