Maternal Lipopolysaccharide Research Articles

Perinatal inflammation results in decreased oligodendrocyte numbers in adulthood

AimsMaternal inflammation is a risk factor for preterm birth, and premature infants are often exposed to supplemental oxygen as a life-sustaining therapy. While more immature neonates are surviving, rates of neurodevelopmental impairment are not improving. We developed a novel mouse model with clinically relevant exposures to test the hypothesis that systemic maternal inflammation with transient neonatal hyperoxia exposure will induce a phenotype similar to diffuse periventricular leukomalacia (PVL) like that observed in premature human infants. Main methodsTimed-pregnant C3H/HeN mice received intraperitoneal injections of lipopolysaccharide (LPS) or saline on embryonic day 16. Newborn pups were placed in room air (RA) or 85% oxygen (O2) for 14days, followed by 14days in RA recovery. Oligodendroglial and microglial populations were evaluated at 14 and 28days. Key findingsBrain weight to body weight ratios were lower in mice exposed to LPS. Oligodendrocyte numbers were decreased significantly in the cerebral cortex and hippocampus in groups exposed to LPS or LPS/O2 at 14days, and persisted in the cerebral cortex at 28days for LPS/O2 mice. At day 14, cleaved caspase 3 was increased and numbers of microglia were elevated in the cerebral cortex and hippocampus of LPS/O2 animals. SignificanceThese data indicate that combining systemic maternal LPS and neonatal hyperoxic exposure impairs myelination, and suggests that this novel mouse model may represent a subtle, diffuse form of periventricular white matter injury that could provide a clinically relevant platform for further study of perinatal brain injury.

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

Receptors for advanced glycation end products (RAGE) have been implicated in fibrotic processes. We hypothesized that lung fibrosis induced by maternal lipopolysaccharide (LPS)-mediated inflammation and neonatal hyperoxia involves RAGE in newborn rats. Pregnant Sprague-Dawley rats received intraperitoneal injections of LPS or normal saline (NS) on 20 and 21 d of gestation. The pups were reared in room air (RA) or an O2-enrich atmosphere (O2), creating the four study groups, NS + RA, NS + O2, LPS + RA, and LPS + O2. The O2 treatment was >95% O2 for 7 d, followed by 60% O2 for 14 d. Rat pups born to LPS-injected dams exhibited significantly higher lung interferon-γ and interleukin-1β (IL-1β) on postnatal day 7 than the pups born to NS-injected dams. Rat pups reared in hyperoxia expressed higher lung IL-10 on postnatal day 7, compared with the RA-reared pups. The LPS + O2 group had significantly higher total collagen and transforming growth factor-β1 on postnatal days 7 and 21 than the NS+RA group. RAGE mRNA and sRAGE protein expression were significantly lower in the LPS + O2 group on postnatal day 7 than the NS+RA group. RAGE may be involved in the pathogenesis of lung fibrosis induced by maternal systemic inflammation and postnatal hyperoxia in rat neonates.

Folic acid supplementation during pregnancy protects against lipopolysaccharide-induced neural tube defects in mice

Folic acid is a water-soluble B-complex vitamin. Increasing evidence demonstrates that physiological supply of folic acid during pregnancy prevents folic acid deficiency-related neural tube defects (NTDs). Previous studies showed that maternal lipopolysaccharide (LPS) exposure caused NTDs in rodents. The aim of this study was to investigate the effects of high-dose folic acid supplementation during pregnancy on LPS-induced NTDs. Pregnant mice were intraperitoneally injected with LPS (20μg/kg/d) from gestational day (GD) 8 to GD12. As expected, a five-day LPS injection resulted in 19.96% of fetuses with NTDs. Interestingly, supplementation with folic acid (3mg/kg/d) during pregnancy significantly alleviated LPS-induced NTDs. Additionally, folic acid significantly attenuated LPS-induced fetal growth restriction and skeletal malformations. Additional experiment showed that folic acid attenuated LPS-induced glutathione (GSH) depletion in maternal liver and placentas. Moreover, folic acid significantly attenuated LPS-induced expression of placental MyD88. Additionally, folic acid inhibited LPS-induced c-Jun NH2-terminal kinase (JNK) phosphorylation and nuclear factor kappa B (NF-κB) activation in placentas. Correspondingly, folic acid significantly attenuated LPS-induced tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in placentas, maternal serum and amniotic fluid. In conclusion, supplementation with high-dose folic acid during pregnancy protects against LPS-induced NTDs through its anti-inflammatory and anti-oxidative effects.

19. Lipopolysaccharide exposure reduces maternal serum Zn, Mg, Se and Mn concentrations in rats

We previously showed that prenatal lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces behavioral, brain and immunological changes in the offspring. Bacterial infections can also induce changes in the balance of chemical elements (e.g., metals) in our body. For example, proinflammatory cytokines liberated after LPS exposure produces metallothionein, which sequestrates zinc (Zn). Deficient or increased levels of some of those metals can be harmful and toxic to the fetus during pregnancy. Because maternal deficiency of some metals as a result of exposure to LPS may be responsible for damage in offspring, the aim of this study was to measure the concentration of some chemical elements, especially the ones involved in pregnancy and infection/inflammation. We exposed Wistar rats to LPS (100 μg/kg, intraperitoneally) or to saline (vehicle), on gestational day 9.5. 24 h after the treatment we evaluated the maternal serum Zn, magnesium (Mg), copper (Cu), selenium (Se) and manganese (Mn) concentrations with a high resolution inductively coupled plasma mass spectrometry (HR-ICPMS). Our results showed that the concentration of Zn, Mg, Se and Mn was reduced in the LPS group, when compared with their respective controls. In all cases, results were considered significant if p < 0.05. Thus, maternal LPS exposure reduced the concentration of specific chemical elements that are involved in impairments found in the offspring. FAPESP.

The efficacy of intravenous immunoglobulin on lipopolysaccharide-induced fetal brain inflammation in preterm rats

Interleukin-1 is accepted as one of the major cytokines; it is involved in inflammatory processes and systemic fetal inflammatory response that is triggered by maternal lipopolysaccharide (LPS) injection. Because it is an antiinflammatory agent, we investigated (in the brain damage of rat pups) the role of intravenous immunoglobulin (IVIG) in decreasing interleukin-1 beta (IL-1β) expression and caspase 3 activity that was induced by maternal LPS administration. Dams were divided into 3 groups. Pyrogen-free saline solution (NS) was administered intraperitoneally to group 1; LPS (0.3mg/kg) suspension in NS was administered to groups 2 and 3 at 19 days of gestation. Two hours after the first injection, a second injection of NS was administered intravenously to group 1 (NS+ NS), of IVIG was administered intravenously to group 2 (LPS+ IVIG), and of NS was administered intravenously to group 3 (LPS+ NS). Hysterectomy was performed in one-half of the dams 2 hours after the second injection and in the other one-half of the dams 22 hours after the second injection. Pups were delivered, and the brains were extracted just after delivery. IL-1β expression and caspase 3 activity were determined in brain tissues. For the pups at 4 hours, the IL-1β expression of group 2was significantly lower than groups 1 and 3. For the pups at 24hours, the IL-1β expression of group 2 was significantly lower than group 3 but was similar to group 1. For the pups at 24 hours, caspase 3 activity of groups 1 and 2 were significantly lower than group3. Maternal IVIG administration decreased IL-1β expression and caspase 3 activity in the brain tissue of rat pups, which had been induced by maternal LPS-administration.

Maternal Exposure to Lipopolysaccharide Leads to Transient Motor Dysfunction in Neonatal Rats

Epidemiological and experimental data implicate maternal infection and inflammation in the etiology of brain white matter injury, which may lead to cerebral palsy in preterm newborns. Our aim was to investigate motor development of the offspring after maternal administration of lipopolysaccharide (LPS). Wistar rats were intraperitoneally injected with Escherichia coli LPS or saline on gestational days 19 and 20. From birth to 3 weeks, pups were tested for neurobehavioral development, neurological signs and reflexes. From 3 to 6 weeks, motor coordination was investigated. At 4 months, animals were tested for locomotion. Brain myelination was assessed by myelin basic protein immunohistochemistry. Days of appearance of several neurological reflexes were significantly delayed, and neonate LPS pups displayed retarded performance in righting, gait and negative geotaxis. At the juvenile stage, LPS animals showed important impairment in coordination. However, although the LPS group performed worse in most tests, they reached vehicle levels by 5 weeks. At 4 months, LPS animals did not show variations in locomotion performances compared to vehicle. No myelination differences have been observed in the brains at adulthood. Maternal LPS administration results in delayed motor development even though these alterations fade to reach control level by 5 weeks. Motor impairments observed at the early stage in this study could be linked to previously reported hypomyelination of the white matter induced by maternal LPS challenge in the neonates. Finally, the normal myelination shown here at adulthood may explain the functional recovery of the animals and suggest either a potential remyelination of the brain or a delayed myelination in LPS pups.

Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation–induced offspring cerebral injury shown on magnetic resonance imaging

Maternal infection or inflammation may induce fetal inflammatory responses associated with fetal injury and cerebral palsy. We sought to assess the inflammation-associated neuroprotective potential of prophylactic N-acetyl-cysteine (NAC). We examined the effect of NAC on prevention of maternal lipopolysaccharide (LPS)-induced neonatal brain injury using magnetic resonance imaging. Pregnant Sprague Dawley dams (n = 5-8) at embryonic day 18 received intraperitoneal injection of LPS or saline at time 0. Animals were randomized to receive 2 intravenous injections of NAC or saline (time -30 and 120 minutes). Pups were delivered spontaneously and allowed to mature until postnatal day 25. Female offspring were examined by magnetic resonance brain imaging and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess white matter injury and diffusion tensor imaging for apparent diffusion coefficient (ADC) to assess white and gray matter injury. Offspring of LPS-treated dams exhibited significantly increased T2 levels and increased ADC levels in white and gray matter (eg, hypothalamus, motor cortex, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of NAC-treated LPS dams demonstrated similar T2 and ADC levels as control in both white and gray matter. Maternal NAC treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. These studies suggest that maternal NAC therapy may be effective in human deliveries associated with maternal/fetal inflammation.

Effect of Maternal Lipopolysaccharide Administration on the Development of Dopaminergic Receptors and Transporter in the Rat Offspring

Epidemiological evidence supports that maternal infection during gestation are notable risk factors for developmental mental illnesses including schizophrenia and autism. In prenatal lipopolysaccharide (LPS) model of immune activation in rats, the offspring exhibit significant impairments in behaviors mediated by central dopamine (DA) system. This study aimed to examine the temporal and regional pattern of postnatal DA development in the male offspring of pregnant Sprague-Dawley rats administered with 100 µg/kg LPS or saline at gestational days 15/16. Using ligand autoradiography, D1 and D2 dopamine receptors (D1R, D2R) and dopamine transporter (DAT) binding levels were measured in the prefrontal cortex (PFC) and sub cortical regions (dorsal striatum and nucleus accumbens core and shell) at pre pubertal (P35) and post pubertal ages (P60). We found a significant decrease in D2R ligand [3H] YM-90151-2 binding in the medial PFC (mPFC) in prenatal LPS-treated animals at P35 and P60 compared to respective saline groups. The decrease in D2R levels was not observed in the striatum or accumbens of maternal LPS-treated animals. No significant changes were observed in [3H] SCH23390 binding to D1R. However, the level of [125I] RTI-121 binding to DAT was selectively reduced in the nucleus accumbens core and shell at P35 in the prenatal LPS group. Immunohistochemical analysis showed that number of D2R immunopositive cells in infralimbic/prelimbic (IL/PL) part of mPFC was significantly reduced in the LPS group at P60. Prenatal LPS treatment did not significantly affect either the total number of mature neurons or parvalbumin (PV)-immunopositive interneurons in this region. However the number of PV and D2R co-labeled neurons was significantly reduced in the IL/PL subregion of PFC of LPS treated animals. Our data suggests D2R deficit in the PFC and PV interneurons may be relevant to understanding mechanisms of cortical dysfunctions described in prenatal infection animal models as well as schizophrenia.

Aberrant Cerebellar Neurotrophin-3 Expression Induced by Lipopolysaccharide Exposure During Brain Development

Autism is a developmental disorder affecting communication, social interaction, motor skills, and cerebellar structure and functions. Recent studies have indicated that maternal infection during brain development may be one of the risk factors for autism. We have previously demonstrated the abnormal overexpression of neurotrophin-3 (NT-3) in autistic cerebellum. To examine further the potential link between autism and maternal infection, and specifically NT-3 expression in the cerebellum, we used maternal lipopolysaccharide (LPS)-exposed rat model of infection. In group 1, pregnant female rats were exposed to 200μg/kg body weight LPS delivered subcutaneously from gestational days (G) 10 to G15, and pups were exposed to LPS from postnatal days (P) 5 to P10, whereas in group 2, pups were exposed to the same dose of LPS from P5 to P10. There was no change in body mass of pups and mothers following LPS treatment. Cerebellar NT-3 levels were examined by enzyme-linked immunosorbent assay on P6, P12, and P21. We report here that cerebellar NT-3 levels were elevated in pups of both LPS groups as compared to the controls on P21. Our results suggest that altered neurotrophin levels may affect normal brain development and contribute to autistic pathology.

Prenatal immunological stress affects the development of reproductive system.

Event Abstract Back to Event Prenatal immunological stress affects the development of reproductive system. Viktoriya Sharova1*, Marina Izvolskaia1 and Liudmila Zakharova1 1 Koltsov Institute of Developmental Biology Russian academy of Sciences, Histogenesis, Russia Immune and reproductive systems closely interact in critical periods of early ontogeny. The leading role in programming of reproductive and immune system development and functioning belongs to hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH). GnRH neurons originate in olfactory epithelium and migrate to the forebrain on the surface of olfactory/vomeronasal nerves in prenatal life. Immunomediators are involved in regulatory and morphogenetic processes of GnRH system development during perinatal period. Rats were injected intraperitoneally with lipopolysaccharide (LPS) (18 μg/kg) on the 12th day of pregnancy and GnRH-immunoreactive neuron fractions were count along the migration route on 17th and 19th embryonic days (E). Body weights, the day of vaginal opening was recorded in prenatally LPS-treated and control offspring. Hypothalamic GnRH content was detected by radioimmunoassay on 5th, 14th and 30th postnatal days (P). The receptors to proinflammatory cytokines (IL-6, MCP-1, LIF) in GnRH-neurons were detected in untreated fetuses using double immunohistochemistry. The rate of GnRH neuron migration was decreased in nasal area on E17 after maternal LPS treatment, GnRH neuron distribution wasn’t changed on E19. The body weight of postnatal LPS-treated animals was decreased and vaginal opening was also delayed. GnRH content was diminished on 25% in both sexes on P60. GnRH neurons were positive to IL-6R, LIFR and MCP-1 (CCR) in different areas of migration route. Thus, maternal infection on early stages of pregnancy affects GnRH neuron migration in fetuses and as a result GnRH synthesis is suppressed in postpubertal animals. Possible regulators of GnRH neuron migration might be the proinflammatory cytokines. Keywords: proinflammatory cytokines, receptors, GnRH-neurons, Embryo, Mammalian, offspring Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune receptors and signaling Citation: Sharova V, Izvolskaia M and Zakharova L (2013). Prenatal immunological stress affects the development of reproductive system.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00667 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Viktoriya Sharova, Koltsov Institute of Developmental Biology Russian academy of Sciences, Histogenesis, Moscow, 119334, Russia, sarovav@mail.ru Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract Supplemental Data The Authors in Frontiers Viktoriya Sharova Marina Izvolskaia Liudmila Zakharova Google Viktoriya Sharova Marina Izvolskaia Liudmila Zakharova Google Scholar Viktoriya Sharova Marina Izvolskaia Liudmila Zakharova PubMed Viktoriya Sharova Marina Izvolskaia Liudmila Zakharova Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

76: Prophylactic maternal N-acetyl-cysteine (NAC) prevents maternal inflammation-induced offspring cerebral injury evident by magnetic resonance imaging (MRI)

Maternal infection or inflammation may induce fetal inflammatory responses associated with fetal injury and cerebral palsy. We sought to assess the inflammation-associated neuroprotective potential of prophylactic NAC, a known anti-inflammatory agent. We examined the effect of NAC on prevention of maternal lipopolysaccharide (LPS) - induced neonatal brain injury using MRI.

Maternal N-acetyl-cysteine (NAC) protects the rat fetal brain from inflammatory cytokine responses to lipopolysaccharide (LPS)

Objective: Inflammatory cytokines, play a central role in the genesis of preterm parturition and fetal brain injury. Lipopolysaccharide (LPS) may activate cytokine pathways via induction of oxidative stress pathways. We hypothesized that enhanced maternal antioxidant activity may blunt fetal brain inflammatory responses to maternal LPS injection in pregnant rats. Methods: Pregnant Sprague-Dawley rats at 18 and 20 days gestation received intraperitoneal (ip) LPS injection and pre- and post-treatment with the antioxidant N-acetyl-cysteine (NAC) or saline. Six hours after the LPS injection, rats were sacrificed, interleukin (IL)-6 and IL-10 mRNA expression in the fetal brains was determined by real time polymerase chain reaction. Results: Maternal ip LPS induced significant increase in fetal brain IL-6 mRNA expression at E18 (3.1 ± 0.6 vs 1.0 ± 0.10 AU) and E20 (29.01 + 13.06 vs 0.95 + 0.05 AU; p < 0.05) compared to Control, only at E20 maternal LPS induced increase in fetal brain IL-10 compared to control. NAC administered prior to and after LPS significantly reduced fetal brain IL-6 at E18 and E20 and IL-10 at E20. Conclusion: Maternal NAC can protect the fetal brain from inflammatory cytokine responses to maternal LPS injection. These results suggest that NAC may potentially protect fetus from inflammation-associated brain injury and potential long term sequelae.

Maternal lipopolysaccharide alters the newborn oxidative stress and C-reactive protein levels in response to an inflammatory stress.

Maternal infection is associated with oxidative stress (OS) and inflammatory responses. We have previously shown that maternal exposure to lipopolysaccharide (LPS) at E18 alters the subsequent offspring immune response. As immune responses are mediated, in part, by OS, we sought to determine if maternal inflammation during pregnancy programs offspring OS and C-reactive protein (CRP) levels. Pregnant Sprague-Dawley rats received intraperitoneal (i.p.) injections of saline or LPS at 18 days' gestation (n = 4), and pups delivered spontaneously at term. At postnatal day 24, male and female offspring received i.p. injection of LPS. Serum lipid peroxides formation (PD) and CRP levels were determined before and at 4 h following the LPS injection. Pups of LPS-exposed dams had significantly higher basal OS (PD 29.4 ± 5.4 v. 10.1 ± 4.8 nmol/ml) compared with controls. In response to LPS, CRP levels (20.4 ± 2.8 v. 5.7 ± 1.0 ng/ml) were significantly higher among pups of LPS-exposed dams than controls. Prenatal maternal exposure to LPS increases baseline OS levels in neonates and CRP levels in response to LPS. These results suggest that maternal inflammation during the antenatal period may induce long-term sequelae in the offspring that may predispose to adult disease.

Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism.

Physical exercise ameliorates memory impairment in rat pups with maternal lipopolysaccharide-induced cerebral palsy

Maternal lipopolysaccharide (LPS) exposure increases the incidence of cerebral palsy (CP). In the present study, we investigated the effects of treadmill exercise on memory in relation to the expression of brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) in the brain using rat pups of a maternal LPS-induced cerebral palsy model. There were two groups of pregnant rats, an LPS-injection group and a control group. During pregnancy, the rats in the LPS-injection group received a 1 mL intracervical injection of 0.15 mg/kg LPS. After birth, the neonatal rats were divided into three groups: a control group, an LPS-injection group, and a LPS-injection and exercise group. Five weeks after birth, the rat pups in the LPS-injection and exercise group were forced to run on a motorized treadmill for 30 min per day, five times per week for 4 weeks. Rat pups in the maternal LPS injection group showed decreased memory with suppressed BDNF expression, its receptor tyrosine kinase B (TrkB), 5-HT, and its synthesis enzyme tryptophan hydroxylase (TPH). Rat pups in the maternal LPS injection group that exercised showed alleviated memory impairment with enhanced expression of BDNF, TrkB, 5-HT, and TPH. We suggest that treadmill exercise increases 5-HT synthesis in the dorsal raphe, which, in turn, enhances BDNF expression in the hippocampus, resulting in the restoration of memory function. Treadmill exercise may be a useful strategy to mitigate neurodegenerative disorders in offspring that have been induced with an LPS injection during pregnancy.

Mouse maternal systemic inflammation at the zygote stage causes blunted cytokine responsiveness in lipopolysaccharide-challenged adult offspring

BackgroundThe preimplantation embryo is sensitive to culture conditions in vitro and poor maternal diet in vivo. Such environmental perturbations can have long-lasting detrimental consequences for offspring health and physiology. However, early embryo susceptibility to other aspects of maternal health and their potential long-term influence into adulthood is relatively unexplored. In this study, we established an in vivo mouse model of maternal periconceptional systemic inflammation by intraperitoneal lipopolysaccharide (LPS) administration on the day of zygote formation and investigated the consequences into adulthood.ResultsIn the short term, maternal LPS challenge induced a transient and typical maternal sickness response (elevated serum proinflammatory cytokines and hypoactive behaviour). Maternal LPS challenge altered preimplantation embryo morphogenesis and cell lineage allocation, resulting in reduced blastocyst inner cell mass (ICM) cell number and a reduced ICM:trophectoderm cell ratio. In the long term, diverse aspects of offspring physiology were affected by maternal LPS treatment. Whilst birthweight, growth and adult blood pressure were unaltered, reduced activity in an open-field behaviour test, increased fat pad:body weight ratio and increased body mass index were observed in male, but not female, offspring. Most importantly, the maternal LPS challenge caused corticosterone-independent blunting of the serum proinflammatory cytokine response to innate immune challenge in both male and female offspring. The suppressed state of innate immunity in challenged offspring was dose-dependent with respect to the maternal LPS concentration administered.ConclusionsThese results demonstrate for the first time that the preimplantation embryo in vivo is sensitive to maternal systemic inflammation, with effects on blastocyst cell lineage allocation and consequences for behaviour, adiposity and innate immune response in adult offspring. Critically, we identify a novel mechanism mediated through maternal-embryonic interactions that confers plasticity in the development of the innate immune system, which is potentially important in setting postnatal tolerance to environmental pathogens. Our study extends the concept of developmental programming of health and disease to include maternal health at the time of conception.

Early, Time-Dependent Disturbances of Hippocampal Synaptic Transmission and Plasticity After In Utero Immune Challenge

Maternal infection during pregnancy is a recognized risk factor for the occurrence of a broad spectrum of psychiatric and neurologic disorders, including schizophrenia, autism, and cerebral palsy. Prenatal exposure of rats to lipopolysaccharide (LPS) leads to impaired learning and psychotic-like behavior in mature offspring, together with an enduring modification of glutamatergic excitatory synaptic transmission. The question that arises is whether any alterations of excitatory transmission and plasticity occurred at early developmental stages after in utero LPS exposure. Electrophysiological experiments were carried out on the CA1 area of hippocampal slices from prenatally LPS-exposed male offspring from 4 to 190 days old to study the developmental profiles of long-term depression (LTD) triggered by delivering 900 shocks either single- or paired-pulse (50-msec interval) at 1 Hz and the N-methyl-D-aspartate receptor (NMDAr) contribution to synaptic transmission. The age-dependent drop of LTD is accelerated in prenatally LPS-exposed animals, and LTD is transiently converted into a slow-onset long-term potentiation between 16 and 25 days old. This long-term potentiation depends on Group I metabotropic glutamate receptors and protein kinase A activations and is independent of NMDArs. Maternal LPS challenge also leads to a rapid developmental impairment of synaptic NMDArs. This was associated with a concomitant reduced expression of GluN1, without any detectable alteration in the developmental switch of NMDAr GluN2 subunits. Aberrant forms of synaptic plasticity can be detected at early developmental stages after prenatal LPS challenge concomitant with a clear hypo-functioning of the NMDAr in the hippocampus. This might result in later-occurring brain dysfunctions.

Melatonin alleviates lipopolysaccharide‐induced placental cellular stress response in mice

Melatonin protects mice from lipopolysaccharide (LPS)-induced fetal death and intra-uterine growth retardation. Nevertheless, its molecular mechanism remains obscure. In the present study, we investigated the effects of melatonin on LPS-induced cellular stress in placenta. Pregnant mice were given with melatonin [5.0 mg/kg, intraperitoneal (i.p.)] 30 min before and 150 min after LPS (300 μg/kg, i.p.) on gestational day 15. Oxidative stress, endoplasmic reticulum (ER) stress, hypoxic stress, and heat stress in placenta were analyzed at 4 hr after LPS. As expected, maternal LPS administration resulted in placental glutathione (GSH) depletion and up-regulated the expression of placental antioxidative enzymes. In addition, LPS significantly increased the level of inducible nitric oxide synthase (iNOS) and enhanced the intensity of placental 3-nitrotyrosine residues. An ER stress, as determined by a decreased GRP78 expression, an obvious eIF2α and JNK phosphorylation, and an increased CHOP expression, were observed in placenta of pregnant mice injected with LPS. In addition, LPS significantly increased mRNA level of placental HIF-1α, VEGF, and ET-1, the markers of hypoxic stress. Heme oxygenase (HO)-1, a marker of heat stress, was also up-regulated in placenta of LPS-treated pregnant mice. Interestingly, LPS-induced placental oxidative stress, hypoxic stress, and ER stress were significantly alleviated when pregnant mice were given with melatonin, whereas melatonin had little effect on LPS-evoked placental HO-1 expression. In conclusion, maternally administered melatonin alleviates LPS-induced cellular stress in the placenta. Melatonin may be useful as pharmacological agents to protect the fetuses against LPS-induced intra-uterine fetal death and intra-uterine growth restriction.

Effects of endogenous glucocorticoid secretion on the interleukin-6 response to bacterial endotoxin in pregnant and non-pregnant rats

Glucocorticoids (GCs) are released in response to immune activation by the bacterial endotoxin, lipopolysaccharide (LPS). However, GC secretion in response to immune activation and other stressors is attenuated at term of pregnancy. GCs are important modulators of the immune response, and both pro- and anti-inflammatory effects are described. Here, we examined whether GC secretion in response to LPS is maintained in earlier pregnancy before term, and investigated the role of endogenous GCs in modulating LPS-induced circulating cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), in pregnant compared to non-pregnant female rats. Plasma corticosterone (Cort) and ACTH responses to LPS were well maintained in pregnant rats at embryonic days 15/16 (E15/16) and E18/19 compared to non-pregnant rats. At E19, maternal LPS administration increased fetal plasma Cort and decreased testosterone in male fetuses. In non-pregnant animals, pretreatment with the GC synthesis inhibitor, metyrapone, inhibited the LPS-induced increase in IL-6, and the IL-6 response was restored by Cort replacement, indicating that LPS induction of IL-6 is Cort-dependent. In E15 pregnant animals, metyrapone had no effect on LPS-induced IL-6 levels, indicating that LPS-induction of IL-6 is not dependent on Cort. These contrasting patterns of IL-6 induction in non-pregnant and pregnant animals were reflected in levels of hypothalamic Socs3 mRNA, an indicator of IL-6 signaling pathway activation. In both non-pregnant and pregnant rats, LPS-induced plasma TNF-α responses were inhibited by metyrapone but not re-instated by Cort replacement. It is suggested that altered GC regulation of IL-6 may be required to sustain specialized functions of IL-6 during pregnancy.

231: Maternal lipopolysaccharide (LPS) alters the newborn oxidative stress and CRP levels in response to stress

231: Maternal lipopolysaccharide (LPS) alters the newborn oxidative stress and CRP levels in response to stress