Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status

Rodríguez-Rodríguez, Pilar; Pablo, Ángel L. López de; Condezo-Hoyos, Luis; Martín‐Cabrejas, Maria A.; Aguilera, Yolanda; Ruiz‐Hurtado, Gema; Gutiérrez-Arzapalo, Perla Yareli; Ramiro-Cortijo, David; Fernández-Alfonso, Marı́a S.; González, Marı́a del Carmen; Arribas, Silvia M.

doi:10.1016/j.jnutbio.2015.08.004

Cited by 48 publications

(60 citation statements)

References 64 publications

(81 reference statements)

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“…However, maternal protein restriction failed to program adult hypertension in female rats, as well as did not induced any alteration in plasma antioxidant status, suggesting that female rat offspring may be protected against the maternal protein restriction induced‐hypertension. In this way, many researchers have focused their efforts exclusively on offspring of one sex and possibly the findings found in the present study cannot be extrapolated to female rats.…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies have shown that male and female offspring exhibit different pathophysiological response when exposed to insults in utero and suggested that males are more susceptible to developing cardio-metabolic dysfunctions. 18,19 Thus, the aim of this study was to assess the effects of maternal protein restriction on the oxidative state in the medulla oblongata in male adult offspring and to test the hypothesis that hypertension in this model is associated with medullary oxidative dysfunction at transcriptional and functional levels.…”

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confidence: 99%

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Maternal protein restriction induced‐hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata

Alves

Oliveira

Ferreira

et al. 2016

Clin Exp Pharma Physio

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Maternal protein restriction during pregnancy and lactation predisposes the adult offspring to sympathetic overactivity and arterial hypertension. Although the underlying mechanisms are poorly understood, dysregulation of the oxidative balance has been proposed as a putative trigger of neural-induced hypertension. The aim of the study was to evaluate the association between the oxidative status at transcriptional and functional levels in the medulla oblongata and maternal protein restriction induced-hypertension. Wistar rat dams were fed a control (normal protein; 17% protein) or a low protein ((Lp); 8% protein) diet during pregnancy and lactation, and male offspring was studied at 90 days of age. Direct measurements of baseline arterial blood pressure (ABP) and heart rate (HR) were recorded in awakened offspring. In addition, quantitative RT-PCR was used to assess the mRNA expression of superoxide dismutase 1 (SOD1) and 2 (SOD2), catalase (CAT), glutathione peroxidase (GPx), Glutamatergic receptors (Grin1, Gria1 and Grm1) and GABA(A)-receptor-associated protein like 1 (Gabarapl1). Malondialdehyde (MDA) levels, CAT and SOD activities were examined in ventral and dorsal medulla. Lp rats exhibited higher ABP. The mRNA expression levels of SOD2, GPx and Gabarapl1 were down regulated in medullary tissue of Lp rats (P<.05, t test). In addition, we observed that higher MDA levels were associated to decreased SOD (approximately 45%) and CAT (approximately 50%) activities in ventral medulla. Taken together, our data suggest that maternal protein restriction induced-hypertension is associated with medullary oxidative dysfunction at transcriptional level and with impaired antioxidant capacity in the ventral medulla.

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Maternal protein restriction induced‐hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata

Alves

Oliveira

Ferreira

et al. 2016

Clin Exp Pharma Physio

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“…Differences in developmental patterns between male and female fetuses were evident and significant, indicating protective strategies for the adequate growth and postnatal survival of the females including the fact that both male and female fetuses prioritized brain development, but female fetuses were still able to maintain the development of other organs such as liver, intestine, and kidneys. In the rat model of maternal nutrient restriction, [93] male offspring showed severe hypertension and exhibited the highest increase in carbonyls whereas female offspring remained normotensive and did not exhibit differences in any of the oxidative stress biomarkers compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction

Muralimanoharan

Nakayasu

et al. 2017

Journal of Molecular and Cellular Cardiology

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Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p<0.05) in male IUGR s. Expression of cardiac fibrotic markers TGFβ, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p<0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and. females (p<0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4α, and NFκB p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk.

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“…The model of global nutrient restriction in rats (MUN) was established as previously described (Rodríguez‐Rodríguez et al . ). The observation of sperm in the vaginal smear in the dams was considered as day 1 of gestation.…”

Section: Methodsmentioning

confidence: 97%

“…To test this hypothesis we have used a rat model of fetal nutrient restriction induced by maternal undernutrition during gestation (MUN), in which only male offspring develop hypertension (Rodríguez‐Rodríguez et al . , ). We have established two experimental groups (MUN and Control) and compared the following variables in both male and female animals at three age points (birth, weaning period and adult life).…”

Section: Introductionmentioning

confidence: 99%

Role of fetal nutrient restriction and postnatal catch‐up growth on structural and mechanical alterations of rat aorta

Gutiérrez-Arzapalo

Rodríguez-Rodríguez

Ramiro-Cortijo

et al. 2018

The Journal of Physiology

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Fetal undernutrition programmes hypertension development, males being more susceptible. Deficient fetal elastogenesis and vascular growth is a possible mechanism. We investigated the role of aortic mechanical alterations in a rat model of hypertension programming, evaluating changes at birth, weaning and adulthood. Dams were fed ad libitum (Control) or 50% of control intake during the second half of gestation (maternal undernutrition, MUN). Offspring aged 3 days, 21 days and 6 months were studied. Blood pressure was evaluated in vivo. In the thoracic aorta we assessed gross structure, mechanical properties (intact and purified elastin), collagen and elastin content and internal elastic lamina (IEL) organization. Only adult MUN males developed hypertension (systolic blood pressure: MUN = 176.6 ± 5.6 mmHg; Control = 136.1 ± 4.9 mmHg). At birth MUN rats were lighter, with smaller aortic cross-sectional area (MUN = (1.51 ± 0.08) × 10 μm , Control = (2.8 ± 0.04) × 10 μm ); during lactation MUN males and females exhibited catch-up growth and aortic hypertrophy (MUN = (14.5 ± 0.5) × 10 μm , Control = (10.4 ± 0.9) × 10 μm ), maintained until adulthood. MUN aortas were more compliant until weaning (functional stiffness: MUN = 1.0 ± 0.04; Control = 1.3 ± 0.03), containing less collagen with larger IEL fenestrae, returning to normal in adulthood. Purified elastin from young MUN offspring was more compliant in both sexes; only MUN adult females maintained larger elastin compliance (slope: MUN = 24.1 ± 1.9; Control = 33.3 ± 2.8). Fetal undernutrition induces deficient aortic development followed by hypertrophic remodelling and larger aortic compliance in the perinatal period, with similar alterations in collagen and elastin in both sexes. The observed alterations argue against an initial mechanical cause for sex differences in hypertension development. However, the maintenance of high elastin compliance in adult females might protect them against blood pressure rise.

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Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status

Cited by 48 publications

References 64 publications

Maternal protein restriction induced‐hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata

Maternal protein restriction induced‐hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata

Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction

Role of fetal nutrient restriction and postnatal catch‐up growth on structural and mechanical alterations of rat aorta

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