Programming Effects of Prenatal Glucocorticoid Exposure with a Postnatal High-Fat Diet in Diabetes Mellitus.
Ontology highlight
ABSTRACT:
SUBMITTER: Sheen JM
PROVIDER: S-EPMC4848989 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Maternal diabetes-induced fetal programming predisposes offspring to type 2 diabetes, cardiovascular disease, and obesity in adulthood. However, lifelong health and disease trajectories depend on several factors and nutrition is one of the main ones. We intend to understand the role of maternal diabetes-induced fetal programming and its association with a high-fat diet during lifelong in the female F1 generation focusing on reproductive outcomes and the possible changes in physiological systems during pregnancy as well as the repercussions on the F2 generation at birth. For this, we composed four groups: F1 female pups from control (OC) or from diabetic dams (OD) and fed with standard (SD) or high-fat diet from weaning to full-term pregnancy. During pregnancy, glucose intolerance and insulin sensitivity were evaluated. In a full-term pregnancy, the maternal blood and liver were collected to evaluate redox status markers. The maternal blood, placental tissue, and fetal blood (pool) were collected to evaluate adiponectin and leptin levels. Maternal reproductive parameters were evaluated as well. Maternal diabetes and high-fat diet consumption, in isolation, were both responsible for increased infertility rates and fasting glucose levels in the F1 generation and fetal growth restriction in the F2 generation. The association of both conditions showed, in addition to those, increased lipoperoxidation in maternal erythrocytes, regardless of the increased endogenous antioxidant enzyme activities, glucose intolerance, decreased number of implantation sites and live fetuses, decreased litter, fetal and placental weight, increased preimplantation losses, and increased fetal leptin serum levels. Thus, our findings show that fetal programming caused by maternal diabetes or lifelong high-fat diet consumption leads to similar repercussions in pregnant rats. In addition, the association of both conditions was responsible for glucose intolerance and oxidative stress in the first generation and increased fetal leptin levels in the second generation. Thus, our findings show both the F1 and F2 generations harmed health after maternal hyperglycemic intrauterine environment and exposure to a high-fat diet from weaning until the end of pregnancy.
| S-EPMC9189289 | biostudies-literature
Project description:BackgroundHypertension may result from high-fat (HF) diet induced-obesity and overexposure to glucocorticoids in utero. Recent studies demonstrated the potent contribution of adipose tissue's renin-angiotensin system (RAS) to systemic RAS, which plays a key role in regulating blood pressure (BP). In this study, we investigated the effects of prenatal dexamethasone (DEX) exposure and postnatal HF diet on RAS of adipose tissue.MethodsRAS and BP of 6-month old rats exposed to prenatal DEX and/or postnatal HF diet were examined.ResultsPrenatal DEX plus postnatal HF exerted a synergistic effect on systolic BP. Prenatal DEX exposure suppressed plasma angiotensin (ANG) I and ANG II, whereas postnatal HF suppressed plasma ANG-(1-7) level. Prenatal DEX increased prorenin receptor and renin levels, but suppressed angiotensinogen (AGT) and angiotensin-converting-enzyme 1 (ACE1) mRNA expressions in adipose tissue. Postnatal HF increased AGT mRNA expression, but suppressed prorenin receptor, renin, ACE2, ANG II type 2 receptor (AT2R), and Mas receptor (MasR) mRNA expression levels.ConclusionsPrenatal GC exposure altered the ACE1/ANG II/ANG II type 1 receptor (AT1R) axis, whereas postnatal HF negatively impacted the ACE2/ANG-(1-7)/MasR axis. Prenatal DEX exposure and postnatal HF synergistically elevated BP through a distinct programming mechanism of systemic and adipose RAS. Adipose RAS might be a target for precise hypertension treatment.
| S-EPMC5853160 | biostudies-literature
Project description:The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11?-hydroxysteroid dehydrogenase enzymes (11?-HSD1 and 11?-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11?-HSD1, while 11?-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11?-HSD1 and 11?-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11?-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of arsenic results in altered fetal programming of the glucocorticoid system.
| S-EPMC4672640 | biostudies-literature
Project description:Prenatal dexamethasone (DEX) exposure and high-fat (HF) intake are linked to hypertension. We examined whether maternal melatonin therapy prevents programmed hypertension synergistically induced by prenatal DEX plus postnatal HF in adult offspring. We also examined whether DEX and melatonin causes renal programming using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received intraperitoneal dexamethasone (0.1 mg/kg) or vehicle from gestational day 16 to 22. In the melatonin-treatment groups (M), rats received 0.01% melatonin in drinking water during their entire pregnancy and lactation. Male offspring were assigned to five groups: control, DEX, HF, DEX+HF, and DEX+HF+M. Male offspring in the HF group were fed a HF diet from weaning to 4 months of age. Prenatal DEX and postnatal HF diet synergistically induced programmed hypertension in adult offspring, which melatonin prevented. Maternal melatonin treatment modified over 3000 renal transcripts in the developing offspring kidney. Our NGS data indicate that PPAR signaling and fatty acid metabolism are two significantly regulated pathways. In addition, maternal melatonin therapy elicits longstanding alterations on renal programming, including regulation of the melatonin signaling pathway and upregulation of Agtr1b and Mas1 expression in the renin-angiotensin system (RAS), to protect male offspring against programmed hypertension. Postnatal HF aggravates prenatal DEX induced programmed hypertension in adult offspring, which melatonin prevented. The protective effects of melatonin on programmed hypertension is associated with regulation of the RAS and melatonin receptors. The long-term effects of maternal melatonin therapy on renal transcriptome require further clarification.
| S-EPMC4675845 | biostudies-other
Project description:Anxiety disorders and depression are well-documented in subjects exposed to adverse childhood events. Recently, maternal obesity and/or maternal consumption of high-fat diets (HFD) have been also proposed as risk factors for offspring mental health. Here using an animal model in rats, we explored the combinatorial effects of a maternal HFD (40% of energy from fat without impact on maternal weight; during gestation and lactation) and maternal separation (MS) in offspring. In the prefrontal cortex (PFC) of pups, MS led to changes in the expression of several genes such as Bdnf (brain derived neurotrophic factor), 5HT-r1a (serotonin receptor 1a) and Rest4 (neuron-restrictive silencer element, repressor element 1, silencing transcription factor (Rest), splicing variant 4). Surprisingly, perinatal HFD strongly attenuated the developmental alterations induced by MS. Furthermore, maternal HFD totally prevented the endophenotypes (anxiety, spatial memory, social behavior, hypothalamic-pituitary-adrenal (HPA) axis response to stress, hippocampal neurogenesis and visceral pain) associated with MS at adulthood. Finally, we also demonstrated that HFD intake reduced anxiety and enhanced maternal care in stressed dams. Overall, our data suggest that a HFD restricted to gestation and lactation, which did not lead to overweight in dams, had limited effects in unstressed offspring, highlighting the role of maternal obesity, rather than fat exposure per se, on brain vulnerability during development.
| S-EPMC5290357 | biostudies-literature
Project description:Obesity and metabolic disease present a danger to long-term health outcomes. It has been hypothesized that epigenetic marks established during early life might program individuals and have either beneficial or harmful consequences later in life. In the present study, we examined whether maternal diet alters DNA methylation and whether such modifications persist after an obesogenic postnatal dietary challenge. During gestation and lactation, male Sprague-Dawley rats were exposed to either a high-fat diet (HF; n = 10) or low-fat diet (LF; n = 10). After weaning, all animals were fed a HF diet for an additional nine weeks. There were no differences observed in food intake or body weight between groups. Hepatic DNA methylation was quantified using both methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme sequencing (MRE-seq). Overall, 1419 differentially methylated regions (DMRs) were identified. DMRs tended to be located in CpG shores and were enriched for genes involved in metabolism and cancer. Gene expression was measured for 31 genes in these pathways. Map3k5 and Igf1r were confirmed to be differentially expressed. Finally, we attempted to quantify the functional relevance of intergenic DMRs. Using chromatin contact data, we saw that conserved DMRs were topologically associated with metabolism genes, which were associated with differential expression of Adh5, Enox1, and Pik3c3. We show that although maternal dietary fat is unable to reverse offspring weight gain in response to a postnatal obesogenic diet, early life diet does program the hepatic methylome. Epigenetic alterations occur primarily in metabolic and cancer pathways and are associated with altered gene expression, but it is unclear whether they bear consequence later in life.
| S-EPMC6769607 | biostudies-literature
Project description:Altered fetal growth, which can occur due to environmental stressors during pregnancy, may program a susceptibility to metabolic disease. Gestational exposure to the air pollutant ozone is associated with fetal growth restriction in humans and rodents. However, the impact of this early life ozone exposure on offspring metabolic risk has not yet been investigated. In this study, fetal growth restriction was induced by maternal inhalation of 0.8 ppm ozone on gestation days 5 and 6 (4 hr/day) in Long Evans rats. To uncover any metabolic inflexibility, or an impaired ability to respond to a high-fat diet (HFD), a subset of peri-adolescent male and female offspring from filtered air or ozone exposed dams were fed HFD (45% kcal from fat) for 3 days. By 6 weeks of age, male and female offspring from ozone-exposed dams were heavier than offspring from air controls. Furthermore, offspring from ozone-exposed dams had greater daily caloric consumption and reduced metabolic rate when fed HFD. In addition to energy imbalance, HFD-fed male offspring from ozone-exposed dams had dyslipidemia and increased adiposity, which was not evident in females. HFD consumption in males resulted in the activation of the protective 5'AMP-activated protein kinase (AMPKα) and sirtuin 1 (SIRT1) pathways in the liver, regardless of maternal exposure. Unlike males, ozone-exposed female offspring failed to activate these pathways, retaining hepatic triglycerides following HFD consumption that resulted in increased inflammatory gene expression and reduced insulin signaling genes. Taken together, maternal ozone exposure in early pregnancy programs impaired metabolic flexibility in offspring, which may increase susceptibility to obesity in males and hepatic dysfunction in females.
| S-EPMC10010258 | biostudies-literature
Project description:Infants born to women with diabetes or obesity are exposed to excess circulating fuels during fetal heart development and are at higher risk of cardiac diseases. We have previously shown that late-gestation diabetes, especially in conjunction with a maternal high-fat (HF) diet, impairs cardiac functions in rat-offspring. This study investigated changes in genome-wide histone modifications in newborn hearts from rat-pups exposed to maternal diabetes and HF-diet. Chromatin-immunoprecipitation-sequencing revealed a differential peak distribution on gene promoters in exposed pups with respect to acetylation of lysines 9 and 14 and to trimethylation of lysines 4 and 27 in histone H3 (all, false discovery rate, FDR < 0.1). In the HF-diet exposed offspring, 54% of the annotated genes showed the gene-activating mark trimethylated lysine 4. Many of these genes (1) are associated with the "metabolic process" in general and particularly with "positive regulation of cholesterol biosynthesis" (FDR = 0.03); (2) overlap with 455 quantitative trait loci for blood pressure, body weight, serum cholesterol (all, FDR < 0.1); and (3) are linked to cardiac disease susceptibility/progression, based on disease ontology analyses and scientific literature. These results indicate that maternal HF-diet changes the cardiac histone signature in offspring suggesting a fuel-mediated epigenetic reprogramming of cardiac tissue in utero.
| S-EPMC5409746 | biostudies-literature
Project description:BACKGROUND:Ambient air pollution and maternal diabetes may affect common biological pathways underlying adverse neurodevelopmental effects. However, joint effects of maternal diabetes and air pollution on autism spectrum disorder (ASD) have not been studied. OBJECTIVE:We evaluated whether prenatal and early-life air pollution exposure interacts with maternal diabetes status to affect ASD risk. METHODS:This retrospective cohort study included 246,420 singleton children born in Kaiser Permanente Southern California hospitals in 1999-2009. Children were followed from birth until age 5, during which 2471 ASD cases were diagnosed. Ozone (O3), particulate matter?<?2.5??m (PM2.5) and <10??m in aerodynamic diameter, and nitrogen dioxide measured at regulatory air monitoring stations were interpolated to estimate exposures during preconception and each pregnancy trimester, and first year of life at each child's birth address. Hazard ratios (HRs) for ASD were estimated adjusting for birth year, KPSC service areas, and relevant maternal and child characteristics. For each exposure window, interactions were tested between pollutants and a 4-category maternal diabetes variable (none, GDM???24 and <24?weeks' gestation, and pre-existing type 2 diabetes). For an exposure window with statistically significant global interaction between pollutant and diabetes (p?<?0.05), pollutant-associated HRs were estimated separately for each category of maternal diabetes. RESULTS:There were associations of ASD with preconception, first and third trimesters, and first year of life PM2.5, but not with other pollutants. There were, however, interactions of maternal diabetes with first trimester and first year of life O3. Increased ASD risk was associated with first trimester O3 among mothers with GDM?<?24?weeks' gestation [adjusted HR 1.50 per 15.7?ppb O3 (95% CI: 1.08-2.09)]. No O3 associations with ASD were observed in other categories of maternal diabetes. CONCLUSIONS:GDM onset early in pregnancy may increase children's susceptibility to prenatal O3-associated ASD risk. These novel findings merit further investigation.
| S-EPMC7250244 | biostudies-literature
Project description:Epigenetic processes are primary candidates when searching for mechanisms that can stably modulate gene expression and metabolic pathways according to early life conditions. To test the effects of gestational diabetes mellitus (GDM) on the epigenome of the next generation, cord blood and placenta tissue were obtained from 88 newborns of mothers with dietetically treated GDM, 98 with insulin-dependent GDM, and 65 without GDM. Bisulfite pyrosequencing was used to compare the methylation levels of seven imprinted genes involved in prenatal and postnatal growth, four genes involved in energy metabolism, one anti-inflammatory gene, one tumor suppressor gene, one pluripotency gene, and two repetitive DNA families. The maternally imprinted MEST gene, the nonimprinted glucocorticoid receptor NR3C1 gene, and interspersed ALU repeats showed significantly decreased methylation levels (4-7 percentage points for MEST, 1-2 for NR3C1, and one for ALUs) in both GDM groups, compared with controls, in both analyzed tissues. Significantly decreased blood MEST methylation (3 percentage points) also was observed in adults with morbid obesity compared with normal-weight controls. Our results support the idea that intrauterine exposure to GDM has long-lasting effects on the epigenome of the offspring. Specifically, epigenetic malprogramming of MEST may contribute to obesity predisposition throughout life.
| S-EPMC3609586 | biostudies-literature