Fetal Programming of Gene Expression in Growth-Restricted Rats Depends on the Cause of Low Birth Weight

Abstract

Low birth weight and intrauterine growth restriction (IUGR) can be caused by numerous different conditions. In many experimental settings, however, these different causes are not accounted for. This study aimed at comparing the impact of two frequent causes of IUGR (low utero-placental blood flow vs. malnutrition) on fetal programming of gene expression. We studied offspring of dams treated by uterine artery ligation or sham operation compared with untreated controls and offspring of dams that were fed either a low protein or normal protein diet. After Cesarean section at term, placental and fetal hepatic expression of key "metabolic" and "vasoregulative" genes was investigated by quantitative RT-PCR. Ligation neonates showed IUGR, reduced expression of placental leptin, placental and hepatic IGF-I, hepatic inducible nitric oxide synthase, and increased expression of placental IGF binding protein 1, hepatic IGF-II receptor and erythropoietin (EPO). Low protein offspring also showed IUGR but increased expression of placental leptin; IGF-I; placental and hepatic inducible nitric oxide synthase; hepatic insulin, IGF-I, and IGF-II receptors; and reduced expression of placental IGF binding protein 1, IGF-II, leptin-receptor type A, placental and hepatic leptin receptor type B, and EPO. Expression was independent of sex, birth weight, fetal intrauterine position, and EPO expression. In conclusion, the impact of IUGR on fetal and placental gene expression depends on the cause of low birth weight. Therefore, morbidity after IUGR should be analyzed referring to its pathophysiological cause rather than referring to low birth weight itself. Fetal hypoxia as estimated by hepatic EPO expression does not seem to be a key regulator of transcriptional activity in our models.

Perinatal High Methyl Donor Alters Gene Expression in IGF System in Male Offspring Without Altering DNA Methylation

“…In the present study, dams had adapted their metabolism to the diet before entering pregnancy, and that may explain the fact that, although the expression of the growth-promoting genes was reduced in the R group, the pups did not suffer from intrauterine growth restriction (IUGR) [52]. It is indeed now established that maternal nutrition may have long-lasting consequences on offspring metabolic outcomes without any impact on birth weight, both in humans [78] and animal models [12,79–80], and these consequences rely more on the time-window and nature of the nutritional insult than on growth restriction per se [80]. …”

Maternal Hypoxia Increases the Susceptibility of Adult Rat Male Offspring to High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease

“…A series of epidemiological studies have demonstrated that poor growth in utero is associated with increased risk of developing obesity and other MetS (14,15). Experimentally, a number of animal models resorting to maternal malnutrition during pregnancy (16,17), fetal exposure to elevated glucocorticoid levels (18,19), or surgical ligation of the uterine arteries (20) have been used. It has been reported that uteroplacental insufficiency in rats caused impaired glucose tolerance, hyperinsulinemia as well as elevated plasma triglycerides and leptin levels in adult offspring (21).…”

Detection of Expressional Changes Induced by Intrauterine Growth Restriction in the Developing Rat Mammary Gland via Exploratory Pathways Analysis

“…Following veterinarian judgment, buprenorphine hydrochloride was injected when pain or discomfort was imminent. Our animal model was previously described in detail [8], [22]. Virgin female Wistar rats were obtained from Charles River Laboratories International, Inc. (Sulzfeld, Germany) and housed at the University's animal facility.…”

“…The pregnant dams were then randomized into two dietary groups, normal and low protein (casein) (NP and LP respectively). Throughout pregnancy animals were fed a semi-purified diet, as previously described [22]: NP rats (n = 8) received 25 g/d of Altromin C1000 containing 17.0% protein, while LP animals (n = 8) were fed 25 g/d of Altromin C1003 containing 8.8% protein. Diets were isocaloric.…”

“…Samples were stored at −80°C until further processing. Gender verification was carried out via SRY gene PCR as previously described [24] and verified via ovarectomy at the day of sacrifice.…”