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1.
Mol Hum Reprod ; 26(8): 624-635, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618997

RESUMO

In studies of human IVF, as compared to frozen embryo transfer (ET), fresh ET is associated with smaller infants and higher risk of small for gestational age infants. Recent observations suggest that ET using vitrified embryos is associated with higher pregnancy and live birth rates compared to fresh ET, but increased rates of large for gestational age infants. The mechanisms underlying these associations are largely unknown, and available evidence suggests that the influence of IVF, vitrification and the superovulated (SO) uterine environment on placental function and fetal growth is complex. This warrants further investigation given the prevalent practice in human IVF of both fresh ET into a SO uterine environment, and vitrification with ET into a more physiologic uterine environment. Using a mouse model that closely resembles human IVF, we investigated if vitrification of IVF embryos better preserves placental function and results in better pregnancy outcomes as compared to fresh ET because of transfer into a more physiologic endometrium. We found that the SO environment, independent of vitrification status, reduced implantation rates, inhibited placental mechanistic target of rapamycin signaling and induced placental stress signaling, resulting in fetal growth restriction (1.080 ± 0.05 g estrous fresh (n = 17 litters), 1.176 ± 0.05 g estrous vitrified (n = 12), 0.771 ± 0.06 g SO fresh (n = 15), 0.895 ± 0.08 g SO vitrified (n = 10), P < 0.0001). In addition, our study suggests that vitrification impairs the developmental potential of IVF blastocysts that resulted in a significantly smaller litter size (2.6 ± 2.3 fresh estrous vs 2.5 ± 2.4 fresh SO vs 1.6 ± 1.7 estrous vitrified vs 1.7 ± 1.8 SO vitrified, P = 0.019), with no effect on fetal growth or placental function at term. Our findings suggest that vitrification may negatively impact early embryonic viability, while the SO maternal uterine environment impairs both placental development and fetal growth in IVF.


Assuntos
Troca Materno-Fetal/fisiologia , Animais , Coeficiente de Natalidade , Blastocisto/citologia , Blastocisto/metabolismo , Implantação do Embrião/fisiologia , Transferência Embrionária , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Troca Materno-Fetal/genética , Camundongos , Gravidez , Vitrificação
2.
J Mol Endocrinol ; 63(4): 239-248, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31505460

RESUMO

Excess maternal glucocorticoids reduce placental amino acid transport and fetal growth, but whether these effects are mediated directly on the syncytiotrophoblast remains unknown. We hypothesised that glucocorticoids inhibit mechanistic target of rapamycin (mTOR) signaling and insulin-stimulated System A amino acid transport activity in primary human trophoblast (PHT) cells. Syncytialised PHTs, isolated from term placentas (n = 15), were treated with either cortisol (1 µM) or dexamethasone (1 µM), ± insulin (1 nM) for 24 h. Compared to vehicle, dexamethasone increased mRNA expression, but not protein abundance of the mTOR suppressor, regulated in development and DNA damage response 1 (REDD1). Dexamethasone enhanced insulin receptor abundance, activated mTOR complex 1 and 2 signaling and stimulated System A activity, measured by Na+-dependent 14C-methylaminoisobutyric acid uptake. Cortisol also activated mTORC1 without significantly altering insulin receptor or mTORC2 read-outs or System A activity. Both glucocorticoids downregulated expression of the glucocorticoid receptor and the System A transporter genes SLC38A1, SLC38A2 and SLC38A4, without altering SNAT1 or SNAT4 protein abundance. Neither cortisol nor dexamethasone affected System L amino acid transport. Insulin further enhanced mTOR and System A activity, irrespective of glucocorticoid treatment and despite downregulating its own receptor. Contrary to our hypothesis, glucocorticoids do not inhibit mTOR signaling or cause insulin resistance in cultured PHT cells. We speculate that glucocorticoids stimulate System A activity in PHT cells by activating mTOR signaling, which regulates amino acid transporters post-translationally. We conclude that downregulation of placental nutrient transport in vivo following excess maternal glucocorticoids is not mediated by a direct effect on the placenta.


Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Glucocorticoides/metabolismo , Trofoblastos/metabolismo , Aminoácidos/metabolismo , Transporte Biológico/efeitos dos fármacos , Biomarcadores , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Recém-Nascido , Insulina/metabolismo , Masculino , Troca Materno-Fetal , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Receptor de Insulina/metabolismo , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos
3.
Am J Physiol Endocrinol Metab ; 316(5): E810-E816, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30835509

RESUMO

Apelin is an insulin-sensitizing hormone increased in abundance with obesity. Apelin and its receptor, APJ, are expressed in the human placenta, but whether apelin regulates placental function in normal body mass index (BMI) and obese pregnant women remains unknown. We hypothesized that apelin stimulates amino acid transport in cultured primary human trophoblast (PHT) cells and that maternal circulating apelin levels are elevated in obese pregnant women delivering large babies. Treating PHT cells with physiological concentrations of the pyroglutamated form [Pyr1]apelin-13 (0.1-10.0 ng/ml) for 24 h dose-dependently increased System A amino acid transport (P < 0.05) but did not affect System L transport activity. Mechanistic target of rapamycin (mTOR), extracellular signal-regulated kinase-1/2 (ERK1/2), and AMP-activated protein kinase-α (AMPKα) signaling were unaffected by apelin (P > 0.05). Plasma apelin was not different in obese women (BMI 35.8 ± 0.7, n = 21) with large babies compared with normal-BMI women (23.1 ± 0.5, n = 16) delivering normal birth weight infants. Apelin was highly expressed in placental villous tissue (20-fold higher vs. adipose), and APJ was present in syncytiotrophoblast microvillous membrane, but neither differed in abundance between normal-BMI and obese women. Phosphorylation (Thr172) of placental AMPKα strongly correlated with microvillous membrane APJ expression (P < 0.01, R = 0.63) but negatively correlated with placental apelin abundance (P < 0.01, R = -0.62). Neither placental APJ nor apelin abundance correlated with maternal BMI, plasma insulin, birth weight, or mTOR or ERK1/2 signaling (P > 0.05). Hence, apelin stimulates trophoblast amino acid uptake, establishing a novel mechanism regulating placental function. We found no evidence that apelin constitutes an endocrine link between maternal obesity and fetal overgrowth.


Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Apelina/metabolismo , Obesidade Materna/metabolismo , Trofoblastos/metabolismo , Proteínas Quinases Ativadas por AMP , Adulto , Sistema A de Transporte de Aminoácidos/metabolismo , Sistema L de Transporte de Aminoácidos/metabolismo , Receptores de Apelina/metabolismo , Peso ao Nascer , Estudos de Casos e Controles , Feminino , Macrossomia Fetal/metabolismo , Humanos , Recém-Nascido , Insulina/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Microvilosidades/metabolismo , Placenta/metabolismo , Gravidez , Cultura Primária de Células , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
4.
PLoS One ; 13(5): e0195375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29768418

RESUMO

BACKGROUND: Prenatal exposures have known adverse effects on maternal and neonatal outcomes. Professional societies recommend routine screening for environmental, occupational, and dietary exposures to reduce exposures and their associated sequelae. OBJECTIVE: Our objective was to determine the frequency of environmental exposure screening by obstetricians and gynecologists (OBGYNs) at initial patient visits. STUDY DESIGN: Practicing OBGYNs were approached at the University of Colorado and by social media. The survey instrument queried demographics, environmental literacy, and screening practices. Statistical analysis was performed using Chi-square and two-sample t-test. RESULTS: We received 312 online survey responses (response rate of 12%). Responding OBGYNs were predominantly female (96%), board-certified (78%), generalists (65%) with a mean age of 37.1 years. Fewer than half of physicians screened for the following factors: occupational exposures, environmental chemicals, air pollution, pesticide use, personal care products, household cleaners, water source, use of plastics for food storage, and lead and mercury exposure. Eighty five percent of respondents reported that they did not feel comfortable obtaining an environmental history and 58% respondents reported that they performed no regular screening of environmental exposures. A higher frequency of screening was associated with > 4 years of practice (p = 0.001), and having read the environmental committee opinion (p = <0.001). CONCLUSION: The majority of OBGYNs did not incorporate screening for known environmental exposures into routine practice. Reading the environmental committee opinions was strongly and significantly associated with a higher rate of screening. Improving physician comfort in counseling patients may enhance screening for exposures that affect reproductive health.


Assuntos
Exposição Ambiental/análise , Ginecologia/normas , Conhecimentos, Atitudes e Prática em Saúde , Programas de Rastreamento/normas , Obstetrícia/normas , Padrões de Prática Médica/normas , Diagnóstico Pré-Natal/normas , Adulto , Atitude do Pessoal de Saúde , Estudos Transversais , Saúde Ambiental , Feminino , Humanos , Masculino , Gravidez
5.
Sci Rep ; 8(1): 6086, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29666409

RESUMO

Phthalates are known endocrine disruptors and associated with decreased fecundity, pregnancy loss, and adverse obstetrical outcomes, however the underlying mechanisms remain to be established. Environmental factors can influence gene expression and cell function by modifying epigenetic marks, impacting the developing embryo as well as future generations of offspring. The impact of phthalates on placental gene methylation and expression is largely unknown. We studied the effect of maternal phthalate exposure on the human placental DNA methylome and transcriptome. We determined epigenome-wide DNA methylation marks (Illumina Infinium Human Methylation 850k BeadChip) and gene expression (Agilent whole human genome array) associated with phthalate exposure in first trimester placenta. Integrative genomic analysis of candidate genes was performed to define gene methylation-expression relationships. We identified 39 genes with significantly altered methylation and gene expression in the high phthalate exposure group. Most of these relationships were inversely correlated. This analysis identified epidermal growth factor receptor (EGFR) as a critical candidate gene mediating the effects of phthalates on early placental function. Although additional studies are needed to determine the functional consequences of these changes, our findings are consistent with the model that phthalates impact placental function by modulating the expression of critical placental genes through epigenetic regulation.


Assuntos
Metilação de DNA/efeitos dos fármacos , Disruptores Endócrinos/efeitos adversos , Exposição Materna/efeitos adversos , Ácidos Ftálicos/efeitos adversos , Placenta/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Adulto , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Placenta/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Adulto Jovem
6.
Prog Mol Biol Transl Sci ; 145: 217-251, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28110752

RESUMO

The fetus requires amino acids for the processes of protein synthesis, carbon accretion, oxidative metabolism, and biosynthesis, which ultimately determine growth rate in utero. The fetal supply of amino acids is critically dependent on the transport capacity of the placenta. System A amino acid transporters in the syncytiotrophoblast microvillous plasma membrane, directed toward maternal blood, actively accumulate amino acids, while system L exchangers mediate uptake of essential amino acids from the maternal circulation. The functional capacity and protein abundance of these transporters in the placenta are related to fetal growth in both humans and experimental animals. Maternal nutritional and endocrine signals including insulin, insulin-like growth factors, adipokines, and steroid hormones regulate placental amino acid transport, against the background of growth signals originating from the fetus. Anabolic signals of abundant maternal resource availability stimulate placental amino acid transport to optimize offspring fitness, whereas catabolic signals reduce placental amino acid transport in an attempt to ensure survival and long-term reproductive capacity of the mother when resources are scarce. These signals regulate placental amino acid transport by controlling transcription, translation, plasma membrane trafficking, and degradation of transporters. Adaptations in placental amino acid transport capacity may underlie either under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered as a result of altered maternal nutrition or metabolic disease. Strategies to modulate placental amino acid transport may prove effective to normalize fetal growth in intrauterine growth restriction and fetal overgrowth.


Assuntos
Aminoácidos/metabolismo , Desenvolvimento Fetal/fisiologia , Placenta/metabolismo , Animais , Transporte Biológico , Feminino , Humanos , Modelos Biológicos , Gravidez , Transdução de Sinais
7.
Dev Cogn Neurosci ; 17: 19-27, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26615571

RESUMO

Working memory (WM) - temporary storage and manipulation of information in the mind - is a key component of cognitive maturation, and structural brain changes throughout development are associated with refinements in WM. Recent functional neuroimaging studies have shown that there is greater activation in prefrontal and parietal brain regions with increasing age, with adults showing more refined, localized patterns of activations. However, few studies have investigated the neural basis of verbal WM development, as the majority of reports examine visuo-spatial WM. We used fMRI and a 1-back verbal WM task with six levels of difficulty to examine the neurodevelopmental changes in WM function in 40 participants, twenty-four children (ages 9-15 yr) and sixteen young adults (ages 20-25 yr). Children and adults both demonstrated an opposing system of cognitive processes with increasing cognitive demand, where areas related to WM (frontal and parietal regions) increased in activity, and areas associated with the default mode network decreased in activity. Although there were many similarities in the neural activation patterns associated with increasing verbal WM capacity in children and adults, significant changes in the fMRI responses were seen with age. Adults showed greater load-dependent changes than children in WM in the bilateral superior parietal gyri, inferior frontal and left middle frontal gyri and right cerebellum. Compared to children, adults also showed greater decreasing activation across WM load in the bilateral anterior cingulate, anterior medial prefrontal gyrus, right superior lateral temporal gyrus and left posterior cingulate. These results demonstrate that while children and adults activate similar neural networks in response to verbal WM tasks, the extent to which they rely on these areas in response to increasing cognitive load evolves between childhood and adulthood.


Assuntos
Encéfalo/crescimento & desenvolvimento , Desenvolvimento Infantil/fisiologia , Memória de Curto Prazo/fisiologia , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologia , Aprendizagem Verbal/fisiologia , Adolescente , Adulto , Encéfalo/fisiologia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Tempo de Reação/fisiologia , Adulto Jovem
8.
Placenta ; 36(7): 709-15, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25972077

RESUMO

BACKGROUND: The prevalence of maternal obesity is rising rapidly worldwide and constitutes a major obstetric problem, increasing mortality and morbidity in both mother and offspring. Obese women are predisposed to pregnancy complications such as gestational diabetes mellitus (GDM), and children of obese mothers are more likely to develop cardiovascular and metabolic disease in later life. Maternal obesity and GDM may be associated with a state of chronic, low-grade inflammation termed "metainflammation", as opposed to an acute inflammatory response. This inflammatory environment may be one mechanism by which offspring of obese women are programmed to develop adult disorders. METHODS: Herein we review the evidence that maternal obesity and GDM are associated with changes in the maternal, fetal and placental inflammatory profile. RESULTS: Maternal inflammation in obesity and GDM may not always be associated with fetal inflammation. CONCLUSION: We propose that the placenta 'senses' and adapts to the maternal inflammatory environment, and plays a central role as both a target and producer of inflammatory mediators. In this manner, maternal obesity and GDM may indirectly program the fetus for later disease by influencing placental function.


Assuntos
Diabetes Gestacional , Inflamação/complicações , Obesidade/complicações , Complicações na Gravidez , Animais , Proteína C-Reativa/análise , Feminino , Doenças Fetais/etiologia , Humanos , Sistema Imunitário/fisiopatologia , Inflamação/embriologia , Inflamação/fisiopatologia , Resistência à Insulina , Interleucina-6/sangue , Placenta/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fator de Necrose Tumoral alfa/sangue
9.
Placenta ; 35(12): 1007-12, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25454472

RESUMO

INTRODUCTION: Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. METHODS: Placental tissue was collected from healthy, term pregnancies (n = 15 no-labor; n = 12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFĸB p65 and PPARγ DNA binding activity was measured in isolated nuclei. RESULTS: Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFĸB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. DISCUSSION AND CONCLUSION: Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor.


Assuntos
Trabalho de Parto/metabolismo , Complexos Multiproteicos/metabolismo , Placenta/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Adulto , Caspase 1/metabolismo , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Fosforilação , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Trofoblastos/metabolismo , Adulto Jovem
10.
Placenta ; 35(7): 523-5, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24844436

RESUMO

Fatty acids can function as signaling molecules, acting through receptors in the cytosol or on the cell surface. G-Protein Receptor (GPR)120 is a membrane-bound receptor mediating anti-inflammatory and insulin-sensitizing effects of the omega-3 fatty acid docohexaenoic acid (DHA). GPR120 dysfunction is associated with obesity in humans. Cellular localization of GPR120 and the influence of maternal obesity on GPR120 protein expression in the placenta are unknown. Herein we demonstrate that GPR120 is predominantly expressed in the microvillous membrane (MVM) of human placenta and that the expression level of this receptor in MVM is not altered by maternal body mass index (BMI).


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Placenta/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino , Microvilosidades/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Sobrepeso/complicações , Sobrepeso/metabolismo , Gravidez , Complicações na Gravidez/metabolismo
11.
Placenta ; 34 Suppl: S40-5, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23245987

RESUMO

Adiponectin has well-established insulin-sensitizing effects in non-pregnant individuals. Pregnant women who are obese or have gestational diabetes typically have low circulating levels of adiponectin, which is associated with increased fetal growth. Lean women, on the other hand, have high circulating levels of adiponectin. As a result, maternal serum adiponectin is inversely correlated to fetal growth across the full range of birth weights, suggesting that maternal adiponectin may limit fetal growth. In the mother, adiponectin is predicted to promote insulin sensitivity and stimulate glucose uptake in maternal skeletal muscle thereby reducing nutrient availability for placental transfer. Adiponectin prevents insulin-stimulated amino acid uptake in cultured primary human trophoblast cells by modulating insulin receptor substrate phosphorylation. Furthermore, chronic administration of adiponectin to pregnant mice inhibits placental insulin and mammalian target of rapamycin complex 1 (mTORC1) signaling, down-regulates the activity and expression of key placental nutrient transporters and decreases fetal growth. Preliminary findings indicate that adiponectin binds to the adiponectin receptor-2 on the trophoblast cell and activates p38 MAPK and PPAR-α, which inhibits the insulin/IGF-1 signaling pathway. In contrast to maternal adiponectin, recent reports suggest that fetal adiponectin may promote expansion of adipose tissue and stimulate fetal growth. Regulation of placental function by adiponectin constitutes a novel physiological mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth. These findings may help us better understand the factors determining birth weight in normal pregnancies and in pregnancy complications associated with altered maternal adiponectin levels such as obesity and gestational diabetes.


Assuntos
Adiponectina/fisiologia , Adiposidade/fisiologia , Desenvolvimento Fetal/fisiologia , Placenta/metabolismo , Animais , Transporte Biológico/fisiologia , Feminino , Humanos , Troca Materno-Fetal/fisiologia , Camundongos , Gravidez
12.
J Dev Orig Health Dis ; 4(2): 101-15, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25054676

RESUMO

The mechanisms linking maternal nutrition to fetal growth and programming of adult disease remain to be fully established. We review data on changes in placental transport in response to altered maternal nutrition, including compromized utero-placental blood flow. In human intrauterine growth restriction and in most animal models involving maternal undernutrition or restricted placental blood flow, the activity of placental transporters, in particular for amino acids, is decreased in late pregnancy. The effect of maternal overnutrition on placental transport remains largely unexplored. However, some, but not all, studies in women with diabetes giving birth to large babies indicate an upregulation of placental transporters for amino acids, glucose and fatty acids. These data support the concept that the placenta responds to maternal nutritional cues by altering placental function to match fetal growth to the ability of the maternal supply line to allocate resources to the fetus. On the other hand, some findings in humans and mice suggest that placental transporters are regulated in response to fetal demand signals. These observations are consistent with the idea that fetal signals regulate placental function to compensate for changes in nutrient availability. We propose that the placenta integrates maternal and fetal nutritional cues with information from intrinsic nutrient sensors. Together, these signals regulate placental growth and nutrient transport to balance fetal demand with the ability of the mother to support pregnancy. Thus, the placenta plays a critical role in modulating maternal-fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring.

13.
Placenta ; 32(2): 121-7, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21144584

RESUMO

Maternal obesity and gestational diabetes (GDM) are conditions associated with fetal overgrowth and excessive fat accumulation in the fetus, implicating an increased placental nutrient transfer in these pregnancies. Obese and GDM mothers have altered metabolism and hormone levels, including elevation of maternal circulatory lipids and pro-inflammatory cytokines. We tested the hypothesis that interleukin (IL)-6 and tumor necrosis factor (TNF)-α stimulate placental fatty acid transport, as these pro-inflammatory cytokines have been shown to affect lipid metabolism in other tissues. In cultured primary human trophoblast cells IL-6, but not TNF-α, stimulated fatty acid accumulation, as measured by BODIPY fluorescence. The increased fatty acid accumulation could not be explained by an increased expression of key components in placental fatty acid transport, such as adipophilin, fatty acid transport protein (FATP)1, FATP4, or lipoprotein lipase. In a cohort of lean and overweight/obese pregnant women, increasing maternal third trimester IL-6 plasma concentrations correlated with decreasing placental lipoprotein lipase activity. However, as no effect on lipoprotein lipase activity was observed in cultured trophoblast cells after exposure to either IL-6 or TNF-α, the correlation between maternal circulatory IL-6 levels and placental lipoprotein lipase activity at term is unlikely to represent a cause-and-effect relationship. In conclusion, high levels of IL-6 stimulate trophoblast fatty acid accumulation, which could contribute to an excessive nutrient transfer in conditions associated with elevated maternal IL-6 such as obesity and gestational diabetes.


Assuntos
Ácidos Graxos/metabolismo , Interleucina-6/farmacologia , Trofoblastos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Células Cultivadas , Feminino , Humanos , Lipase Lipoproteica/metabolismo , Obesidade/metabolismo , Sobrepeso/metabolismo , Placenta/citologia , Placenta/metabolismo , Gravidez , Complicações na Gravidez/metabolismo , Terceiro Trimestre da Gravidez , Trofoblastos/efeitos dos fármacos
14.
Am J Physiol Cell Physiol ; 297(5): C1228-35, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19741197

RESUMO

Changes in placental nutrient transport are closely associated with abnormal fetal growth. However, the molecular mechanisms underlying the regulation of placental amino acid transporters are unknown. We demonstrate that physiological concentrations of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha stimulate the activity of amino acid transporter system A, but not system L, in cultured human primary trophoblast cells. Both cytokines increased the gene and protein expression of the Na(+)-coupled neutral amino acid transporter (SNAT)2 isoform and upregulated SNAT1 protein expression. IL-6 increased Tyr705 phosphorylation of signal transducer and activator of transcription 3 (STAT3). In cells transfected with small interfering RNA (siRNA) targeting STAT3, the RNA and protein expression of SNAT2, but not SNAT1, was reduced and the stimulating effect of IL-6 on system A activity was abolished. Despite eliciting similar responses in amino acid transport activity and transporter expression, TNF-alpha effects on system A activity were not mediated through the JAK/STAT pathway. In conclusion, we have identified a novel regulatory pathway involving increased gene expression of the SNAT2 isoform mediated by a STAT-dependent pathway, which links IL-6 to increased activity of system A, a ubiquitously expressed transporter of neutral amino acids. From these new findings, we propose that upregulation of amino acid transporters by cytokines may contribute to increased placental nutrient transport and fetal overgrowth, which are commonly found in pregnancies complicated by maternal diabetes and obesity.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Regulação da Expressão Gênica , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Trofoblastos/metabolismo , Sistema A de Transporte de Aminoácidos/genética , Sistema A de Transporte de Aminoácidos/fisiologia , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica , Humanos , Interleucina-6 , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
15.
Am J Physiol Cell Physiol ; 297(3): C723-31, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19587219

RESUMO

Inhibition of mammalian target of rapamycin (mTOR) signaling in cultured human primary trophoblast cells reduces the activity of key placental amino acid transporters. However, the upstream regulators of placental mTOR are unknown. We hypothesized that glucose, insulin, and IGF-I regulate placental amino acid transporters by inducing changes in mTOR signaling. Primary human trophoblast cells were cultured for 24 h with media containing various glucose concentrations, insulin, or IGF-I, with or without the mTOR inhibitor rapamycin, and, subsequently, the activity of system A, system L, and taurine (TAUT) transporters was measured. Glucose deprivation (0.5 mM glucose) did not significantly affect Thr172-AMP-activated protein kinase phosphorylation or REDD1 expression but decreased S6 kinase 1 phosphorylation at Thr389. The activity of system L decreased in a dose-dependent manner in response to decreasing glucose concentrations. This effect was abolished in the presence of rapamycin. Glucose deprivation had two opposing effects on system A activity: 1) an "adaptive" upregulation mediated by an mTOR-independent mechanism and 2) downregulation by an mTOR-dependent mechanism. TAUT activity was increased after incubating cells with glucose-deprived media, and this effect was largely independent of mTOR signaling. Insulin and IGF-I increased system A activity and insulin stimulated system L activity, effects that were abolished by rapamycin. We conclude that the mTOR pathway represents an important intracellular regulatory link between nutrient and growth factor concentrations and amino acid transport in the human placenta.


Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Glucose/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteínas Quinases/metabolismo , Trofoblastos/metabolismo , Apoptose/fisiologia , Biomarcadores , Sobrevivência Celular , Células Cultivadas , Regulação da Expressão Gênica/fisiologia , Glucose/metabolismo , Humanos , Insulina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR
16.
Am J Physiol Cell Physiol ; 296(1): C142-50, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18987252

RESUMO

The activity of placental amino acid transporters is decreased in intrauterine growth restriction (IUGR), but the underlying regulatory mechanisms have not been established. Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has been shown to decrease the activity of the system L amino acid transporter in human placental villous fragments, and placental mTOR activity is decreased in IUGR. In the present study, we used cultured primary trophoblast cells to study mTOR regulation of placental amino acid transporters in more detail and to test the hypothesis that mTOR alters amino acid transport activity by changes in transporter expression. Inhibition of mTOR by rapamycin significantly reduced the activity of system A (-17%), system L (-28%), and taurine (-40%) amino acid transporters. mRNA expression of isoforms of the three amino acid transporter systems in response to mTOR inhibition was measured using quantitative real-time PCR. mRNA expression of l-type amino acid transporter 1 (LAT1; a system L isoform) and taurine transporter was reduced by 13% and 50%, respectively; however, mTOR inhibition did not alter the mRNA expression of system A isoforms (sodium-coupled neutral amino acid transporter-1, -2, and -4), LAT2, or 4F2hc. Rapamycin treatment did not significantly affect the protein expression of any of the transporter isoforms. We conclude that mTOR signaling regulates the activity of key placental amino acid transporters and that this effect is not due to a decrease in total protein expression. These data suggest that mTOR regulates placental amino acid transporters by posttranslational modifications or by affecting transporter translocation to the plasma membrane.


Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Proteínas Quinases/metabolismo , Trofoblastos/metabolismo , Sistema A de Transporte de Aminoácidos/metabolismo , Sistema L de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Apoptose , Sobrevivência Celular , Células Cultivadas , Feminino , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Gravidez , Proteínas Quinases/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Transporte Proteico , RNA Mensageiro/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Fatores de Tempo , Trofoblastos/efeitos dos fármacos
17.
Placenta ; 28(8-9): 763-74, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17582493

RESUMO

Fetal growth is primarily determined by nutrient availability, which is intimately related to placental nutrient transport. Detailed information on the regulation of placental nutrient transporters is therefore critical in order to understand the mechanisms underlying altered fetal growth and fetal programming. After briefly summarizing the cellular mechanisms for placental transport of glucose, amino acids and free fatty acids, we will discuss factors shown to regulate placental nutrient transporters and review the data describing how these factors are altered in pregnancy complications associated with abnormal fetal growth. We propose an integrated model of regulation of placental nutrient transport by maternal and placental factors in IUGR.


Assuntos
Retardo do Crescimento Fetal , Placenta , Aminoácidos/metabolismo , Desenvolvimento Fetal , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Humanos , Placenta/metabolismo
18.
J Lipid Res ; 47(11): 2551-61, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16926441

RESUMO

The fetal demand for FFA increases as gestation proceeds, and LPL represents one potential mechanism for increasing placental lipid transport. We examined LPL activity and protein expression in first trimester and term human placenta. The LPL activity was 3-fold higher in term (n = 7; P < 0.05) compared with first trimester (n = 6) placentas. The LPL expression appeared lower in microvillous membrane from first trimester (n = 2) compared with term (n = 2) placentas. We incubated isolated placental villous fragments with a variety of effectors [GW 1929, estradiol, insulin, cortisol, epinephrine, insulin-like growth factor-1 (IGF-1), and tumor necrosis factor-alpha] for 1, 3, and 24 h to investigate potential regulatory mechanisms. Decreased LPL activity was observed after 24 h of incubation with estradiol (1 micro g/ml), insulin, cortisol, and IGF-1 (n = 12; P < 0.05). We observed an increase in LPL activity after 3 h of incubation with estradiol (20 ng/ml) or hyperglycemic medium plus insulin (n = 7; P < 0.05). To conclude, we suggest that the gestational increase in placental LPL activity represents an important mechanism to enhance placental FFA transport in late pregnancy. Hormonal regulation of placental LPL activity by insulin, cortisol, IGF-1, and estradiol may be involved in gestational changes and in alterations in LPL activity in pregnancies complicated by altered fetal growth.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Lipase Lipoproteica/biossíntese , Lipase Lipoproteica/genética , Placenta/enzimologia , Trifosfato de Adenosina/metabolismo , Transporte Biológico , Membrana Celular/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Hidrocortisona/farmacologia , Insulina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Lipídeos/química , Microvilosidades/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Fatores de Tempo
19.
Placenta ; 27 Suppl A: S109-13, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16542722

RESUMO

Fetal overgrowth in pregnancies complicated by diabetes is the result of an increased substrate availability which stimulates fetal insulin secretion and fetal growth. However, despite strict glycemic control in modern clinical management of the pregnant woman with diabetes, fetal overgrowth remains an important clinical problem. Recent studies in vivo provide evidence for increased delivery of amino acids to the fetus in gestational diabetes (GDM) even when metabolic control is strict. This could be due to that truly normal maternal substrate levels cannot be achieved in diabetic pregnancies and/or caused by altered placental nutrient transport and metabolism. Studies in vitro demonstrate an up-regulation of placental transport systems for certain amino acids in GDM associated with fetal overgrowth. GDM is also characterized by changes in placental gene expression, including up-regulation of inflammatory mediators and Leptin. In type-I diabetes with fetal overgrowth the in vitro activity of placental transporters for both glucose and certain amino acids as well as placental lipoprotein lipase is increased. Furthermore, both clinical observations in type-I diabetic pregnancies and preliminary animal experimental studies suggest that even brief periods of metabolic perturbation early in pregnancy may affect placental growth and transport function for the remainder of pregnancy, thereby contributing to fetal overgrowth. Ultrasound measurements of fetal fat deposits and abdominal circumference as well as 3D ultrasound assessment of placental volume represent non-invasive techniques for in utero diagnosis of fetal and placental overgrowth. It is proposed that these methods represent valuable additions to the clinical management of the diabetic pregnancy. In conclusion, altered placental function may be a mechanism contributing to fetal overgrowth in diabetic pregnancies with apparent optimal metabolic control. It is proposed that detailed information on placental metabolism and transport functions obtained in vitro and in vivo represent a placental phenotype that provides important information and may facilitate diagnosis and improve clinical management of fetal overgrowth.


Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Retardo do Crescimento Fetal/metabolismo , Troca Materno-Fetal , Placenta/metabolismo , Animais , Transporte Biológico , Diabetes Gestacional/metabolismo , Feminino , Macrossomia Fetal , Humanos , Insulina/fisiologia , Transporte de Íons , Gravidez , Gravidez em Diabéticas , Regulação para Cima
20.
Placenta ; 27 Suppl A: S91-7, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16442615

RESUMO

Intrauterine growth restriction is associated with a range of alterations in placental transport functions: the activity of a number of transporters is reduced (Systems A, L and Tau, transporters for cationic amino acids, the sodium-proton exchanger and the sodium pump), placental glucose transporter activity and expression are unchanged whereas the activity of the calcium pump is increased. In contrast, accelerated fetal growth in association to diabetes is characterized by increased activity of placental Systems A and L and glucose transporters. Evidence suggests that these placental transport alterations are the result of specific regulation and that they, at least in part, contribute to the development of pathological fetal growth rather than representing a consequence to altered fetal growth. One interpretation of this data is that the placenta functions as a nutrient sensor, altering placental transport functions according to the ability of the maternal supply line to provide nutrients. Placental transporters are subjected to regulation by hormones. Insulin up-regulates several key placental transporters and maternal insulin may represent a "good nutrition" signal to increase placental nutrient transfer and the growth of the fetus. Preliminary evidence suggests that placental mammalian target of rapamycin, a protein kinase regulating protein translation and transcription in response to nutrient stimuli, may be involved in placental nutrient sensing.


Assuntos
Desenvolvimento Fetal , Retardo do Crescimento Fetal/metabolismo , Placenta/fisiologia , Sistemas de Transporte de Aminoácidos/metabolismo , Distinções e Prêmios , Transporte Biológico , Feminino , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Transporte de Íons , Placenta/irrigação sanguínea , Circulação Placentária , Gravidez , Sociedades Científicas
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