Effects of maternal high‐fat/high sucrose diet on hepatic lipid metabolism in rat offspring

Maternal obesity and/or high‐fat diet during pregnancy predispose the offspring to metabolic disease. It is however unclear how pre‐natal and post‐natal exposure respectively affect the risk of hepatic steatosis and the trajectory towards non‐alcoholic steatohepatitis in the offspring. We investigate hepatic lipid metabolism and how these factors are related to metabolic outcome in new born and young rats. Rat dams were exposed to a high‐fat/high sucrose (HFHS) diet for 17 weeks prior to mating and during pregnancy. After birth, female offspring were killed and male offspring were cross‐fostered, creating four groups; Control‐born pups lactated by control (CC) or HFHS dams (CH) and HFHS‐born pups lactated by control (HC) or HFHS dams (HH). At 4 weeks of age, pups were killed and metabolic markers in plasma were assayed, together with hepatic lipid composition and expression of relevant genes. Female HFHS neonates had smaller livers at birth (P < .05), a reduced hepatic lipid content (P < .05) and altered lipid composition. The post‐natal environment dominated the metabolic profile in the male offspring at 4 weeks of age. Offspring exposed to a HFHS environment post‐natally had increased adiposity (P < .0001), increased hepatic triacylglycrol accumulation (P < .0001), and an altered lipid profile with elevated n‐6 polyunsaturated fatty acid (PUFA) levels (P < .0001) and a reduction in ceramide (P < .001) and monounsaturated fatty acid (MUFA) (P < .0001). In summary, maternal HFHS diet during gestation affects the hepatic lipid profile in neonates. The pre‐natal exposure becomes less pronounced in young male offspring at 4 weeks of age, where the post‐natal diet has the largest impact.     

Impact of maternal cigarette smoke exposure on brain and kidney health outcomes in female offspring

Increased oxidative stress in the brain can lead to increased sympathetic tone that may further induce kidney dysfunction. Previously we have shown that maternal cigarette smoke exposure (SE) leads to significantly increased oxidative stress and inflammation in both brain and kidney, as well as reduced brain and kidney mitochondrial activity. This is closely associated with significant kidney underdevelopment and abnormal function in adulthood in the male offspring. This study aimed to investigate the impact of maternal SE on brain and kidney health in the female offspring. In this study, the mouse dams were exposed to two cigarettes, twice daily for 6 weeks prior to gestation, during pregnancy and lactation. Brains and kidneys from the female offspring were collected at 20 days (P20) and 13 weeks (W13) and were subject to further analysis. We found that mRNA expression of brain inflammatory markers interleukin‐1 receptor and Toll‐like receptor 4 were significantly increased in the SE offspring at both P20 and W13. Their brain mitochondrial activity markers were however increased at W13 with increased antioxidant activity. Kidney development and function in the female SE offspring were not different from the control offspring. We concluded that although brain inflammatory markers were upregulated in the SE female offspring, they were protected from some of the indicators of brain oxidative stress, such as endogenous antioxidant and mitochondrial dysfunction, as well as abnormal kidney development and function in adulthood.     

Consumption of a high-fat diet does not potentiate the deleterious effects on lipid and protein levels and body development in rats subjected to maternal protein restriction

Maternal undernutrition may cause injuries in several organs of the offspring, as well as lead to diseases in adulthood. Obesity and/or the consumption of a high-fat diet may also induce metabolic and cardiorespiratory diseases. We hypothesized that the consumption of a post-weaning high-fat diet would potentiate the deleterious effects of maternal protein undernutrition. This study evaluated the effects of the association of a low-protein diet during gestation and lactation with a post-weaning high-fat diet on the biochemical and ventilatory parameters of rats. Male Wistar rats from mothers who received a low-protein (9% of protein) or normoprotein diet during pregnancy and lactation received a high-fat (32% of total kilocalories from lipids) or a normal fat diet after weaning. Mass gain and somatic growth of the offspring were monitored. Also examined were biochemical chemical parameters and respiratory frequency, tidal volume (volume of air displaced in each normal respiratory cycle when extra effort is not applied), and pulmonary ventilation. Offspring from undernourished mothers presented lower birth weight (P = .0225), which remained until the end of lactation (P < .01). The rats that consumed high-fat diet and had been submitted to maternal undernutrition presented higher tidal volume when compared to the ones that consumed control diet at the 21st day of life (P ˂ .05). At 30 and 90 days, no further ventilatory changes were observed. Our data show that the consumption of a high-fat diet post-weaning did not seem to potentiate the changes induced by maternal undernutrition.     

Supplementation of the maternal diet during pregnancy with chocolate and fructose interacts with the high‐fat diet of the young to facilitate the onset of metabolic disorders in rat offspring

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The effects of vitamin A supplementation to rats during gestation and lactation upon redox parameters: Increased oxidative stress and redox modulation in mothers and their offspring

Vitamin A is an essential nutrient required in adequate amounts for reproduction and development. Subtle variations in the status of maternal nutrition may affect physiological and metabolic parameters in the fetus. Evidence suggests a key role for oxidative stress in these events. Literature is controversial about the effects of vitamin A supplementation. Here, we studied the effects of vitamin A supplementation on female Wistar rats during gestation and lactation on oxidative stress parameters of maternal and offspring tissues. Rats received daily doses of vitamin A at 2500, 12,500 and 25,000 IU/kg. We observed an increase of oxidative damage markers in the reproductive tissues and plasma of dams. The activity of glutathione-S-transferase was modulated by vitamin A supplementation. It was found to be increased in the liver of dams and decreased in the kidneys of mothers and offspring. In pups, supplementation decreased the total antioxidant potential of the liver along with decreased superoxide dismutase/catalase activity ratio in the kidney. The levels of lipoperoxidation were increased in male offspring, but decreased in female pups. Collectively, the results suggest that excessive vitamin A intake during gestation and lactation might be toxic for mothers with adverse effects for the developing offspring.     

Maternal fructose intake during pregnancy modulates hepatic and hypothalamic AMP‐activated protein kinase signalling in a sex‐specific manner in offspring

Dietary fructose ingestion during gestation affects carbohydrate metabolism in the offspring. In the present study, we investigated the effects of excess fructose intake during pregnancy on hepatic and hypothalamic AMP‐activated kinase (AMPK) expression and phosphorylation, as well as hepatic glucose‐6‐phosphatase (G6Pase) activity in offspring. Pregnant Wistar rats received normal chow and 100 g/L fructose solution or normal water during gestation ad libitum. On gestational Day 21, some dams were killed and plasma samples and fetuses were collected. The remaining dams received normal water after spontaneous delivery during lactation. Pups were killed on postnatal Day 22 and the plasma, liver and hypothalamus were collected and analysed. Plasma glucose and insulin levels increased in female but not male offspring in the fructose group. Although the mRNA and total protein levels of AMPKα were unchanged, levels of phosphorylated AMPKα protein in the fructose group of female offspring were significantly lower in the liver and 4.6‐fold higher in the hypothalamus. The hepatic protein level of sirtuin 1, which is involved in AMPK phosphorylation and activation, was significantly reduced in the fructose group of female offspring. The activity of G6Pase, which plays a role in gluconeogenesis, was significantly enhanced in the liver of female offspring from fructose‐fed dams. These changes were not observed in male offspring. In conclusion, we found that excessively high fructose intake during pregnancy may modulate the hepatic and hypothalamic AMPK signalling pathways in female offspring after birth.     

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.     

Alpha‐Tocopherol during lactation and after weaning alters the programming effect of prenatal high salt intake on cardiac and renal functions of adult male offspring

Maternal salt overload programs cardiovascular and renal alterations in the offspring. However, beneficial and harmful effects of high dose vitamin E supplementation have been described in humans and animals. We investigated the hypothesis as to whether cardiac and renal alterations can be programmed by gestational salt overload, and can become further modified during lactation and after weaning. Male Wistar rats were used, being the offspring of mothers that drank either tap water or 0.3 mol/L NaCl for 20 days before and during pregnancy. α‐Tocopherol (0.35 g/kg) was administered to mothers daily during lactation or to their offspring for 3 weeks post‐weaning. Systolic blood pressure (tcSBP) was measured in juvenile rats aged 210 days. The response of mean arterial pressure (MAP) and heart rate (HR) to intravenous infusion of angiotensin II (Ang II) was also examined. Left ventricle plasma membrane (PMCA) and sarcoplasmic reticulum Ca²⁺‐ATPase (SERCA) activities, and certain parameters of renal function, were measured. Maternal saline programmed for increased body mass and kidney mass/body mass ratio, increased tcSBP, increased mean arterial pressure and heart rate with anomalous response to infused Ang II. In the heart, saline increased PMCA and α‐Tocopherol per se increased PMCA/SERCA. In the kidney, the most remarkable result was the silent saline programming of Cr_Cl, which was sensitized for a sharp decrease after α‐Tocopherol. In conclusion, the combination of maternal saline overload and high α‐Tocopherol immediately after birth leads to simultaneous cardiovascular and renal alterations in the young offspring, like those encountered in type V cardiorenal syndrome.     

F0 maternal BPA exposure induced glucose intolerance of F2 generation through DNA methylation change in Gck

BPA, a common environmental endocrine disruptor, has been reported to induce epigenetic changes and disrupt glucose homeostasis in F1 offspring through maternal exposure. However, no studies have examined whether maternal BPA exposure can exert multigenerational effects of glucose metabolic disorder on F2 generation through the altered epigenetic information. The aim of the current study was to investigate whether BPA exposure can disrupt glucose homeostasis in F2 offspring and the underlying epigenetic mechanism. In the present study, F0 pregnant dams were orally administered at a daily dose of 40 μg/kg body weight during gestation and lactation. The F1 and F2 generations were obtained and not exposed to BPA anymore. The glucose and insulin tolerance tests were carried out to evaluate the glucose homeostasis level. The relative hormone level and the relative gene expression were also examined. F2 generation was found to exhibited glucose intolerance and insulin resistance in ipGTT and ipITT, as well as the downregulation of glucokinase (Gck) gene in liver. DNA methylation pattern of Gck promoter in the F2 generation of hepatic tissue and F1 generation of sperm was then performed. The Gck promoter in F2 hepatic tissue became completely methylated in the all CpG sites compared with five unmethylated sites in controls. In the F1 sperm, the global DNA methylation was decreased. However, there is only CpG site −314 was differently methylated between BPA and controls in sperm. In conclusion, F0 maternal BPA exposure during gestation and lactation can induce impaired glucose homeostasis in the F2 offspring through the transmission of sperm. The underlying epigenetic modifications in the sperm of F1 generation remain to be further elucidated     

Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl‐l‐carnitine and nicotinamide treatment in dyslipidaemic insulin‐resistant rats

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The CD147/MMP‐2 signaling pathway may regulate early stage cardiac remodelling in spontaneously hypertensive rats

Previous studies have reported that decreased matrix metalloproteinase‐2 (MMP‐2) is associated with early stage (age 8–16 weeks) ventricular remodelling in spontaneously hypertensive rats (SHR). We hypothesized that inhibited CD147/MMP‐2 signalling might down‐regulate MMP‐2 expression and augment remodelling in spontaneously hypertensive rats. Twenty‐nine male SHR (8 weeks) were randomly assigned to SHR, CD147, and CD147+DOX groups. The control group included eight age‐matched WKY rats. CD147 and CD147+DOX groups received recombinant human CD147 (600 ng/kg in 1.5 mL saline, weekly). The SHR and WKY groups received the vehicle. The CD147+DOX group also received doxycycline, an inhibitor of MMPs (daily, 30 mg/kg in 1.5 mL saline, iG). On day 56 echocardiography and left ventricular mass index (LVWI) measurements were collected and histological sections were stained for cell and collagen content. Myocardium MMP‐2, TIMP‐1, CD147, and collagens types I and III were estimated by western blot. CD147 and the ratio of MMP‐2/TIMP‐1 were lower in SHR than WKY rats (P<.05). Myocyte hypertrophy, partial fibre breaks, plasmolysis, necrosis and collagen content (collagen volume fraction [CVF], I and III) in SHR were above control levels (P<.05). CD147 rats showed CD147, MMP‐2 and MMP‐2/TIMP‐1 were increased (P<.05), CVF, LVWI, and collagen I and III were decreased (P<.05) and myocyte morphology was improved. CD147 levels did not differ between CD147+DOX and CD147 groups, CVF, collagens type I and III and partial fiber breaks were more abundant in CD147+DOX (P<.05). In summary, an inhibited CD147/MMP‐2 pathway was associated with early stage cardiac remodelling, and CD147 supplementation may attenuate this response.     

Pancreatic impairment and Igf2 hypermethylation induced by developmental exposure to bisphenol A can be counteracted by maternal folate supplementation

Increasing evidence indicates that bisphenol A (BPA), a widely manufactured environmental pollutant, can induce changes in DNA methylation paatterns, which is a potential mechanism linking this environmental exposure to disease development. We investigated the influence of developmental exposure to BPA on pancreatic DNA methylation patterns and whether maternal folate supplementation can modify the epigenetic status and pancreatic impairment induced by BPA. Our results showed that maternal dietary folate supplementation in rats exposed to BPA counteracted the observed BPA‐induced pancreatic impairments in the offspring, which included disrupted insulin secretion and glucose intolerance, and impaired morphology and ultrastructure of β cells. Moreover, these pancreatic dysfunctions were shown to be associated with low expression and DNA hypermethylation of insulin‐like growth factor‐2 (Igf2 ) in islets induced by exposure to BPA during the developmental period. Importantly, maternal dietary folate supplementation was demonstrated to negate this Igf2 DNA hypermethylation in the offspring, which was consistent with the upregulation of Igf2 expression. Overall, our results suggest that early developmental exposure to BPA alters the DNA methylation of Igf2 , that these altered methylation patterns are associated with impaired β‐cell function in the offspring and that these effects can be counteracted by maternal folate supplementation. Copyright © 2017 John Wiley & Sons, Ltd.     

Developmental programming: Sex‐specific programming of growth upon prenatal bisphenol A exposure

In both human and animals, in utero exposure to bisphenol A (BPA), an endocrine‐disrupting chemical used in the production of plastics and epoxy resins, has been shown to affect offspring reproductive and metabolic health during adult life. We hypothesized that the effect of prenatal exposure to environmentally relevant doses of BPA will be evident during fetal organogenesis and fetal/postnatal growth trajectory. Pregnant ewes were administered BPA subcutaneously from 30 to 90 days of gestation (term 147 days). Fetal organ weight, anthropometric measures, maternal/fetal hormones and postnatal growth trajectory were measured in both sexes. Gestational BPA administration resulted in higher accumulation in male than female fetuses only at fetal day 65, with minimal impact on fetal/maternal steroid milieu in both sexes at both time points. BPA‐treated male fetuses were heavier than BPA‐treated female fetuses at fetal day 90 whereas this sex difference was not evident in the control group. At the organ level, liver weight was reduced in prenatal BPA‐treated female fetuses, while heart and thyroid gland weights were increased in BPA‐treated male fetuses relative to their sex‐matched control groups. Prenatal BPA treatment also altered the postnatal growth trajectory in a sex‐specific manner. Males grew slower during the early postnatal period and caught up later. Females, in contrast, demonstrated the opposite growth trend. Prenatal BPA‐induced changes in fetal organ differentiation and early life growth strongly implicate translational relevance of in utero contributions to reproductive and metabolic defects previously reported in adult female offspring.     

In Utero and Lactational Exposure to Fluoxetine in Wistar Rats: Pregnancy Outcomes and Sexual Development

This study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and oestrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Oestrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine were observed. Finally, pup birthweight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic‐like doses.     

Transgenerational left ventricular hypertrophy and hypertension in offspring after uteroplacental insufficiency in male rats

Epidemiological studies have shown an association between low birthweight and adult disease development with transmission to subsequent generations. The aim of the present study was to examine the effect of intrauterine growth restriction in rats, induced by uteroplacental insufficiency, on cardiac structure, number, size, nuclearity, and adult blood pressure in first (F1) and second (F2) generation male offspring. Uteroplacental insufficiency or sham surgery was induced in F0 Wistar‐Kyoto pregnant rats in late gestation giving rise to F1 restricted and control offspring, respectively. F1 control and restricted females were mated with normal males, resulting in F2 control and restricted offspring, respectively. F1 restricted male offspring were significantly lighter at birth (P < 0.05), but there were no differences in birthweight of F2 offspring. Left ventricular weights and volumes were significantly increased (P < 0.05) in F1 and F2 restricted offspring at day 35. Left ventricular cardiomyocyte number was not different in F1 and F2 restricted offspring. At 6 months‐of‐age, F1 and F2 restricted offspring had elevated blood pressure (8–15 mmHg, P < 0.05). Our findings demonstrate the emergence of left ventricular hypertrophy and hypertension, with no change in cardiomyocyte number, in F1 restricted male offspring, and this was transmitted to the F2 offspring. The findings support transgenerational programming effects.     

Role of proteinuria in defining pre‐eclampsia: Clinical outcomes for women and babies

1. The presence of proteinuria is not essential to the diagnosis of pre‐eclampsia under many diagnostic consensus statements. The aim of the present study was to assess maternal and perinatal outcomes after proteinuric pre‐eclampsia compared with other non‐proteinuric disease presentations. 2. An individual patient data review (n = 670) was undertaken for 2003–2006 at a tertiary referral centre in Sydney (NSW, Australia). Women were diagnosed in accordance with the Australasian Society for the Study of Hypertension in Pregnancy Consensus Statement. Data were analysed with the Chi‐squared test, t‐tests and non‐parametric tests. Statistical significance was set at P < 0.05. 3. The proteinuric cohort had higher systolic and diastolic blood pressure recordings than the non‐proteinuric cohort (160/102 and 149/94 mmHg, respectively; P < 0.001), and were also administered magnesium sulphate more frequently (44 vs 22%, respectively; P < 0.001), delivered at earlier gestation (37 vs 38 weeks, respectively; P < 0.001), required operative delivery more frequently (63 vs 48%, respectively; P < 0.001) and received more antihypertensive medications during the antenatal period (72 vs 57%, respectively; P < 0.001). Acute renal failure and acute pulmonary oedema were rare. Four cases of eclampsia all occurred in non‐proteinuric women. The perinatal mortality rate was lower for the offspring of women with proteinuric pre‐eclampsia compared with offspring of non‐proteinuric women (13/1000 and 31/1000, respectively; P = 0.006). 4. The results of the present study indicate that the presence of proteinuria denotes a group of women who have higher antenatal blood pressure, who deliver at earlier gestation and require operative delivery more commonly, although it is not an indicator of other markers of maternal morbidity or perinatal mortality.     

Prorenin receptor mediates inflammation in renal ischemia

We hypothesized that PRR contributes to renal inflammation in the 2‐kidney, 1‐clip (2K1C) renal ischaemia model. Male Sprague‐Dawley rats were fed normal sodium diet. Blood pressure (BP) was obtained on days 0 and 28 after left renal artery clipping that reduced renal blood flow by 40%. Renal expression of TNF‐α, COX‐2, NF‐κB, IL‐1β, MCP‐1 and collagen type I were assessed in sham and 2K1C rats with or without left renal administration of scramble or PRR shRNA. At baseline, there were no differences in BP. Compared to sham, MAP significantly increased in clipped animals (sham 102 ± 1.9 vs 2K1C 131.8 ± 3.09 mmHg, P < .05) and was not influenced by scramble or PRR shRNA treatment. Compared to sham and contra lateral (non‐clipped) kidney, there was upregulation in mRNA and protein expression of PRR (99% and 45%, P < .01), TNF‐α (72% and 50%, P < .05), COX‐2 (72% and 39%, P < .05), p‐NF‐κB (92%, P < .05), MCP‐1 (87%, P < .05) and immunostaining of collagen type I in the clipped kidney. These increases were not influenced by scramble shRNA. Compared to 2K1C and scramble shRNA, PRR shRNA treatment in the clipped kidney significantly reduced the expression of PRR (62% and 57%, P < .01), TNF‐α (51% and 50%, P < .05), COX‐2 (50% and 56%, P < .05), p‐NF‐κB by 68% (P < .05), MCP‐1 by 73% (P < .05) and collagen type I respectively. Ang II was increased in both kidneys and did not change in response to scramble or PRR shRNA treatments. We conclude that PRR mediates renal inflammation in renal ischaemia independent of blood pressure and Ang II.     

Early life programming of cardiometabolic disease in the Western Australian pregnancy cohort (Raine) study

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