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1.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
2.
BMC Med ; 17(1): 77, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971237

RESUMO

BACKGROUND: The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants. METHOD: In a mother-child cohort in northern Argentina (n = 169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log2-transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D3). RESULTS: Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2-0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n = 98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n = 88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony. CONCLUSIONS: Elevated exposure to boron, lithium, arsenic, and antimony was associated with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations.


Assuntos
Antioxidantes/administração & dosagem , Exposição Ambiental/análise , Exposição Materna , Fenômenos Fisiológicos da Nutrição Materna , Metais Pesados/toxicidade , Homeostase do Telômero/fisiologia , Telômero/fisiologia , Adolescente , Adulto , Argentina/epidemiologia , Criança , Estudos de Coortes , Dieta , Exposição Ambiental/prevenção & controle , Feminino , Sangue Fetal/efeitos dos fármacos , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Exposição Materna/estatística & dados numéricos , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/genética , Metais Pesados/análise , Metais Pesados/sangue , Metais Pesados/urina , Mães , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Telômero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Adulto Jovem
3.
Biochem Biophys Res Commun ; 502(3): 375-381, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29852171

RESUMO

Thyroid hormones (TH) of maternal origin are crucial regulator of mammalian brain development during embryonic period. Although maternal TH deficiency during the critical periods of embryonic neo-cortical development often results in irreversible clinical outcomes, the fundamental basis of these abnormalities at a molecular level is still obscure. One of the key developmental process affected by maternal TH insufficiency is the delay in astrocyte maturation. Glial fibrillary acidic protein (Gfap) is a predominant cell marker of mature astrocyte and is regulated by TH status. Inspite, of being a TH responsive gene during neocortical development the mechanistic basis of Gfap transcriptional regulation by TH has remained elusive. In this study using rat model of maternal hypothyroidism, we provide evidence for an epigenetic silencing of Gfap under TH insufficiency and its recovery upon TH supplementation. Our results demonstrate increased DNA methylation coupled with decreased histone acetylation at the Gfap promoter leading to suppression of Gfap expression under maternal hypothyroidism. In concordance, we also observed a significant increase in histone deacetylase (HDAC) activity in neocortex of TH deficient embryos. Collectively, these results provide novel insight into the role of TH regulated epigenetic mechanisms, including DNA methylation, and histone modifications, which are critically important in mediating precise temporal neural gene regulation.


Assuntos
Epigênese Genética , Proteína Glial Fibrilar Ácida/genética , Hipotireoidismo/complicações , Hipotireoidismo/genética , Complicações na Gravidez/genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Inativação Gênica , Histona Desacetilases/metabolismo , Hipotireoidismo/tratamento farmacológico , Troca Materno-Fetal/genética , Neurogênese/genética , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Hormônios Tireóideos/administração & dosagem , Hormônios Tireóideos/deficiência
4.
Nihon Eiseigaku Zasshi ; 73(2): 105-109, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29848859

RESUMO

In Japan, the prevalence of low birth weight (< 2,500 g) has been increasing, probably owing to leanness, exposure to toxic chemicals and smoking. Epidemiological studies revealed that low birth weight poses risks of hypertension, coronary heart diseases and diabetes. Although the precise mechanism has not been understood, there is an urgent need for appropriate public health interventions. MicroRNA (miRNA) is a small RNA consisting of approximately 22 nucleotides and distributed in a wide variety of organs and body fluids. miRNAs are involved in the pathogenesis of various human diseases and expected to be their potential biomarkers. The interest on the study on miRNA in the research field of developmental origins of health and disease (DOHaD) has been growing, and the number of related papers has been increasing. There are several molecular epidemiological studies on the relationship between maternal miRNA and fetal development. The effects of smoking and dietary factors on miRNA expression and fetal development have been investigated in epidemiological and experimental studies. However, the role of maternal miRNA in fetal development has not been well understood so far. In this review, the current status of studies on miRNA expression in DOHaD research is described and future perspectives are discussed.


Assuntos
Dieta , Desenvolvimento Fetal , Recém-Nascido de Baixo Peso , Troca Materno-Fetal/genética , Troca Materno-Fetal/fisiologia , MicroRNAs , Animais , Doença das Coronárias/etiologia , Diabetes Mellitus/etiologia , Feminino , Desenvolvimento Fetal/genética , Expressão Gênica , Humanos , Hipertensão/etiologia , Japão/epidemiologia , MicroRNAs/genética , MicroRNAs/fisiologia , Gravidez , Risco , Fumar/efeitos adversos
5.
RNA ; 24(6): 865-879, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29540511

RESUMO

The emergence of microRNA as regulators of organogenesis and tissue differentiation has stimulated interest in the ablation of microRNA expression and function during discrete periods of development. To this end, inducible, conditional modulation of microRNA expression with doxycycline-based tetracycline-controlled transactivator and tamoxifen-based estrogen receptor systems has found widespread use. However, the induction agents and components of genome recombination systems negatively impact pregnancy, parturition, and postnatal development; thereby limiting the use of these technologies between late gestation and the early postnatal period. MicroRNA inhibitor (antimiR) administration also represents a means of neutralizing microRNA function in vitro and in vivo. To date, these studies have used direct (parenteral) administration of antimiRs to experimental animals. As an extension of this approach, an alternative means of regulating microRNA expression and function is described here: the maternal-placental-fetal transmission of antimiRs. When administered to pregnant dams, antimiRs were detected in offspring and resulted in a pronounced and persistent reduction in detectable steady-state free microRNA levels in the heart, kidney, liver, lungs, and brain. This effect was comparable to direct injection of newborn mouse pups with antimiRs, although maternal delivery resulted in fewer off-target effects. Furthermore, depletion of steady-state microRNA levels via the maternal route resulted in concomitant increases in steady-state levels of selected microRNA targets. This novel methodology permits the temporal regulation of microRNA function during late gestation and in neonates, without recourse to conventional approaches that rely on doxycycline and tamoxifen, which may confound studies on developmental processes.


Assuntos
Feto/metabolismo , Troca Materno-Fetal/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Placenta/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/administração & dosagem , Células NIH 3T3 , Gravidez
6.
Medisan ; 22(2)feb. 2018. tab
Artigo em Espanhol | LILACS | ID: biblio-894684

RESUMO

Se realizó un estudio analítico, observacional, de casos y controles, en niños de los círculos infantiles Pétalos de Rosa y La Espiguita, pertenecientes al área de salud del Policlínico Docente Armando García Aspurú de Santiago de Cuba, durante el período de febrero de 2015 a marzo de 2016, con vistas a determinar los factores maternos y neonatales asociados al retraso en la aparición de dientes temporales. La población quedó conformada por 150 niños de 2do a 4to años de vida, de los cuales se tomaron 2 controles (N=100) por cada caso (N=50). En la serie se obtuvo asociación estadísticamente significativa de las variables estado nutricional de la madre, ganancia de peso de la madre, enfermedades maternas, lactancia materna y peso del niño al nacer, con la alteración del brote dentario temporal en los niños. Se recomendó realizar intervenciones educativas en los círculos infantiles y las comunidades para apoyar el trabajo del médico de la familia


An analytic, observational, of cases and controls study, in children from Pétalos de Rosa and La Espiguita day care centers, belonging to the health area of Armando García Aspurú Teaching Polyclinic was carried out in Santiago de Cuba, during February, 2015 to March, 2016, aimed at determining the maternal and neonatal factors associated with the delay in the emergence of the temporary teeth. The population was conformed by 150 children from 2nd to 4th years of life, from whom 2 controls were taken (N=100) for each case (N=50). In the series a statistically significant association of the variables mother's nutritional state, mother's weight gain, maternal diseases, breast feeding and child birth weight was obtained, with the disorder of the temporary teething eruption in the children. It was suggested to carry out educational interventions in the day care centers and communities to support the family doctor's work


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Dente Decíduo/fisiopatologia , Erupção Dentária/fisiologia , Fatores de Risco , Relações Materno-Fetais/fisiologia , Troca Materno-Fetal/fisiologia , Dente Decíduo/anormalidades , Troca Materno-Fetal/genética
7.
Front Immunol ; 9: 3142, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30687334

RESUMO

Dysfunction of decidual macrophages (DMs) is considered a critical event in the pathogenesis of pre-eclampsia (PE). T cell immunoglobulin mucin 3 (Tim-3) is an important negative regulatory molecule that induces immune tolerance by interacting with its ligand Galectin-9 (Gal-9) and thus modulating function of various immune cells, including macrophages. However, the regulatory effects of Tim-3/Gal-9 signaling on DMs polarization and its role in PE remain unclear. In this study, we established a PE-like rat model by administering 1.0 µg/kg lipopolysaccharide (LPS) to normal pregnant Sprague-Dawley rats via the tail vein at embryonic day 5 (E5). Apart from the pre-eclamptic manifestations, increased M1 subtype and decreased M2 subtype were observed at the maternal-fetal interface, as well as increased pro-inflammatory cytokines (TNF-α and IL-1ß) and reduced anti-inflammatory cytokines (TGF-ß and IL-10). Moreover, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were reduced. After administration of recombinant Galectin-9 (rGal-9) protein, we found that liver and renal injuries and maternofetal placental functional deficiency, including inadequate trophoblast cells invasion, impaired spiral artery remodeling and fetal capillary development, were reversed. In addition, the polarization of DMs was inclined to M2 subtype, which was similar to the polarization of DMs in the control rats but contrary to the PE-like rats. Interestingly, at E9, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were significantly increased in the rGal-9 protein intervention group. Taken together, our findings show that administration of rGal-9 protein can alleviate the PE-like rat manifestations induced by LPS. This finding may be related to the activation of the Tim-3/Gal-9 signaling pathway, which promotes DMs polarization dominantly shifting to M2 subtype. Moreover, upregulation of Tim-3 in DMs and Gal-9 at the maternal-fetal interface at E9 suggests that Tim-3/Gal-9 pathway may play some important roles in early pregnancy and even embryo development.


Assuntos
Decídua/imunologia , Decídua/metabolismo , Galectinas/metabolismo , Lipopolissacarídeos/efeitos adversos , Macrófagos/imunologia , Macrófagos/metabolismo , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Animais , Pressão Sanguínea , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunofluorescência , Galectinas/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Hipertensão , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Rim/imunologia , Rim/metabolismo , Rim/patologia , Lipopolissacarídeos/imunologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos/imunologia , Troca Materno-Fetal/genética , Troca Materno-Fetal/imunologia , Modelos Biológicos , Placenta/imunologia , Placenta/metabolismo , Placenta/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Proteinúria/imunologia , Proteinúria/metabolismo , Ratos , Transdução de Sinais
8.
World J Gastroenterol ; 23(45): 8017-8026, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29259377

RESUMO

AIM: To investigate the rates of pretransplantation fetal-maternal microchimerism (MC) and its effect on rejection in children receiving maternal liver grafts. METHODS: DNA or blood samples before liver transplantation (LT) were available in 45 pediatric patients and their mothers. The presence of pretransplantation MC to non-inherited maternal antigens (NIMAs) (NIMA-MC) in the peripheral blood was tested using nested PCR-single-strand conformation polymorphism analysis for the human leukocyte antigen (HLA)-DRB1 alleles. NIMA-MC was successfully evaluated in 26 of the 45 children. Among these 45 pediatric LT recipients, 23 children (51.1%) received transplants from maternal donors and the other 22 from non-maternal donors. RESULTS: Among these 26 children, pretransplantation NIMA-MC was detected in 23.1% (n = 6), 6.1 (range, 0.8-14) years after birth. Among the children with a maternal donor, the rate of biopsy-proven cellular rejection (BPCR) was 0% in patients with NIMA-MC positivity (0/3) and those with HLA-DR identity with the mother (0/4), but it was 50% in those with NIMA-MC negativity (5/10). Patients with NIMA-MC positivity or HLA-DR identity with the mother showed significantly lower BPCR rate compared with NIMA-MC-negative patients (0% vs 50%, P = 0.04). NIMA-MC-positive patients tended to show lower BPCR rate compared with NIMA-MC-negative patients (P = 0.23). CONCLUSION: The presence of pretransplantation NIMA-MC or HLA-DR identity with the mother could be associated with BPCR-free survival in pediatric recipients of LT from maternal donors.


Assuntos
Quimerismo , Rejeição de Enxerto/genética , Antígenos HLA-DR/genética , Transplante de Fígado/efeitos adversos , Troca Materno-Fetal/genética , Adolescente , Aloenxertos/imunologia , Aloenxertos/patologia , Biópsia , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Antígenos HLA-DR/sangue , Antígenos HLA-DR/imunologia , Humanos , Lactente , Recém-Nascido , Fígado/imunologia , Fígado/patologia , Falência Hepática/cirurgia , Transplante de Fígado/métodos , Masculino , Troca Materno-Fetal/imunologia , Mães , Gravidez , Período Pré-Operatório , Doadores de Tecidos
9.
J Clin Endocrinol Metab ; 102(11): 4072-4079, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938476

RESUMO

Objective: Several genetic polymorphisms determine vitamin D status. We aimed to estimate the strength of association of established 25-hydroyxvitamin D (25OHD)-associated variants in the mother and in the fetus, with 25OHD concentration in newborn umbilical cord plasma. Methods: We randomly selected 578 mother and child dyads from the prospective Norwegian Mother and Child Cohort study. 25OHD was assayed in maternal samples taken shortly after delivery and in cord samples. We genotyped the mother and child for single nucleotide polymorphisms in or near GC, DHCR7, CYP2R1, and CYP24A1, previously confirmed to be associated with 25OHD, and computed genetic risk score (GRS). The genetic associations were replicated in an independent sample of 594 subjects. Results: Although both fetal and maternal GRS were associated with cord 25OHD, only fetal GRS remained significantly associated with cord 25OHD in a regression model with maternal and fetal GRS simultaneously (1.6 nmol/L per fetal 25OHD-increasing allele; 95% confidence interval, 0.6 to 2.5, P = 0.0001). Two fetal single nucleotide polymorphisms in the GC gene (rs2282679 and rs222040) were the strongest genetic predictors of cord 25OHD [4.0 (2.1 to 5.9) and 3.0 (1.3 to 4.8) nmol/L per fetal allele, P < 0.001], followed by rs12785878 in DHCR7 [2.0 (0.1 to 3.8) nmol/L, P = 0.037]. The independent replication sample gave similar results. With fetal genotype included in a regression model with environmental factors, R2 for cord 25OHD was 0.28. Conclusions: We show that fetal 25OHD-modifying genotype was a stronger predictor of cord 25OHD than corresponding maternal genotype. This raises interesting questions about fetal acquisition and placental transfer of 25OHD.


Assuntos
Estado Nutricional/genética , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/congênito , Deficiência de Vitamina D/genética , Vitamina D/sangue , Adulto , Estudos de Coortes , Suplementos Nutricionais , Feminino , Feto/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Troca Materno-Fetal/genética , Mães , Gravidez , Cuidado Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangue , Adulto Jovem
10.
Epigenetics ; 12(9): 804-810, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28758828

RESUMO

Healthy feto-maternal communication is critical during pregnancy and is orchestrated by the placenta. Dysfunction of the placenta leads to fetal growth complications; however, the underlying biological mechanisms have yet to be fully elucidated. Circulating extracellular microRNAs (exmiRNAs) in the blood have been implicated in cell-to-cell communication. Therefore, exmiRNAs may provide useful biological information about communication between the mother, the fetus, and the placenta during pregnancy. We used logistic regression to determine the association of exmiRNAs with abnormal fetal growth by comparing mothers of infants classified as small-for-gestational age (SGA) (n = 36) and large-for-gestational age (LGA) (n = 13) to appropriate-for-gestational age (AGA), matched by gestational age at delivery and infant sex. In addition, we used linear regression to determine associations between exmiRNAs and birth weight-for-gestational age (BWGA) z-score (n = 100), adjusting for maternal age, body mass index, and parity. We found that higher levels of miR-20b-5p, miR-942-5p, miR-324-3p, miR-223-5p, and miR-127-3p in maternal serum were associated with lower odds for having a SGA vs. AGA infant, and higher levels of miR-661, miR-212-3p, and miR-197-3p were associated with higher odds for having a LGA vs. AGA infant. We also found associations between miR-483-5p, miR-10a-5p, miR-204-5p, miR-202-3p, miR-345-5p, miR-885-5p, miR-127-3p, miR-148b-3p, miR-324-3p, miR-1290, miR-597-5p, miR-139-5p, miR-215-5p, and miR-99b-5p and BWGA z-score. We also found sex-specific associations with exmiRNAs and fetal growth. Our findings suggest that exmiRNAs circulating in maternal blood at second trimester are associated with fetal growth. Validation of our findings may lead to the development of minimally-invasive biomarkers of fetal growth during pregnancy.


Assuntos
Comunicação Celular/genética , MicroRNAs/sangue , Adulto , Biomarcadores/sangue , Feminino , Desenvolvimento Fetal , Idade Gestacional , Humanos , Modelos Logísticos , Masculino , Troca Materno-Fetal/genética , Placenta , Gravidez , Segundo Trimestre da Gravidez , Fatores Sexuais
11.
J Genet ; 96(3): 465-482, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28761010

RESUMO

While much of our understanding of genetic inheritance is based on the genome of the organism, it is becoming clear that there is an ample amount of epigenetic inheritance, which though reversible, escapes erasing process during gametogenesis and goes on to the next generation. Several examples of transgenerational inheritance of epigenetic features with potential impact on embryonic development and subsequent adult life have come to light. In placental mammals, the placenta is an additional route for epigenetic information flow. This information does not go through any meiotic reprogramming and is, therefore, likely to have a more profound influence on the organism. This also has the implication of providing epigenetic instructions for several months, which is clearly a maternal advantage. Although less well-known, there is also an impact of the embryo in emitting genetic information to the maternal system that remains well beyond the completion of the pregnancy. In this review, we discuss several factors in the context of the evolution of this mammal-specific phenomenon, including genomic imprinting, micromosaicism, and assisted reproduction. We also highlight how this kind of inheritance might require attention in the modern lifestyle within the larger context of the evolutionary process.


Assuntos
Epigênese Genética , Impressão Genômica , Padrões de Herança , Placenta/metabolismo , Animais , Desenvolvimento Embrionário/genética , Feminino , Humanos , Troca Materno-Fetal/genética , Placenta/embriologia , Gravidez
12.
Proc Natl Acad Sci U S A ; 114(36): 9671-9676, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28831005

RESUMO

Certain MHC-II or HLA-D alleles dominantly protect from particular autoimmune diseases. For example, expression of the MHC-II Eα:Eß complex potently protects nonobese diabetic (NOD) mice, which normally lack this isotype, from spontaneous development of type 1 diabetes. However, the underlying mechanisms remain debated. We investigated MHC-II-mediated protection from type 1 diabetes using a previously reported NOD mouse line expressing an Eα transgene and, thereby, the Eα:Eß complex. Eα16/NOD females vertically protected their NOD offspring from diabetes and insulitis, an effect that was dependent on the intestinal microbiota; moreover, they developed autoimmunity when treated with certain antibiotics or raised in a germ-free environment. Genomic and proteomic analyses revealed NOD and Eα16/NOD mice to host mild but significant differences in the intestinal microbiotas during a critical early window of ontogeny, and transfer of cecal contents from the latter to the former suppressed insulitis. Thus, protection from autoimmunity afforded by particular MHC/HLA alleles can operate via intestinal microbes, highlighting potentially important societal implications of treating infants, or even just their pregnant mothers, with antibiotics.


Assuntos
Diabetes Mellitus Tipo 1/microbiologia , Diabetes Mellitus Tipo 1/prevenção & controle , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe II , Alelos , Animais , Antibacterianos/efeitos adversos , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Diabetes Mellitus Tipo 1/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Recém-Nascido , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Masculino , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/genética , Troca Materno-Fetal/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Gravidez
13.
Reproduction ; 154(3): 217-228, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28592665

RESUMO

Circulating miRNAs were proposed to be indicators of normal or complicated pregnancies. Based on this knowledge and our recent transcriptomic approach showing expression of miRNAs in the porcine endometrium, conceptuses and uterine extracellular vesicles during pregnancy, we have hypothesized that signs of ongoing local embryo-maternal crosstalk involving miRNAs can be detected in the circulation of pregnant gilts as early as a few days after maternal recognition of pregnancy. By applying several molecular biology techniques that differ in dynamic range and precision in maternal serum of Day 16 pregnant pigs, we were able to show for the first time increased levels of several miRNAs, previously reported to be expressed in either conceptuses and extracellular vesicles (miR-26a and miR-125b) or pregnant endometrium (miR-23b). Our results clearly showed that real-time RT-PCR and digital PCR are the most reliable methods, being able to detect small-fold changes of low-abundant circulating miRNAs. Further validation in a separate group of gilts confirmed an increase in miR-23b and miR-125b levels. In silico analyses identified pregnancy-related biological processes and pathways affected by these miRNAs. Target prediction analysis revealed hundreds of porcine transcripts with conserved sites for these miRNAs, which were classified into signaling pathways relevant to pregnancy. We conclude that a unique set of miRNAs can already be observed in the circulation of pigs during the first weeks of pregnancy, as a result of the initiation of embryo-maternal communication.


Assuntos
Embrião de Mamíferos/fisiologia , Troca Materno-Fetal/genética , MicroRNAs/genética , Prenhez , Animais , Embrião de Mamíferos/citologia , Feminino , Gravidez , Suínos , Transcriptoma
14.
Fertil Steril ; 107(6): 1269-1272, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28577615

RESUMO

Immunological adjustments are needed to accommodate the close contact between two genetically different individuals, the mother and her baby, during mammalian pregnancy. Contact occurs between fetal somatic or placental cells that enter the maternal systemic circulation or between uterine immune cells and the invading extravillous trophoblast. Here we discuss two main types of maternal allo-recognition of the fetus. One depends on avoidance of maternal T cells recognizing and responding to paternally-derived non-self human leukocyte antigens class I and class I allotypes. The other is natural killer allo-recognition where maternally-inherited variable killer immunoglobulin-like receptors expressed by uterine natural killer cells bind to polymorphic fetal human leukocyte antigens-C molecules displayed by extravillous trophoblast. Genetic studies indicate that natural killer cell allo-recognition regulates placentation and the allocation of resources to the fetus.


Assuntos
Feto , Linfócitos/imunologia , Troca Materno-Fetal/genética , Troca Materno-Fetal/imunologia , Placenta/imunologia , Placentação/genética , Placentação/imunologia , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Feminino , Feto/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Imunidade Materno-Adquirida/genética , Imunidade Materno-Adquirida/imunologia , Modelos Genéticos , Modelos Imunológicos , Gravidez , Trofoblastos/imunologia
15.
Psychiatry Res ; 255: 17-26, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28511050

RESUMO

The experience of maternal distress in pregnancy is often linked with poorer obstetric outcomes for women as well as adverse outcomes for offspring. Alterations in placental glucocorticoid signalling and subsequent increased fetal exposure to cortisol have been suggested to underlie this relationship. In the current study, 121 pregnant women completed the Perceived Stress Scale, State Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale in the third trimester of pregnancy. Placental samples were collected after delivery. Maternal history of psychiatric illness and miscarriage were significant predictors of poorer mental health in pregnancy. Higher anxiety was associated with an increase in women delivering via elective Caesarean Section, and an increase in bottle-feeding. Birth temperature was mildly reduced among infants of women with high levels of depressive symptomology. Babies of mothers who scored high in all stress (cumulative distress) measures had reduced 5-min Apgar scores. High cumulative distress reduced the expression of placental HSD11B2 mRNA and increased the expression of placental NR3C1 mRNA. These data support a role for prenatal distress as a risk factor for altered obstetric outcomes. The alterations in placental gene expression support a role for altered placental glucocorticoid signalling in the relationship between maternal prenatal distress and adverse outcomes.


Assuntos
Glucocorticoides/metabolismo , Hidrocortisona/metabolismo , Complicações do Trabalho de Parto/genética , Placenta/metabolismo , Estresse Psicológico/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adulto , Ansiedade/genética , Feminino , Humanos , Troca Materno-Fetal/genética , Complicações do Trabalho de Parto/psicologia , Gravidez , Terceiro Trimestre da Gravidez/genética , Terceiro Trimestre da Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/psicologia , Escalas de Graduação Psiquiátrica , Transdução de Sinais/genética , Estresse Psicológico/metabolismo
16.
Mol Reprod Dev ; 84(9): 926-933, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28390179

RESUMO

Porcine Reproductive and Respiratory Syndrome (PRRS) causes severe reproductive failure in sows as well as transplacental transfer of PRRS virus (PRRSV) to late-gestation fetuses, resulting in abortions, early farrowing, increased number of stillborn piglets, and weak neonatal piglets. PRRSV-infected boars present with anorexia and lethargy, and have decreased sperm quality. The gene for the cellular receptor that the PRRSV uses, Cluster of differentiation 163 (CD163), was edited using Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene-editing technology to create biallelic DNA edits to the CD163 gene in 100% of the offspring. CD163-null pigs challenged with virus were completely resistant to both Type 1 and Type 2 PRRSV isolates, as measured by clinical signs, viremia, antibody response, and lung histopathology. In vitro studies showed that CD163-null alveolar macrophages were also not permissive to infection by a panel of six Type 1 and nine Type 2 viral isolates. Thus, DNA editing of the CD163 gene prevented PRRSV infection and reproductive losses associated with infection.


Assuntos
Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Edição de Genes , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Troca Materno-Fetal/genética , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Receptores de Superfície Celular , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Feminino , Síndrome Respiratória e Reprodutiva Suína/genética , Síndrome Respiratória e Reprodutiva Suína/metabolismo , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Gravidez , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Suínos
17.
Development ; 144(1): 63-73, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28049690

RESUMO

Adapting the energy metabolism state to changing bioenergetic demands is essential for mammalian development accompanying massive cell proliferation and cell differentiation. However, it remains unclear how developing embryos meet the changing bioenergetic demands during the chorioallantoic branching (CB) stage, when the maternal-fetal exchange of gases and nutrients is promoted. In this study, using metabolome analysis with mass-labeled glucose, we found that developing embryos redirected glucose carbon flow into the pentose phosphate pathway via suppression of the key glycolytic enzymes PFK-1 and aldolase during CB. Concomitantly, embryos exhibited an increase in lactate pool size and in the fractional contribution of glycolysis to lactate biosynthesis. Imaging mass spectrometry visualized lactate-rich tissues, such as the dorsal or posterior neural tube, somites and head mesenchyme. Furthermore, we found that the heterochronic gene Lin28a could act as a regulator of the metabolic changes observed during CB. Perturbation of glucose metabolism rewiring by suppressing Lin28a downregulation resulted in perinatal lethality. Thus, our work demonstrates that developing embryos rewire glucose metabolism following CB for normal development.


Assuntos
Membrana Corioalantoide/embriologia , Membrana Corioalantoide/metabolismo , Metabolismo Energético/genética , Frutose-Bifosfato Aldolase/genética , Glucose/metabolismo , Fosfofrutoquinase-1/genética , Animais , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Frutose-Bifosfato Aldolase/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Glicólise/genética , Troca Materno-Fetal/genética , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Fosfofrutoquinase-1/metabolismo , Gravidez , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia
18.
Adv Exp Med Biol ; 924: 67-70, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27753021

RESUMO

Fetal and Neonatal alloimmune thrombocytopenia (FNAIT) is a condition which could occur when pregnant women develop an alloimmunization against paternally inherited antigens of the fetal platelets. Approximately 80 % of FNAIT cases are caused by anti-HPA-1a, about 15 % by anti-HPA-5b and 5 % by other HPA antibodies. Only 2 % of the total population is HPA-1a negative (HPA-1b1b). The HPA-1a allele differs by one single nucleotide from HPA-1b allele, yet it represents around 27 % of total severe thrombocytopenias. HPA-1 was studied in serum cDNA from 12 volunteer pregnant women to determine their HPA-1 genotype by HRM (high resolution melting) PCR. When an homozygous HPA-1 gene was detected in a mother, a COLD HRM was performed to determine whether or not the fetal genotype differs from the mother's.The differences in the melting curve shapes allow us to accurately distinguish the three pregnants genotypes. The fetal heterozygous genotype of homozygous pregnant women was correctly detected by COLD PCR HRM in maternal serum. HPA-1 genotyping by HRM may be a useful aproach for genotyping all pregnant women in inexpensively. Moreover, when HPA-1 homozygosis was detected in a pregnant woman, fetal heterozygosis may be diagnosed by COLD HRM to select pregnancies for preventive monitoring.


Assuntos
Plaquetas/metabolismo , Troca Materno-Fetal/imunologia , Diagnóstico Pré-Natal/métodos , Trombocitopenia Neonatal Aloimune/imunologia , Antígenos de Plaquetas Humanas/sangue , Antígenos de Plaquetas Humanas/genética , Antígenos de Plaquetas Humanas/imunologia , Análise Custo-Benefício , DNA/sangue , DNA/genética , Feminino , Genótipo , Técnicas de Genotipagem/economia , Técnicas de Genotipagem/métodos , Humanos , Recém-Nascido , Troca Materno-Fetal/genética , Desnaturação de Ácido Nucleico , Reação em Cadeia da Polimerase/métodos , Gravidez , Reprodutibilidade dos Testes , Análise de Sequência de DNA/métodos , Trombocitopenia Neonatal Aloimune/sangue , Trombocitopenia Neonatal Aloimune/genética
19.
Endocrinology ; 157(11): 4246-4256, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27583789

RESUMO

Obesity during pregnancy has a long-term effect on the health of the offspring including risk of developing the metabolic syndrome. Using a mouse model of maternal diet-induced obesity, we employed a genome-wide approach to investigate the microRNA (miRNA) and miRNA transcription profile in adipose tissue to understand mechanisms through which this occurs. Male offspring of diet-induced obese mothers, fed a control diet from weaning, showed no differences in body weight or adiposity at 8 weeks of age. However, offspring from the obese dams had up-regulated cytokine (Tnfα; P < .05) and chemokine (Ccl2 and Ccl7; P < .05) signaling in their adipose tissue. This was accompanied by reduced expression of miR-706, which we showed can directly regulate translation of the inflammatory proteins IL-33 (41% up-regulated; P < .05) and calcium/calmodulin-dependent protein kinase 1D (30% up-regulated; P < .01). We conclude that exposure to obesity during development primes an inflammatory environment in adipose tissue that is independent of offspring adiposity. Programming of adipose tissue miRNAs that regulate expression of inflammatory signaling molecules may be a contributing mechanism.


Assuntos
Tecido Adiposo/metabolismo , Troca Materno-Fetal/fisiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Tecido Adiposo/imunologia , Adiposidade/genética , Adiposidade/fisiologia , Animais , Peso Corporal/fisiologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Interleucina-33/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Troca Materno-Fetal/genética , Camundongos , MicroRNAs , Gravidez
20.
Proc Natl Acad Sci U S A ; 113(40): 11255-11260, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27621448

RESUMO

Pregnancy success and life-long health depend on a cooperative interaction between the mother and the fetus in the allocation of resources. As the site of materno-fetal nutrient transfer, the placenta is central to this interplay; however, the relative importance of the maternal versus fetal genotypes in modifying the allocation of resources to the fetus is unknown. Using genetic inactivation of the growth and metabolism regulator, Pik3ca (encoding PIK3CA also known as p110α, α/+), we examined the interplay between the maternal genome and the fetal genome on placental phenotype in litters of mixed genotype generated through reciprocal crosses of WT and α/+ mice. We demonstrate that placental growth and structure were impaired and associated with reduced growth of α/+ fetuses. Despite its defective development, the α/+ placenta adapted functionally to increase the supply of maternal glucose and amino acid to the fetus. The specific nature of these changes, however, depended on whether the mother was α/+ or WT and related to alterations in endocrine and metabolic profile induced by maternal p110α deficiency. Our findings thus show that the maternal genotype and environment programs placental growth and function and identify the placenta as critical in integrating both intrinsic and extrinsic signals governing materno-fetal resource allocation.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feto/metabolismo , Genoma , Troca Materno-Fetal/genética , Placenta/metabolismo , Transdução de Sinais , 3-O-Metilglucose/metabolismo , Animais , Transporte Biológico , Peso Corporal , Linhagem da Célula/genética , Classe I de Fosfatidilinositol 3-Quinases/deficiência , Sistema Endócrino/metabolismo , Ativação Enzimática , Feminino , Desenvolvimento Fetal , Regulação da Expressão Gênica no Desenvolvimento , Fígado/anatomia & histologia , Metabolômica , Camundongos Knockout , Modelos Biológicos , Tamanho do Órgão , Placenta/anatomia & histologia , Gravidez , beta-Alanina/análogos & derivados , beta-Alanina/metabolismo
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