Influence of Low Protein Diet-Induced Fetal Growth Restriction on the Neuroplacental Corticosterone Axis in the Rat

Abstract

Objectives: Placental steroid metabolism is linked to the fetal hypothalamus-pituitary-adrenal axis. Intrauterine growth restriction (IUGR) might alter this cross-talk and lead to maternal stress, in turn contributing to the pathogenesis of anxiety-related disorders of the offspring, which might be mediated by fetal overexposure to, or a reduced local enzymatic protection against maternal glucocorticoids. So far, direct evidence of altered levels of circulating/local glucocorticoids is scarce. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) allows quantitative endocrine assessment of blood and tissue. Using a rat model of maternal protein restriction (low protein [LP] vs. normal protein [NP]) to induce IUGR, we analyzed fetal and maternal steroid levels via LC-MS/MS along with the local expression of 11beta-hydroxysteroid-dehydrogenase (Hsd11b).Methods: Pregnant Wistar dams were fed a low protein (8%, LP; IUGR) or an isocaloric normal protein diet (17%, NP; controls). At E18.5, the expression of Hsd11b1 and 2 was determined by RT-PCR in fetal placenta and brain. Steroid profiling of maternal and fetal whole blood, fetal brain, and placenta was performed via LC-MS/MS.Results: In animals with LP-induced reduced body (p < 0.001) and placental weights (p < 0.05) we did not observe any difference in the expressional Hsd11b1/2-ratio in brain or placenta. Moreover, LP diet did not alter corticosterone (Cort) or 11-dehydrocorticosterone (DH-Cort) levels in dams, while fetal whole blood levels of Cort were significantly lower in the LP group (p < 0.001) and concomitantly in LP brain (p = 0.003) and LP placenta (p = 0.002). Maternal and fetal progesterone levels (whole blood and tissue) were not influenced by LP diet.Conclusion: Various rat models of intrauterine stress show profound alterations in placental Hsd11b2 gatekeeper function and fetal overexposure to corticosterone. In contrast, LP diet in our model induced IUGR without altering maternal steroid levels or placental enzymatic glucocorticoid barrier function. In fact, IUGR offspring showed significantly reduced levels of circulating and local corticosterone. Thus, our LP model might not represent a genuine model of intrauterine stress. Hypothetically, the observed changes might reflect a fetal attempt to maintain anabolic conditions in the light of protein restriction to sustain regular brain development. This may contribute to fetal origins of later neurodevelopmental sequelae.

Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology

“…The level of IUGR in our rats, as determined by fetal weight, was comparable to our previous experience with this model [36,62]. Additionally, the observed level of fetal and placental weight reduction in eNOS −/− mice (18% and 22%, respectively; E18.5) was similar to findings from the literature (11% and 10%, respectively; E17 [28]), when compared to C57BL/6 control mice.…”

“…This might be due to the divergent use of maternal diets (i.e., isocaloric protein restriction vs. total caloric reduction). We have just recently shown that our diet does not resemble a stress-model, unlike other models of total intake restriction [36]. Furthermore, models with total calorie restriction [51,52] seem more prone to develop insulin resistance after IUGR.…”

“…Animal procedures and the dietary regimen were carried out as previously described by us in detail [36]. Wistar rats were ordered from Charles River (Sulzfeld, Germany).…”

“…To expand our findings from third trimester human placenta [1], we investigated Rarres1, Rarres2, and Cmklr1 expression in third trimester rodent placenta. Moreover, we analyzed the influence of maternal protein restriction in rats (IUGR-like features [35,36]) on placental Rarres1 and 2 expression. We additionally compared placentas in the context of fetal sex, given the differences in Rarres2 expression that were already described by Watts et al [37] for male and female fetuses.…”

Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors

“…The hyperphagia is mostly contributed by food consumption at the night-day transition (around ZT0), in keeping with hypothalamic transcriptional profiles at the same time point showing deregulation of orexigenic and anorexigenic circuits. These phenotypes remind of a developmentally programmed hyperphagia and susceptibility to metabolic diseases as a consequence of in utero adverse conditions and FGR ( 52 , 53 , 65 – 68 ). Analysis of placenta and fetal liver reveals a transcriptional signature of FGR in offspring of circadian disrupted fathers, which is interestingly uncoupled from overt morphological and developmental alterations (placenta morphology and placental and fetal weights are normal) but associated to reduced placental efficiency and in line with the adult phenotypes.…”