Adult Male Rat Offspring Research Articles

Maternal undernutrition programs the apelinergic system of adipose tissue in adult male rat offspring.

Based on the Developmental Origin of Health and Disease concept, maternal undernutrition has been shown to sensitize adult offspring to metabolic pathologies such as obesity. Using a model of maternal 70% food restriction in pregnant female rats throughout gestation (called FR30), we previously reported that obesity-prone adult male rat offspring displayed hyperleptinemia with modifications in leptin and leptin receptor messenger RNA (mRNA) levels in white adipose tissue (WAT). Apelin is a member of the adipokine family that regulates various aspects of energy metabolism and WAT functionality. We investigated whether apelin and its receptor APJ could be a target of maternal undernutrition. Adult male rat offspring from FR30 dams showed increased plasma apelin levels and apelin gene expression in WAT. Post-weaning high-fat diet led to marked increase in APJ mRNA and protein levels in offspring's WAT. We demonstrate that maternal undernutrition and post-weaning diet have long-term consequences on the apelinergic system of adult male rat offspring.

Maternal hypoxia increases hippocampal cell susceptibility to ischemia after middle cerebral artery occlusion in rat offspring.

<i><B>Introduction</B>: Maternal hypoxia induces an adverse uterine environment and may induce long-term effects in offspring. This study investigated whether maternal hypoxia increases hippocampal cell vulnerability and exacerbates neurological impairments in adult rat offspring following ischemia. <B>Material and methods</B>: Pregnant Sprague-Dawley rats were randomly assigned to no maternal hypoxia or maternal hypoxia treatment groups. Adult male rat offspring were subjected to middle cerebral artery occlusion (MCAO). There were four groups: maternal + sham (MH + Sham), sham (Sham), maternal hypoxia + MCAO (MH + MCAO), and MCAO only (MCAO). Neurological deficits were evaluated. Hippocampal cell damage was observed by hematoxylin and eosin (HE) staining. Cell apoptosis in the hippocampus was detected by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. Caspase-3, cytochrome c, Bax, and bcl-2 expression in the hippocampus was detected by Western blot. <B>Results</B>: More severe hippocampal cell damage was found in the MH + MCAO group than in the MCAO group. Additionally, neurological deficits, percentage of TUNEL positive cells, and expression of caspase-3, cytochrome c, and Bax in the hippocampus were significantly higher (p < 0.05), whereas bcl-2 expression was significantly lower (p < 0.05) in the MH + MCAO group compared to the MCAO group. <B>Conclusions</B>: These findings suggest that maternal hypoxia may exacerbate hippocampal cell apoptosis in rat offspring after MCAO via alterations in the expression of cytochrome c, caspase-3, Bax, and bcl-2, which ultimately affects ischemic stroke prognosis. To our knowledge, this is the first study demonstrating that maternal hypoxia increases hippocampal cell susceptibility to ischemia in adult rat offspring. </i>.

Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels

A growing body of evidence indicates that prenatal alcohol exposure (PAE) may predispose individuals to secondary medical disabilities later in life. Animal models of PAE reveal neuroimmune sequelae such as elevated brain astrocyte and microglial activation with corresponding region-specific changes in immune signaling molecules such as cytokines and chemokines. The aim of this study was to evaluate the effects of moderate PAE on the development and maintenance of allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in adult male rat offspring. Because CCI allodynia requires the actions of glial cytokines, we analyzed lumbar spinal cord glial and immune cell surface markers indicative of their activation levels, as well as sciatic nerve and dorsal root ganglia (DRG) cytokines in PAE offspring in adulthood. While PAE did not alter basal sensory thresholds before or after sham manipulations, PAE significantly potentiated adult onset and maintenance of allodynia. Microscopic analysis revealed exaggerated astrocyte and microglial activation, while flow cytometry data demonstrated increased proportions of immune cells with cell surface major histocompatibility complex II (MHCII) and β-integrin adhesion molecules, which are indicative of PAE-induced immune cell activation. Sciatic nerves from CCI rats revealed that PAE potentiated the proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha (TNFα) protein levels with a simultaneous robust suppression of the anti-inflammatory cytokine, IL-10. A profound reduction in IL-10 expression in the DRG of PAE neuropathic rats was also observed. Taken together, our results provide novel insights into the vulnerability that PAE produces for adult-onset central nervous system (CNS) pathological conditions from peripheral nerve injury.

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats

Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10mg/kg/day) or vehicle from postnatal day 60 for 21days. Adult offspring were divided into four groups: 1) prenatal stress+duloxetine treatment, 2) prenatal stress+vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions.

Perinatal Nicotine Exposure Increases Obesity Susceptibility in Adult Male Rat Offspring by Altering Early Adipogenesis.

The present study aims to evaluate whether perinatal nicotine (NIC) exposure increases obesity susceptibility in adult male rat offspring by altering early adipogenesis. NIC was sc administered (2.0 mg/kg per day) to pregnant rats from gestational day 9 to the time of weaning (postnatal day 28). At weaning, NIC-exposed male pups had an increased body weight and inguinal sc fat mass and a decreased average cell area of adipocyte, which was accompanied by an overexpression of adipogenic and lipogenic genes in the epididymal white adipose tissue. Additionally, the hepatic lipogenic gene levels from NIC-exposed male pups were also affected. At 12 and 26 weeks of age, body weight and fat mass were increased, whereas there was no change in food intake in NIC-exposed male offspring. Adipogenic and lipogenic genes, glucose transporter 4, and leptin mRNA levels were increased, whereas adiponectin mRNA levels were decreased in the epididymal white adipose tissue of NIC-exposed males. The hepatic lipogenic gene expression of NIC-exposed males was increased. NIC-exposed male offspring showed normal glycemia and a higher serum insulin level, homeostasis model assessment of insulin resistance, and homeostasis model assessment of β-cell function. Furthermore, the NIC-exposed male offspring showed higher serum lipids and Castelli index I and lower nonesterified fatty acid. At 26 weeks, in the ip glucose and insulin tolerance tests, the glucose clearance was delayed, and the area under the curve was higher in the NIC-exposed male offspring. In conclusion, perinatal NIC exposure increased obesity susceptibility in adult male rat offspring by altering early adipogenesis.

The Effect of Prenatal Exposures to Chronic Heterogeneous Stress on Anxiety-Like Behaviors in Adult Male Offspring in Rats

The Effect of Prenatal Exposures to Chronic Heterogeneous Stress on Anxiety-Like Behaviors in Adult Male Offspring in Rats

Maternal high-fat diet inversely affects insulin sensitivity in dams and young adult male rat offspring.

This study attempts to further clarify the potential effects of maternal high-fat (HF) diet on glucose homeostasis in dams and young adult male rat offspring. Female rats were divided into control (CON dams) and HF (HF dams) diet groups, which received the diet 4 weeks prior to and through pregnancy and lactation periods. Blood samples were taken to determine metabolic parameters, then an intraperitoneal glucose tolerance test (IPGTT) was performed. Maternal HF diet increased intra-abdominal fat mass and plasma corticosterone level, but decreased leptin concentration in dams. In HF offspring intra-abdominal fat mass, plasma leptin, and corticosterone levels decreased. Following IPGTT, the plasma insulin level of HF dams was higher than the controls. In HF offspring plasma insulin level was not significantly different from the controls, but a steeper decrease of their plasma glucose concentration was observed.

Prenatal nicotine exposure results in the myocardial fibrosis in the adult male offspring rats

Our previous study showed that prenatal nicotine exposure could increase the heart rate of adult male offspring rats, but little is known about the mechanism. The aim of this study was to investigate the mechanism. Nicotine was subcutaneously administered to pregnant rats at a dose of 1.5mgkg−1 from the gestational days 3–21; the control group received the same volume of saline by the same route. The offsprings’ heart weight, ejection function, ultrastructure, and blood hormones were determined. The present study exhibited that prenatal nicotine exposure significantly decreased the offsprings’ heart and body weight at gestational day 21 and at day 15 after birth, but had no effect on the heart and body weight at 90 days after birth. The hearts were fibrosed in the nicotine exposed male offsprings, and the heart ejection functions of the nicotine male offsprings at 90 days after birth were decreased, including SV, FS and EF. In addition, prenatal nicotine exposure significantly increased the offspring’s blood adrenaline and norepinephrine levels. These data suggest that the increased heart rate caused by prenatal nicotine exposure may be a result of myocardial fibrosis, which leads to heart function decreases, and these data imply a myocardial fibrosis risk of prenatal nicotine exposure.

Prenatal Nicotine Exposure Results in the Inhibition of Baroreflex Sensitivity Induced by Intravenous Injection Angiotensin II in the Adult Male Offspring Rats.

Epidemiological studies show that maternal cigarette smoking is associated with an increased risk of cardiovascular diseases in postnatal life. Baroreflex sensitivity (BRS) is an important index for evaluating the homeostasis of the cardiovascular system. This experiment was designed to investigate the possible mechanism of prenatal nicotine on the adult male offspring's heart rate (HR) increase due to BRS. Pregnant rats received the 0.3ml of saline or nicotine (1.5mgkg-1) by subcutaneous injection from gestational days 3 to 21. The male offsprings of saline injected dams were the control group, and the male offsprings of the nicotine injected dams were the nicotine group. The 90-day-old male offsprings' funny current (I f) of their sinoatrial node (SAN) cells, BRS induced by intravenous injection of angiotensin (Ang) II in the presence or absence of the L-nitro-arginine methylester (L-NAME), cervical vagal activity, c-fos protein levels of the cervical spinal cord-8 to the thoracic spinal cord-5 (C8-T5) lateral horn neuron, and blood hormones were tested. The results showed that prenatal nicotine exposure had no effect on the offsprings' I f of their SAN cells, but it significantly decreased the offsprings' BRS. The c-fos protein levels of the C8-T5 lateral horn neurons and the blood catecholamine levels were increased in the nicotine group, but the cervical vagal activity was not changed. After intraventricular injection of L-NAME, the nicotine exposed offsprings' BRS was partly recovered. These data suggest that prenatal nicotine exposure results in hyper reactivity of the spinal sympathetic nerve center and a higher peripheral catecholamine hormone state of 90-day-old male offsprings, and these may be the reason for the BRS inhibition and HR increase. Nitric oxide (NO) may participate in the process acting as an important neurotransmitter.

Maternal high-salt diet altered PKC/MLC20 pathway and increased ANG II receptor-mediated vasoconstriction in adult male rat offspring.

High-salt diet (HSD) is associated with cardiovascular diseases. This study aims at ascertaining the influence of maternal HSD on offspring's angiotensin II (ANG II)-mediated vasoconstriction and the underlying mechanisms. In comparison to a normal-salt diet, HSD used in pregnancy in rats changed the ultrastructures of the coronary artery (CA) in 5-month-old male offspring, and increased ANG II-mediated CA contractility. Measurement of [Ca(2+) ]i in CA using fluorescent fura-2, a Ca(2+) indicator, showed that ANG II-mediated increases in [Ca(2+) ]i were the same between HSD and normal-salt diet groups, but the ratio of diameter change/[Ca(2+) ]i induced by ANG II were significantly higher in HSD groups. Angiotensin II receptor type 1, not angiotensin II receptor type 2, caused ANG II-mediated vasoconstriction. Protein kinase C (PKC) inhibitor GF109203X attenuated the ANG II-mediated vasoconstriction, PKC agonist phorbol12,13-dibutyrate produced a greater contraction. There was an increase in PKCβ mRNA and the corresponding protein abundance in the offspring, whereas other PKC subunits PKCα, PKCδ, and PKCε did not change. Moreover, 20 kDa myosin light chain phosphorylation levels were increased in HSD group. Maternal HSD affected the developmental programing for the offspring CA, with increased ANG II-mediated vasoconstrictions. The angiotensin II receptor type 1-PKC-20 kDa myosin light chain phosphorylation pathway was the possible mediated cellular mechanism.

The effects of prenatal stress on the astrocytes after cerebral ischemia/reperfusion injury in adult offspring rats

To investigate the effects of prenatal stress on astrocytes after ischemia/reperfusion of cerebral middle artery in adult offspring rats. Pregnant rats were randomly assigned to prenatal stress treatment group, which was exposed to restraint three times daily in the last week of pregnancy, and no prenatal stress treatment group. Adult male offspring rats were subjected to transient focal cerebral ischemia by middle cerebral artery occlusion (MCAO). There were three groups:prenatal stress+sham group, MCAO group and prenatal stress+MCAO group (n=10). After 5 days of reperfusion, the infarct size was evaluated. The morphology of astrocytes, co-local-ization of erythropoietin-producing hepatocellular receptor A4 (EphA4) and glial fibrillary acidic protein (GFAP) were detected by double im-munofluorescent staining. And the protein expressions of EphA4, GFAP and Neurocan in peri-ischemic regions were detected by Western blot. The infarct size and the expression of EphA4, GFAP and Neurocan were significantly increased in prenatal stress+MCAO group compared with MCAO group (all P<0.05). And the morphological changes of GFAP-positive astrocytes and co-localization of EphA4/GFAP were more obvious in prenatal stress+MCAO group compared with MCAO group. Prenatal stress may upregulate the expression of EphA4 on astrocytes in the offspring rats after cerebral ischemia/reperfusion, which promotes the reactivity of astrocyte and increases the ex-pression of neurocan.

Litter Size Reduction Alters the Lipid Metabolism of Adult Male Rat Offspring of Dams Fed a Diet with Caloric Restriction

Recent studies have showed that nutritional changes during critical periods of development can lead to permanent alterations in the metabolism of the offspring which can become more susceptible to chronic diseases in adult age. The aim of this study was to evaluate the effect of litter size on the body weight and the lipid metabolism of adult male offspring rats born to caloric restricted dams. Dams were fed with either ad libitum standard diet (C) or a 30% caloric restricted diet (R) throughout gestation. After birth, litters were reduced to eight pups or four pups in both C and R dams. All dams were fed ad libitum during lactation. After weaning (3 wk), the male rat offspring born to control dams (C8 and C4) and male rat offspring born to restricted dams (R8 and R4) were maintained in individual cages until they were 20 weeks old. An interaction between the diet of control or restricted dams and the litter size was observed for the hepatic lipid % (P=0.015). Reduction of litter size decreased the hepatic lipid % in control rats but increased it in rats to restricted dams. The caloric restriction in the dams decreased the hepatic lipids only in the large litter offspring, but no effect on the small litter was observed. There was no interaction between litter size reduction and the diet of the dams (P=0.689). The reduction of litter size induced an increase (P=0.035) of carcass weight, regardless the diet of the dams. No effects of caloric restriction during gestation and of the litter size on body weight (P=0.187) and on blood cholesterol (P=0.171) were found in C or R adult male rat offspring. It is concluded that the effect of reduction of litter size on hepatic lipid metabolism depends on the diet of the dams during gestation. The increase of carcass weight resulting from litter size reduction is not affected by the diet of the dams.Support or Funding InformationResearch supported by Institute of Biosciences

Cardiovascular Susceptibility to Acute Myocardial Ischemic Injury in Male And Female Rat Offspring Born Growth Restricted

BackgroundIschemic heart disease causes the greatest mortality in the world today. Epidemiological and animal studies have shown that populations who suffer intrauterine growth restriction (IUGR), one of the most common consequences of complicated pregnancies, are more susceptible to develop cardiovascular disorders in later life. We tested the hypothesis that adult male and female IUGR rat offspring are more susceptible to develop cardiac dysfunction following acute myocardial ischemic injury.MethodsMale and female control or IUGR rat offspring (created by exposing pregnant dams to hypoxia, 11.0±0.5% O2, for the last third of pregnancy) were randomly assigned to undergo sham or myocardial infarction (MI) surgery (by ligation of the left anterior descending coronary artery) at the age of 12 weeks. Thus the experimental groups consisted of: Control‐sham, Control‐MI, IUGR‐sham, and IUGR‐MI. One week after MI surgery, echocardiography was performed to assess cardiac morphometry, systolic function and diastolic function.ResultsFemale, but not male, IUGR offspring had lower body weight compared to controls at 12 weeks of age post 1 week of MI. Anterior left ventricular (LV) wall thickness was decreased whereas LV internal diameter during diastole was significantly increased in both control‐MI and IUGR‐MI groups independent of sex or IUGR; indicating wall thinning and LV dilatation due to MI. Ejection fraction, fractional shortening and fractional area change were significantly decreased in both control‐MI and IUGR‐MI groups in male and female offspring. The Tei index was significantly increased in both control‐MI and IUGR‐MI male groups. Interestingly, E/E’ ratio, an index of ventricular filling pressure, was significantly increased in only male IUGR‐MI group compared to IUGR‐Sham (IUGR‐Sham vs IUGR‐MI: 19.84 ± 2.13 vs 35.21 ± 3.66, P&lt;0.05) and control‐MI (Control‐MI vs IUGR‐MI: 22.37 ± 1.73 vs 35.21 ± 3.66, P&lt;0.01).ConclusionIschemic heart disease such as MI was shown to alter LV wall morphometry leading to LV dilatation in both sexes. MI impaired systolic function independent of being born growth‐restricted or sex. However, male IUGR offspring were more susceptible to develop diastolic dysfunction following acute MI. These studies indicate a susceptibility of the male IUGR population to develop diastolic heart failure due to acute myocardial ischemia.Support or Funding InformationThis work is funded by grants from the Canadian Institutes of Health Research (CIHR); and the Women and Children's Health Research Institute (WCHRI) through the generous contributions of the Stollery Children's Hospital Foundation (SCHF) and the Royal Alexandra Hospital Foundation (RAHF). A shah is supported by fellowships from the Heart and Stroke Foundation of Canada.

Protein Restriction During the Last Third of Pregnancy Malprograms the Neuroendocrine Axes to Induce Metabolic Syndrome in Adult Male Rat Offspring.

Metabolic malprogramming has been associated with low birth weight; however, the interplay between insulin secretion disruption and adrenal function upon lipid metabolism is unclear in adult offspring from protein-malnourished mothers during the last third of gestation. Thus, we aimed to study the effects of a maternal low-protein diet during the last third of pregnancy on adult offspring metabolism, including pancreatic islet function and morphophysiological aspects of the liver, adrenal gland, white adipose tissue, and pancreas. Virgin female Wistar rats (age 70 d) were mated and fed a protein-restricted diet (4%, intrauterine protein restricted [IUPR]) from day 14 of pregnancy until delivery, whereas control dams were fed a 20.5% protein diet. At age 91 d, their body composition, glucose-insulin homeostasis, ACTH, corticosterone, leptin, adiponectin, lipid profile, pancreatic islet function and liver, adrenal gland, and pancreas morphology were assessed. The birth weights of the IUPR rats were 20% lower than the control rats (P < .001). Adult IUPR rats were heavier, hyperphagic, hyperglycemic, hyperinsulinemic, hyperleptinemic, and hypercorticosteronemic (P < .05) with higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol, adiponectin, ACTH, and insulin sensitivity index levels (P < .01). The insulinotropic action of glucose and acetylcholine as well as muscarinic and adrenergic receptor function were impaired in the IUPR rats (P < .05). Maternal undernutrition during the last third of gestation disrupts the pancreatic islet insulinotropic response and induces obesity-associated complications. Such alterations lead to a high risk of metabolic syndrome, characterized by insulin resistance, visceral obesity, and lower high-density lipoprotein cholesterol.

Perinatal consumption of flaxseed oil and flaxseed flour has beneficial effects on cardiac fibrosis of male offspring from rat dams with experimental diabetes

Maternal diabetes during critical periods of development can affect the health of adult offspring. Nevertheless, studies suggest that the presence of functional foods, such as flaxseed, can reverse the effects of metabolic programming. This study evaluated the effect of maternal consumption of flaxseed flour and a flaxseed oil based diets in left ventricular histomorphometry and in blood pressure in adult male offspring of diabetic rats. Rats (n=24) were induced into diabetes with a high-fat diet (60% lipid) and streptozotocin (35mg·kg−1). After diabetes confirmation (glucose>300mg/dL), rats were sent to mating, and afterward pregnancy confirmed, they were allocated into four groups: control group (CG), high fat group (HG), flaxseed oil group (FOG) and flaxseed flour group (FFG). At weaning, six males of each group were separated and fed with a commercial diet chow until they reached 100days of life, moment in which they were euthanized. The systolic blood pressure, the thickness of the left ventricular wall and collagen volume density were analyzed. Exposure to a hyperglycemic environment led to an increased systolic blood pressure, nevertheless FOG showed a significant reduction when compared to HG (p<0.001). The left ventricular wall thickness was significantly lower in FFG (p=0.030) and a minor amount of collagen in the left ventricle was found in FOG and FFG (p<0.001). Those results suggest that a diet with flaxseed flour and flaxseed oil avoids the cardiac remodeling of offspring from diabetic dams.

Maternal conjugated linoleic acid supplementation reverses high-fat diet-induced skeletal muscle atrophy and inflammation in adult male rat offspring.

A high-saturated-fat diet (HFD) during pregnancy and lactation leads to metabolic disorders in offspring concomitant with increased adiposity and a proinflammatory phenotype in later life. During the fetal period, the impact of maternal diet on skeletal muscle development is poorly described, despite this tissue exerting a major influence on life-long metabolic health. This study investigated the effect of a maternal HFD on skeletal muscle anabolic, catabolic, and inflammatory signaling in adult rat offspring. Furthermore, the actions of maternal-supplemented conjugated linoleic acid (CLA) on these measures of muscle phenotype were investigated. A purified control diet (CD; 10% kcal fat), a CD supplemented with CLA (CLA; 10% kcal fat, 1% total fat as CLA), a high-fat (HFD; 45% kcal fat from lard), or a HFD supplemented with CLA (HFCLA; 45% kcal fat from lard, 1% total fat as CLA) was fed ad libitum to female Sprague-Dawley rats for 10 days before mating and throughout gestation and lactation. Male offspring received a standard chow diet from weaning, and the gastrocnemius was collected for analysis at day 150. Offspring from HF and HFCLA mothers displayed lower muscular protein content accompanied by elevated monocyte chemotactic protein-1, IL-6, and IL-1β concentrations. Phosphorylation of NF-κBp65 (Ser(536)) and expression of the catabolic E3 ligase muscle ring finger 1 (MuRF1) were increased in HF offspring, an effect reversed by maternal CLA supplementation. The present study demonstrates the importance of early life interventions to ameliorate the negative effects of poor maternal diet on offspring skeletal muscle development.

Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high-fat diet.

Prenatal hypoxia, a common outcome of pregnancy complications, predisposes offspring to the development of metabolic and cardiovascular disorders in later life. We have previously observed that resveratrol improved cardiovascular and metabolic health in adult male rat offspring exposed to prenatal hypoxia and a postnatal high-fat (HF) diet; however, the effects of resveratrol in female rat offspring are not known. Our aim was to identify the mechanism(s) by which resveratrol may prevent metabolic and cardiac dysfunction in both male and female rat offspring exposed to prenatal hypoxia and a postnatal HF diet. Offspring that experienced normoxia or hypoxia in utero were fed a HF diet or a HF diet supplemented with resveratrol for 9 weeks following weaning. Body composition, metabolic function, in vivo cardiac function and ex vivo cardiac susceptibility to ischaemia-reperfusion (I/R) injury were assessed at 12 weeks of age. Prenatal hypoxia impaired metabolic function in male, but not female, rat offspring fed a HF diet and this was improved by resveratrol supplementation. Prenatal hypoxia also led to reduced recovery from cardiac I/R injury in male, and to a lesser extent in female, rat offspring fed a HF diet. Indices of cardiac oxidative stress after I/R were enhanced in both male and female rat offspring exposed to prenatal hypoxia. Resveratrol improved cardiac recovery from I/R injury and attenuated superoxide levels in both male and female rat offspring. In conclusion, prenatal hypoxia impaired metabolic and cardiac function in a sex-specific manner. Resveratrol supplementation may improve metabolic and cardiovascular health in adult male and female rat offspring exposed to prenatal hypoxia.

Maternal flaxseed diet during lactation changes adrenal function in adult male rat offspring.

Flaxseed (Linum usitatissimum L.) has been a focus of interest in the field of functional foods because of its potential health benefits. However, we hypothesised that maternal flaxseed intake during lactation could induce several metabolic dysfunctions in adult offspring. In the present study, we aimed to characterise the adrenal function of adult offspring whose dams were supplemented with whole flaxseed during lactation. At birth, lactating Wistar rats were divided into two groups: rats from dams fed the flaxseed diet (FLAX) with 25% of flaxseed and controls dams. Pups received standard diet after weaning and male offspring were killed at age 180 days old to collect blood and tissues. We evaluated body weight and food intake during development, corticosteronaemia, adrenal catecholamine content, hepatic cholesterol, TAG and glycogen contents, and the protein expression of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and adrenaline β2 receptor at postnatal day 180 (PN180). After weaning, pups from the FLAX group had a higher body weight (+10 %) and food intake (+10%). At PN180, the FLAX offspring exhibited higher serum corticosterone (+48%) and lower adrenal catecholamine ( - 23%) contents, lower glycogen ( - 30%), higher cholesterol (4-fold increase) and TAG (3-fold-increase) contents in the liver, and higher 11β-HSD1 (+62%) protein expression. Although the protein expression of hypothalamic CRH was unaffected, the FLAX offspring had lower protein expression of pituitary ACTH ( - 34%). Therefore, induction of hypercorticosteronaemia by dietary flaxseed during lactation may be due to an increased hepatic activation of 11β-HSD1 and suppression of ACTH. The changes in the liver fat content of the FLAX group are suggestive of steatosis, in which hypercorticosteronaemia may play an important role. Thus, it is recommended that lactating women restrict the intake of flaxseed during lactation.

Maternal High-Fat Diet Causes a Sex-Dependent Increase in AGTR2 Expression and Cardiac Dysfunction in Adult Male Rat Offspring.

Maternal high-fat diet (HFD) is associated with cardiovascular disease later in life. This study tested the hypothesis that maternal HFD causes programming of increased cardiac angiotensin II receptor type 2 (AGTR2) expression, resulting in heightened cardiac susceptibility to ischemic injury in male offspring in a sex-dependent manner. Pregnant rats were divided between control and HFD (HFD-fed during gestation) groups. Maternal HFD resulted in cardiac hypertrophy in only male offspring, but had no effect on cardiac systolic and diastolic function in both male and female offspring. In addition, maternal HFD increased heart susceptibility to ischemia-reperfusion injury in adult male offspring, but not female offspring. There was an increase in Agtr2 mRNA and protein abundance in male, but not female offspring. However, maternal HFD had no effect on angiotensin II receptor type 1 (AGTR1) expression in both male and female offspring. HFD resulted in decreased glucocorticoid receptors (GRs) binding to the glucocorticoid response elements at the Agtr2 promoter, which was due to decreased GRs in the hearts of adult male offspring. Inhibition of AGTR2 with PD123319 abrogated maternal HFD-induced increase in cardiac ischemic vulnerability in male adult rats. The results demonstrate that maternal HFD causes programming of increased Agtr2 gene expression in the heart by downregulation of GR, contributing to the heightened cardiac vulnerability to ischemic injury in adult male offspring in a sex-dependent manner.

Maternal lipopolysaccharide treatment differentially affects 5-HT2A and mGlu2/3 receptor function in the adult male and female rat offspring

Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. However, it is still not fully understood which biochemical mechanisms are responsible for the emergence of neuropsychiatric symptoms following prenatal immune activation. The serotonin (5-hydroxytryptamine, 5-HT) and glutamate system have prominently been associated with the schizophrenia pathophysiology but also with the mechanism of antipsychotic drug actions. Here, we investigated the behavioral and cellular response to 5-HT2A and metabotropic glutamate (mGlu)2/3 receptor stimulation in male and female offspring born to lipopolysaccharide (LPS)-treated mothers. Additionally, we assessed protein expression levels of prefrontal 5-HT2A and mGlu2 receptors. Prenatally LPS-exposed male and female offspring showed locomotor hyperactivity and increased head-twitch behavior in response to the 5-HT2A receptor agonist DOI. In LPS-exposed male offspring, the mGlu2/3 receptor agonist LY379268 failed to reduce DOI-induced prepulse inhibition deficits. In LPS-males, the behavioral changes were further accompanied by enhanced DOI-induced c-Fos protein expression and an up-regulation of prefrontal 5-HT2A receptors. No changes in either 5-HT2A or mGlu2 receptor protein levels were found in female offspring. Our data support the hypothesis of an involvement of maternal infection during pregnancy contributing, at least partially, to the pathology of schizophrenia. Identifying biochemical alterations that parallel the behavioral deficits may help to improve therapeutic strategies in the treatment of this mental illness. Since most studies in rodents almost exclusively include male subjects, our data further contribute to elucidating possible gender differences in the effects of prenatal infection on 5-HT2A and mGlu2/3 receptor function.