Adult Rat Offspring Research Articles

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.

A maternal high-fat diet during pregnancy and lactation induced depression-like behavior in offspring and myelin-related changes in the rat prefrontal cortex.

In accordance with the developmental origins of health and disease, early-life environmental exposures, such as maternal diet, can enhance the probability and gravity of health concerns in their offspring in the future. Over the past few years, compelling evidence has emerged suggesting that prenatal exposure to a maternal high-fat diet (HFD) could trigger neuropsychiatric disorders in the offspring, such as depression. The majority of brain development takes place before birth and during lactation. Nevertheless, our understanding of the impact of HFD on myelination in the offspring's brain during both gestation and lactation remains limited. In the present study, we investigated the effects of maternal HFD (60% energy from fat) on depressive-like and myelin-related changes in adolescent and adult rat offspring. Maternal HFD increased immobility time during the forced swimming test in both adolescent and adult offspring. Correspondingly, the depressive-like phenotype in offspring correlated with dysregulation of several genes and proteins in the prefrontal cortex, especially of myelin-oligodendrocyte glycoprotein (MOG), myelin and lymphocyte protein (MAL), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), kallikrein 6, and transferrin in male offspring, as well as of MOG and kallikrein 6 in female offspring, which persist even into adulthood. Maternal HFD also induced long-lasting adaptations manifested by the reduction of immature and mature oligodendrocytes in the prefrontal cortex in adult offspring. In summary, maternal HFD-induced changes in myelin-related genes are correlated with depressive-like behavior in adolescent offspring, which persists even to adulthood.

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.

Developmental exposure to methylmercury alters GAD67 immunoreactivity and morphology of endothelial cells and capillaries of midbrain and hindbrain regions of adult rat offspring

IntroductionMethylmercury (MeHg) is an environmental contaminant that is of particular concern in Northern Arctic Canadian populations. Specifically, organic mercury compounds such as MeHg are potent toxicants that affect multiple bodily systems including the nervous system. Developmental exposure to MeHg is a major concern, as the developing fetus and neonate are thought to be especially vulnerable to the toxic effects of MeHg. The objective of this study was to examine developmental exposure to low doses of MeHg and effects upon the adult central nervous system (CNS). The doses of MeHg chosen were scaled to be proportional to the concentrations of MeHg that have been reported in human maternal blood samples in Northern Arctic Canadian populations. MethodOffspring were exposed to MeHg maternally where pregnant Sprague Dawley rats were fed cookies that contained MeHg or vehicle (vehicle corn oil; MeHg 0.02 mg/kg/body weight or 2.0 mg/kg/body weight) daily, throughout gestation (21 days) and lactation (21 days). Offspring were not exposed to MeHg after the lactation period and were euthanized on postnatal day 450. Brains were extracted, fixed, frozen, and sectioned for immunohistochemical analysis. A battery of markers of brain structure and function were selected including neuronal GABAergic enzymatic marker glutamic acid decarboxylase-67 (GAD67), apoptotic/necrotic marker cleaved caspase-3 (CC3), catecholamine marker tyrosine hydroxylase (TH), immune inflammatory marker microglia (Cd11b), endothelial cell marker rat endothelial cell antigen-1 (RECA-1), doublecortin (DCX), Bergmann glia (glial fibrillary acidic protein (GFAP)), and general nucleic acid and cellular stains Hoechst, and cresyl violet, respectively. Oxidative stress marker lipofuscin (autofluorescence) was also assessed. Both male and female offspring were included in analysis. Two-way analysis of variance (ANOVA) was utilized where sex and treatment were considered as between-subject factors (p* <0.05). ImageJ was used to assess immunohistochemical results. ResultsIn comparison with controls, adult rat offspring exposed to both doses of MeHg were observed to have (1) increased GAD67 in the cerebellum; (2) decreased lipofuscin in the locus coeruleus; and (3) decreased GAD67 in the anterior CA1 region. Furthermore, in the substantia nigra and periaqueductal gray, adult male offspring consistently had a larger endothelial cell and capillary perimeter in comparison to females. The maternal high dose of MeHg influenced RECA-1 immunoreactivity in both the substantia nigra and periaqueductal gray of adult rat offspring, where the latter neuronal region also showed statistically significant decreases in RECA-1 immunoreactivity at the maternal low dose exposure level. Lastly, males exposed to high doses of MeHg during development exhibited a statistically significant increase in the perimeter of endothelial cells and capillaries (RECA-1) in the cerebellum, in comparison to male controls. ConclusionFindings suggest that in utero and early postnatal exposure to MeHg at environmentally relevant doses leads to long-lasting and selective changes in the CNS. Exposure to MeHg at low doses may affect GABAergic homeostasis and vascular integrity of the CNS. Such changes may contribute to neurological disturbances in learning, cognition, and memory that have been reported in epidemiological studies.

Post-natal antibiotic exposure in mother rat (F0) induces anxiety like behavior in adult rat offspring (F1) by activating HPA axis and down-regulating the Nr3c1 gene.

Early postnatal administration of antibiotics has been linked to lasting effects on brain development and behavior. Research conducted on animals that are free from germs has demonstrated that the impact of microbiome colonization on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and neuroendocrine pathways is substantial, which play a crucial role in stress management. Nevertheless, it is still uncertain if the exposure to antibiotics in rat dams (F0-generation) before weaning is associated with neurobehavioral changes in rat offspring (F1-generation) during adulthood. In order to investigate the effects, we perturbed the intestinal microbiota of rat dams (F0 generation) by administering cefixime (CEF), an antibiotic commonly used for obstetric purposes, at clinically relevant doses (1 mg/kg, 2.5 mg/kg or 5 mg/kg). Anxiety-like behaviors in adult offspring was evaluated through the utilization of elevated plus maze (EPM) and open field paradigm (OFP) following a six-week interval from birth (PND42). Subsequent to behavioral assessments, the rats were euthanized, and their brains and blood was collected for biochemical analysis. Plasma corticosterone concentration was used to assess HPA activity, whereas the quantitative real-time polymerase chain reaction (PCR) was employed to determine the transcription levels of the glucocorticoid receptor (GR) Nr3c1. The offspring of F1 that were administered antibiotics before being weaned spent less time in the EPM open arm. The alterations were accompanied by increased levels of corticosterone in the bloodstream. The gene expression study revealed a decrease in the levels of mRNA transcription of Nr3c1. This research emphasizes the possible long-term effects of antibiotic exposure before weaning on the development of anxiety in offspring upon adulthood.

Effect of prenatal exposure to stress and extremely low-frequency electromagnetic field on hippocampal and serum BDNF levels in male adult rat offspring.

Prenatal stress (PS) can adversely affect cognitive and psychological functions in the offspring. This study aimed to determine the effect of PS and extremely low-frequency electromagnetic field (ELF-EMF) on spatial memory, serum corticosterone, brain-derived neurotrophic factor (BDNF) concentrations, and hippocampal BDNF levels in adult male offspring. Female Wistar rats were randomly divided into four groups (n=6): Control, Stress, ELF-EMF (exposure to ELF-EMF), and S+EMF (simultaneous exposure to stress and the ELF-EMF) groups. Animals received interven-tions for 21 days before and 21 days during pregnancy (a total of 42 days). On the offspring's 90th postnatal day (PND), spatial memory was tested using Morris Water Maze, serum Corticosterone and BDNF levels were measured by the ELISA method, and hippocampal BDNF levels were measured by Western blotting. PS did not affect spatial memory in the adult male offspring; however, it significantly (P<0.05) increased se-rum corticosterone levels compared to the control and EMF groups. Simultaneous induction of stress with ELF-EMF disrupted the memory acquisition phase. Serum and hippocampal BDNF levels increased signifi-cantly (P<0.05) in the EMF group compared to the stress group. Based on our findings, PS can increase serum corticosterone levels without affecting spatial memory. Howev-er, induction of ELF-EMF with stress has a destructive effect on spatial memory with no change in the corti-costerone levels. Compared to stress, prenatal exposure to ELF-EMF increases serum and hippocampal BDNF levels. Further studies are needed to determine the underlying mechanisms of these findings.

The high-expression programming of SR-B1 mediates adrenal dysfunction in female offspring induced by prenatal caffeine exposure and its cholesterol accumulation mechanism.

The cholesterol metabolism and homeostasis of adrenal are important for steroidogenesis. Our previous studies found that prenatal caffeine exposure (PCE) can inhibit adrenal steroidogenesis in offspring, but whether the mechanism is related to local imbalance of cholesterol metabolism remains unknown. Here, we found that PCE inhibited adrenal steroidogenesis and increased the expression of cell pyroptosis and inflammatory-related indicators (NLRP3, caspase-1 and IL-1β) in female adult offspring rats, and at the same time, the cholesterol levels in serum and adrenal gland also significantly increased. In vitro, the high level of cholesterol could inhibit adrenal corticosteroid synthesis through pyroptosis and an inflammatory response. It suggested that the low adrenal steroidogenesis in PCE female adult offspring is related to local cholesterol accumulation-mediated pyroptosis and inflammation. Furthermore, dating back to the intrauterine period, PCE increased the serum CORT level in female fetal rats, and increased the expression of the adrenal cholesterol intake gene SR-B1, which persisted after birth and even into adulthood. At the cellular level, silencing SR-B1 could reverse the increase of intracellular cholesterol content caused by high levels of cortisol in NCI-H295R cells. Finally, we confirmed that high concentrations of glucocorticoids increased the expression and H3K14ac level of the promoter region in SR-B1 by upregulating the GR/SREBP1/p300 pathway in vivo and in vitro. In conclusion, we clarified that the high-expression programming of SR-B1 mediates adrenal dysfunction in PCE female offspring and its cholesterol accumulation mechanism, which provided a favorable basis for finding novel targets to prevent and treat fetal-originated diseases.

Peripheral clock gene oscillations are perturbed in neonatal and adult rat offspring raised under adverse limited bedding conditions

Circadian (24-h) rhythms in the suprachiasmatic nucleus (SCN) are established in utero in rodents, but rhythmicity of peripheral circadian clocks appears later in postnatal development. Since peripheral oscillators can be influenced by maternal feeding and behavior, we investigated whether exposure to the adverse environmental conditions of limited bedding (LB) during postnatal life would alter rhythmicity in the SCN, adrenal gland and liver in neonatal (postnatal day PND10), juvenile (PND28) and adult rats. We also examined locomotor activity in adults. Limited bedding increased nursing time and slightly increased fragmentation of maternal behavior. Exposure to LB reduced the amplitude of Per2 in the SCN on PND10. Adrenal clock gene expression (Bmal1, Per2, Cry1, Rev-erbα, Dbp) and corticosterone secretion were rhythmic at all ages in NB offspring, whereas rhythmicity of Bmal1, Cry1 and corticosterone was abolished in neonatal LB pups. Circadian gene expression in the adrenal and liver was well established by PND28. In adults, liver expression of several circadian genes was increased at specific daytimes by LB and the microstructure of locomotor behavior was altered. Thus, changes in maternal care and behavior might provide important signals to the maturing peripheral oscillators and modify, in particular their output functions in the long-term.

Pre-weaning antibiotic exposure in maternal rat (F0) causes neurobehavioral effects in adult rat offspring (F1) via activation of HPA axis, and down-regulation of NR3C1 and TPH2 gene

Pre-weaning antibiotic exposure in maternal rat (F0) causes neurobehavioral effects in adult rat offspring (F1) via activation of HPA axis, and down-regulation of NR3C1 and TPH2 gene

Microglia are necessary for probiotics supplementation to improve impaired fear extinction caused by pregnancy stress in adult offspring of rats

The prevention and treatment of fear-related disorders in offspring affected by pregnancy stress remains challenging at clinic. Here, we examined the effects of gut microbiota of stressed pregnant rats on the fear extinction of their offsprings, and the potential mechanisms. We found that gut microbiota transplantation from rats with pregnancy stress to normal pregnant rats impaired fear extinction, induced microglial activation and synaptic phagocytosis, increased synapse loss in offsprings. Probiotics supplement during pregnancy stress partly normalized pregnancy stress-induced gut microbiota dysbiosis of pregnant rats, and promoted fear memory extinction, inhibited fear memory reappearance, and limited microglial activation and synaptic phagocytosis in offsprings. These data revealed that gut microbiota of stressed pregnant mother improved the development of fear-related disorders of offspring, which may be associated with microglial synaptic pruning.

Sucrose consumption modifies the urethrogenital reflex and histological organization of the bulbospongiosus muscle in the male rat

Disorders of the bulbospongiosus muscle (Bsm) are associated with male sexual dysfunction, such as premature ejaculation. We determined the effect of sucrose-water consumption during pregnancy-lactation and postnatal on reflex responses and morphology of Bsm fibers in adult male Wistar rat offspring. Female rats were mated and grouped into consumed tap water mothers and sucrose-water (5 %) mothers during pregnancy-lactation to obtain experimental groups. Male pups were weaned and assigned into four groups (n = 12; each group). Those from control mothers who continued drinking tap water (CM–CO group) or sucrose water (CM–SO group), and those from sucrose mothers who drank tap water (SM–CO group) or continued drinking sucrose water (SM–SO group) until adult life. In male rat offspring (n = 6 per group) was recorded the electrical activity of Bsm was recorded during penile stimulation and urethrogenital reflex (UGR). Other male rat offspring were designated for histological analysis (n = 6 per group). Sucrose consumption during prenatal stages increased the frequency of the Bsm during UGR, while pre and postnatal consumption modified muscle fiber cross-sectional area and increased the collagen content, suggesting that a combination of a diet with pre- and postnatal sucrose changes the Bsm morphophysiology possibly causing male sexual dysfunctions.

Ultrasound-Induced Prenatal Stress: New Possibilities for Modeling Mental Disorders

The development of animal models of mental disorders is an important task since such models are useful for studying the neurobiological mechanisms of psychopathologies and for trial of new therapeutic drugs. One way to model pathologies of the nervous system is to impair fetal neurodevelopment through stress of the pregnant future mother, or prenatal stress (PS). The use of variable frequency ultrasound (US) in rodents is a promising method of imitating psychological stress, to which women in modern society are most often subjected. The aim of our study was to investigate the effect of PS induced by exposure to variable frequency ultrasound (US PS) throughout the gestational period on the adult rat offspring, namely, to identify features of behavioral alterations and neurochemical brain parameters that can be associated with certain mental disorders in humans, to determine the possibility of creating a new model of psychopathology. Our study included a study of some behavioral characteristics of male and female rats in the elevated plus maze, open-field test, object recognition test, social interaction test, sucrose preference test, latent inhibition test, Morris water maze, forced swimming test, acoustic startle reflex, and prepulse inhibition tests. We also determined the activity of the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems in the hippocampus and frontal cortex by HPLC-ED. Concentration of norepinephrine, dopamine, DOPAC, serotonin, and HIAA, as well as DOPAC/dopamine and HIAA/serotonin ratios were determined. A correlation analysis of behavioral and neurochemical parameters in male and female rats was performed based on the data obtained. The results of the study showed that US PS altered the behavioral phenotype of the rat offspring. US PS increased the level of anxious behavior, impaired orientation-research behavior, increased grooming activity, decreased the desire for social contacts, shifted behavioral reactions from social interaction to interaction with inanimate objects, impaired latent inhibition, and decreased the startle reflex. US PS activated the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems of the rat frontal cortex and hippocampus. A correlation between neurochemical and behavioral parameters was revealed. Our study showed that US PS leads to a certain dysfunction on behavioral and neurochemical levels in rats that is most closely associated with symptoms of schizophrenia or autism. We hypothesize that this could potentially be an indicator of face validity for a model of psychopathology based on neurodevelopmental impairment.

Comparison of maternal versus postweaning ingestion of a high fat, high sucrose diet on depression-related behavior, novelty reactivity, and corticosterone levels in young, adult rat offspring

Consumption of a Western-type diet, high in fat and sugar, by mothers as well as maternal weight gain and obesity during gestation and lactation may impact offspring risk for mood and cognitive disorders. The objective of this study was to determine if ingestion of a high fat, high sucrose (HFS) diet by rat dams during gestation and lactation or by their pups after weaning impacted these behaviors and stress responsivity in young, adult offspring. To accomplish this, dams consumed either a 45% fat/high sucrose (HFS) diet or the AIN93G control diet during gestation and lactation. At weaning, pups from dams that consumed the HFS diet were weaned to the control diet. Pups from dams assigned to the control diet were weaned to either the control or HFS diet. Pup behavioral testing began at 10 weeks of age. Pups whose dams consumed the HFS diet during gestation and lactation exhibited increased depression-related behavior and baseline serum corticosterone levels, but no difference in peak levels in response to stress. Male pups of these dams displayed increased working memory during acquisition of the holeboard task and tended to exhibit more anxiety-related behavior in the elevated O-maze test. Regardless of when consumed, the HFS diet increased novelty reactivity in the open field test. These data indicate that diet but not maternal weight gain during gestation impacts offspring behavior and elevates stress hormone levels. Also, regardless of when consumed, the HFS diet increases novelty reactivity, a risk factor for depression and addiction.

Prenatal alcohol alters inflammatory signatures in enteric portal tissues following adult-onset cerebrovascular ischemic stroke

Prenatal alcohol exposure (PAE) impairs recovery from cerebrovascular ischemic stroke in adult rodents. Since the gut becomes dysbiotic following stroke, we assessed links between PAE and enteric portal inflammation. Adult control and PAE rat offspring received a unilateral endothelin-1-induced occlusion of the middle cerebral artery. Post-stroke behavioral disabilities and brain cytokines were assessed. Mesenteric adipose and liver transcriptomes were assessed from stroke-exposed and stroke-naive offspring. We identified, in the liver of stroke-naive animals, a moderate correlation between PAE and a gene network for inflammatory necroptosis. PAE inhibited the acute-phase brain inflammatory cytokine response to stroke. Post-stroke neurological function was correlated with an adipose gene network associated with B-lymphocyte differentiation and nuclear factor κB (NF-κB) signaling and with a liver pro-inflammatory gene network. Collectively, PAE inhibits brain inflammation but results in an inflammatory signature in enteric portal tissues after stroke, suggesting that PAE persistently and adversely impacts the gut-brain axis following adult-onset disease.

Developmental Exposure to Kynurenine Affects Zebrafish and Rat Behavior.

Proper nutrition and supplementation during pregnancy and breastfeeding are crucial for the development of offspring. Kynurenine (KYN) is the central metabolite of the kynurenine pathway and a direct precursor of other metabolites that possess immunoprotective or neuroactive properties, with the ultimate effect on fetal neurodevelopment. To date, no studies have evaluated the effects of KYN on early embryonic development. Thus, the aim of our study was to determine the effect of incubation of larvae with KYN in different developmental periods on the behavior of 5-day-old zebrafish. Additionally, the effects exerted by KYN administered on embryonic days 1-7 (ED 1-7) on the behavior of adult offspring of rats were elucidated. Our study revealed that the incubation with KYN induced changes in zebrafish behavior, especially when zebrafish embryos or larvae were incubated with KYN from 1 to 72 h post-fertilization (hpf) and from 49 to 72 hpf. KYN administered early during pregnancy induced subtle differences in the neurobehavioral development of adult offspring. Further research is required to understand the mechanism of these changes. The larval zebrafish model can be useful for studying disturbances in early brain development processes and their late behavioral consequences. The zebrafish-medium system may be applicable in monitoring drug metabolism in zebrafish.

Abstract P202: Changes In Cerebral Mitochondrial Function In Intrauterine Growth-Restricted Offspring Before The Development Of Hypertension And Cerebrovascular Dysfunction

Background: Preeclampsia (PE), new-onset gestational hypertension (HTN) affects 3-8% of all births in the USA. PE is the leading cause for intrauterine growth restriction (IUGR). IUGR children have increased risks of HTN and cerebrovascular disease (CVD) later in life. Prior studies in our lab show adult male IUGR rat offspring (OS) to develop HTN, CVD, and cerebral mitochondrial dysfunction (mtDys) at 17 weeks while female IUGR OS exhibit CVD. The role of mtDys in HTN is unknown and is the focus of our study. We hypothesize that IUGR OS will have mtDys prior to HTN. Methods: Our surgical PE animal model utilized the reduced-uterine-perfusion pressure (RUPP) surgery at GD 14. OS from NP served as controls (CON) while OS from RUPP mothers were IUGR. At 12 weeks, OS BP was measured alongside cerebral mtDys through mitochondrial fusion and fission, electron-transport chain (ETC) proteins, and respiration. Results: BP did not change between sexes or among IUGR and CON offspring. Male IUGR OS showed elevated mtRes (State 2: 199 ± 1.08 v. 76 ± 1.13 pmol/mg, p &lt; .05; State 3: 555 ± 3.02 v. 245 ± 1.77 pmol/mg, p &lt; .05; State 4: 346 ± 1.66 v. 85 ± 1.12 pmol/mg, p &lt; .05). Female IUGR and CON OS had no changes in BP or mtRes. Male IUGR OS had increased mito-fusion proteins MFN-1 (176 ± 1.68 v. 100 ± .57 IU/protein/CON %, p &lt; .05), MFN-2 (155 ± 1.36 v. 100 ± .74 IU/protein/CON %, p &lt; .05) and OPA-1 (166 ± 1.99 v. 100 ± .73 IU/protein/CON %, p &lt; .05). DRP-1 had no changes in males; females had no changes in fusion or fission. Male IUGR OS had changes in ETC proteins (CI: 8 ± 9.34 v. 100 ± .82 IU/protein/CON %, p &lt; .05; CII: 23 ± .53 v. 100 ± .52 IU/protein/CON %, p &lt; .05; CIII: 26 ± .23 v. 100 ± .41 IU/protein/CON %, p &lt; .05), as did female IUGR OS (CI: 12 ± .24 v. 100 ± .86 IU/protein/CON %, p &lt; .05; CII: 29 ± .39 v. 100 ± .61 IU/protein/CON %, p &lt; .05; CIII: 39 ± .56 v. 100 ± .62 IU/protein/CON %, p &lt; .05; CIV: 76 ± .74 v. 100 ± .73 IU/protein/CON %, p &lt; .05) vs. CON OS. Summary: Male IUGR OS have elevated mtRes, changed ETC proteins, and fusion proteins that may lead to mtDys and HTN development. This study is clinically relevant because specific cerebral therapy for mtDys for IUGR OS may prevent HTN and CVD development. Future studies will examine changes in mtDys causing male HTN and protection from HTN in females.

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects.

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons. Here we explored how gestational exposure to dexamethasone, a synthetic glucocorticoid commonly used in clinical practice, has lasting effects on offspring's learning and memory. Adult offspring rats of prenatal dexamethasone exposure (PDE) displayed significant impairments in novelty recognition and spatial learning memory, with some phenotypes maintained transgenerationally. PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations, and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory, but these changes failed to carry over to offspring of F5 and F7 generations. Mechanistically, altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission, which might be related to oocyte-specific high expression and transmission of miR-133a-3p. Together, PDE affects hippocampal excitatory synaptic transmission, with lasting consequences across generations, and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

Maternal Di-(2-Ethylhexyl) Phthalate (DEHP) Exposure Impairs Insulin Signal in the Liver and Gastrocnemius Muscles of Female Offspring Rats

Di-(2-Ethylhexyl) Phthalate (DEHP) is a potent endocrine disruptor that is commonly present in consumer products and cosmetics. Exposure to DEHP during gestational and lactational periods can adversely affect glucoregulation and lead to the onset of diabetes in progeny. The liver and gastrocnemius muscles play an important role in regulating glucose metabolism and insulin action. This study was designed to investigate the effect of maternal DEHP exposure on insulin signaling molecules in the liver and gastrocnemius muscles of adult female offspring rats. Rat dams were given DEHP (10 and 100 mg/kg b.wt./day) by oral gavage from gestation day 9 (GD 9) to the end of the lactation period Postnatal Day (PND) 21. On PND 80, female offspring rats in diestrus were euthanized and found reduced body weight, organ (liver and gastrocnemius) weight, and hyperglycemia in DEHP-exposed rats. Western blots revealed a dose-dependent reduction in the expression of Insulin Receptor - (IR), IRS, Akt, and GSK-3β proteins as well as their phosphorylated forms in the liver and gastrocnemius muscles of DEHP-exposed offspring rats. Maternal DEHP exposure reduced the levels of GLUT2 and GLUT4 level in the liver and gastrocnemius muscles, respectively. Liver and renal function markers were dose-dependently increased in the serum of offspring female rats born to DEHP exposed mother during gestation and lactation. Thus, the study revealed that maternal DEHP exposure impaired the expression of insulin signaling molecules in the two important tissues involved in glucose metabolism, the liver and gastrocnemius muscles, suggesting that phthalates exposure during development may contribute to the onset of diabetes in female offspring.

Melatonin Corrects Depressive-like Behaviour and Anxiety in Male and Female Offspring Rats in a Model of Prenatal Melatonin Deficit

Melatonin deficiency caused by a prolonged light regime leads to a disturbance in the circadian rhythmicity of a number of physiological and biochemical parameters, including disruption of the synchronizing role of the hormone on endocrine and metabolic functions in the body. The aim of the present study was to explore the sex-dependent consequences of prenatal exposure to constant light (CL) on behavioural responses of rat adult offspring. In addition, the effect of melatonin supplementation on pregnant rats exposed to CL was evaluated on emotional disturbance due to melatonin deficiency. Chronic exposure to CL during pregnancy induced impaired emotional responses in male and female adult offspring, including decreased visits to aversive central zone in the open field test and elevated plus maze test and reduced consumption of sweet solutions. The elevated anxiety and anhedonia was corrected in a generation of prenatal melatonin-deficient rats of the two sexes. Our results suggest that prenatal rat exposure to CL provokes long-term behavioural impairments in male and female adult offspring. The beneficial role of melatonin supplementation on these disturbed responses suggests that our prenatal model induces melatonin deficiency that causes sustainable changes in offspring. Further data are needed to ascertain the mechanism underlying the prenatal-induced deleterious effect of melatonin deficiency and possible therapeutic options.

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.