Short- and long-term effects of maternal dyslipidaemia on blood pressure and baroreflex sensitivity in male rat offspring.

Maternal dyslipidaemia is a predisposing factor for arterial hypertension in male rat offspring at adulthood. This study was designed to investigate the short- and long-term effects of maternal dyslipidaemia on blood pressure (BP) and baroreflex control in male rat offspring. Animals were obtained from mothers who received a dyslipidaemic (DLP, n = 7) or control (CTL, n = 7) diet during pregnancy and lactation. At 30 and 90 days of age, arterial pressure (AP), heart rate (HR) and baroreflex function were evaluated. In addition, spectral analysis of the systolic AP, diastolic AP, mean AP, HR, and spontaneous baroreflex were assessed. Data were expressed as mean ± SEM and Student's t-test was used for comparison among groups, with statistical significance considered to be P < .05. At 30 days of age, male offspring had similar BP, HR and preserved baroreflex sensitivity. In addition, low frequency (LF) oscillation, high frequency (HF) oscillation and LF/HF ratio of AP and HR were similar in juvenile rats. At 90 days of age, male offspring from dyslipidaemic dams had augmented BP (P < .05) when compared to CTL group. Adult male rats from dyslipidaemic dams had a reduction in baroreflex control (P < .05) in comparison to CTL rats. The present study indicates that offspring from dams fed on a dyslipidaemic diet during pregnancy and lactation do not show alteration in blood pressure and baroreflex control in early life, but display a decline in baroreflex control and hypertension in adulthood.

Oxidative injuries induced by maternal low-protein diet in female brainstem.

Many studies have shown that a maternal low-protein diet increases the susceptibility of offspring to cardiovascular disease in later-life. Moreover, a lower incidence of cardiovascular disease in females than in males is understood to be largely due to the protective effect of high levels of estrogens throughout a woman's reproductive life. However, to our knowledge, the role of estradiol in moderating the later-life susceptibility of offspring of nutrient-deprived mothers to cardiovascular disease is not fully understood. The present study is aimed at investigating whether oxidative stress in the brainstem caused by a maternal low-protein diet administered during a critical period of fetal/neonatal brain development (i.e during gestation and lactation) is affected by estradiol levels. Female Wistar rat offspring were divided into four groups according to their mothers' diets and to the serum estradiol levels of the offspring at the time of testing: (1) 22 days of age/control diet: (2) 22 days of age/low-protein diet; (3) 122 days of age/control diet: (4) 122 days of age/low-protein diet. Undernutrition in the context of low serum estradiol compared to undernutrition in a higher estradiol context resulted in increased levels of oxidative stress biomarkers and a reduction in enzymatic and non-enzymatic antioxidant defenses. Total global oxy-score showed oxidative damage in 22-day-old rats whose mothers had received a low-protein diet. In the 122-day-old group, we observed a decrease in oxidative stress biomarkers, increased enzymatic antioxidant activity, and a positive oxy-score when compared to control. We conclude from these results that following a protein deficiency in the maternal diet during early development of the offspring, estrogens present at high levels at reproductive age may confer resistance to the oxidative damage in the brainstem that is very apparent in pre-pubertal rats.

Fighting Oxidative Stress: Increased Resistance of Male Rat Cerebellum at Weaning Induced by Low Omega 6/Omega 3 Ratio in a Protein-Deficient Diet.

The cerebellum is vulnerable to malnutrition effects. Notwithstanding, it is able to incorporate higher amount of docosahexaenoic acid (DHA) than the cerebral cortex (Cx) when low n-6/n-3 fatty acid ratio is present in a multideficient diet. Considering importance of DHA for brain redox balance, we hypothesize that this cerebellum feature improves its antioxidant status compared to the Cx. A chronic malnutrition status was induced on dams before mating and kept until weaning or adulthood (offspring). A group nutritionally rehabilitated from weaning was also analyzed. Morphometric parameters, total-superoxide dismutase (t-SOD) and catalase activities, lipoperoxidation (LP), nitric oxide (NO), reduced (GSH) and oxidized (GSSG) glutathione, reactive oxygen species (ROS), and reduced nicotinamide adenine dinucleotide/phosphate levels were assessed. Both ROS and LP levels were increased (∼53 %) in the Cx of malnourished young animals while the opposite was seen in the cerebellum (72 and 20 % of the control, respectively). Consistently, lower (∼35 %) and higher t-SOD (∼153 %) and catalase (CAT) (∼38 %) activities were respectively detected in the Cx and cerebellum compared to the control. In malnourished adult animals, redox balance was maintained in the cerebellum and recovered in the Cx (lower ROS and LP levels and higher GSH/GSSG ratio). NO production was impaired by malnutrition at either age, mainly in the cerebellum. The findings suggest that despite a multinutrient deficiency and a modified structural development, a low dietary n-6/n-3 ratio favors early antioxidant resources in the male cerebellum and indicates an important role of astrocytes in the redox balance recovery of Cx in adulthood.

Omega-3 deficiency and neurodegeneration in the substantia nigra: involvement of increased nitric oxide production and reduced BDNF expression.

BACKGROUND: Our previous study demonstrated that essential fatty acid (EFA) dietary restriction over two generations induced midbrain dopaminergic cell loss and oxidative stress in the substantia nigra (SN) but not in the striatum of young rats. In the present study we hypothesized that omega-3 deficiency until adulthood would reduce striatum's resilience, increase nitric oxide (NO) levels and the number of BDNF-expressing neurons, both potential mechanisms involved in SN neurodegeneration. METHODS: Second generation rats were raised from gestation on control or EFA-restricted diets until young or adulthood. Lipoperoxidation, NO content, total superoxide dismutase (t-SOD) and catalase enzymatic activities were assessed in the SN and striatum. The number of tyrosine hydroxylase (TH)- and BDNF-expressing neurons was analyzed in the SN. RESULTS: Increased NO levels were observed in the striatum of both young and adult EFA-deficient animals but not in the SN, despite a similar omega-3 depletion (~65%) in these regions. Increased lipoperoxidation and decreased catalase activity were found in both regions, while lower tSOD activity was observed only in the striatum. Fewer TH- (~40%) and BDNF-positive cells (~20%) were detected at the SN compared to the control. CONCLUSION: The present findings demonstrate a differential effect of omega-3 deficiency on NO production in the rat's nigrostriatal system. Prolonging omega-3 depletion until adulthood impaired striatum's anti-oxidant resources and BDNF distribution in the SN, worsening dopaminergic cell degeneration. GENERAL SIGNIFICANCE: Omega-3 deficiency can reduce the nigrostriatal system's ability to maintain homeostasis under oxidative conditions, which may enhance the risk of Parkinson's disease.

Maternal low-protein diet reduces skeletal muscle protein synthesis and mass via Akt-mTOR pathway in adult rats.

Several studies have demonstrated that a maternal low-protein diet induces long-term metabolic disorders, but the involved mechanisms are unclear. This study investigated the molecular effects of a low-protein diet during pregnancy and lactation on glucose and protein metabolism in soleus muscle isolated from adult male rats. Female rats were fed either a normal protein diet or low-protein diet during gestation and lactation. After weaning, all pups were fed a normal protein diet until the 210th day postpartum. In the 7th month of life, mass, contractile function, protein and glucose metabolism, and the Akt-mTOR pathway were measured in the soleus muscles of male pups. Dry weight and contractile function of soleus muscle in the low-protein diet group rats were found to be lower compared to the control group. Lipid synthesis was evaluated by measuring palmitate incorporation in white adipose tissue. Palmitate incorporation was higher in the white adipose tissue of the low-protein diet group. When incubated soleus muscles were stimulated with insulin, protein synthesis, total amino acid incorporation and free amino acid content, glucose incorporation and uptake, and glycogen synthesis were found to be reduced in low-protein diet group rats. Fasting glycemia was higher in the low-protein diet group. These metabolic changes were associated with a decrease in Akt and GSK-3ß signaling responses to insulin and a reduction in RPS6 in the absence of the hormone. There was also notably lower expression of Akt in the isolated soleus muscle of low-protein diet group rats. This study is the first to demonstrate how maternal diet restriction can reduce skeletal muscle protein and mass by downregulating the Akt-mTOR pathway in adulthood.

Maternal low protein diet induces persistent expression changes in metabolic genes in male rats.

BACKGROUND: Perinatal exposure to a poor nutritional environment predisposes the progeny to the development of metabolic disease at the adult age, both in experimental models and humans. Numerous adaptive responses to maternal protein restriction have been reported in metabolic tissues. However, the expression of glucose/fatty acid metabolism-related genes in adipose tissue and liver needs to be described. AIM: To evaluate the metabolic impact of perinatal malnutrition, we determined malnutrition-associated gene expression alterations in liver and adipose tissue. METHODS: In the present study, we evaluated the alterations in gene expression of glycolytic/Krebs cycle genes (Pyruvate dehydrogenase kinase 4 and citrate synthase), adipogenic and lipolytic genes and leptin in the adipose tissue of offspring rats at 30 d and 90 d of age exposed to maternal isocaloric low protein (LP) diet throughout gestation and lactation. We also evaluated, in the livers of the same animals, the same set of genes as well as the gene expression of the transcription factors peroxisome proliferator-activated receptor gamma coactivator 1, forkhead box protein O1 and hepatocyte nuclear factor 4 and of gluconeogenic genes. RESULTS: In the adipose tissue, we observed a transitory (i.e., at 30 d) downregulation of pyruvate dehydrogenase kinase 4, citrate synthase and carnitine palmitoyl transferase 1b gene expression. Such transcriptional changes did not persist in adult LP rats (90 d), but we observed a tendency towards a decreased gene expression of leptin (P = 0.052). The liver featured some gene expression alterations comparable to the adipose tissue, such as pyruvate dehydrogenase kinase 4 downregulation at 30 d and displayed other tissue-specific changes, including citrate synthase and fatty acid synthase upregulation, but pyruvate kinase downregulation at 30 d in the LP group and carnitine palmitoyl transferase 1b downregulation at 90 d. These gene alterations, together with previously described changes in gene expression in skeletal muscle, may account for the metabolic adaptations in response to maternal LP diet and highlight the occurrence of persistent transcriptional defects in key metabolic genes that may contribute to the development of metabolic alterations during the adult life as a consequence of perinatal malnutrition. CONCLUSION: We conclude that perinatal malnutrition relays long-lasting transcriptional alterations in metabolically active organs, i.e., liver and adipose tissue.

Influence of maternal protein malnutrition on oxidative stress and regulators of mitochondrial biogenesis in female rat hearts over succeeding generations.

AIMS: We sought to evaluate the effects of maternal protein restriction (LP) on oxidative balance and transcription factors for mitochondrial biogenesis in the hearts of young female rats of both the first (F1) and second (F2) generation. MAIN METHODS: We evaluated oxidative stress biomarkers (lipid peroxidation and protein oxidation), enzymatic antioxidant defense (activity of superoxide dismutase-SOD, catalase, and glutathione-S-transferase-GST), nonenzymatic antioxidant defense (reduced glutathione-GSH and sulfhydryl groups) and gene expression of AMPK, PGC-1α and TFAM. KEY FINDINGS: Interestingly, lipid peroxidation was decreased (49%, p < 0.001) in the LP-F1 group and 59% (p < 0.001) in LP-F2. In enzymatic defense, we observed increases in SOD activity in the LP-F1 group (79%, p = 0.036) and in CAT activity (approximately 40%, p = 0.041). GSH was increased in F2 in both groups (LP 546%, p < 0.0001 and in NP 491.7%, p < 0.0001). With respect to mitochondrial biogenesis gene transcription, we observed a decrease in AMPK (60%, p < 0. 0001) and an increase in PGC-1α (340%, p < 0.001) in LP compared to NP in the F1 generation. TFAM was decreased in LP-F2L compared to NP-F2L (42%, p = 0.0069) and increased in LP-F2 compared to LP-F1 (160%, p = 0.0037). SIGNIFICANCE: Our study contributes to knowledge of inheritance, showing that despite the potential mitochondrial 'inheritance' of cardiovascular damage caused by maternal malnutrition, that damage is not cross-generational and can be eliminated with proper nutrition in the F1 generation.