Maternal-Fetal Inflammation in the Placenta and the Developmental Origins of Health and Disease

Goldstein, Jeffrey A.; Gallagher, Kelly; Beck, Celeste; Kumar, Rajesh; Gernand, Alison D.

doi:10.3389/fimmu.2020.531543

Cited by 179 publications

(112 citation statements)

References 162 publications

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“…In the case of Cxcl8 and Il1b , high levels of cytokine transcription were noted in the placenta of a dam that had been euthanized while delivering stillborn pups at 56 dGA (these placentas are represented as open circles in Figures 3 , 4 , and Figure S4 ). The elevated transcription of these cytokines may not be specific to GPCMV infection and instead be inflammatory markers of preterm labor or in utero fetal demise ( 70 , 71 ). Cumulatively, our gene expression analyses of GPCMV-infected placenta suggest that the immune response is dysregulated by GPCMV infection after mid-gestation but not after infection earlier in pregnancy.…”

Section: Resultsmentioning

confidence: 99%

The Placental Response to Guinea Pig Cytomegalovirus Depends Upon the Timing of Maternal Infection

et al. 2021

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Human cytomegalovirus (HCMV) infects the placenta, and these placental infections can cause fetal injury and/or demise. The timing of maternal HCMV infection during pregnancy is a determinant of fetal outcomes, but how development affects the placenta’s susceptibility to infection, the likelihood of placental injury post-infection, and the frequency of transplacental HCMV transmission remains unclear. In this study, guinea pig cytomegalovirus (GPCMV) was used to model primary maternal infection and compare the effects of infection at two different times on the placenta. When guinea pigs were infected with GPCMV at either 21- or 35-days gestation (dGA), maternal and placental viral loads, as determined by droplet digital PCR, were not significantly affected by the timing of maternal infection. However, when the transcriptomes of gestational age-matched GPCMV-infected and control placentas were compared, significant infection-associated changes in gene expression were only observed after maternal infection at 35 dGA. Notably, transcripts associated with immune activation (e.g. Cxcl10, Ido1, Tgtp1, and Tlr8) were upregulated in the infected placenta. A GPCMV-specific in situ hybridization assay detected rare infected cells in the main placenta after maternal infection at either time, and maternal infection at 35 dGA also caused large areas of GPCMV-infected cells in the junctional zone. As GPCMV infection after mid-gestation is known to cause high rates of stillbirth and/or fetal growth restriction, our results suggest that the placenta becomes sensitized to infection-associated injury late in gestation, conferring an increased risk of adverse pregnancy outcomes after cytomegalovirus infection.

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Section: Resultsmentioning

confidence: 99%

The Placental Response to Guinea Pig Cytomegalovirus Depends Upon the Timing of Maternal Infection

et al. 2021

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“…Thus, the redox status of the placental tissues of Sofosbuvir-exposed mothers indicate a state of cell death and in ammation. The structural changes and maladaptation in the placenta may cause in ammatory shock to the fetus that may results in long-term adverse outcomes, including asthma, cerebral palsy, abnormal neurodevelopment, and autism spectrum disorder [21,22].…”

Section: Discussionmentioning

confidence: 99%

The Pre-Conception Maternal Exposure To Sofosbuvir Impacts The Mitochondrial Biogenesis In Prenatal Fetal Tissues: Experimental Study On Rats

Shaker

Abdel-Aziz

Khafaga

et al. 2021

Preprint

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Hepatitis C virus (HCV) infection is a global public health problem and Egypt has the highest HCV prevalence worldwide. Hence, global efforts target to eliminate HCV by 2030. Sofosbuvir is a nucleotide analogue inhibitor of HCV polymerase essential for viral replication. Animal studies prove that Sofosbuvir metabolites cross the placenta and are excreted in the milk of nursing animals. We aimed to investigate the possible effects of preconception maternal exposure to Sofosbuvir on the mitochondrial biogenesis in prenatal fetal liver, skeletal muscle and placental tissues using female rats. The study was conducted on 20 female albino rats classified into 2 groups, control group including 10 healthy rats receiving placebo, and exposed group including 10 rats receiving 4 mg/kg of Sofosbuvir. At the end of the 3-month treatment period, pregnancy was induced in both groups by mating with healthy male rats overnight. At gestational day 17, all pregnant female rats were sacrificed. Each fetus was dissected to obtain the fetal liver, skeletal muscle and placental tissues. The results of our study indicated that the preconception exposure of young female rats to Sofosbuvir affects pregnancy outcomes, decreases fertility, and impacts mitochondrial biogenesis and functions in prenatal fetal liver, skeletal muscle and placental.

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“…How could LPS trigger the opening of these channels in the context of fetal programming? As mentioned above, maternal administration of LPS causes an acute phase of systemic inflammation that goes hand in hand with the production of placental inflammatory mediators, which occurs at crucial developmental stages of the fetal brain [43]. Although LPS induces the activation of Cx43 hemichannels in cultured astrocytes and C6 glioma cells [152,171], the ability of prenatal LPS exposure to promote the opening of these channels likely relies on downstream interactions of cytokines with placental receptors, which significantly and permanently affect the structure and functional capacity of the fetal brain.…”

Section: Connecting Maternal Inflammation With the Activation Of Hemichannels And Pannexons In Offspring Astrocytesmentioning

confidence: 99%

“…The myriad of inflammatory factors produced by infections or noninfectious pathological stimuli during gestation induces diverse pathophysiological processes in the maternal, placental, and fetal compartments [4]. Part of these mediators can cross the blood-placental barrier, triggering systemic fetal inflammation and oxidative stress [43] and affecting the brain, with potentially damaging consequences for neuronal and glial cell function, synaptic transmission and plasticity, and behavior [44]. In the CNS, the innate immune system integrates these complex immune responses, whose central member is the microglia.…”

Section: Introductionmentioning

confidence: 99%

Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders

Prieto-Villalobos

Alvear

Liberona

et al. 2021

IJMS

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Maternal inflammation during pregnancy causes later-in-life alterations of the offspring’s brain structure and function. These abnormalities increase the risk of developing several psychiatric and neurological disorders, including schizophrenia, intellectual disability, bipolar disorder, autism spectrum disorder, microcephaly, and cerebral palsy. Here, we discuss how astrocytes might contribute to postnatal brain dysfunction following maternal inflammation, focusing on the signaling mediated by two families of plasma membrane channels: hemi-channels and pannexons. [Ca2+]i imbalance linked to the opening of astrocytic hemichannels and pannexons could disturb essential functions that sustain astrocytic survival and astrocyte-to-neuron support, including energy and redox homeostasis, uptake of K+ and glutamate, and the delivery of neurotrophic factors and energy-rich metabolites. Both phenomena could make neurons more susceptible to the harmful effect of prenatal inflammation and the experience of a second immune challenge during adulthood. On the other hand, maternal inflammation could cause excitotoxicity by producing the release of high amounts of gliotransmitters via astrocytic hemichannels/pannexons, eliciting further neuronal damage. Understanding how hemichannels and pannexons participate in maternal inflammation-induced brain abnormalities could be critical for developing pharmacological therapies against neurological disorders observed in the offspring.

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Maternal-Fetal Inflammation in the Placenta and the Developmental Origins of Health and Disease

Cited by 179 publications

References 162 publications

The Placental Response to Guinea Pig Cytomegalovirus Depends Upon the Timing of Maternal Infection

The Placental Response to Guinea Pig Cytomegalovirus Depends Upon the Timing of Maternal Infection

The Pre-Conception Maternal Exposure To Sofosbuvir Impacts The Mitochondrial Biogenesis In Prenatal Fetal Tissues: Experimental Study On Rats

Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders

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