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This document provides supplementary guidance on specific topics for the allergenicity risk assessment of genetically modified plants. In particular, it supplements general recommendations outlined in previous EFSA GMO Panel guidelines and Implementing Regulation (EU) No 503/2013. The topics addressed are non-IgE-mediated adverse immune reactions to foods, in vitro protein digestibility tests and endogenous allergenicity. New scientific and regulatory developments regarding these three topics are described in this document. Considerations on the practical implementation of those developments in the risk assessment of genetically modified plants are discussed and recommended, where appropriate.
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BACKGROUND: In genetically modified (GM) crops there is a risk that the inserted genes may introduce new allergens and/or adjuvants into the food and feed chain. The MON810 maize, expressing the insecticidal Cry1Ab toxin, is grown in many countries worldwide. In animal models, intranasal and intraperitoneal immunisations with the purified Cry1Ab proteins have induced immune responses, and feeding trials with Cry1Ab-containing feed have revealed some altered immune responses. Previous investigations have primarily measured antibody responses to the protein, while investigations of clinical food allergy symptoms, or allergy promotion (adjuvant effect) associated with the Cry1Ab protein are largely missing. We aimed to investigate immunogenic, allergenic and adjuvant properties of purified Cry1Ab toxin (trypCry1Ab, i.e., trypsin activated Cry1Ab) in a mouse model of food allergy. METHOD: Female C3H/HeJ mice were immunized by intragastric gavage of 10 µg purified, trypsin activated Cry1Ab toxin (trypCry1Ab) alone or together with the food allergen lupin. Cholera toxin was added as a positive control for adjuvant effect to break oral tolerance. Clinical symptoms (anaphylaxis) as well as humoral and cellular responses were assessed. RESULTS: In contrast to results from previous airway investigations, we observed no indication of immunogenic properties of trypCry1Ab protein after repeated intragastric exposures to one dose, with or without CT as adjuvant. Moreover, the results indicated that trypCry1Ab given by the intragastric route was not able to promote allergic responses or anaphylactic reactions against the co-administered allergen lupin at the given dose. CONCLUSION: The study suggests no immunogenic, allergenic or adjuvant capacity of the given dose of trypCry1Ab protein after intragastric exposure of prime aged mice.
Assuntos
Alérgenos/imunologia , Criptocromos/imunologia , Hipersensibilidade Alimentar/imunologia , Proteínas de Insetos/imunologia , Intestinos/imunologia , Extratos Vegetais/imunologia , Zea mays/imunologia , Animais , Toxinas Bacterianas/imunologia , Criptocromos/metabolismo , Grão Comestível , Feminino , Alimentos Geneticamente Modificados , Imunoglobulina E/metabolismo , Intestinos/microbiologia , Lupinus/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Organismos Geneticamente Modificados , Proteólise , Tripsina/metabolismo , Zea mays/genéticaRESUMO
The impact of early life exposure to bisphenol A (BPA) through drinking water was investigated in mouse models of respiratory allergy, food allergy and oral tolerance. Balb/c mice were exposed to BPA (0, 10 or 100 µg/ml), and the offspring were intranasally exposed to the allergen ovalbumin (OVA). C3H/HeJ offspring were sensitized with the food allergen lupin by intragastric gavage, after exposure to BPA (0, 1, 10 or 100 µg/ml). In separate offspring, oral tolerance was induced by gavage of 5 mg lupin one week before entering the protocol for the food allergy induction. In the airway allergy model, BPA (100 µg/ml) caused increased eosinophil numbers in bronchoalveolar lavage fluid (BALF) and a trend of increased OVA-specific IgE levels. In the food allergy and tolerance models, BPA did not alter the clinical anaphylaxis or antibody responses, but induced alterations in splenocyte cytokines and decreased mouse mast cell protease (MMCP)-1 serum levels. In conclusion, early life exposure to BPA through drinking water modestly augmented allergic responses in a mouse model of airway allergy only at high doses, and not in mouse models for food allergy and tolerance. Thus, our data do not support that BPA promotes allergy development at exposure levels relevant for humans.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Hipersensibilidade Alimentar/etiologia , Tolerância Imunológica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Hipersensibilidade Respiratória/induzido quimicamente , Animais , Animais Recém-Nascidos , Compostos Benzidrílicos/administração & dosagem , Células Cultivadas , Cruzamentos Genéticos , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Estrogênios não Esteroides/administração & dosagem , Estrogênios não Esteroides/toxicidade , Feminino , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Hipersensibilidade Alimentar/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Lactação , Masculino , Camundongos Endogâmicos BALB C , Fenóis/administração & dosagem , Gravidez , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Baço/patologia , Poluentes Químicos da Água/administração & dosagem , Poluentes Químicos da Água/toxicidadeRESUMO
Type 1 diabetes mellitus (T1DM) is an autoimmune destruction of insulin producing pancreatic beta-cells due to a genetic predisposition and can be triggered by environmental factors. We have previously shown that bisphenol A (BPA) accelerates the spontaneous development of diabetes in non-obese diabetic (NOD) mice. Here, we hypothesized that oral exposure to a mixture of the endocrine disruptors BPA and phthalates, relevant for human exposure, would accelerate diabetes development compared to BPA alone. NOD mice were exposed to BPA (1 mg/l), a mixture of phthalates (DEHP 1 mg/l, DBP 0.2 mg/l, BBP 10 mg/l and DiBP 20 mg/l) or a combination of BPA and the phthalate mixture through drinking water from conception and throughout life. Previous observations that BPA exposure increased the prevalence of diabetes and insulitis and decreased the number of tissue resident macrophages in pancreas were confirmed, and extended by demonstrating that BPA exposure also impaired the phagocytic activity of peritoneal macrophages. None of these effects were observed after phthalate exposure alone. The phthalate exposure in combination with BPA seemed to dampen the BPA effects on macrophage number and function as well as diabetes development, but not insulitis development. Exposure to BPA alone or in combination with phthalates decreased cytokine release (TNFα, IL-6, IL-10, IFNγ, IL-4) from in vitro stimulated splenocytes and lymph node cells, indicating systemic changes in immune function. In conclusion, exposure to BPA, but not to phthalates or mixed exposure to BPA and phthalates, accelerated diabetes development in NOD mice, apparently in part via systemic immune alterations including decreased macrophage function.
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Epidemiological evidence suggesting that exposure to traffic air pollution may enhance sensitization to common allergens in children is increasing, and animal studies support biological plausibility and causality. The effect of air pollution on respiratory symptoms was suggested to be gender dependent. Previous studies showed that allergy-promoting activity of polystyrene particles (PSP) increased with decreasing particle size after footpad injection of mice. The primary aim of this study was to confirm the influence of particle size on the immunoglobulin E (IgE)-promoting capacity of particles in an airway allergy model. A second aim was to examine whether the allergy-promoting capacity of particles was influenced by gender. Female and male mice were intranasally exposed to the allergen ovalbumin (OVA) with or without ultrafine, fine, or coarse PSP modeling the core of ambient air particles. After intranasal booster immunizations with OVA, serum levels of OVA-specific IgE antibodies, and also markers of airway inflammation and cellular responses in the lung-draining mediastinal lymph nodes (MLN), were determined. PSP of all sizes promoted allergic responses, measured as increased serum concentrations of OVA-specific IgE antibodies. Further, PSP produced eosinophilic airway inflammation and elevated MLN cell numbers as well as numerically reducing the percentage of regulatory T cells. Ultrafine PSP produced stronger allergic responses to OVA than fine and coarse PSP. Although PSP enhanced sensitization in both female and male mice, significantly higher IgE levels and numbers of eosinophils were observed in females than males. However, the allergy-promoting effect of PSP was apparently independent of gender. Thus, our data support the notion that ambient air particle pollution may affect development of allergy in both female and male individuals.
Assuntos
Hipersensibilidade/patologia , Ovalbumina/efeitos adversos , Material Particulado/efeitos adversos , Poliestirenos/efeitos adversos , Hipersensibilidade Respiratória/induzido quimicamente , Animais , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Imunoglobulina E/sangue , Inflamação/induzido quimicamente , Inflamação/patologia , Linfonodos/citologia , Masculino , Camundongos , Tamanho da Partícula , Fatores Sexuais , Linfócitos T Auxiliares-Indutores , Linfócitos T ReguladoresRESUMO
BACKGROUND: Maternal exposure to dioxins and dioxin-like compounds may affect fetal growth and development. We evaluated the association between in utero dioxin-like activity and birth outcomes in a prospective European mother-child study. METHODS: We measured dioxin-like activity in maternal and cord blood plasma samples collected at delivery using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX) bioassay in 967 mother-child pairs, in Denmark, Greece, Norway, Spain, and England. Multiple linear regression models were used to investigate the associations with birth weight, gestational age, and head circumference. RESULTS: Plasma dioxin-like activity was higher in maternal sample than in cord samples. Birth weight was lower with medium (-58 g [95% confidence interval (CI) = -176 to 62]) and high (-82 g [-216 to 53]) tertiles of exposure (cord blood) compared with the lowest tertile. Gestational age was shorter by approximately half a week in the highest compared with the lowest (-0.4 weeks [95% CI = -0.8 to -0.1]). This association was stronger in boys than in girls, although the statistical evidence for interaction was weak (P = 0.22). Analysis based on CALUX-toxic equivalents expressed per milliliter of plasma showed similar trends. We found no association between dioxin-like activity in maternal plasma and birth outcomes. CONCLUSIONS: Results from this international general population study suggest an association between low-level prenatal dioxin-like activity and shorter gestational age, particularly in boys, with weaker associations for birth weight.
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Peso ao Nascer/efeitos dos fármacos , Dioxinas/toxicidade , Poluentes Ambientais/toxicidade , Exposição Materna/efeitos adversos , Nascimento Prematuro/induzido quimicamente , Adulto , Bioensaio , Dioxinas/sangue , Poluentes Ambientais/sangue , Europa (Continente) , Feminino , Sangue Fetal/química , Idade Gestacional , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Gravidez , Estudos Prospectivos , Fatores SexuaisRESUMO
Diabetes mellitus type 1 is an autoimmune disease with a genetic predisposition that is triggered by environmental factors during early life. Epidemiological studies show that bisphenol A (BPA), an endocrine disruptor, has been detected in about 90% of all analyzed human urine samples. In this study, BPA was found to increase the severity of insulitis and the incidence of diabetes in female non obese diabetic (NOD) mice offspring after transmaternal exposure through the dams' drinking water (0, 0.1, 1, and 10mg/l). Both the severity of insulitis in the pancreatic islets at 11 weeks of age and the diabetes prevalence at 20 weeks were significantly increased for female offspring in the highest exposure group compared to the control group. Increased numbers of apoptotic cells, a reduction in tissue resident macrophages and an increase in regulatory T cells were observed in islets prior to insulitis development in transmaternally exposed offspring. The detectable apoptotic cells were identified as mostly glucagon producing alpha-cells but also tissue resident macrophages and beta-cells. In the local (pancreatic) lymph node neither regulatory T cell nor NKT cell populations were affected by maternal BPA exposure. Maternal BPA exposure may have induced systemic immune changes in offspring, as evidenced by alterations in LPS- and ConA-induced cytokine secretion in splenocytes. In conclusion, transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life.
Assuntos
Compostos Benzidrílicos/toxicidade , Diabetes Mellitus Tipo 1/induzido quimicamente , Disruptores Endócrinos/toxicidade , Exposição Materna/efeitos adversos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/farmacocinética , Glicemia/análise , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Disruptores Endócrinos/farmacocinética , Feminino , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Fenóis/farmacocinética , Gravidez , Baço/crescimento & desenvolvimento , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
BACKGROUND: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development. OBJECTIVES: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. METHODS: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. RESULTS: Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN. CONCLUSION: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.
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Biomarcadores/análise , Carcinógenos/análise , Sangue Fetal/citologia , Hormônios/análise , Leucemia/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Linfócitos T/química , Carcinógenos/toxicidade , Criança , Estudos de Coortes , Adutos de DNA/efeitos adversos , Adutos de DNA/análise , Europa (Continente)/epidemiologia , Feminino , Sangue Fetal/química , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Hormônios/efeitos adversos , Humanos , Leucemia/induzido quimicamente , Malondialdeído/efeitos adversos , Malondialdeído/análise , Testes para Micronúcleos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Linfócitos T/efeitos dos fármacosRESUMO
There is a growing concern for the possible health impact of nanoparticles. The main objective of this study was to investigate the allergy-promoting capacity of four different carbon nanofiber (CNF) samples in an injection and an airway mouse model of allergy. Secondly, the potency of the CNF was compared to the previously reported allergy-promoting capacity of carbon nanotubes (CNT) in the airway model. Ultrafine carbon black particles (ufCBP) were used as a positive control. Particles were given together with the allergen ovalbumin (OVA) either by subcutaneous injection into the footpad or intranasally to BALB/cA mice. After allergen booster, OVA-specific IgE, IgG1, and IgG2a in serum were measured. In the airway model, inflammation was determined as influx of inflammatory cells (eosinophils, neutrophils, lymphocytes, and macrophages) and by mediators (MCP-1 and TNF-α present in bronchoalveolar fluid (BALF)). CNF and CNT both increased OVA-specific IgE levels in the two models, but in the airway model, the CNT gave a significantly stronger IgE response than the CNF. Furthermore, the CNT and not the CNF promoted eosinophil lung inflammation. Our data therefore suggest that nanotube-associated properties are particularly potent in promoting allergic responses.
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Imunoglobulina E/imunologia , Pulmão/metabolismo , Nanofibras/administração & dosagem , Nanotubos de Carbono/química , Adjuvantes Imunológicos , Animais , Carbono/química , Carbono/imunologia , Modelos Animais de Doenças , Hipersensibilidade , Imunoglobulina E/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Nanofibras/química , Ovalbumina/química , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PROBLEM: Maternal immune responses may interfere with offspring allergy development as maternal immunization may suppress IgE development, while maternal allergy may promote allergy. Therefore, we investigated the effect of two different maternal treatments on airway allergy in female and male offspring. METHOD OF STUDY: Pregnant mice were immunized (IMM) with ovalbumin (OVA) or immunized and airway-challenged (IMM+AI). At different ages, airway allergy to OVA was induced in offspring by intranasal sensitization. RESULTS: Maternal IgG1 was found at higher levels in IMM+AI than in IMM offspring. After sensitization, the suppression of OVA-specific IgE and IgG1 was complete in juvenile offspring but waned with age concurrently with maternal IgG1 levels. Cytokine secretion, lung inflammation, and B cell priming were not suppressed although IgE responses were. CONCLUSIONS: High compared with low levels of maternal IgG1 were associated with lower TH 2 antibody production after adult offspring were re-exposed to OVA. Thus, offspring allergy-related responses appeared to be shaped by maternal antibody levels.
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Linfócitos B/imunologia , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Hipersensibilidade Respiratória/imunologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Materno-Adquirida/imunologia , Imunização , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Terapia de Imunossupressão , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos , Ovalbumina/imunologia , Gravidez , Hipersensibilidade Respiratória/induzido quimicamenteRESUMO
Exposure to the endocrine disruptor (ED) bisphenol A (BPA) used in polycarbonate plastic and epoxy resins appears ubiquitous since BPA can be found in over 90% of analyzed urine samples from all age groups. There is a parallel occurrence of increased prevalence in type 1 diabetes mellitus (T1DM) and an increased exposure to EDs the last decades. T1DM is caused by insulin deficiency due to autoimmune destruction of insulin producing pancreatic beta cells and has been suggested to be induced by various environmental factors acting together with a genetic predisposition. The objective of the present study was to investigate the effect of BPA (0, 1 and 100 mg/l BPA in the drinking water) on T1DM development in nonobese diabetic (NOD) mice, spontaneously developing T1DM. Histological evaluation of pancreas from 12-weeks-old female mice revealed significantly increased insulitis in mice exposed to 1 mg/l BPA, while the insulitis was less severe at the higher BPA exposure. Serum glucose levels in the 1 mg/ml BPA group tended to be hyperglycaemic, also indicating an accelerated onset of T1DM. The high BPA exposure seemed to counteract the diabetes development in females and also in male NOD mice for both BPA concentrations. Prior to insulitis, both BPA concentrations resulted in increased apoptosis and reduced numbers of tissue resident macrophages in pancreatic islets. In conclusion, long-term BPA exposure at a dose three times higher than the tolerable daily intake of 50 µg/kg, appeared to accelerate spontaneous insulitis and diabetes development in NOD mice.
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Compostos Benzidrílicos/toxicidade , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Disruptores Endócrinos/toxicidade , Predisposição Genética para Doença , Pâncreas/efeitos dos fármacos , Fenóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Autoanticorpos/sangue , Glicemia/análise , Citocinas/sangue , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Relação Dose-Resposta a Droga , Feminino , Interação Gene-Ambiente , Insulina/imunologia , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD , Pâncreas/imunologia , Pâncreas/metabolismo , Pâncreas/patologiaRESUMO
Perfluoroalkyl substances (PFAS) are suggested to have immunosuppressive effects; exposure in utero and in the first years of life is of special concern as fetuses and small children are highly vulnerable to toxicant exposure. The objective of this study was to investigate the effect of pre-natal exposure to PFAS on responses to pediatric vaccines and immune-related health outcomes in children up to 3 years of age. In the prospective birth-cohort BraMat, a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa), pregnant women from Oslo and Akershus, Norway, were recruited during 2007-2008. Three annual questionnaire-based follow-ups were performed. Blood samples were collected from the mothers at the time of delivery and from the children at the age of 3 years. As a measure of pre-natal exposure to PFAS, the concentrations of perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) were determined in maternal blood from 99 BraMat participants. Main outcome measures were anti-vaccine antibody levels, common infectious diseases and allergy- and asthma-related health outcomes in the children up to the age of 3 years. There was an inverse association between the level of anti-rubella antibodies in the children's serum at age 3 years and the concentrations of the four PFAS. Furthermore, there was a positive association between the maternal concentrations of PFOA and PFNA and the number of episodes of common cold for the children, and between PFOA and PFHxS and the number of episodes of gastroenteritis. No associations were found between maternal PFAS concentrations and the allergy- and asthma-related health outcomes investigated. The results indicate that pre-natal exposure to PFAS may be associated with immunosuppression in early childhood.
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Alcenos/toxicidade , Asma/epidemiologia , Resfriado Comum/epidemiologia , Gastroenterite/epidemiologia , Hipersensibilidade/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Ácidos Alcanossulfônicos/sangue , Anticorpos Antivirais/sangue , Asma/imunologia , Caprilatos/sangue , Pré-Escolar , Estudos de Coortes , Resfriado Comum/imunologia , Feminino , Fluorocarbonos/efeitos adversos , Fluorocarbonos/sangue , Fluorocarbonos/toxicidade , Seguimentos , Gastroenterite/imunologia , Humanos , Hipersensibilidade/imunologia , Terapia de Imunossupressão , Incidência , Masculino , Noruega , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Prevalência , Estudos Prospectivos , Resultado do Tratamento , VacinasRESUMO
BACKGROUND: High-molecular-weight phthalates in indoor dust have been associated with asthma in children, but few studies have evaluated phthalate biomarkers in association with respiratory outcomes. OBJECTIVES: We explored the association between urinary concentrations of phthalate metabolites and current asthma. METHODS: In a cross-sectional analysis, 11 metabolites of 8 phthalates [including four metabolites of di(2-ethylhexyl) phthalate] were measured in one first morning void collected from 2001 through 2004 from 623 10-year-old Norwegian children. Logistic regression models controlling for urine specific gravity, sex, parental asthma, and income were used to estimate associations between current asthma and phthalate metabolite concentrations by quartiles or as log10-transformed variables. RESULTS: Current asthma was associated with both mono(carboxyoctyl) phthalate (MCOP) and mono(carboxynonyl) phthalate (MCNP), although the association was limited to those in the highest quartile of these chemicals. The adjusted odds ratio (aOR) for current asthma was 1.9 (95% CI: 1.0, 3.3) for the highest MCOP quartile compared with the lowest quartile, and 1.3 (95% CI: 0.98, 1.7) for an interquartile-range increase. The aOR for current asthma was 2.2 (95% CI: 1.2, 4.0) for the highest MCNP quartile and 1.3 (95% CI: 1.0, 1.7) for an interquartile-range increase. The other phthalate metabolites were not associated with current asthma. CONCLUSIONS: Current asthma was associated with the highest quartiles of MCOP and MCNP, metabolites of two high molecular weight phthalates, diisononyl phthalate and diisodecyl phthalate, respectively. Given the short biological half-life of the phthalates and the cross-sectional design, our findings should be interpreted cautiously.
Assuntos
Asma/induzido quimicamente , Biomarcadores/urina , Ácidos Ftálicos/toxicidade , Carga Corporal (Radioterapia) , Criança , Estudos Transversais , Humanos , Noruega , Ácidos Ftálicos/farmacocinética , Ácidos Ftálicos/urinaRESUMO
We investigated whether prenatal exposure from the maternal diet to the toxicants polychlorinated biphenyls (PCBs) and dioxins is associated with the development of immune-related diseases in childhood. Children participating in BraMat, a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa), were followed in the three first years of life using annual questionnaires (0-3years; n=162, 2-3years; n=180), and blood parameters were examined at three years of age (n=114). The maternal intake of the toxicants was calculated using a validated food frequency questionnaire from MoBa. Maternal exposure to PCBs and dioxins was found to be associated with an increased risk of wheeze and more frequent upper respiratory tract infections. Furthermore, maternal exposure to PCBs and dioxins was found to be associated with reduced antibody response to a measles vaccine. No associations were found between prenatal exposure and immunophenotype data, allergic sensitization and vaccine-induced antibody responses other than measles. Our results suggest that prenatal dietary exposure to PCBs and dioxins may increase the risk of wheeze and the susceptibility to infectious diseases in early childhood.
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Dioxinas/toxicidade , Poluentes Ambientais/toxicidade , Exposição Materna , Bifenilos Policlorados/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Formação de Anticorpos , Pré-Escolar , Feminino , Contaminação de Alimentos , Humanos , Lactente , Vacina contra Sarampo/imunologia , Noruega , Gravidez , Análise de Regressão , Sons Respiratórios/etiologia , Infecções Respiratórias/induzido quimicamente , Infecções Respiratórias/epidemiologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: It has been suggested that fetal carcinogenic exposure might lead to predisposition to develop cancer during childhood or in later life possibly through modulation of the fetal transcriptome. Because gender effects in the incidence of childhood cancers have been described, we hypothesized differences at the transcriptomic level in cord blood between male and female newborns as a consequence of fetal carcinogenic exposure. The objective was to investigate whether transcriptomic responses to dietary genotoxic and nongenotoxic carcinogens show gender-specific mechanisms-of-action relevant for chemical carcinogenesis. METHODS: Global gene expression was applied in umbilical cord blood samples, the CALUX-assay was used for measuring dioxin(-like), androgen(-like), and estrogen(-like) internal exposure, and acrylamide-hemoglobin adduct levels were determined by mass spectrometry adduct-FIRE-procedure(TM). To link gene expression to an established phenotypic biomarker of cancer risk, micronuclei frequencies were investigated. RESULTS: While exposure levels did not differ between sexes at birth, important gender-specific differences were observed in gene expressions associated with these exposures linked with cell cycle, the immune system and more general cellular processes such as posttranslation. Moreover, oppositely correlating leukemia/lymphoma genes between male and female newborns were identified in relation to the different biomarkers of exposure that might be relevant to male-specific predisposition to develop these cancers in childhood. CONCLUSIONS/IMPACT: This study reveals different transcriptomic responses to environmental carcinogens between the sexes. In particular, male-specific TNF-alpha-NF-kB signaling upon dioxin exposure and activation of the Wnt-pathway in boys upon acrylamide exposure might represent possible mechanistic explanations for gender specificity in the incidence of childhood leukemia.
Assuntos
Carcinógenos/toxicidade , Sangue Fetal/metabolismo , Feto/efeitos dos fármacos , Perfilação da Expressão Gênica , Acrilamida/metabolismo , Adulto , Biomarcadores , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Masculino , Micronúcleos com Defeito Cromossômico/estatística & dados numéricos , Gravidez , Receptores Androgênicos/genética , Caracteres Sexuais , Transdução de SinaisRESUMO
BACKGROUND: Childhood allergy is influenced by maternal factors and allergen exposure in early life, but the factors that determine the development of allergy and tolerance are unknown. Therefore, we compared the effects of two early life interventions, i.e. maternal allergen immunization and postnatal intranasal allergen exposure, as well as a combination of both treatments on allergic responses in the offspring. METHODS: Female mice were immunized with ovalbumin (OVA) or vehicle during pregnancy. After birth, half the offspring from each group were exposed intranasally to low doses of OVA or vehicle weekly for 5 weeks before intraperitoneal immunization with OVA. RESULTS: Maternal immunization reduced OVA-specific IgE and IgG1, but increased IgG2a and T(H)2 cytokine responses in the offspring after immunization. Postnatal intranasal OVA exposure similarly reduced both IgE and IgG1, but also spleen cell numbers and cytokine secretion. Following airway challenges of the offspring, IgE and airway inflammation were suppressed only by intranasal exposure, but not by maternal immunization, the effect of which also waned with age. Differential gene expression in the spleen of offspring supported that IgE suppression by the two interventions was caused by different mechanisms. Despite this, tolerance development after mucosal exposure was obtained in the offspring of immunized dams. CONCLUSIONS: The study suggests that prevention of allergy is possible if initiated in early life, and early mucosal allergen exposure may play a protective role independent of the maternal immune responses.
Assuntos
Alérgenos/administração & dosagem , Hipersensibilidade Imediata/prevenção & controle , Tolerância Imunológica , Imunidade Materno-Adquirida , Imunidade nas Mucosas , Imunização , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Feminino , Humanos , Hipersensibilidade Imediata/imunologia , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Masculino , Camundongos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Gravidez , Células Th2/imunologiaRESUMO
The Norwegian Food Allergy Register was established at the Norwegian Institute of Public Health in 2000. The purpose of the register is to gain information about severe allergic reactions to food in Norway and to survey food products in relation to allergen labelling and contamination. Cases are reported on a voluntary basis by first line doctors, and submitted together with a serum sample for specific IgE analysis. The register has received a total of 877 reports from 1 July, 2000 to 31 December, 2010. Two age groups, small children and young adults are over-represented, and the overall gender distribution is 40:60 males-females. The legumes lupine and fenugreek have been identified as two "new" allergens in processed foods and cases of contamination and faults in production of processed foods have been revealed. The highest frequency of food specific IgE is to hazelnuts and peanuts, with a marked increase in reactions to hazelnuts during the last three years. The Food Allergy Register has improved our knowledge about causes and severity of food allergic reactions in Norway. The results show the usefulness of population based national food allergy registers in providing information for health authorities and to secure safe food for individuals with food allergies.
Assuntos
Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/etiologia , Sistema de Registros , Adolescente , Adulto , Distribuição por Idade , Idoso , Criança , Pré-Escolar , Feminino , Hipersensibilidade Alimentar/diagnóstico , Humanos , Imunoglobulina E/sangue , Lactente , Recém-Nascido , Lupinus/imunologia , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Distribuição por Sexo , Trigonella/imunologiaRESUMO
The birth cohort BraMat (n = 205; a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health) was established to study whether prenatal exposure to toxicants from the maternal diet affects immunological health outcomes in children. We here report on the environmental pollutants polychlorinated biphenyls (PCBs) and dioxins, as well as acrylamide generated in food during heat treatment. The frequency of common infections, eczema or itchiness, and periods of more than 10 days of dry cough, chest tightness or wheeze (called wheeze) in the children during the first year of life was assessed by questionnaire data (n = 195). Prenatal dietary exposure to the toxicants was estimated using a validated food frequency questionnaire from MoBa. Prenatal exposure to PCBs and dioxins was found to be associated with increased risk of wheeze and exanthema subitum, and also with increased frequency of upper respiratory tract infections. We found no associations between prenatal exposure to acrylamide and the health outcomes investigated. Our results suggest that prenatal dietary exposure to dioxins and PCBs may increase the risk of wheeze and infectious diseases during the first year of life.
Assuntos
Dioxinas/toxicidade , Exposição Materna/efeitos adversos , Bifenilos Policlorados/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Sons Respiratórios/fisiopatologia , Infecções Respiratórias/induzido quimicamente , Acrilamida/toxicidade , Adulto , Estudos de Coortes , Ingestão de Alimentos , Poluentes Ambientais/toxicidade , Feminino , Humanos , Lactente , Noruega , Gravidez , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Investigating the immunotoxic effects of exposure to chemicals usually comprises evaluation of weight and histopathology of lymphoid tissues, various lymphocyte parameters in the circulation, and immune function. Immunotoxicity assessment is time consuming in humans or requires a high number of animals, making it expensive. Furthermore, reducing the use of animals in research is an important ethical and political issue. Immunotoxicogenomics represents a novel approach to investigate immunotoxicity able of overcoming these limitations. The current research, embedded in the European Union project NewGeneris, aimed to retrieve gene expression profiles that are indicative of exposure to immunotoxicants. To this end, whole-genome gene expression was investigated in human peripheral blood mononuclear cells in response to in vitro exposure to a range of immunotoxic chemicals (4-hydroxy-2-nonenal, aflatoxin B1, benzo[a]pyrene, deoxynivalenol, ethanol, malondialdehyde, polychlorinated biphenyl 153, and 2,3,7,8-tetrachlorodibenzo-p-dioxin) and nonimmunotoxic chemicals (acrylamide, dimethylnitrosamine, 2-amino-3-methyl-3H-imidazo[4,5-F]quinoline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine). Using Agilent oligonucleotide microarrays, whole-genome gene expression profiles were generated, which were analyzed using Genedata's Expressionist software. Using Recursive Feature Elimination and Support Vector Machine, a set of 48 genes was identified that distinguishes the immunotoxic from the nonimmunotoxic compounds. Analysis for enrichment of biological processes showed the gene set to be highly biologically and immunologically relevant. We conclude that we have identified a promising transcriptomic profile indicative of immunotoxic exposure.