The effects of dietary fructose and salt on maternal, fetal and adult offspring growth, metabolic status and cardiovascular health

The modern Western diet is typically high in salt and fructose. Variations in maternal diet can have delayed developmental effects on the adult offspring’s cardiovascular function leading to acute or chronic hypertension. The aim of the work in this thesis was to determine the effect of moderate dietary salt and/or fructose intake on maternal and fetal growth, metabolic status and cardiovascular health of the adult offspring. Sprague Dawley rats were fed either 1) control diet (chow) with tap water, 2) salt diet, 4% NaCl, 3) fructose diet, purified chow plus 10% fructose in tap water or 4) fructose and salt diet for 28 days prior to conception, through gestation and lactation. Data were collected on the non-pregnant and pregnant dam, the fetus and neonate and the adult offspring. Cardiovascular data in adult offspring were recorded between the ages of 10-15 weeks by implanted radiotelemetry probes. Dams fed fructose prior to and during gestation increased caloric intake (P<0.001) from fructose water with a consequential decrease in total energy intake (P<0.001) from food. Increases in plasma glucose (P=0.04) (without an effect on insulin), triglyceride (P<0.014), non-esterified fatty acids (P<=0.05), cholesterol (P<0.001) and uric acid (P<0.004) were all increased by the consumption of fructose in pre-gestational females. Dams consuming salt prior to and during gestation elicited an increase in cardiac (P<0.001) and kidney tissue mass (P<0.001). Fructose-fed dams also displayed a significant redistribution of regional fat depots i.e. visceral fat increased (P<0.001) whilst gonadal fat decreased (P<0.008). Fructose also increased liver weight (P<0.001) and intra-hepatic triglyceride concentration was also observed to be increased (P<0.007). However, few effects on the fetus but subtle effects on fetal and neonatal growth were observed at this stage. Fructose and salt combined reduced litter size (7 vs. 14 pups) (P<0.001) without an effect on birth weight. Maternal fructose diet skewed the sex ratio in favour of males (60:40) (P<0.001) and maternal salt influenced placental architecture (decreased labyrinthine (P<0.007), increased trophoblast layer (P=0.03)) and had marked effects on maternal osmolality (P<0.001). Male (P=0.07) and female (P<0.02) offspring from fructose-fed mothers had relatively heavier livers. In the adult offspring male and female offspring plasma osmolality was significantly increased in offspring fed prenatal salt (P<0.001). In the offspring, maternal salt diet significantly increased (~15mmHg) basal mean arterial pressure (MAP) in the adult male offspring (P<0.001), but significantly decreased basal MAP (~8mmHg) in the adult female offspring. Both fructose and salt diet had effects on the circadian variation in blood pressure and heart rate. Subsequent cardiovascular challenges revealed little beyond an altered cardiovascular set-point in these offspring. The study emphasizes the importance of quality rather than quantity when assessing maternal diet, particularly in terms of its mineral and simple sugar content. In conclusion, data within this thesis demonstrates for the first time a moderate maternal dietary intake of salt and fructose can affect offspring osmolality profile and blood pressure in a sex-specific manner and produce a pattern of symptoms resembling NAFLD which, in part, are passed vertically to the offspring

Magnesium sulfate has sex-specific, dose-dependent vasodilator effects on preterm placental vessels

Background Women at risk of preterm delivery receive magnesium sulfate (MgSO 4 ) in the pre-delivery phase to reduce their child\u27s risk of neurodevelopmental complications associated with preterm birth. However, the mechanisms underpinning its placental vascular role remain uncertain. Methods The aim of this study was to examine MgSO 4 action on vascular tone in male and female human placental vessels from term and preterm deliveries. Vessels were obtained from placental biopsy following birth at term (37-41 weeks) or preterm gestation (gestation). The vessels were mounted on a pressure myograph, pre-constricted with synthetic endoperoxide prostaglandin PGH 2 (U46619) (0.1-100 μmol/l), and percentage of relaxation was calculated following incubation with bradykinin. Experiments were carried out in the presence of MgSO 4 (0.2 mmol/l), N Ψ -nitro-L-arginine methyl ester (L-NAME) (0.1 mmol/l), indomethacin (10 μmol/l), Ca 2+ -activated K + channel blocker TRAM-34 (1 μM) and apamin (3 μM) to assess mechanisms of vascular function. Vascular [calcium ions (Ca 2+ )] was analysed using a colorimetric calcium assay. Results Vasodilation in vessels from preterm males was significantly blunted in the presence of MgSO 4 when compared to preterm female and term male and female vessels. Overall, MgSO 4 was observed to differentially modulate placental vascular tone and vascular calcium concentrations in a sex-specific manner. Conclusions As MgSO 4 regulates human placental blood flow via specific pathways, foetal sex-specific MgSO 4 treatment regimes may be necessary. In an era of increasing awareness of individualised medicine, sex-specific effects may be of importance when developing strategies to optimise care in high-risk patients

Excess maternal salt or fructose intake programmes sex-specific, stress- and fructose-sensitive hypertension in the offspring

The Western diet is typically high in salt and fructose, which have pressor activity. Maternal diet can affect offspring blood pressure, but the extent to which maternal intake of excess salt and fructose may influence cardiovascular function of the offspring is unknown. We sought to determine the effect of moderate maternal dietary intake of salt and/or fructose on resting and stimulated cardiovascular function of the adult male and female offspring. Pregnant rats were fed purified diets (±4 % salt) and water (±10 % fructose) before and during gestation and through lactation. Male and female offspring were weaned onto standard laboratory chow. From 9 to 14 weeks of age, cardiovascular parameters (basal, circadian and stimulated) were assessed continuously by radiotelemetry. Maternal salt intake rendered opposite-sex siblings with a 25-mmHg difference in blood pressure as adults; male offspring were hypertensive (15 mmHg mean arterial pressure (MAP)) and female offspring were hypotensive (10 mmHg MAP) above and below controls, respectively. Sex differences were unrelated to endothelial nitric oxide activity in vivo, but isolation-induced anxiety revealed a significantly steeper coupling between blood pressure and heart rate in salt-exposed male offspring but not in female offspring. MAP of all offspring was refractory to salt loading but sensitive to subsequent dietary fructose, an effect exacerbated in female offspring from fructose-fed dams. Circadian analyses of pressure in all offspring revealed higher mean set-point for heart rate and relative non-dipping of nocturnal pressure. In conclusion, increased salt and fructose in the maternal diet has lasting effects on offspring cardiovascular function that is sex-dependent and related to the offspring’s stress–response axis

Maternal fructose and/or salt intake and reproductive outcome in the rat: effects on growth, fertility, sex ratio, and birth order

Maternal diet can significantly skew the secondary sex ratio away from the expected value of 0.5 (proportion males), but the details of how diet may do this are unclear. Here, we altered dietary levels of salt (4% salt in the feed) and/or fructose (10% in the drinking water) of pregnant rats to model potential effects that consumption of a "Western diet" might have on maternofetal growth, development, and sex ratio. We demonstrate that excess fructose consumption before and during pregnancy lead to a marked skew in the secondary sex ratio (proportion of males, 0.60; P < 0.006). The effect was not mediated by selective developmental arrest of female embryos or influenced by fetal position in the uterine horn or sex-specific effects on sperm motility, suggesting a direct effect of glycolyzable monosaccharide on the maternal ovary and/or ovulated oocyte. Furthermore, combined excess maternal consumption of salt and fructose-sweetened beverage significantly reduced fertility, reflected as a 50% reduction in preimplantation and term litter size. In addition, we also noted birth order effects in the rat, with sequential implantation sites tending to be occupied by the same sex

Preterm‐born individuals: a vulnerable population at risk of cardiovascular morbidity and mortality during thermal extremes?

New Findings: What is the topic of this review? Thermal extremes disproportionately affect populations with cardiovascular conditions. Preterm birth, across all gestational age ranges below 37 weeks, has been identified as a non‐modifiable risk factor for cardiovascular disease. The hypothesis is presented that individuals born preterm are at an increased risk of cardiovascular morbidity and mortality during thermal extremes. What advances does it highlight? Cardiovascular stress tests performed in preterm‐born populations, from infancy through adulthood, highlight a progression of cardiovascular dysfunction accelerating through adolescence and adulthood. This dysfunction has many similarities with populations known to be at risk in thermal extremes. Abstract: Preterm‐born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro‐ and micro‐physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later‐life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes

Nitrous oxide improves cardiovascular, respiratory, and thermal stability during prolonged isoflurane anesthesia in juvenile guinea pigs

Anesthesia is frequently used to facilitate physiological monitoring during interventional animal studies. However, its use may induce cardiovascular (central and peripheral), respiratory, and thermoregulatory depression, confounding results in anesthetized animals. Despite the wide utility of guinea pigs as a translational platform, anesthetic protocols remain unstandardized for extended physiological studies in this species. Therefore, optimizing an anesthetic protocol that balances stable anesthesia with intact cardiorespiratory and metabolic function is crucial. To achieve this, 12 age and sex-matched juvenile Dunkin Hartley guinea pigs underwent extended anesthesia (≤150 min) with either (a) isoflurane (ISO: 1.5%), or (b) isoflurane + N2O (ISO+ N2O: 0.8% +70%), in this randomized cross-over designed study. Cardiovascular (HR, SBP, peripheral microvascular blood flow), respiratory (respiratory rate, SpO2), and thermal (Tre and Tsk) measures were recorded continuously throughout anesthesia. Blood gas measures pre- and post- anesthesia were performed. Incorporation of 70% N2O allowed for significant reductions in isoflurane (to 0.8%) while maintaining an effective anesthetic depth for prolonged noninvasive physiological examination in guinea pigs. ISO+N2O maintained heart rate, peripheral blood flow, respiratory rate, and thermoregulatory function at levels closest to those of conscious animals, especially in females; however, it did not fully rescue anesthesia-induced hypotension. These results suggest that for studies requiring prolonged physiological examination (≤150 min) in guinea pigs, 0.8% isoflurane with a 70% N2O adjuvant provides adequate anesthesia, while minimizing associated cardiorespiratory depression. The preservation of cardiorespiratory status is most marked throughout the first hour of anesthesia

Outcomes of 23- and 24-weeks gestation infants in Wellington, New Zealand: A single centre experience

Optimal perinatal care of infants born less than 24 weeks gestation remains contentious due to uncertainty about the long-term neurodevelopment of resuscitated infants. Our aim was to determine the short-term mortality and major morbidity outcomes from a cohort of inborn infants born at 23 and 24 weeks gestation and to assess if these parameters differed significantly between infants born at 23 vs. 24 weeks gestation. We report survival rates at 2-year follow-up of 22/38 (58%) at 23 weeks gestation and 36/60 (60%) at 24 weeks gestation. Neuroanatomical injury at the time of discharge (IVH ≥ Grade 3 and/or PVL) occurred in in 3/23 (13%) and 1/40 (3%) of surviving 23 and 24 weeks gestation infants respectively. Rates of disability at 2 years corrected postnatal age were not different between infants born at 23 and 24 weeks gestation. We show evidence that with maximal perinatal care in a tertiary setting it is possible to achieve comparable rates of survival free of significant neuroanatomical injury or severe disability at age 2 in infants born at 23-week and 24-weeks gestation

A novel whole-body thermal stress test for monitoring cardiovascular responses in guinea pigs

Cardiovascular disease is a leading cause of morbidity and mortality worldwide. Stress tests are frequently employed to expose early signs of cardiovascular dysfunction or disease and can be employed, for example, in the context of preterm birth. We aimed to establish a safe and effective thermal stress test to examine cardiovascular function. Guinea pigs were anaesthetized using a 0.8% isoflurane, 70% N2O mix. ECG, non-invasive blood pressure, laser Doppler flowmetry, respiratory rate, and an array of skin and rectal thermistors were applied. A physiologically relevant heating and a cooling thermal stress test was developed. Upper and lower thermal limits for core body temperature were set at 41.5 OC and 34 OC, for the safe recovery of animals. This protocol therefore presents a viable thermal stress test for use in guinea pig models of health and disease that facilitates exploration of whole-system cardiovascular function