RESUMO
Maternal obesity is increasingly prevalent and is associated with elevated morbidity and mortality rates in both mothers and children. At the interface between the mother and the fetus, the placenta mediates the impact of the maternal environment on fetal development. Most of the literature presents data on the effects of maternal obesity on placental functions and does not exclude potentially confounding factors such as metabolic diseases (e.g., gestational diabetes). In this context, the focus of this review mainly lies on the impact of maternal obesity (in the absence of gestational diabetes) on (i) endocrine function, (ii) morphological characteristics, (iii) nutrient exchanges and metabolism, (iv) inflammatory/immune status, (v) oxidative stress, and (vi) transcriptome. Moreover, some of those placental changes in response to maternal obesity could be supported by fetal sex. A better understanding of sex-specific placental responses to maternal obesity seems to be crucial for improving pregnancy outcomes and the health of mothers and children.
Assuntos
Diabetes Gestacional , Obesidade Materna , Masculino , Criança , Humanos , Gravidez , Feminino , Placenta/metabolismo , Obesidade Materna/metabolismo , Diabetes Gestacional/metabolismo , Obesidade/metabolismo , Desenvolvimento Fetal/fisiologiaRESUMO
The objectives of the present study were to determine whether obesity impacts human decidualization and the endometrial control of trophoblast invasion (both of which are required for embryo implantation) and evaluate the potential involvement of endometrial extracellular vesicles (EVs) in the regulation of these physiological processes. Using primary human cell cultures, we first demonstrated that obesity is associated with significantly lower in vitro decidualization of endometrial stromal cells (ESCs). We then showed that a trophoblastic cell line's invasive ability was greater in the presence of conditioned media from cultures of ESCs from obese women. The results of functional assays indicated that supplementation of the culture medium with EVs from nonobese women can rescue (at least in part) the defect in in vitro decidualization described in ESCs from obese women. Furthermore, exposure to endometrial EVs from obese women (vs. nonobese women) was associated with significantly greater invasive activity by HTR-8/SVneo cells. Using mass-spectrometry-based quantitative proteomics, we found that EVs isolated from uterine supernatants of biopsies from obese women (vs. nonobese women) presented a molecular signature focused on cell remodelling and angiogenesis. The proteomics analysis revealed two differentially expressed proteins (fibronectin and angiotensin-converting enzyme) that might be involved specifically in the rescue of the decidualization capacity in ESCs from obese women; both of these proteins are abundantly present in endometrial EVs from nonobese women, and both are involved in the decidualization process. In conclusion, our results provided new insights into the endometrial EVs' pivotal role in the poor uterine receptivity observed in obese women.
RESUMO
Maternal obesity is associated with complications of pregnancy and increases the infant's risk of developing obesity, diabetes and cardiovascular disease later in life. The placenta has an important role in determining the pregnancy outcome, and the syncytiotrophoblast (ST) is the main component of the placenta that supports the relationship between the mother and fetus. The differentiation of the cytotrophoblast (CT) into the ST is accompanied by changes in mitochondrial functions and dynamics. The objective of the present study was to investigate the effects of maternal obesity (without gestational diabetes) on the in vitro differentiation capacities of human CT isolated from term placenta by focusing on mitochondrial status. We found that, during human CT differentiation process, maternal obesity is associated with (i) a lower progesterone secretion, (ii) a transient impairment in the ST's fusion potential (via syncytin-2 and its receptor), (iii) a lower mitochondrial content, and (iv) weaker mRNA expression of oestrogen-related receptor-gamma (a key mitobiogenesis gene). Moreover, maternal obesity altered the time course of ATP and reactive oxygen species production throughout CT differentiation. The mitochondrial dysfunctions observed in isolated human CTs of obese women might explain the observed decrease in progesterone production. Our results demonstrated that obesity in pregnancy is associated with a functional impairment of the ST which might alter the foetal-maternal dialogue.
Assuntos
Obesidade Materna , Trofoblastos , Diferenciação Celular , Feminino , Humanos , Mitocôndrias/metabolismo , Obesidade/complicações , Placenta/metabolismo , Gravidez , Progesterona/metabolismo , Trofoblastos/metabolismoRESUMO
BACKGROUND: Successful human embryo implantation requires the differentiation of endometrial stromal cells (ESCs) into decidual cells during a process called decidualization. ESCs express specific markers of decidualization, including prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1), and connexin-43. Decidual cells also control of trophoblast invasion by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases. Preimplantation factor (PIF) is a recently identified, embryo-derived peptide with activities at the fetal-maternal interface. It creates a favorable pro-inflammatory environment in human endometrium and directly controls placental development by increasing the human trophoblastic cells' ability to invade the endometrium. We hypothesized that PIF's effects on the endometrium counteract its pro-invasive effects. METHODS: We tested sPIF effect on the expression of three decidualization markers by RT-qPCR and/or immunochemiluminescence assay. We examined sPIF effect on human ESC migration by performing an in vitro wound healing assay. We analyzed sPIF effect on endometrial control of human trophoblast invasion by performing a zymography and an invasion assay. RESULTS: Firstly, we found that a synthetic analog of PIF (sPIF) significantly upregulates the mRNA expression of IGFBP-1 and connexin-43, and prolactin secretion in ESCs - suggesting a pro-differentiation effect. Secondly, we showed that the HTR-8/SVneo trophoblastic cell line's invasive ability was low in the presence of conditioned media from ESCs cultured with sPIF. Thirdly, this PIF's anti-invasive action was associated with a specifically decrease in MMP-9 activity. CONCLUSION: Taken as a whole, our results suggest that PIF accentuates the decidualization process and the production of endometrial factors that limit trophoblast invasion. By controlling both trophoblast and endometrial cells, PIF therefore appears to be a pivotal player in the human embryo implantation process.
Assuntos
Decídua/citologia , Decídua/efeitos dos fármacos , Endométrio/citologia , Endométrio/efeitos dos fármacos , Proteínas da Gravidez/administração & dosagem , Trofoblastos/efeitos dos fármacos , Adulto , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Decídua/fisiologia , Endométrio/fisiologia , Feminino , Humanos , Células Estromais/efeitos dos fármacos , Células Estromais/fisiologia , Trofoblastos/fisiologiaRESUMO
CONTEXT: Maternal obesity has a significant impact on placental development. However, this impact on the placenta's structure and function (ie, nutrient transport and hormone and cytokine production) is a controversial subject. OBJECTIVE: We hypothesized that maternal obesity is associated with morphologic, secretory, and nutrient-related changes and elevated levels of inflammation in the placenta. DESIGN: We collected samples of placental tissue from 2 well-defined groups of pregnant women from 2017 to 2019. We compared the 2 groups regarding placental cytokine and hormone secretion, immune cell content, morphology, and placental nutrient transporter expressions. SETTING: Placenta were collected after caesarean section performed by experienced clinicians at Centre Hospitalier Intercommunal (CHI) of Poissy-Saint-Germain-en-Laye. PATIENTS: The main inclusion criteria were an age between 27 and 37 years old, no complications of pregnancy, and a first-trimester body mass index of 18-25 kg/m2 for the nonobese (control) group and 30-40 kg/m2 for the obese group. RESULTS: In contrast to our starting hypothesis, we observed that maternal obesity was associated with (1) lower placental IL-6 expression and macrophage/leukocyte infiltration, (2) lower placental expression of GLUT1 and SNAT1-2, (3) a lower placental vessel density, and (4) lower levels of placental leptin and human chorionic gonadotropin production. CONCLUSION: These results suggest that the placenta is a plastic organ and could optimize fetal growth. A better understanding of placental adaptation is required because these changes may partly determine the fetal outcome in cases of maternal obesity.
Assuntos
Inflamação/etiologia , Nutrientes/farmacocinética , Obesidade Materna , Placenta , Adulto , Cesárea , Feminino , França , Humanos , Inflamação/metabolismo , Inflamação/patologia , Obesidade Materna/complicações , Obesidade Materna/metabolismo , Obesidade Materna/patologia , Obesidade Materna/cirurgia , Tamanho do Órgão , Placenta/metabolismo , Placenta/patologia , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Complicações na Gravidez/cirurgia , Nascimento a Termo/fisiologiaRESUMO
BACKGROUND: It is well established that obesity is associated with dysregulation of the ratio between the two major adipokines leptin and adiponectin. Furthermore, it was recently reported that maternal obesity has a significant impact on placental development. Leptin and adiponectin are present at the fetal-maternal interface and are involved in the development of a functional placenta. However, less is known about leptin and adiponectin's involvement in the placental alterations described in obese women. Hence, the objective of the present study was to characterize the placental expression and DNA methylation of these two adipokine systems (ligands and receptors) in obese women. RESULTS: Biopsies were collected from the fetal and maternal sides of third-trimester placenta in obese and non-obese (control) women. In both groups, leptin levels were higher on the fetal side than the maternal side, suggesting that this cytokine has a pivotal role in fetal growth. Secondly, maternal obesity (in the absence of gestational diabetes) was associated with (i) elevated DNA methylation of the leptin promoter on fetal side only, (ii) hypomethylation of the adiponectin promoter on the maternal side only, (iii) significantly low levels of leptin receptor protein (albeit in the absence of differences in mRNA levels and promoter DNA methylation), (iv) significantly low levels of adiponectin receptor 1 mRNA expression on the maternal side only, and (v) elevated DNA methylation of the adiponectin receptor 2 promoter on the maternal side only. CONCLUSION: Our present results showed that maternal obesity is associated with the downregulation of both leptin/adiponectin systems in term placenta, and thus a loss of the beneficial effects of these two adipokines on placental development. Maternal obesity was also associated with epigenetic changes in leptin and adiponectin systems; this highlighted the molecular mechanisms involved in the placenta's adaptation to a harmful maternal environment.
Assuntos
Adiponectina/genética , Metilação de DNA , Leptina/genética , Obesidade/complicações , Placenta/química , Receptores de Adiponectina/genética , Receptores para Leptina/genética , Adulto , Estudos de Casos e Controles , Regulação para Baixo , Epigênese Genética , Feminino , Humanos , Masculino , Idade Materna , Obesidade/genética , Gravidez , Terceiro Trimestre da Gravidez/genética , Regiões Promotoras GenéticasRESUMO
We identified, through a genome-wide search for new imprinted genes in the human placenta, DSCAM (Down Syndrome Cellular Adhesion Molecule) as a paternally expressed imprinted gene. Our work revealed the presence of a Differentially Methylated Region (DMR), located within intron 1 that might regulate the imprinting in the region. This DMR showed a maternal allele methylation, compatible with its paternal expression. We showed that DSCAM is present in endothelial cells and the syncytiotrophoblast layer of the human placenta. In mouse, Dscam expression is biallelic in foetal brain and placenta excluding any possible imprinting in these tissues. This gene encodes a cellular adhesion molecule mainly known for its role in neurone development but its function in the placenta remains unclear. We report here the first imprinted gene located on human chromosome 21 with potential clinical implications.
Assuntos
Moléculas de Adesão Celular/genética , Cromossomos Humanos Par 21/genética , Impressão Genômica , Placenta/metabolismo , Animais , Células COS , Células Cultivadas , Chlorocebus aethiops , Metilação de DNA , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , GravidezRESUMO
Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e. histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules that are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetalmaternal interface have not yet been characterized. Among the various factors acting at the fetalmaternal interface, we focused on adiponectin an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression, (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions, (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human villous trophoblasts. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetalmaternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta.
Assuntos
Adiponectina/farmacologia , Glicogênio/metabolismo , Trifosfato de Adenosina/metabolismo , Células Cultivadas , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Citometria de Fluxo , Humanos , Microscopia Confocal , GravidezRESUMO
AIM: The aim of this study was to investigate whether recurrent pregnancy loss (RPL) is associated with adipokine gene polymorphisms (namely the leptin -2548 (G/A), adiponectin 276 (G/T), and adiponectin 45 (T/G) polymorphisms) and/or adipokine serum levels. METHODS: A total of 145 women participated in the study. For the analysis of serum adipokine levels, 19 healthy fertile women (control group) and 60 women suffering from RPL were included. For the polymorphism analysis, 126 women suffering from RPL were included. Serum adipokine levels were determined using a commercial radioimmunoassay kit. Adipokine polymorphisms were analyzed using an allele-specific polymerase chain reaction (PCR). RESULTS: Our immunoassays revealed that serum leptin levels were similar in control and RPL groups (17.34 and 20.16 ng/mL, respectively). In contrast, serum adiponectin levels were significantly higher in women with RPL than in controls (9.83 and 6.89 µg/mL, respectively; P < 0.05). Unfortunately, our allele-specific PCR experiments did not reveal any significant differences in allele frequency between women with RPL and NCBI allele frequencies. CONCLUSION: This study demonstrates that adiponectinemia is increased in patients suffering from RPL. However, association of adiponectin with adverse pregnancy outcomes remains to be elucidated.
Assuntos
Aborto Habitual/sangue , Adiponectina/sangue , Leptina/sangue , Aborto Habitual/genética , Adiponectina/genética , Adulto , Feminino , Humanos , Leptina/genéticaRESUMO
Successful human embryo implantation requires a proper differentiation of endometrial stromal cells (ESCs) into decidual cells, during a process called decidualization. ESCs express specific molecules, such as prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1) and connexin-43. Decidual cells are also involved in the control of trophoblast invasion, by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-proliferative effects. At the embryo-maternal interface, adiponectin promotes differentiation and invasion of human trophoblastic cells. We hypothesize that the effects of adiponectin on endometrium could counteract its pro-invasive effects previously described in the human trophoblast. In this context, we have firstly demonstrated that adiponectin downregulates IGFBP-1 and connexin-43 mRNA expressions, as well as prolactin secretion in ESCs, suggesting an anti-differentiative effect of adiponectin. Secondly, we found that invasive capacities of trophoblastic cell line HTR-8/SVneo are reduced in the presence of conditioned media from ESC cultured in the presence of adiponectin. Adiponectin's anti-invasive action is associated with a decreased activity of MMP-2 and MMP-9, and an increased TIMP-3 mRNA expression in ESCs. Finally, adiponectin receptors (ADIPOR1 and ADIPOR2) knockdown abolishes the anti-differentiative and anti-invasive effects of adiponectin in human ESCs. Altogether, our results suggest that adiponectin reduces the decidualization process and inversely induces the production of endometrial factors that limit trophoblast invasion. Thus, through a dual control in trophoblast and endometrial cells, adiponectin appears as a pivotal actor of the embryo implantation process.
Assuntos
Adiponectina/metabolismo , Diferenciação Celular , Endométrio/citologia , Endométrio/metabolismo , Trofoblastos/metabolismo , Adiponectina/genética , Adulto , Biópsia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Implantação do Embrião , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , RNA Mensageiro/genética , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Inibidores Teciduais de Metaloproteinases/genética , Trofoblastos/citologia , Adulto JovemRESUMO
From the earliest stages of gestation, embryonic-maternal interaction has a key role in a successful pregnancy. Various factors present during gestation may significantly influence this type of juxta/paracrine interaction. PreImplantation Factor (PIF) is a recently identified factor with activity at the fetomaternal interface. PIF is secreted by viable embryos and directly controls placental development by increasing the invasive capacity of human extravillous trophoblasts (EVTs). To further specify PIF's role in the human placenta, we analyzed the genome-wide expression profile of the EVT in the presence of a synthetic PIF analog (sPIF). We found that sPIF exposure altered several pathways related to p53 signaling, survival and the immune response. Functional assays revealed that sPIF acts through the p53 pathway to reduce both early and late trophoblast apoptosis. More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser-15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2-associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels. Furthermore, invalidation experiments of TP53 allowed us to demonstrate that PIF's effects on placental apoptosis seemed to be essentially mediated by this gene. We have clearly shown that p53 and sPIF pathways could interact in human trophoblast and thus promotes cell survival. Furthermore, sPIF was found to regulate a gene network related to immune tolerance in the EVT, which emphasizes the beneficial effect of this peptide on the human placenta. Finally, the PIF protein levels in placentas from pregnancies affected by preeclampsia or intra-uterine growth restriction were significantly lower than in gestational age-matched control placentas. Taken as a whole, our results suggest that sPIF protects the EVT's functional status through a variety of mechanisms. Clinical application of sPIF in the treatment of disorders of early pregnancy can be envisioned.
Assuntos
Apoptose , Proteínas da Gravidez/metabolismo , Transdução de Sinais , Trofoblastos/citologia , Trofoblastos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Peptídeos/farmacologia , Placenta/efeitos dos fármacos , Placenta/metabolismo , Placenta/patologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Gravidez , Mapas de Interação de Proteínas/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Trofoblastos/efeitos dos fármacos , Proteína Supressora de Tumor p53/genéticaRESUMO
The placenta exchanges nutrients between the mother and the fetus and requires a constant abundant energy supply. Adiponectin (a cytokine produced primarily by adipose tissue) controls glucose and lipid homeostasis. It is well-known that maternal serum adiponectin levels are inversely related to birth weight, suggesting that adiponectin has a negative effect on fetal growth. This effect appears to be related to the control of nutrient transporters in human placenta. However, the underlying molecular mechanisms have not yet been characterized. In the present work, we studied adiponectin's direct effect on human primary cytotrophoblasts from first-trimester placenta. Our result showed that in placental cells, adiponectin 1) inhibits the expression of the major glucose transporters (GLUT1 and GLUT12) and sodium-coupled neutral amino acid transporters (SNAT1, SNAT2, and SNAT4), 2) enhances total ATP production but decreases lactate production, 3) inhibits mitochondrial biogenesis and function, and 4) stimulates cell death by enhancing the expression of the pro-apoptotic B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) and tumor protein P53 (TP53) gene expression and inducing the caspase activity. Small-interfering RNA mediating the down-regulation of adiponectin receptors (ADIPOR1 and ADIPOR2) was used to demonstrate that adiponectin effects on placental nutrient transport and apoptosis seemed to be essentially mediated by these specific receptors. Taken as a whole, these results strongly suggest that adiponectin regulates human placental function by limiting nutrient transporter expression and inducing apoptosis. These findings may help us to better understand adiponectin's role in placental pathologies such as intrauterine growth restriction, which is characterized by fetal weight loss and drastic apoptosis of placental cells.
Assuntos
Adiponectina/farmacologia , Vilosidades Coriônicas/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Trofoblastos/efeitos dos fármacos , Adulto , Apoptose/efeitos dos fármacos , Células Cultivadas , Vilosidades Coriônicas/metabolismo , Vilosidades Coriônicas/fisiologia , Feminino , Retardo do Crescimento Fetal/metabolismo , Alimentos , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Humanos , Placenta/metabolismo , Gravidez , Trofoblastos/fisiologia , Adulto JovemRESUMO
Infertility now affects one in seven couples, and the prevalence of this condition continues to increase. Ovulatory defects and unknown causes account for more than half of the cases of infertility. It has been postulated that a significant proportion of these cases are directly or indirectly related to obesity, since the presence of excess adipose tissue has a variety of effects on reproductive function. Here, we review on the effects of the two major adipokines (leptin and adiponectin) on fertility, with a focus on the first steps in embryo implantation and the key components of fetal-maternal interface (the placenta and the endometrium). These adipokines are reportedly involved in the regulation of cell proliferation and differentiation, and as such affect local angiogenesis, immune tolerance and inflammatory processes in placental and endometrial tissues. In placental cells, leptin and adiponectin also modulate trophoblast invasiveness and the nutrient supply. These observations strongly suggest by interfering with the placenta and endometrium, adipokines can create a favorable environment for embryo implantation and have a key role in fetal-maternal metabolism, fetal-maternal communication, and gestation. Given that reproductive functions are tightly coupled to the energy balance, metabolic abnormalities may lead to the development of complications of pregnancy and changes in fetal growth. In this context, we suggest that the leptin/adiponectin ratio may be a clinically valuable marker for detecting a number of pathologies in pregnancy.
Assuntos
Adiponectina/fisiologia , Leptina/fisiologia , Troca Materno-Fetal , Obesidade/metabolismo , Adiponectina/metabolismo , Implantação do Embrião , Endométrio/metabolismo , Feminino , Desenvolvimento Fetal , Humanos , Leptina/metabolismo , Placenta/metabolismo , Gravidez , Complicações na Gravidez/metabolismoRESUMO
OBJECTIVE: To measure mitochondrial content and the expression of estrogen-related receptor-γ (ERRγ, a major inducer of mitochondrial biogenesis) in placentas from women with intrauterine growth restriction (IUGR) associated or not with pre-eclampsia (PE), relative to control placentas. DESIGN: Case-control study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Thirty-nine placentas from women with IUGR, 8 IUGR+PE, and 30 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mitochondrial DNA and protein content, gene and protein expression. RESULT(S): We observed significantly lower placental mitochondrial DNA and protein contents (associated with down-regulation of ERRγ expression) in IUGR and IUGR+PE placentas, relative to control placentas. Our results also revealed that the placental mitochondrial DNA content was directly correlated with fetal weight. Moreover, we observed significantly lower peroxisome proliferator-activated receptor-γ coactivator-1α and sirtuin 1 messenger RNA expression levels in IUGR+PE placentas, relative to control placentas. CONCLUSION(S): The low mitochondrial DNA and protein contents observed in IUGR placentas are probably due to down-regulation of ERRγ expression. This finding suggests that ERRγ has a major role in the control of placental development.
Assuntos
DNA Mitocondrial/biossíntese , Retardo do Crescimento Fetal/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Receptores de Estrogênio/biossíntese , Adulto , Estudos de Casos e Controles , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/epidemiologia , Humanos , Recém-Nascido , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/epidemiologia , GravidezRESUMO
Human pregnancy needs a correct placentation which depends on adequate cytotrophoblast proliferation, differentiation and invasion. In this study, using specific mitochondrial respiratory chain inhibitors, we observed a decrease of hormone production (hCG and leptin) and cell fusion of human primary villous cytotrophoblasts (CT). These results demonstrated that mitochondria are involved in the control of CT differentiation process. Moreover, we also observed a decrease of mitochondrial mass associated with an increase of mitochondrial DNA during CT differentiation. Furthermore, lactate production increased during CT differentiation suggesting that anaerobic metabolism was enhanced in differentiated CTs, and that the role of mitochondria in CT fusion is not only related to its energetic function. Otherwise, the orphan nuclear receptor, estrogen-related receptor γ (ERRγ) is known to orchestrate transcriptional control of energy metabolism genes. In this study, using RNA knockdown and transcriptional activation with DY131 (an ERRγ agonist), we clearly demonstrated that ERRγ promotes hormone production and cell fusion indicating that ERRγ is a key positive transcriptional factor involved in CT differentiation. Finally, we showed that ERRγ promotes mitochondrial biogenesis and function during CT differentiation, and that the role of ERRγ during trophoblast differentiation is mainly mediated by the control of mitochondrial functions.
Assuntos
Trofoblastos/citologia , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Técnicas In Vitro , Mitocôndrias/metabolismo , Placenta/citologia , Placenta/metabolismo , Gravidez , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Trofoblastos/metabolismo , Adulto JovemRESUMO
Preimplantation factor (PIF) is a peptide secreted by viable mammalian embryos. Moreover, it can be detected in the circulation of pregnant women. Recently, it was shown that PIF promotes invasion in trophoblast cell lines in vitro. Successful human embryo implantation depends on a deep and highly controlled invasion of extravillous trophoblast (EVT) in the maternal endometrium. Trophoblast invasion is regulated in part by matrix metalloproteinase (MMP) activity and integrin expression. The present study demonstrates the presence of PIF in early pregnancy and characterizes its effects on primary human trophoblast invasion. At the fetomaternal interface, intense PIF labeling by immunohistochemistry was present during early gestation in villous trophoblasts and EVTs. A decrease of labeling was observed at term. Furthermore, PIF significantly promoted invasion of human EVT isolated from first-trimester placenta. The proinvasive regulatory effect of PIF in EVT was associated with 1) increased MMP9 activity and 2) reduced tissue inhibitor of metalloproteinase-1 (TIMP1) mRNA expression. PIF also regulated alpha v and alpha 1 integrin mRNA expressions. Last, the proinvasive effect of PIF appeared to be mediated by the mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), and Janus-kinase signal transducer and activator of transcription (JAK-STAT) signaling pathways. In summary, this work describes the direct, positive effect of PIF on the control of human trophoblastic cell invasion by modulation of MMP/TIMP balance and integrin expression. Moreover, these results suggest that PIF is involved in pathological pregnancies characterized by insufficient or excessive trophoblast invasion.
Assuntos
Peptídeos/farmacologia , Trofoblastos/fisiologia , Adulto , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Células Cultivadas , Implantação do Embrião/efeitos dos fármacos , Implantação do Embrião/genética , Feminino , Idade Gestacional , Humanos , Queratinas/metabolismo , Peptídeos/fisiologia , Placenta/metabolismo , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismo , Proteínas da Gravidez/fisiologia , Trofoblastos/efeitos dos fármacos , Adulto JovemRESUMO
Fertility is a quantitative, complex character governed by a considerable number of genes. Despite clinical and scientific advances, several cases of human infertility remain unexplained. In the present study, using a positional cloning approach in a mouse model of interspecific recombinant lines, a candidate gene, ALPP, encoding the placental alkaline phosphatase, was identified as being potentially involved in recurrent spontaneous abortion. We then analyzed patients for detecting putative associations between ALPP polymorphisms, in vitro fertilization failures, and miscarriages. ALPP was sequenced in 100 controls and 100 patients affected by recurrent spontaneous abortion, from the same ethnic background. The frequency of several alleles and allelic combinations were different between recurrent spontaneous abortion and control women. One polymorphism induced a coding substitution (Ile89Leu) that was associated with a decreased risk of abortion and in vitro fertilization failure. Thereafter, the population was increased by the analysis of 92 additional controls and 612 additional patients for the coding polymorphism Ile89Leu. We finally show, by functional analysis, that the 89Leu placental alkaline phosphatase has an enhanced alkaline phosphatase activity. This study suggests that ALPP genotyping could be a strong predictor of implantation success.
Assuntos
Aborto Espontâneo/enzimologia , Aborto Espontâneo/genética , Fosfatase Alcalina/genética , Fertilização in vitro , Predisposição Genética para Doença , Isoenzimas/genética , Polimorfismo de Nucleotídeo Único/genética , Animais , Células COS , Chlorocebus aethiops , Estudos de Coortes , Feminino , Proteínas Ligadas por GPI/genética , Técnicas de Genotipagem , Humanos , Camundongos , Gravidez , Recidiva , Reprodutibilidade dos Testes , TransfecçãoRESUMO
Adiponectin is an adipocyte-derived cytokine that acts as a major regulator of insulin sensitivity. Adiponectin deficiency can result in severe diabetes and metabolic disorders in humans. Since its discovery, our understanding of adiponectin's biological functions has expanded from insulin sensitization properties to new effects on inflammation, immunology, and human reproduction. Indeed, both obesity and excessive leanness are associated with reproductive dysfunction. The objective of this chapter is to review such biological actions and the potential roles of adiponectin on human reproduction. There is accumulative evidence for direct effects of this adipokine on the late stages of folliculogenesis and on the development of a functional placenta. In addition, clinical and genomic studies associate hypoadiponectinemia with pregnancy-related disorders, including polycystic ovarian syndrome.
Assuntos
Adiponectina/fisiologia , Reprodução/fisiologia , Adiponectina/deficiência , Feminino , Desenvolvimento Fetal , Humanos , Resistência à Insulina/fisiologia , Folículo Ovariano/fisiologia , Placenta/fisiologia , Síndrome do Ovário Policístico , Gravidez , Complicações na Gravidez/etiologia , Transdução de Sinais , Esteroides/biossínteseRESUMO
OBJECTIVE: To measure the expression of adiponectin, leptin, and their respective receptors in the human endometria of fertile women compared with women with unexplained recurrent implantation failure (IF) during the window of implantation. DESIGN: Controlled, prospective, clinical study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Thirty-one endometrial biopsies from women with IF and 19 fertile controls. INTERVENTION(S): Human endometrial biopsies. MAIN OUTCOME MEASURE(S): Gene and protein expression of endometrial biopsies. RESULT(S): Endometrial leptin expression was significantly lower in the IF group compared with fertile women. In contrast, leptin receptor (Ob-R) expression was higher in endometria of women with IF. Concerning the adiponectin system, adiponectin was expressed to the same extent in both groups. Conversely, the expression of its two receptors, AdipoR1 and AdipoR2, was reduced in endometria of women with IF compared with fertile women. CONCLUSION(S): Although progesterone resistance seems to be a common state of the endometrium in some human reproductive disorders, such as endometriosis or polycystic ovary syndrome, modification in leptin endometrial expression seems to be specific to IF. These results strongly suggest that changes in Ob-R and AdipoR expression profiles [1] should be implicated in the development of uterine receptivity, and [2] may therefore be potential new targets for prediction of IF.
Assuntos
Adiponectina/análise , Implantação do Embrião , Endométrio/química , Infertilidade Feminina/metabolismo , Leptina/análise , Receptores de Adiponectina/análise , Receptores para Leptina/análise , Adiponectina/genética , Adulto , Biópsia , Estudos de Casos e Controles , Transferência Embrionária , Feminino , Fertilização in vitro , Regulação da Expressão Gênica , Hospitais de Ensino , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/fisiopatologia , Infertilidade Feminina/terapia , Leptina/genética , Paris , Gravidez , Estudos Prospectivos , RNA Mensageiro/análise , Receptores de Adiponectina/genética , Receptores para Leptina/genética , Falha de TratamentoRESUMO
Different studies performed in rodents revealed that bisphenol-A (BPA), an environmental compound, altered early embryonic development. However, little is known concerning the direct effects of BPA on human implantation process. Thus, we decided to study in vitro BPA's effects on proliferative capacities of the human trophoblastic cell line, JEG-3. For this purpose, we first have shown that JEG-3 cells express the specific BPA receptor, namely estrogen-related receptor γ1 (ERRγ1). Secondly, we demonstrated that BPA did not exert any cytotoxic action in JEG-3 cells up to 10(-6)M. Moreover [(3)H]-thymidine incorporation experiments revealed that BPA significantly reduced cell proliferation. The results also showed that BPA induced JEG-3 apoptosis capacity as reflected by DNA fragmentation experiments. In conclusion, we describe here the direct impact of BPA on trophoblastic cell number mediated through both anti-proliferative and pro-apoptotic effects.