Environmental Stressors Impact Placentation Through Actions On Trophoblast, Immune, and Endothelial Cell Dynamics
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE178407 | GEO | 2021/06/18
REPOSITORIES: GEO
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Project description:Our environment is replete with chemicals that can affect embryonic and extraembryonic development. Dioxins, such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), are compounds affecting development through the aryl hydrocarbon receptor (AHR). TCDD exposures can lead to placental adaptations and at higher doses pregnancy termination. Deep intrauterine endovascular trophoblast cell invasion was a prominent placentation site adaptation to TCDD. TCDD-mediated placental adaptations were dependent upon maternal AHR signaling but not placental or fetal AHR nor the presence of a prominent AHR target, cytochrome P450 1A1 (CYP1A1). At the placentation site, TCDD stimulated CYP1A1 transcription within endothelial cells but not trophoblast cells. Immune and trophoblast cell behaviors at the uterine-placental interface were guided by the actions of TCDD on endothelial cells. In summary, we have identified an AHR regulatory pathway activated by environmental stressors affecting uterine and trophoblast cell dynamics and the formation of the hemochorial placenta.
2021-11-30 | GSE166659 | GEO
Project description:Our environment is replete with chemicals that can affect embryonic and extraembryonic development. Dioxins, such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), are compounds affecting development through the aryl hydrocarbon receptor (AHR). TCDD exposures can lead to placental adaptations and at higher doses pregnancy termination. Deep intrauterine endovascular trophoblast cell invasion was a prominent placentation site adaptation to TCDD. TCDD-mediated placental adaptations were dependent upon maternal AHR signaling but not placental or fetal AHR nor the presence of a prominent AHR target, cytochrome P450 1A1 (CYP1A1). At the placentation site, TCDD stimulated CYP1A1 transcription within endothelial cells but not trophoblast cells. Immune and trophoblast cell behaviors at the uterine-placental interface were guided by the actions of TCDD on endothelial cells. In summary, we have identified an AHR regulatory pathway activated by environmental stressors affecting uterine and trophoblast cell dynamics and the formation of the hemochorial placenta.
2021-11-30 | GSE166604 | GEO
Project description:The hemochorial placentation site is characterized by a dynamic interplay between trophoblast cells and maternal cells. These cells cooperate to establish an interface required for nutrient delivery to promote fetal growth. In the human, trophoblast cells penetrate deep into the uterus. This is not a consistent feature of hemochorial placentation and has hindered the establishment of suitable animal models. The rat represents an intriguing model for investigating hemochorial placentation with deep trophoblast cell invasion. In this study, we used single cell RNA sequencing to characterize the transcriptome of the invasive trophoblast cell lineage, as well as other cell populations within the rat uterine-placental interface during early (gestation day, gd, 15.5) and late (gd 19.5) stages of intrauterine trophoblast cell invasion. We identified a robust set of transcripts that define invasive trophoblast cells, as well as transcripts that distinguished endothelial, smooth muscle, natural killer, and macrophage cells. Invasive trophoblast, immune, and endothelial cell populations exhibited distinct spatial relationships within the uterine-placental interface. Furthermore, the maturation stage of invasive trophoblast cell development could be determined by assessing gestation-stage dependent changes in transcript expression. Finally, and most importantly, expression of a prominent subset of rat invasive trophoblast cell transcripts is conserved in the invasive extravillous trophoblast cell lineage of the human placenta. These findings provide foundational data to identify and interrogate key conserved regulatory mechanisms essential for development and function of an important compartment within the hemochorial placentation site that is essential for a healthy pregnancy.
2022-09-20 | GSE206086 | GEO
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
2023-05-18 | GSE203192 | GEO
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
2023-05-18 | GSE202338 | GEO
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
2023-05-18 | GSE202337 | GEO
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
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Project description:The ligand-activated transcription factor Aryl Hydrocarbon Receptor (AHR) regulates cellular detoxification, proliferation, and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-seq to identify the signature of AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGFR1, and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein Scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression is elevated in a subset of colon cancer patient samples, which also contain elevated β-catenin levels. Remarkably, SCIN expression promotes nuclear translocation of β-catenin and activates the WNT pathway. Our study identified a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of β-catenin.
2023-06-12 | GSE212795 | GEO
Project description:Conventional biochemical and molecular techniques identified previously several genes whose expression is regulated by the aryl hydrocarbon receptor (AHR). We sought to map the complete spectrum of AHR-dependent genes in male adult liver using expression arrays to contrast mRNA profiles in Ahr-null mice (Ahrâ/â) with those in mice with wild-type AHR (Ahr+/+). Transcript profiles were determined both in untreated mice and in mice treated 19 h earlier with 1000 µg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Expression of 456 ProbeSets was significantly altered by TCDD in an AHR-dependent manner, including members of the classic AHRE-I gene battery, such as Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1. In the absence of exogenous ligand, AHR status alone affected expression of 392 ProbeSets, suggesting that the AHR has multiple functions in normal physiology. In Ahrâ/â mice, only 32 ProbeSets exhibited responses to TCDD, indicating that the AHR is required for virtually all transcriptional responses to dioxin exposure in liver. The flavin-containing monooxygenases, Fmo2 and Fmo3, considered previously to be uninducible, were highly induced by TCDD in an AHR-dependent manner. The estrogen receptor alpha as well as two estrogen-receptor-related genes (alpha and gamma) exhibit AHR-dependent expression, thereby extending cross-talk opportunities between the intensively studied AHR and estrogen receptor pathways. p53 binding sites are over-represented in genes down-regulated by TCDD, suggesting that TCDD inhibits p53 transcriptional activity. Overall, our study identifies a wide range of genes that depend on the AHR, either for constitutive expression or for response to TCDD. Experiment Overall Design: Mice bearing wild-type or genetically deleted AHRs were treated with corn oil vehicle or TCDD, and their livers analyzed by expression arrays.
2008-11-13 | E-GEOD-10082 | biostudies-arrayexpress
Project description:Conventional biochemical and molecular techniques identified previously several genes whose expression is regulated by the aryl hydrocarbon receptor (AHR). We sought to map the complete spectrum of AHR-dependent genes in male adult liver using expression arrays to contrast mRNA profiles in Ahr-null mice (Ahr–/–) with those in mice with wild-type AHR (Ahr+/+). Transcript profiles were determined both in untreated mice and in mice treated 19 h earlier with 1000 µg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Expression of 456 ProbeSets was significantly altered by TCDD in an AHR-dependent manner, including members of the classic AHRE-I gene battery, such as Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1. In the absence of exogenous ligand, AHR status alone affected expression of 392 ProbeSets, suggesting that the AHR has multiple functions in normal physiology. In Ahr–/– mice, only 32 ProbeSets exhibited responses to TCDD, indicating that the AHR is required for virtually all transcriptional responses to dioxin exposure in liver. The flavin-containing monooxygenases, Fmo2 and Fmo3, considered previously to be uninducible, were highly induced by TCDD in an AHR-dependent manner. The estrogen receptor alpha as well as two estrogen-receptor-related genes (alpha and gamma) exhibit AHR-dependent expression, thereby extending cross-talk opportunities between the intensively studied AHR and estrogen receptor pathways. p53 binding sites are over-represented in genes down-regulated by TCDD, suggesting that TCDD inhibits p53 transcriptional activity. Overall, our study identifies a wide range of genes that depend on the AHR, either for constitutive expression or for response to TCDD. Keywords: treatment-control and mutant-wildtype
2008-11-01 | GSE10082 | GEO