Infection of the murine placenta by Listeria monocytogenes induces sex-specific responses in the fetal brain
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213619 | GEO | 2022/09/22
REPOSITORIES: GEO
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Project description:Maternal exposure to stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. The mechanisms through which the effects of maternal stress are transmitted to the fetus are unclear, however the placenta, as the interface between mother and fetus, is likely to play a key role. Using a rat model, we investigated a role for placental oxidative stress in conveying the effects of maternal social stress to the fetus and the potential for treatment using a nanoparticle-bound antioxidant to prevent adverse outcomes in the offspring. Maternal psychosocial stress increased circulating corticosterone in the mother, but not in the fetuses. Maternal stress also induced oxidative stress in the placenta, but not in the fetal brain. Blocking oxidative stress using an antioxidant prevented the prenatal stress-induced anxiety phenotype in the male offspring, and prevented sex-specific neurobiological changes, specifically a reduction in dendrite lengths in the hippocampus, as well as reductions in the number of parvalbumin-positive neurons and GABA receptor subunits in the hippocampus and basolateral amygdala of the male offspring. Importantly, many of these effects were mimicked in neuronal cultures by application of placental-conditioned medium or fetal plasma from stressed pregnancies, indicating molecules released from the placenta may mediate the effects of prenatal stress on the fetal brain. Indeed, both placenta-conditioned medium and fetal plasma contained differentially abundant microRNAs following maternal stress, and their predicted targets were enriched for genes relevant to nervous system development and psychiatric disorders. The results highlight placental oxidative stress as a key mediator in transmitting the maternal social stress effects on the offspring's brain and behaviour, and offer a potential intervention to prevent stress-induced fetal programming of affective disorders.
2020-12-01 | GSE130573 | GEO
Project description:Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder that significantly jeopardizes the physical and mental well-being of children. Autism spectrum disorder results from a combination of environmental and genetic factors. Hyperandrogenic exposure during pregnancy increases their risk of developing autism. Nevertheless, the prenatal exposure to androgens affects offspring neurodevelopment and the underlying mechanisms have not been fully elucidated. In the present study, administration of excessive dihydrotestosterone (DHT) to pregnant mice was found to impair neuronal development and dendritic spine formation in offspring, inducing autism-like behaviors. Furthermore, through mRNA transcriptome sequencing technology, the key molecule Nr4a2 was identified during this process of change. Overexpression of Nr4a2 and treatment with amodiaquine (AQ) significantly improved the abnormal phenotypes in offspring caused by prenatal exposure to androgens. Overall, Nr4a2 emerges as a crucial molecule involved in the impairment of offspring neurodevelopment due to prenatal androgen exposure, which provides a new perspective for the in-depth study of the influencing factors and underlying mechanisms.
2023-11-04 | GSE246534 | GEO
Project description:Prenatal development is a critical period for programming of neurological disease. Preeclampsia, a pregnancy complication involving oxidative stress in the placenta, has been associated with long-term health implications for the child, including an increased risk of developing schizophrenia and autism spectrum disorders in later life. We have shown previously, in a rodent model of placental oxidative stress, that culture medium conditioned by the placenta alters neuronal characteristics when applied to primary cortical cultures in vitro and mimics many of the neurodevelopmental changes observed in the offspring brain. To further investigate if molecules released by the placenta may be important mediators in foetal programming of the brain, we analysed if placental tissue delivered from patients with preeclampsia secreted molecules that could affect cortical cells in culture. Application of culture medium conditioned by preeclamptic placentae to mixed cortical cultures caused changes in neurons and astrocytes that were related to key changes observed in brains of patients with schizophrenia and autism, including effects on dendrite lengths, astrocyte number as well as glutamate and GABA receptors. Treatment of the placental explants with an antioxidant prevented neuronal abnormalities. Furthermore, we identified that bidirectional communication between neurons and astrocytes, potentially via glutamate, is required to produce the effects of preeclamptic placenta medium on cortical cells. Analysis of possible signalling molecules in the placenta conditioned medium showed that the secretion profile of extracellular microRNA, small posttranscriptional regulators, was altered in preeclampsia and partially rescued by antioxidant treatment of the placental explants. Predicted targets of these differentially abundant microRNAs were linked to neurodevelopment and the placenta. The presented study provides further evidence that the diseased placenta may release factors that damage cortical cells in the brain and suggests the possibility of targeted antioxidant treatment of the placenta to prevent neurodevelopmental disorders.
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Project description:Prenatal exposure to toxic metals is associated with altered placental function and adverse health outcomes. The underlying mechanisms linking in utero toxic metal exposures with later-in-life health remain unclear, though placental inflammation is posited as a potential driver. The aim of this study was to evaluate whether in utero metals presence is associated with sex-specific changes in placental protein expression. We hypothesized that sex-specific patterns of metal-associated placental protein expression would be observed, and metals presence would be positively associated with the altered expression of inflammation-associated pathways Using samples banked from the Extremely Low Gestational Age Newborn Study (ELGAN), umbilical cord tissue samples were analyzed via ICP-MS/MS for trace elements, and placental samples underwent a global untargeted proteomics analysis via LC-MS/MS. This work highlights the linkage between prenatal metals exposure and an altered placental proteome, revealing that metals in cord tissue were associated with largely distinct differences in placental protein expression, in a sexually-dimorphic manner.
2023-10-24 | PXD041694 | Pride
Project description:Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Given that SSRIs can cross the placental and blood-brain barriers, these drugs potentially affect serotonergic neurotransmission and neurodevelopment in the fetus. Although no gross SSRI-related teratogenic effect has been reported, infants born following prenatal exposure to SSRIs have a higher risk for various behavioral abnormalities. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, on social and cognitive behavior in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males with augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons in the medial prefrontal cortex (mPFC). Moreover, fast-spiking interneurons in the layer 5 mPFC exhibited enhanced basal intrinsic excitability, augmented serotonin-induced neuronal excitability, and increased inhibitory synaptic transmission onto the layer 5 pyramidal neurons due to augmented 5-HT2A receptor (5-HT2AR) signaling. More importantly, the observed behavioral deficits of in utero fluoxetine-treated mice could be reversed by acute systemic application of 5-HT2AR antagonist. Taken together, our findings support the notion that alterations in serotonin-mediated inhibitory neuronal modulation result in reduced cortical network activities and cognitive impairment following prenatal exposure to SSRIs.
2018-03-07 | GSE111491 | GEO
Project description:Prenatal exposure to infectious or inflammatory insults can increase the risk of neuropsychiatric disorders with neurodevelopmental components, including schizophrenia and autism. The molecular processes underlying this pathological association are only partially understood. Here, we implemented an unbiased genome-wide transcriptional profiling of the prefrontal cortex of mice exposed to prenatal infection on GD17 compared to control subjects in order to elucidate the long term molecular signature of late prenatal infection. We used microarray analysis to investigate the long lasting gene expression changes in a well-established mouse model that is based on maternal treatment with the viral mimic poly(I:C) during pregnancy C57BL/6 mice were treated with the synthetic viral mimetic poly(I:C) (5 mg/kg, i.v.) or control (saline, i.v.) solution on gestation day 17. Offspring were subjected to cognitive and behavioral testing in adulthood, and then whole genome gene expression analysis with Affymetrix Microarray and subsequent q-PCR validation were performed on the prefrontal Cortex.
2016-03-01 | E-GEOD-77972 | biostudies-arrayexpress
Project description:Prenatal exposure to infectious or inflammatory insults can increase the risk of neuropsychiatric disorders with neurodevelopmental components, including schizophrenia and autism. The molecular processes underlying this pathological association are only partially understood. Here, we implemented an unbiased genome-wide transcriptional profiling of the nucleus accumbens of mice exposed to prenatal infection on GD17 compared to control subjects in order to elucidate the long term molecular signature of late prenatal infection. We used microarray analysis to investigate the long lasting gene expression changes in a well-established mouse model that is based on maternal treatment with the viral mimic poly(I:C) during pregnancy C57BL/6 mice were treated with the synthetic viral mimetic poly(I:C) (5 mg/kg, i.v.) or control (saline, i.v.) solution on gestation day 17. Offspring were subjected to cognitive and behavioral testing in adulthood, and then whole genome gene expression analysis with Affymetrix Microarray and subsequent q-PCR validation were performed on the nucleus accumbens.
2016-03-01 | E-GEOD-77971 | biostudies-arrayexpress
Project description:Background: The placenta is vital for fetal development and its contributions to various developmental issues, such as pregnancy complications, fetal growth restriction, and maternal exposure, have been extensively studied in mice. Contrary to popular belief, the placenta forms mainly from fetal tissue; therefore, it has the same biological sex as the fetus it supports. However, while placental function is linked to increased risks of pregnancy complications and neurodevelopmental diseases in male offspring in particular, the sex-specific epigenetic (e.g., DNA methylation) and transcriptomic features of the late-gestation mouse placenta remain largely unknown.Methods: We collected male and female mouse placentas at late gestation (E18.5, n = 3/sex) and performed next-generation sequencing to identify genome-wide sex-specific differences in transcription and DNA methylation. Results: Our sex-specific analysis revealed 358 differentially expressed genes (DEGs) on autosomes, which were associated with signaling pathways involved in transmembrane transport and the responses to viruses and external stimuli. X chromosome DEGs (n = 39) were associated with different pathways, including those regulating chromatin modification and small GTPase-mediated signal transduction. Sex-specific differentially methylated regions (DMRs) were more common on the X chromosomes (n = 3756) than on autosomes (n = 1705). Interestingly, while most X chromosome DMRs had higher DNA methylation levels in female placentas and tended to be included in CpG dinucleotide-rich regions, 73% of autosomal DMRs had higher methylation levels in male placentas and were distant from CpG-rich regions. Several sex-specific DEGs were correlated with sex-specific DMRs. A subset of the sex-specific DMRs present in late-stage placentas were already established in mid-gestation (E10.5) placentas, while others were acquired later in placental development.Conclusion: Our study provides comprehensive lists of sex-specific DEGs and DMRs that collectively cause profound differences in the DNA methylation and gene expression profiles of late-gestation mouse placentas. Our results demonstrate the importance of incorporating sex-specific analyses into epigenetic and transcription studies to enhance the accuracy and comprehensiveness of their conclusions and help address the significant knowledge gap regarding how sex differences influence placental function.
2023-12-30 | GSE252283 | GEO
Project description:Background: The placenta is vital for fetal development and its contributions to various developmental issues, such as pregnancy complications, fetal growth restriction, and maternal exposure, have been extensively studied in mice. Contrary to popular belief, the placenta forms mainly from fetal tissue; therefore, it has the same biological sex as the fetus it supports. However, while placental function is linked to increased risks of pregnancy complications and neurodevelopmental diseases in male offspring in particular, the sex-specific epigenetic (e.g., DNA methylation) and transcriptomic features of the late-gestation mouse placenta remain largely unknown.Methods: We collected male and female mouse placentas at late gestation (E18.5, n = 3/sex) and performed next-generation sequencing to identify genome-wide sex-specific differences in transcription and DNA methylation. Results: Our sex-specific analysis revealed 358 differentially expressed genes (DEGs) on autosomes, which were associated with signaling pathways involved in transmembrane transport and the responses to viruses and external stimuli. X chromosome DEGs (n = 39) were associated with different pathways, including those regulating chromatin modification and small GTPase-mediated signal transduction. Sex-specific differentially methylated regions (DMRs) were more common on the X chromosomes (n = 3756) than on autosomes (n = 1705). Interestingly, while most X chromosome DMRs had higher DNA methylation levels in female placentas and tended to be included in CpG dinucleotide-rich regions, 73% of autosomal DMRs had higher methylation levels in male placentas and were distant from CpG-rich regions. Several sex-specific DEGs were correlated with sex-specific DMRs. A subset of the sex-specific DMRs present in late-stage placentas were already established in mid-gestation (E10.5) placentas, while others were acquired later in placental development.Conclusion: Our study provides comprehensive lists of sex-specific DEGs and DMRs that collectively cause profound differences in the DNA methylation and gene expression profiles of late-gestation mouse placentas. Our results demonstrate the importance of incorporating sex-specific analyses into epigenetic and transcription studies to enhance the accuracy and comprehensiveness of their conclusions and help address the significant knowledge gap regarding how sex differences influence placental function.
2023-12-30 | GSE252281 | GEO
Project description:Placental immunity is critical for fetal health during pregnancy, as invading pathogens spread from the parental blood to the fetus through this organ. However, inflammatory responses in the placenta can adversely affect both the fetus and the pregnant person, and the balance between protective placental immune response and detrimental inflammation is poorly understood. Extracellular vesicles (EVs) are membrane-enclosed vesicles that play a critical role in placental immunity. EVs produced by placental trophoblasts mediate immune tolerance to the fetus and to the placenta itself, but these EVs can also activate detrimental inflammatory responses. The regulation of these effects is not well-characterized, and the role of trophoblast EVs (tEVs) in the response to infection has yet to be defined. The Gram-positive pathogen Listera monocytogenes (Lm) infects the placenta, serving as a model to study tEV function in this context. We investigated the effect of Lm infection on the production and function of tEVs, using a trophoblast stem cell (TSC) model. We found that tEVs from infected TSCs can induce the production of the pro-inflammatory cytokine TNF-α in recipient cells. Surprisingly, this tEV treatment could confer increased susceptibility to subsequent Lm infection, which has not previously been reported as an effect of EVs. Proteomic analysis and RNA-sequencing revealed that tEVs from infected TSCs had altered cargo compared to those from uninfected TSCs. However, no Lm proteins were detected in tEVs from infected TSCs. Together, these results suggest an immunomodulatory role for tEVs during prenatal infection.
2022-09-12 | GSE212928 | GEO