Adult Female Rat Offspring Research Articles

The effects of moderate prenatal alcohol exposure on performance in hippocampal-sensitive spatial memory and anxiety tasks by adult male and female rat offspring

Moderate prenatal alcohol exposure (mPAE) results in structural alterations to the hippocampus. Previous studies have reported impairments in hippocampal-sensitive tasks, but have not compared performance between male and female animals. In the present study, performance in hippocampal-sensitive spatial memory and anxiety behavior tests were compared across adult male and female saccharin (SACC) control mPAE Long-Evans rat offspring. Two tests of spatial memory were conducted that were aimed at assessing memory for recently acquired spatial information: A delayed spatial alternation task using an M-shaped maze and a delayed match-to-place task in the Morris water task. In both tasks, rats in SACC and mPAE groups showed similar learning and retention of a spatial location even after a 2-h interval between encoding and retention. A separate group of adult male and female SACC and mPAE rat offspring were tested for anxiety-like behaviors in the elevated plus-maze paradigm. In this test, both male and female mPAE rats exhibited a significantly greater amount of time and a greater number of head dips in the open arms, while locomotion and open arm entries did not differ between groups. The results suggest that mPAE produces a reduction in anxiety-like behaviors in both male and female rats in the elevated plus-maze.

Butyrate reduction and HDAC4 increase underlie maternal high fructose-induced metabolic dysfunction in hippocampal astrocytes in female rats

Maternal nutrient intake influences the health of the offspring via microenvironmental systems in digestion and absorption. Maternal high fructose diet (HFD) impairs hippocampus-dependent memory in adult female rat offspring. However, the underlying mechanisms remain largely unclear. Maternal HFD causes microbiota dysbiosis. In this study, we find that the plasma level of butyrate, a major metabolite of microbiota, is significantly decreased in the adult female maternal HFD offspring. In these rats, GPR43, a butyrate receptor was downregulated in the hippocampus. Moreover, the expressions of mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) were downregulated in the hippocampus. The decreases of these functional proteins were reversed by fructooligosaccharides (FOS, a probiotic) treatment in adulthood. Astrocytes are critical for energy metabolism in the brain. Primary astrocyte culture from female maternal HFD offspring indicated that GPR43 and the mitochondrial biogenesis were significantly suppressed, which was reversed by supplemental butyrate incubation. The oxygen consumption rate (OCR) was reduced in the HFD group and rescued by butyrate. Intriguingly, the nuclear histone deacetylase 4 (HDAC4) was enhanced in the HFD group, suggesting an inhibitory role of butyrate on histone deacetylase activity. Inhibition of HDAC4 effectively restored the OCR, bioenergetics, and biogenesis of mitochondria. Together, these results suggested that the impaired butyrate signaling by maternal HFD could underlie the reduced mitochondrial functions in the hippocampus via HDAC4-mediated epigenetic changes.

Protein-caloric-restriction diet during lactation programs lean phenotype and improves the antioxidative system in adult female rat offspring.

Nutritional insults early in life, such as during the suckling phase, are associated with phenotypic alterations and promote adverse permanent effects that impair the capacity to maintain energy balance in adulthood. This study aimed to evaluate the long-term effects of a low-protein (LP) diet during lactation on the metabolism and antioxidant systems of adult female rat offspring. Dams were fed a low-protein diet (4% protein) during the first two weeks of lactation or a normal-protein (NP) diet (20% protein) during the entire lactation period. The female offspring received a standard diet throughout the experiment. At 90 days of age, female LP offspring exhibited decreased body weight, feeding efficiency, and fat pad stores. The adult LP female offspring displayed brown adipose tissue hyperplasia without alterations in glucose homeostasis. The LP diet decreased liver triglyceride content and improved the antioxidant system compared to the NP group. The LP diet during the suckling phase promotes a lean phenotype and improves the hepatocyte antioxidant system in adult female offspring. Thus, the LP diet may play an important role in homeostasis and the prevention of metabolic damage.

Inhibition of miR-6215 rescued low subchondral bone mass caused by maternal exposure to dexamethasone in female offspring rats

Osteoporotic osteoarthritis is primarily associated with low subchondral bone mass. However, the mechanisms and therapeutic targets of osteoporotic osteoarthritis caused by prenatal dexamethasone exposure (PDE) in offspring remain unclear. In this study, pregnant Wistar rats were injected with dexamethasone to obtain bone tissue from fetal and postnatal rat offspring for analysis. Bone marrow mesenchymal stem cells (BMSCs) were isolated in vitro to elucidate the underlying molecular mechanisms. We determined in vivo that PDE reduced subchondral bone mass in adult female rat offspring, which originated from dysplasia of the subchondral bone. PDE led to a continuous increase in miR-6215 expression, accompanied by a decrease in FERM domain-containing protein 6 (FRMD6) expression. In vitro, dexamethasone upregulated miR-6215 expression through the glucocorticoid receptor, thereby inhibiting FRMD6 expression, promoting the translocation of yes-associated protein 1 (YAP1) into the nucleus of BMSCs, and downregulating downstream osteogenic marker genes. Finally, the rAAV-miR-6215 inhibitor rescued the low subchondral bone mass and osteoarthritis susceptibility caused by PDE in rat offspring. In conclusion, increased expression of miR-6215 mediates low subchondral bone mass caused by PDE through FRMD6/YAP1 signaling. Therefore, miR-6215 is a promising therapeutic target for PDE-induced low subchondral bone mass in offspring.

Maternal high-fat diet alters the neurobehavioral, biochemical and inflammatory parameters of their adult female rat offspring

BackgroundLipid metabolism dysregulations have been associated with depressive and anxious behaviors which can affect pregnant and lactating individuals, with indications that such changes extend to the offspring. Therefore, the aim of this study was to evaluate the effect of a maternal high-fat diet on the neurobehavioral, biochemical and inflammatory parameters of their adult female offspring. MethodsWistar rats ± 90 days old were mated. The dams were allocated to consume a control (CTL) or high-fat (HFD) diet during pregnancy and lactation. After weaning, the female offspring from the CTL (N = 10) and HFD (N = 10) groups received standard chow. The offspring behavioral tests were started at 120 days old. Then, the somatic measures were evaluated followed by euthanasia, histological and biochemical analyses. ResultsThe HFD group had less ambulation and longer immobility time in the open field test compared to the CTL. The HFD group had lower HDL (48.4%) and a higher adiposity (71.8%) and LDL (62.2%) than the CTL. The CTL had a higher organic acid concentration in the intestine, mainly acetic and butyric acids, however the HFD had a higher citric and acetic acid concentration in the brain and ischemic lesion in the hippocampus with a higher NF-κB concentration. ConclusionThe results demonstrate deleterious effects of a maternal HFD on the neurobehavioral and biochemical parameters of their offspring which may be associated with the role of organic acids and NF-κB in fetal programming.

Prenatal Activation of Glucocorticoid Receptors Induces Memory Impairment in a Sex-Dependent Manner: Role of Cyclooxygenase-2.

Prenatal exposure to dexamethasone (DEX) results in long-lasting effects on cognitive functions such as learning and memory impairment. However, the mechanisms underlying these DEX-induced deleterious effects are not wellknown. Here, we assessed whether cyclooxygenase-2 (COX-2) is involved in the impact of prenatal exposure to DEX on learning and memory during adulthood. Pregnant Sprague-Dawley rats received daily injections of either DEX (0.2mg/kg; i.p.) or saline from gestation day (GD) 14 until GD21. Gene and protein expression of COX-2, as well as presynaptic (synaptophysin) and postsynaptic (postsynaptic density protein-95) proteins, were monitored in the dorsal and ventral hippocampi of adult male and female offspring. A different cohort of adult male and female rat offspring was given daily injections of either vehicle or a specific COX-2 inhibitor (celecoxib 10mg/kg, i.p.) for 5 consecutive days and was subsequently subjected to Morris water maze memory test. Prenatal DEX enhanced the expression of COX-2 protein and cox-2 mRNA in the dorsal hippocampus of adult female but not male rats. This enhanced COX-2 expression was associated with reduced expression in pre- and postsynaptic proteins and altered memory acquisition and retention. Administration of COX-2-specific inhibitor alleviated prenatal DEX-induced memory impairment in adult female rats. This study suggests that prenatal activation of glucocorticoid receptors stimulates COX-2 gene and protein expressionand impairs hippocampal-dependent spatial memory in female but not male rat offspring. Furthermore, COX-2 selective inhibitors can be used to alleviate the long-lasting deleterious effects of corticosteroid medication during pregnancy.

Sulfasalazine exposure during pregnancy and lactation induces alterations in reproductive behavior in adult female rat offspring

AimsSulfasalazine (SAS) is the first line drug in the treatment of chronic inflammatory bowel diseases in pregnant women. SAS and its metabolites cross the placenta and can be transferred through the milk. However, the long-term consequences to the reproductive system of offspring from dams exposed to SAS have not yet been studied. Thus, our study investigated the effects of SAS treatment during gestational and lactational periods on maternal care in F0 and reproductive outcomes in F1 females. Main methodsWistar female rats (n = 10/group) received 300 mg/kg/day of SAS dissolved in carboxymethyl cellulose (CMC), by gavage, from gestational day 0 to lactation day 21 and 3 mg/kg/day of folic acid during gestation. The control group received CMC only. On PND 21, the female pups were selected for reproductive evaluation at different time points: infancy and adulthood. The reproductive parameters evaluated were installation of puberty (vaginal opening and first estrus), estrous cyclicity, reproductive organs weight, histological analysis of the ovary follicles and uterus, analysis of oxidative stress in ovarian tissue, reproductive behavior (sexual and maternal), and fertility. Key findingsSAS treatment decreased the retrieving behavior in F0 females. The F1 females presented an increase in the lordosis score, frequency of lordosis of magnitude 3, and lipid peroxidation of ovarian tissues in both infancy and adult life. SignificanceThe SAS effects observed in the current study represent a relevant concern for public health, as they demonstrated that treatment with SAS compromised the maternal motivation of dams and induced reproductive alterations in F1 females.

Developmental Programming: Physiological Impacts of Prenatal Melatonin Administration on Reproductive Capacity and Serum Triiodothyronine of Adult Female Offspring Rat Born to Moms Exposed to Bisphenol A During Pregnancy.

Gestational bisphenol A (BPA) exposure induced multiple programmed diseases in the adult offsprings. Thus, this study targeted exploring the physiological impacts of melatonin (MEL) as a reprogramming strategy against in utero BPA exposure on reproductive capacity of adult F1 female rat offspring. Forty adult pregnant albino female rats were divided equally into 5 groups (n = 8): group I (control), group II (low-dose BPA; 25μg BPA/kgB.w.t.), group III (low-dose BPA + 10mg MEL/kgB.w.t.), group IV (high-dose BPA; 250μg/kgB.w.t.), and group V (high-dose BPA + MEL). Treatments were given daily by subcutaneous (s/c) injection from the fourth day of pregnancy until full term. After delivery, female offspring were selected, and on postnatal day 60, adult offspring were examined for estrus regularity and then were sacrificed at estrus to collect blood and tissue samples. Findings clarified that in utero BPA exposure (both doses) increased significantly (P < 0.05) the ovarian weights and the serum levels of estrogen but decreased that of triiodothyronine (T3) compared to control groups. Significant increasing of serum malondialdehyde (MDA) and decreasing of total antioxidant capacity (TAC) were also detected. Both doses of BPA disturbed remarkably the estrus cycles and caused marked aberrations in ovarian and uterine tissues. Interestingly, prenatal MEL co-treatment with BPA mitigated significantly all of these degenerative changes. Thus, this study first demonstrated that prenatal MEL therapy could be used as a potent reprogramming intervention against BPA-induced reproductive disorders in the adult F1 female rat offspring.

Prenatal exposure to methamphetamine in rats induces endothelial dysfunction in male but not female adult offspring.

In utero exposure to methamphetamine results in significant developmental, neurological, and behavioral deficits in offspring. However, very little is known about the cardiovascular effects of prenatal methamphetamine exposure in adult offspring. We hypothesized that prenatal methamphetamine exposure causes adverse cardiovascular effects in adult offspring. The aims of this study were to test the effects of prenatal methamphetamine exposure on blood pressure and endothelial function in male and female adult rat offspring. Pregnant rats were injected with methamphetamine (5mgkg-1day-1) or saline throughout pregnancy. Conscious blood pressure and vascular function in mesenteric-resistance arteries were measured in male and female adult offspring using tail cuff and myography, respectively (beginning at 8weeks old). In adult male offspring, but not in adult female offspring, endothelium-dependent relaxation to acetylcholine was impaired in methamphetamine-exposed compared to saline-exposed rats. Vascular relaxation to diethylamine NONOate diethylammonium salt was not impacted by gender or prenatal exposure. Prenatal methamphetamine exposure had no effect on systolic blood pressure in offspring of either gender. These data suggest that prenatal methamphetamine exposure adversely affects endothelial function in a sex-dependent manner. Clinically, these data suggest that adult males with a history of prenatal methamphetamine exposure may be at greater risk of developing cardiovascular disease due to endothelial dysfunction.

Maternal exercise attenuates the lower skeletal muscle glucose uptake and insulin secretion caused by paternal obesity in female adult rat offspring.

Key points Paternal obesity negatively influences metabolic outcomes in adult rat offspring.Maternal voluntary physical activity has previously been reported to improve glucose metabolism in adult rat offspring sired by healthy fathers.Here, we investigated whether a structured programme of maternal exercise training before and during gestation can attenuate the negative impacts that paternal obesity has on insulin sensitivity and secretion in female adult offspring.Exercise before and during pregnancy normalised the lower insulin sensitivity in skeletal muscle and the lower insulin secretion observed in female offspring sired by obese fathers.This paper presents a feasible, low‐cost and translatable intervention strategy that can be applied perinatally to support multifactor interventions to break the cycle of metabolic dysfunction caused by paternal obesity. We investigated whether maternal exercise before and during gestation could attenuate the negative metabolic effects of paternal high‐fat diet‐induced obesity in female adult rat offspring. Fathers consumed a normal chow or high‐fat diet before mating. Mothers exercised on a treadmill before and during gestation or remained sedentary. In adulthood, female offspring were assessed using intraperitoneal insulin and glucose tolerance tests (IPITT and IPGTT, respectively), pancreatic morphology, ex vivo skeletal muscle insulin‐stimulated glucose uptake and mitochondrial respiratory function. Paternal obesity impaired whole‐body and skeletal muscle insulin sensitivity and insulin secretion in adult offspring. Maternal exercise attenuated the lower insulin‐stimulated glucose uptake in offspring sired by obese fathers but distal insulin signalling components (p‐AKT Thr308 and Ser473, p‐TBC1D4 Thr642 and GLUT4) remained unchanged (P > 0.05). Maternal exercise increased citrate synthase activity only in offspring sired by obese fathers. Maternal exercise also reversed the lower insulin secretion in vivo observed in offspring of obese fathers, probably due to an attenuation of the decrease in pancreatic beta cell mass. In summary, maternal exercise before and during pregnancy in rats attenuated skeletal muscle insulin resistance and attenuated the decrease in pancreatic beta cell mass and insulin secretion observed in the female offspring of obese fathers.

Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects.

Gestational diabetes (GD) has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. Oxidative stress is strongly associated with neurodegeneration and cognitive disruption. In the offspring brains in a GD experimental rat model, increased oxidative stress in the prenatal and postnatal stages was reported. However, long-term alterations to offspring behavior and oxidative stress, caused by changes in the cerebral cortex and hippocampus, remain unclear. In this study, we evaluated the effect of GD on young and adult male and female rat offspring in metabolic parameters, cognitive behavior, and oxidative stress. GD was induced using streptozotocin in dams. Next, the offspring were evaluated at two and six months of age. Anxiety-like behavior was evaluated using the elevated plus maze and open field maze; spatial learning and short-term memory were evaluated using the Morris water maze and radial maze, respectively. We determined oxidative stress biomarkers (reactive oxygen species (ROS), lipid peroxidation and glutathione status) and antioxidant enzymes (superoxide dismutase and catalase) in the brain of offspring. We observed that male GD offspring showed a reduced level of anxiety at both ages as they spent less time in the closed arms of the elevated plus maze at adult age ((P = 0.019, d = 1.083 ( size effect)) and spent more time in the open area of an open field (P = 0.0412, d = 0.743) when young and adult age (P = 0.018, d = 0.65). Adult female GD offspring showed a reduced level of anxiety (P = 0.036; d = 0.966), and young female GD offspring showed a deficiency in spatial learning (P = 0.0291 vs. control, d = 3.207). Adult male GD offspring showed a deficiency in short-term memory (P = 0.017, d = 1.795). We found an increase in ROS and lipid peroxidation, a disruption in the glutathione status, and decreased activity of catalase and superoxide dismutase (P < 0.05 vs. control, d > 1.0), in the cerebral cortex and hippocampus of male and female GD offspring. GD altered metabolism; male offspring of both ages and adult females showed a high level of triglycerides and a lower level of high-density lipoprotein-cholesterol (P < 0.05 vs. control, d > 1.0). Young and adult female offspring displayed higher insulin levels (P < 0.05, d > 1.0). These results suggest that gestational diabetes modifies oxidative stress and cognitive behavior in an age- and sex-dependent manner.

The effects of Elateriospermum tapos against obese maternal rat in mitigating obesity development among their adult female offspring

Background: Maternal obesity is a metabolic disorder described by chronic inflammation and dyslipidemia and influences non-communicable diseases in offspring. Elateriospermum tapos is a plant containing high alpha-linolenic acid with antiobesity effect. Objectives: This study was aim to investigate the effect of E. tapos supplementation in obese rat prior pregnancy on the female offspring's body weight, liver and kidney profile, and histological changes of heart, liver, kidney, and retroperitoneal white adipose tissue (RpWAT). Materials and Methods: Thirty female Sprague Dawley rats were used in this study. Six rats were assigned to dams normal diet group fed with standard chow diet. The remaining rats were fed with high-fat and cafeteria diet (HFCD) to generate obesity for 5 weeks. The obese rats were further divided into 4 groups; group1; Dams Negative Control (DNC, normal saline only), group 2; Dams Positive Control (DPC, Orlistat drug 200mg/kg), Dams Treatment 1 (DTX1, E. tapos seed 200 mg/kg) and Dams Treatment 2 (DTX2, E. tapos shell 200mg/kg) extracts for 6 weeks daily prior to mating. The weaning offspring were then designated into 6 groups according to their dam's group (n = 6/group). The offspring were culled at 12th week of age in order to have their blood sample and organs. Results: Adult offspring from DTX2 group showed a decrease in weight gain, alanine aminotransferase, and creatinine level compared to adult offspring from DNC. Histological examination showed that liver and RpWAT of offspring from DTX1 and DTX2 groups were comparable with normal diet group, indicating that the extracts were capable in reversing the high fat diet effect to the organ. Conclusion: E. tapos shell supplementation was effective in reducing the development of obesity with no harmful effect among adult female rat offspring.

Perinatal fluoxetine has enduring sexually differentiated effects on neurobehavioral outcomes related to social behaviors

Selective serotonin reuptake inhibitor medications (SSRIs) are prescribed to up to 10% of pregnant women to treat maternal mood disorders. Exposure to these medications in-utero has raised concerns about altered neurobehavioral outcomes; most recently those related to peer-to-peer social interactions and play. While clinical data show that both perinatal SSRIs (pSSRI) and maternal stress can contribute to social behavioral changes in children, minimal animal work has investigated the effects of pSSRIs in relevant models of maternal stress or the long-term implications of these effects. Therefore the aim of this work was to investigate the long-term effects of pSSRI exposure to fluoxetine on social behaviors, the hypothalamic pituitary adrenal system (HPA) and hippocampal plasticity in adult male and female rat offspring using a model of pre-gestational maternal stress. Adult Sprague-Dawley female and male rat offspring from the following four groups were utilized: 1. Control + Vehicle, 2. Control + Fluoxetine, 3. Pre-gestational Stress + Vehicle, 4. Pre-gestational Stress + Fluoxetine (n = 8–16/female/age groups, n = 8–14/male/age groups). Main findings show pSSRIs increased social investigation in adult females and increased social play (pouncing, nape attacks) in adult males. Perinatal SSRIs also had sexually differentiated effects on hippocampal neurogenesis and GR density. Pre-gestational stress had enduring effects by decreasing social investigation and hippocampal neurogenesis in adult males. Thus pSSRIs, as well as pre-gestational maternal stress, have significant long-term effects on social neurobehavioral outcomes which differ in males and females. This suggests that it would be valuable to consider fetal-sex specific treatments for maternal mental illness.

Cigarette Smoke During Breastfeeding in Rats Changes Glucocorticoid and Vitamin D Status in Obese Adult Offspring.

Maternal smoking increases obesogenesis in the progeny. Obesity is associated with several hormonal dysfunctions. In a rat model of postnatal tobacco smoke exposure, we previously reported increased central fat depot and disruption of some hormonal systems in the adult offspring. As both glucocorticoids and vitamin D alter lipogenesis and adipogenesis, here we evaluated the metabolism of these two hormones in visceral adipose tissue (VAT) and liver by Western blotting, and possible associations with lipogenesis biomarkers in adult rats that were exposed to tobacco smoke during their suckling period. At postnatal day (PN) 3, dams and offspring of both sexes were exposed (S group) or not (C group) to tobacco smoke, 4 × 1 h/day. At PN180, corticosteronemia was lower in S male and higher in S female offspring, without alterations in peripheral glucocorticoid metabolism and receptor. Adrenal ACTH receptor (MC2R) was higher in both sexes of S group. Despite unchanged serum vitamin D, liver 25-hydroxylase was higher in both sexes of S group. Male S offspring had higher 1α-hydroxylase, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) in VAT. Both sexes showed increased ACC protein content and reduced sirtuin mRNA in liver. Male S offspring had lower liver peroxisome proliferator-activated receptor-α. Tobacco exposure during lactation induced abdominal obesity in both sexes via distinct mechanisms. Males and females seem to develop HPA-axis dysfunction instead of changes in glucocorticoid metabolism and action. Lipogenesis in VAT and liver, as well as vitamin D status, are more influenced by postnatal smoke exposure in male than in female adult rat offspring.

Maternal high-fat diet consumption induces sex-dependent alterations of the endocannabinoid system and redox homeostasis in liver of adult rat offspring

Maternal diet plays a critical role in health development. Perinatal overnutrition induces metabolic dysfunctions and obesity in the offspring. Obesity is associated with endocannabinoid system (ECS) over activation and oxidative stress. Liver ECS activation induces hepatic steatosis, inflammation and fibrosis while the antagonism of cannabinoid receptors ameliorates these alterations. Here, we investigated the effect of perinatal maternal high-fat diet (HF, 29% of calories as fat) on the ECS and antioxidant system in liver of male and female adult rat offspring (180 days old). Maternal HF diet increased hepatic cannabinoid receptors, ECS metabolizing enzymes and triglyceride content, with male offspring more affected. ECS changes are likely independent of estradiol serum levels but associated with increased hepatic content of estrogen receptor, which can stimulate the expression of ECS components. Differently, maternal HF diet decreased the activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase, and increased oxidative stress markers in both sexes. Alterations in the redox homeostasis were associated with mitochondria damage but not with liver fibrosis. Our data suggest that maternal HF diet induces ECS over activation in adulthood, and that male offspring are at higher risk to develop liver disease compared with female rats.

Effects of combined pre- and post-natal enrichment on anxiety-like, social, and cognitive behaviours in juvenile and adult rat offspring

The pre- and post-natal periods are characterized by unrivalled growth and are sensitive to environmental changes. A correctly stimulating early environment is essential for developing natural behaviors and maintaining affective wellness. Five litters of rat progeny were co-housed through gestation until juvenile age in housing providing physical and social enrichment. Five control litters were housed separately in standard conditions. Half of the offspring were tested in the elevated plus-maze and the social interaction test as juveniles (five weeks old) with the other half tested in the Morris water maze. As adults (11 weeks old), the testing groups were reversed. Weight was monitored weekly. Enriched offspring had leaner body weights. In the elevated plus-maze, control juvenile progeny spent a higher percentage of time in the open arms, showed greater locomotor activity, less grooming, and more rearing (males only). In the social interaction test, enriched juvenile offspring were found to sniff their conspecific more, display more self-grooming behaviour as well as show less locomotor activity and body contact. In the Morris water maze probe test, enriched rats demonstrated improved memory for the platform position and more effective search strategies with increased platform crossings, middle crossing as well as more time spent in the platform quadrant and less thigmotaxis behaviour. Adult female rat offspring also demonstrated superior memory for the platform position and crossed the maze middle more often. These results suggest that combined pre- and post-natal environmental enrichment influences physiology and behaviour in offspring rats with some of those influences being long-lasting.

Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine‐exposed female adult rat offspring

Clinical and animal studies have indicated that hypercholesterolemia and its associated diseases have intrauterine developmental origins. Our previous studies showed that prenatal caffeine exposure (PCE) led to fetal overexposure to maternal glucocorticoids (GCs) and increased serum total cholesterol levels in adult rat offspring. This study further confirms the intrauterine programming of PCE-induced hypercholesterolemia in female adult rat offspring. Pregnant Wistar rats were intragastrically administered caffeine (30, 60, and 120 mg/kg/d) from gestational day (GD)9 to 20. Female rat offspring were euthanized at GD20 and postnatal wk 12; several adult rat offspring were additionally subjected to ice-water swimming stimulation to induce chronic stress prior to death. The effects of GCs on cholesterol metabolism and epigenetic regulation were verified using the L02 cell line. The results showed that PCE induced hypercholesterolemia in adult offspring, which manifested as significantly higher levels of serum total cholesterol and LDL cholesterol (LDL-C) as well as higher ratios of LDL-C/HDL cholesterol. We further found that the cholesterol levels were increased in fetal livers but were decreased in fetal blood, accompanied by increased maternal blood cholesterol levels and reduced placental cholesterol transport. Furthermore, analysis of PCE offspring in the uterus and in a postnatal basal/chronic stress state and the results of in vitro experiments showed that hepatic cholesterol metabolism underwent GC-dependent changes and was associated with cholesterol synthase via abnormalities in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) histone acetylation. We concluded that, to compensate for intrauterine placentally derived decreases in fetal blood cholesterol levels, high intrauterine GC levels activated fetal hepatic CCAAT enhancer binding protein α signaling and down-regulated Sirtuin1 expression, which mediated the high levels of histone acetylation ( via H3K9ac and H3K14ac) and expression of HMGCR. This GC-dependent cholesterol metabolism programming effect was sustained through adulthood, leading to the occurrence of hypercholesterolemia.-Xu, D., Luo, H. W., Hu, W., Hu, S. W., Yuan, C., Wang, G. H., Zhang, L., Yu, H., Magdalou, J., Chen, L. B., Wang, H. Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine-exposed female adult rat offspring.

Sex-specific cardiovascular susceptibility to ischaemic myocardial injury following exposure to prenatal hypoxia.

Cardiovascular diseases (CVDs) are the leading cause of mortality and hypertension contributes substantially to the incidence of stroke, coronary artery disease, heart failure, atrial fibrillation and peripheral vascular disease. The origin of hypertension is clearly multifactorial, and a complex and multifaceted approach is necessary to decrease its incidence. The most recognizable factors involved in reducing the incidence of hypertension are prevention, early diagnosis and treatment; however, the importance of the foetal environment and early postnatal development has recently been considered. In clinical practice, these factors are still frequently overlooked, probably because of a lack of knowledge about the underlying mechanisms and effective treatment or prevention. Pathophysiological mechanisms underlying the prenatal programming of CVDs were investigated in the study by Shah et al. published recently in Clinical Science (2017) 131(17), 2303-2317. The study explored cardiac susceptibility of adult male and female rat offspring to ischaemic myocardial injury due to prenatal exposure to hypoxia. The results demonstrated significant changes in global cardiac function and left ventricular dilatation following myocardial infarction in rat offspring prenatally exposed to hypoxia. The effects were gender specific and occurred only in males, whereas females were protected. These findings are important from several perspectives. First, they point to the fact that an inadequate foetal environment can increase susceptibility to death from myocardial infarction. Second, during their reproductive life, females are better protected from cardiovascular insult than males, but it is not known if they lose this advantage after menopause, and can be equally at risk as males.

Perinatal nicotine exposure increases obesity susceptibility by peripheral leptin resistance in adult female rat offspring

Maternal nicotine (NIC) exposure causes overweight, hyperleptinemia and metabolic disorders in adult offspring. Our study aims to explore the underlying mechanism of perinatal NIC exposure increases obesity susceptibility in adult female rat offspring. In our model, we found that adult NIC-exposed females presented higher body weight and subcutaneous and visceral fat mass, as well as larger adipocytes, while no change was found in food intake. Serum profile showed a higher serum glucose, insulin and leptin levels in NIC-exposed females. In adipose tissue and liver, the leptin signaling pathway was blocked at 26 weeks, presented lower Janus tyrosine kinase 2 and signal transducer and activator of transcription 3 gene expression, higher suppressor of cytokine signaling 3 gene expression (in adipose tissue) and lower leptin receptors gene expression (in liver), indicating that peripheral leptin resistance occurred in NIC-exposed adult females. In female rats, the expression of lipolysis genes was affected dominantly in adipose tissue, but lipogenesis genes was affected in liver. Furthermore, the glucose and insulin tolerance tests showed a delayed glucose clearance and a higher area under the curve in NIC-exposed females. Therefore, perinatal NIC exposure programed female rats for adipocyte hypertrophy and obesity in adult life, through the leptin resistance in peripheral tissue.

Prenatal caffeine ingestion increases susceptibility to pulmonary inflammation in adult female rat offspring

This study aimed to investigate the association between prenatal caffeine ingestion (PCI) and risk of postnatal pulmonary inflammation. Pregnant Wistar rats were administered 60mg/kg/d caffeine intragastrically from gestational day (GD) 7 to GD 20. The results showed that PCI obviously increased intrauterine growth retardation rate to 39.2% and suppressed weight growth of the offspring. PCI also enhanced the expression of transforming growth factor β, α-smooth muscle actin, interleukin (IL)-1β, and IL-8 in lungs and caused pulmonary interstitial thickening in the offspring. Further, with lipopolysaccharide stimulation on postnatal day 77, PCI offspring showed more serious inflammatory infiltration, higher injury scores, and higher levels of IL-6 and tumor necrosis factor-α in lungs than those of the control. Our findings showed, for the first time, that PCI is a certainly threat to postnatal pulmonary inflammation. The potential mechanism is that PCI alter the expression of pulmonary interstitial thickening-associated genes in the offspring.