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1.
Nutrients ; 13(3)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805588

RESUMO

Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring's risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997-2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.


Assuntos
Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Dieta/efeitos adversos , Exposição Materna/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adulto , Ácido Ascórbico/análise , Doenças Autoimunes/genética , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Dieta/estatística & dados numéricos , Inquéritos sobre Dietas , Suplementos Nutricionais , Feminino , Finlândia , Genótipo , Antígenos HLA/imunologia , Humanos , Lactente , Ferro na Dieta/análise , Ilhotas Pancreáticas/imunologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Regressão
2.
Chemosphere ; 262: 128009, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182144

RESUMO

Increasing evidence has highlighted the critical role of early life environment in shaping the future health outcomes of individuals in subsequent generations. Bisphenol S (BPS) has been widely used as a substitute for various plastic materials due to the limited application of Bisphenol A (BPA) which is an endocrine disruptor. However, the lack of efficient evaluation of BPS leaves doubts about the relevant substitute of BPA. Few studies of transgenerational inheritance have examined the effects of environmental exposures to endocrine disruptors on the immune system. In this study, we analyzed the transgenerational effects of BPS on intestinal inflammation and its consequence in metabolism. In this study, only F0 pregnant mice were exposed to BPS (1.5 µg/kg bw/day) from gestational day 0 until weaning of offspring. In this work, both F1 and F2 male offspring developed an inflammatory response in the ileum and colon at adulthood after F0 mothers were exposed to BPS; this phenomenon disappeared in F3. This inflammatory response in F1 male offspring is associated with a significant decrease of blood cholesterol without modification of metabolic status. Further, in F3 offspring male, the decrease of gut inflammatory response is associated with a decrease of fat weight and with an increase of blood glucose and cholesterol level. A sex-specific profile is observed in female offspring. We also observed that early life exposure to BPS was associated with strong abnormal intestinal immune status. The study presented here demonstrates that the immune system, like other organ systems, is vulnerable to transgenerational effects caused by environmental exposures.


Assuntos
Citocinas/análise , Disruptores Endócrinos/toxicidade , Intestinos/imunologia , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sulfonas/toxicidade , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Fezes/química , Feminino , Inflamação , Intestinos/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
3.
Nat Commun ; 11(1): 5236, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067431

RESUMO

The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Complicações na Gravidez/imunologia , Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/genética , Edição de RNA , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/imunologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Imunidade Materno-Adquirida , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/psicologia , Poli I-C/efeitos adversos , Poli I-C/imunologia , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
4.
Toxicol Lett ; 333: 222-231, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798538

RESUMO

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 µg/mouse for PND 240 and 290, and 50 µg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.


Assuntos
Envelhecimento/imunologia , Genisteína/farmacologia , Pulmão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Envelhecimento/sangue , Alérgenos/imunologia , Animais , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Feminino , Genisteína/administração & dosagem , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Pulmão/embriologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia
5.
PLoS One ; 15(8): e0231609, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760152

RESUMO

Maternal immune activation (MIA) during pregnancy induces a cytokine storm that alters neurodevelopment and behavior in the progeny. In humans, MIA increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD). In mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C)) to pregnant dams. Although the murine model of MIA has been extensively studied, it is not clear whether MIA results in cytokine changes in the progeny at early postnatal stages. Further, the murine model of MIA suffers from a lack of reproducibility and high inter-individual variability. Multivariable (MV) statistical analysis is widely used in human studies to control for confounders and covariates such as sex, age and exposure to environmental factors. We therefore reasoned that animal studies in general and studies on the MIA model in particular could benefit from MV analyses to account for complex phenotype interactions and high inter-individual variability. Here, we used MV statistical analysis to identify cytokines associated with MIA after adjustment for covariates. Besides confirming the association between previously described variables and MIA, we identified new cytokines that could play a role in behavioural alterations in the progeny during the early postnatal period.


Assuntos
Transtorno Autístico/etiologia , Citocinas/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Transtorno do Espectro Autista/induzido quimicamente , Comportamento Animal/fisiologia , Citocinas/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Análise Multivariada , Poli I-C/farmacologia , Gravidez , Reprodutibilidade dos Testes
6.
Life Sci ; 260: 118309, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841664

RESUMO

AIMS: Oral cavity pathogens play an important systemic role, modulating the development of several diseases. Periodontitis is a very common oral disease associated with dental biofilm. It is characterized by gum inflammation, periodontal ligament degeneration, dental cementum and alveolar bone loss. Studies point to the association between maternal periodontitis and adverse outcomes during pregnancy. However, they did not evaluate the impact of maternal periodontitis in the offspring. Thus, our objective was to investigate the effects of maternal periodontitis in the immune system of offspring. MATERIAL AND METHODS: For this evaluation we induced acute lung injury in rat pups. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after the birth, offspring was submitted to acute lung inflammation by administration of lipopolysaccharide (LPS, Salmonella abortus equi, 5 mg/kg, ip). KEY FINDINGS: Our results showed that maternal periodontitis increased myeloperoxidase activity, the levels of TNF-alpha and IL-17A in the bronchoalveolar fluid, the gene expression of TNF-alpha, IL-17A, and cyclooxygenases 1 and 2. In addition, maternal periodontitis did not alter the number of leukocytes migrated into the lung, tracheal responsiveness, expression of TLR4 and NF-KB translocation. SIGNIFICANCE: This study showed prenatal programming of the immune response induced by maternal periodontitis, and reinforces the importance of oral health care during pregnancy.


Assuntos
Lesão Pulmonar Aguda/imunologia , Reprogramação Celular , Periodontite/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Animais Recém-Nascidos , Feminino , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , NF-kappa B/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
7.
Scand J Immunol ; 92(2): e12914, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32533709

RESUMO

Immature immune system and immune tolerance induced by exposure to HBeAg in utero and/or shortly after infection in newborns were reportedly the causes of chronic HBV infection. To investigate the effect of maternal-derived HBeAg on neonatal T cell immunity, we analysed and compared T cell phenotypes and functions among neonates born to HBsAg+ /HBeAg+ mothers (HBeAg+ neonates), HBsAg+ /HBeAg- mothers (HBeAg- neonates) and healthy control mothers (HC neonates), using flow cytometry. The results showed that neonatal T cell phenotypes were similar regardless of HBeAg exposure. Upon anti-CD3 and anti-CD28 stimulation in HBeAg+ neonates, CD4+ T cell production of IFN-γ (P < .05) was significantly enhanced, while CD8+ T cells secreted significantly more IL-2 compared with those in HBeAg- and HC groups (P < .05). Moreover, similar levels of IFN-γ and IL-10 were observed in the culture supernatant after stimulation with rHBsAg, rHBcAg or rHBeAg among HBeAg+ , HBeAg- and HC neonates, whereas HBeAg+ neonates produced more TNF-α than HBeAg- neonates upon stimulation with rHBcAg. In conclusion, the results indicated that the HBsAg+ /HBeAg+ maternal environment did not influence the phenotypes of cord blood T cells but boosted neonatal non-specific Th1-type cytokine production.


Assuntos
Sangue Fetal/imunologia , Antígenos E da Hepatite B/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Linfócitos T/imunologia , Citocinas/imunologia , Feminino , Hepatite B/imunologia , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Gravidez
8.
J Allergy Clin Immunol ; 146(1): 101-109.e1, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32437740

RESUMO

BACKGROUND: Immunologic dysfunction due to coronavirus disease 2019 (COVID-19) is closely related to clinical prognosis, and the inflammatory response of pregnant women may affect the directional differentiation and function of fetal immune cells. OBJECTIVE: We sought to analyze the immune status of newborns from mothers with COVID-19 in the third trimester. METHODS: Along with collecting the clinical data from 51 newborns and their respective mothers, we recorded the immunophenotypes and cytokine and immunoglobulin levels of the newborns. RESULTS: None of the 51 newborns showed fever or respiratory distress during hospitalization. Detection of severe acute respiratory syndrome coronavirus 2 nucleic acid in pharyngeal swabs was negative. Except for the low level of CD16-CD56 cells, the count and proportion of lymphocytes, CD3, CD4, CD8, and CD19 were all in the normal range. Moreover, the serum IgG and IgM levels were within the normal range, whereas IL-6 showed increased levels. There was no correlation between maternal COVID-19 duration and the lymphocyte subsets or cytokine levels (IFN-γ, IL-2, IL-4, IL-6, IL-10, and TNF-α). There was a positive correlation between IL-6 and IL-10 levels and CD16-CD56 cells. One (1.96%) infant with an extremely elevated IL-6 concentration developed necrotizing enterocolitis in the third week after birth, and the remaining 50 infants did not show abnormal symptoms through the end of the follow-up period. CONCLUSIONS: COVID-19 in the third trimester did not significantly affect the cellular and humoral immunity of the fetus, and there was no evidence that the differentiation of lymphocyte subsets was seriously unbalanced.


Assuntos
Infecções por Coronavirus/imunologia , Recém-Nascido/imunologia , Pneumonia Viral/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Betacoronavirus , China , Feminino , Humanos , Subpopulações de Linfócitos/imunologia , Masculino , Pandemias , Gravidez , Terceiro Trimestre da Gravidez
9.
Nanotoxicology ; 14(5): 711-724, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374645

RESUMO

Prenatal particle exposure has been shown to increase allergic responses in offspring. Carbon nanotubes (CNTs) possess immunomodulatory properties, but it is unknown whether maternal exposure to CNTs interferes with offspring immune development. Here, C57Bl/6J female mice were intratracheally instilled with 67 of µg multiwalled CNTs on the day prior to mating. After weaning, tolerance and allergy responses were assessed in the offspring. Offspring of CNT-exposed (CNT offspring) and of sham-exposed dams (CTRL offspring) were intranasally exposed to ovalbumin (OVA) once weekly for 5 weeks to induce airway mucosal tolerance. Subsequent OVA sensitization and aerosol inhalation caused low or no OVA-specific IgE production and no inflammation. However, the CNT offspring presented with significantly lower OVA-specific IgG1 levels than CTRL offspring. In other groups of 5-week-old offspring, low-dose sensitization with OVA and subsequent OVA aerosol inhalation led to significantly lower OVA-specific IgG1 production in CNT compared to CTRL offspring. OVA-specific IgE and airway inflammation were non-significantly reduced in CNT offspring. The immunomodulatory effects of pre-gestational exposure to multiwalled CNTs were unexpected, but very consistent. The observations of suppressed antigen-specific IgG1 production may be of importance for infection or vaccination responses and warrant further investigation.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Antígenos/toxicidade , Hipersensibilidade/etiologia , Nanotubos de Carbono/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Antígenos/química , Feminino , Humanos , Hipersensibilidade/imunologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Nanotubos de Carbono/química , Ovalbumina/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
10.
Environ Health Perspect ; 128(4): 47006, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32293200

RESUMO

BACKGROUND: In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. OBJECTIVE: The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. METHODS: Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8-10 per group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. RESULTS: Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFNγ) in the diencephalon, as well as lower levels of hippocampal IFNγ (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. DISCUSSION: These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Inflamação/imunologia , Locomoção/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estresse Psicológico/psicologia , Aerossóis/análise , Animais , Modelos Animais de Doenças , Feminino , Glicerol/efeitos adversos , Inflamação/induzido quimicamente , Camundongos , Nicotina/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Propilenoglicol/efeitos adversos , Distribuição Aleatória , Estresse Psicológico/induzido quimicamente
11.
Cell ; 180(5): 847-861.e15, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142678

RESUMO

Early life environmental exposure, particularly during perinatal period, can have a life-long impact on organismal development and physiology. The biological rationale for this phenomenon is to promote physiological adaptations to the anticipated environment based on early life experience. However, perinatal exposure to adverse environments can also be associated with adult-onset disorders. Multiple environmental stressors induce glucocorticoids, which prompted us to investigate their role in developmental programming. Here, we report that perinatal glucocorticoid exposure had long-term consequences and resulted in diminished CD8 T cell response in adulthood and impaired control of tumor growth and bacterial infection. We found that perinatal glucocorticoid exposure resulted in persistent alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Consequently, the level of the hormone in adults was significantly reduced, resulting in decreased CD8 T cell function. Our study thus demonstrates that perinatal stress can have long-term consequences on CD8 T cell immunity by altering HPA axis activity.


Assuntos
Infecções Bacterianas/imunologia , Desenvolvimento Embrionário/imunologia , Glucocorticoides/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Dexametasona/farmacologia , Desenvolvimento Embrionário/genética , Feminino , Glucocorticoides/imunologia , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Interleucina-4/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Neoplasias/induzido quimicamente , Neoplasias/genética , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Receptores de Glucocorticoides/genética , Transdução de Sinais/genética
12.
J Med Microbiol ; 69(4): 591-599, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32043953

RESUMO

Introduction. Staphylococcal enterotoxin B (SEB) is an extensively studied super-antigen. A previous study by us suggested that SEB exposure during pregnancy could alter the percentage of CD4+ and CD8+ T cells in the peripheral blood of neonatal offspring rats.Aim. It is unknown whether SEB exposure during pregnancy can influence the development of regulatory T cells (Tregs) in the peripheral blood of neonatal offspring rats.Methodology. Pregnant rats at gestational day 16 were intravenously injected with 15 µg SEB. Peripheral blood was acquired from neonatal offspring rats on days 1, 3 and 5 after delivery and from adult offspring rats for determination of Treg number by cytometry, cytokines by ELISA, and FoxP3 expression by real-time PCR and western blot.Results. SEB given to pregnant rats significantly increased the absolute number of Tregs and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in the peripheral blood of not only neonatal but also adult offspring rats. Furthermore, repeated SEB exposure in adult offspring rats significantly decreased the absolute number of Tregs (P<0.01), and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in their peripheral blood.Conclusion. Prenatal SEB exposure attenuates the development and function of Tregs to repeated SEB exposure in the peripheral blood of adult offspring rats.


Assuntos
Enterotoxinas/imunologia , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Infecções Estafilocócicas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Exposição Materna/efeitos adversos , Gravidez , Complicações na Gravidez/microbiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia , Linfócitos T Reguladores/citologia
13.
Sci Rep ; 10(1): 1982, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029751

RESUMO

People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes in progeny. We investigated whether early gestation [gestational day (GD) 10] or late gestation (GD19) MIA, via viral mimetic polyI:C, produces deficits in inhibitory neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, and hippocampal subregions of male adult rat offspring. In situ hybridisation revealed that polyI:C offspring had: (1) SST mRNA reductions in the cingulate cortex and nucleus accumbens shell, regardless of MIA timing; (2) SSTR2 mRNA reductions in the cortex and striatum of GD19, but not GD10, MIA; (3) no alterations in cortical or striatal GAD1 mRNA of polyI:C offspring, but an expected reduction of PVALB mRNA in the infralimbic cortex, and; (4) no alterations in inhibitory markers in hippocampus. Maternal IL-6 response negatively correlated with adult offspring SST mRNA in cortex and striatum, but not hippocampus. These results show lasting inhibitory-related deficits in cortex and striatum in adult offspring from MIA. SST downregulation in specific cortical and striatal subregions, with additional deficits in somatostatin-related signalling through SSTR2, may contribute to some of the adult behavioural changes resulting from MIA and its timing.


Assuntos
Inibição Neural/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Esquizofrenia/imunologia , Animais , Comportamento Animal , Biomarcadores/análise , Biomarcadores/metabolismo , Córtex Cerebral/patologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Glutamato Descarboxilase/análise , Glutamato Descarboxilase/metabolismo , Hipocampo/patologia , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Interneurônios/imunologia , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Poli I-C/imunologia , Gravidez , Ratos , Receptores de Somatostatina/análise , Receptores de Somatostatina/metabolismo , Esquizofrenia/patologia , Fatores Sexuais , Transdução de Sinais/imunologia , Somatostatina/análise , Somatostatina/metabolismo , Fatores de Tempo
14.
Int J Mol Sci ; 21(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041252

RESUMO

Lead (Pb) is a heavy metal with a proven neurotoxic effect. Exposure is particularly dangerous to the developing brain in the pre- and neonatal periods. One postulated mechanism of its neurotoxicity is induction of inflammation. This study analyzed the effect of exposure of rat pups to Pb during periods of brain development on the concentrations of selected cytokines and prostanoids in the forebrain cortex, hippocampus and cerebellum. METHODS: Administration of 0.1% lead acetate (PbAc) in drinking water ad libitum, from the first day of gestation to postnatal day 21, resulted in blood Pb in rat pups reaching levels below the threshold considered safe for humans by the Centers for Disease Control and Prevention (10 µg/dL). Enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of interleukins IL-1ß, IL-6, transforming growth factor-ß (TGF-ß), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). Western blot and quantitative real-time PCR were used to determine the expression levels of cyclooxygenases COX-1 and COX-2. Finally, Western blot was used to determine the level of nuclear factor kappa B (NF-κB). RESULTS: In all studied brain structures (forebrain cortex, hippocampus and cerebellum), the administration of Pb caused a significant increase in all studied cytokines and prostanoids (IL-1ß, IL-6, TGF-ß, PGE2 and TXB2). The protein and mRNA expression of COX-1 and COX-2 increased in all studied brain structures, as did NF-κB expression. CONCLUSIONS: Chronic pre- and neonatal exposure to Pb induces neuroinflammation in the forebrain cortex, hippocampus and cerebellum of rat pups.


Assuntos
Cerebelo/imunologia , Encefalite/induzido quimicamente , Hipocampo/imunologia , Chumbo/toxicidade , Efeitos Tardios da Exposição Pré-Natal/imunologia , Prosencéfalo/imunologia , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Cerebelo/efeitos dos fármacos , Dinoprostona/metabolismo , Modelos Animais de Doenças , Encefalite/imunologia , Feminino , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Gravidez , Prosencéfalo/efeitos dos fármacos , Ratos , Tromboxano B2/metabolismo , Fator de Crescimento Transformador beta/metabolismo
15.
Eur J Pharmacol ; 872: 172978, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32014487

RESUMO

Evidences from human and animal studies indicate that exposure to infection during early life act as a stressor to impair the hypothalamic-pituitary-adrenal (HPA) axis and may be one of the contributing factors of mental illness of later life. Several atypical antipsychotic drugs (AAPDs) proved to be effective in alleviating psychiatric illness through normalization of HPA axis. However, AAPD are least tried to evaluate their efficacy in modulation of HPA axis impaired under infection. The present study elucidated that the treatment with AAPD paliperidone (PAL: 0.025 mg/kg/bw and 0.05 mg/kg/bw) during periadolescence period (postnatal day 35- postnatal day 56) dose-dependently normalized the HPA axis of the female mice who were gestationally (gestational day 15 and 17) exposed to bacterial endotoxin lipopolysaccharide (LPS: 800 µg/kg/bw; intraperitoneally). The effectiveness of PAL treatment in counteracting the LPS induced hyperactivity of HPA axis was age-related, better observed at postnatal day 120 than at postnatal day 200. The PAL modulation of HPA axis reflected at different levels: inhibition of hypothalamic CRF expression and reduction in plasma levels of adrenocorticotropin and corticosterone. Histopathological alterations such as hypertrophy and/or hyperplasia in cortical zona fasciculata as well as medullary chromaffin cells of adrenal also normalized on PAL treatment. The comparatively long wash out period after drug treatment (postnatal day 57- postnatal day 200) along with age related hormonal imbalance could be correlated to less effectiveness of PAL on HPA axis at postnatal day 200. PAL modulation of HPA axis might be through maintenance of cytokines and reproductive axis homeostasis.


Assuntos
Antipsicóticos/administração & dosagem , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Adolescente , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Fatores Etários , Animais , Células Cromafins/efeitos dos fármacos , Células Cromafins/metabolismo , Corticosterona/sangue , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lipopolissacarídeos/imunologia , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/imunologia , Transtornos Mentais/fisiopatologia , Camundongos , Palmitato de Paliperidona/administração & dosagem , Sistema Hipófise-Suprarrenal/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Adulto Jovem , Zona Fasciculada/efeitos dos fármacos , Zona Fasciculada/metabolismo , Zona Fasciculada/patologia
16.
J Neuroinflammation ; 17(1): 39, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992316

RESUMO

BACKGROUND: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status. METHODS: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis. RESULTS: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1ß, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-ß, IL-10, and IL-15 was associated with neurodevelopmental delay. CONCLUSIONS: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.


Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Deficiências do Desenvolvimento/induzido quimicamente , Deficiências do Desenvolvimento/imunologia , Etanol/efeitos adversos , Sistema Imunitário/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Pré-Escolar , Citocinas/sangue , Deficiências do Desenvolvimento/psicologia , Feminino , Humanos , Sistema Imunitário/efeitos dos fármacos , Lactente , Recém-Nascido , Estudos Longitudinais , Mães , Testes Neuropsicológicos , Gravidez , Ucrânia
17.
Allergol Immunopathol (Madr) ; 48(2): 130-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31477395

RESUMO

BACKGROUND: Several studies suggest that early-life exposure to animal allergens constitutes a relevant risk factor for the development of allergic sensitization. OBJECTIVES: The aim of the present study was to determine the role of interleukin-33 in children sensitive to cat allergen with allergic rhinitis and/or asthma. METHODS: The study included 51 children aged 5-18 years, both sexes, allergic to cats. Sensitization to cat allergen was confirmed by skin prick tests or specific IgE. Children were evaluated for the presence of bronchial asthma, atopic dermatitis, allergic rhinitis. A questionnaire evaluating the occurrence of allergic symptoms in children after contact with the cat and dog was performed. Mothers completed a questionnaire regarding cat exposure: during pregnancy and having a cat at home. A blood sample was taken from all children to measure the level of IL-33 in the serum. RESULTS: Keeping a cat in the home, once in the past, or having a cat in the home during the mother's pregnancy, revealed a statistically significant relationship with IL-33 levels in the studied patients. Also, daily contact with a cat during pregnancy affected the level of IL-33. Higher levels of IL-33 were shown in people with hypersensitivity to cat and pollen allergens and cat and other animals. In patients with bronchial asthma higher levels of IL-33 were found than in patients without bronchial asthma. CONCLUSIONS: Increased serum levels of IL-33 is related with keeping cats during pregnancy and in early childhood and can be associated with the development of asthma in children.


Assuntos
Gatos , Hipersensibilidade/imunologia , Interleucina-33/imunologia , Animais de Estimação/imunologia , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/sangue , Interleucina-33/sangue , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
18.
Gut ; 69(1): 42-51, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31036757

RESUMO

BACKGROUND AND AIMS: Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring's microbiome. METHODS: We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines. RESULTS: Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in Gammaproteobacteria and depletion in Bifidobacteria. Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon. CONCLUSION: Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.


Assuntos
Microbioma Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Complicações na Gravidez/microbiologia , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Imunidade Adaptativa , Adulto , Animais , Bactérias/classificação , Bactérias/isolamento & purificação , Disbiose/imunologia , Disbiose/microbiologia , Transplante de Microbiota Fecal/métodos , Fezes/microbiologia , Feminino , Seguimentos , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Vida Livre de Germes , Humanos , Recém-Nascido , Doenças Inflamatórias Intestinais/imunologia , Masculino , Troca Materno-Fetal , Gravidez , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Estudos Prospectivos
19.
Ecotoxicol Environ Saf ; 188: 109867, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31689658

RESUMO

BACKGROUND: Accumulating epidemiological studies showed that prenatal and early life exposure to ambient air pollution was important contributor to the development of childhood asthma. However, the effects and mechanisms of prenatal exposure to ozone (O3), a type of ambient air pollution, on the progression of asthma in offspring remain unclear. OBJECTIVE: This study aimed to determine the effects and mechanism of asthma in offspring after prenatal O3 exposure. METHODS: Pregnant BALB/c mice were exposed to O3 or air on gestational days (GDs) 13-18. Their offspring were sensitized and challenged to ovalbumin (OVA) to establish asthma model, and the asthma features were evaluated. The splenic natural killer (NK) cells in the offspring were measured to explore the mechanism on the effects of asthma in the offspring. The responses of the pregnant mice and dams after O3 exposure were evaluated. RESULTS: Airway inflammation, mucus secretion, OVA-specific immunoglobulin (Ig) E, T helper (Th) 2-skewed response, the frequency of CD3ε-CD49b+ splenic NK cells, the expression of tumor necrosis factor (TNF)-α, and IL (interleukin)-17 were significantly exacerbated in the OVA-induced asthma offspring after prenatal O3 exposure. In addition, airway inflammation, a lower number of CD3ε-CD49b+ splenic NK cells, and systemic oxidative stress were caused at the end of pregnancy after O3 exposure, which did not recover at the end of lactation for the first two responses. CONCLUSIONS: Prenatal O3 exposure increased the severity of OVA-induced asthma in the offspring, which might be directly induced by CD3ε-CD49b+ splenic NK cells in the offspring and indirectly related to the damaged maternal immune system.


Assuntos
Poluentes Atmosféricos/toxicidade , Asma/induzido quimicamente , Asma/patologia , Ovalbumina , Ozônio/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Asma/imunologia , Feminino , Células Matadoras Naturais/imunologia , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Equilíbrio Th1-Th2
20.
Rev Chil Pediatr ; 90(5): 555-558, 2019 Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-31859740

RESUMO

Autism Spectrum Disorder (ASD) etiology has been related whit complex interaction between ge netic and environmental factors. In the last years, numerous studies have suggested that maternal immune activation during pregnancy could be related to ASD in the offspring. This relation could be explained by the effects of pro-inflammatory cytokines, autoantibodies and microglial synap tic pruning during early embryonic development. Better understanding of Neurodevelopmental Disorders risk factors will support appropriate strategies of screening and management of risk population.


Assuntos
Transtorno do Espectro Autista/imunologia , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Transtorno do Espectro Autista/etiologia , Autoanticorpos/imunologia , Citocinas/imunologia , Feminino , Humanos , Microglia/imunologia , Gravidez , Fatores de Risco
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