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BACKGROUND: Allergies are increasing worldwide. The presence of atopic diseases in the mother propagates the onset of allergic diseases in the offspring with a considerably stronger penetrance than atopic diseases of the father. Such observation challenges genetic predispositions as the sole cause of allergic diseases. Epidemiological studies suggest that caregiver stress in the perinatal period may predispose offspring to asthma. Only one group has studied the link between prenatal stress and neonatal asthma susceptibility in a murine model. OBJECTIVES: We aimed to study if the neonatal increased risk of developing allergic lung inflammation persists after puberty and if there are sex differences in susceptibility. METHODS: Pregnant BALB/c mice were subjected to a single restraint stress exposure at day 15 of gestation. Pups were separated by gender and subjected to a well-known sub-optimal asthma model after puberty. RESULTS: Adult mice born to stressed dams were more susceptible to developing allergic pulmonary inflammation since an increase in the number of eosinophils in bronchoalveolar lavage (BAL), a greater peribronchial and perivascular infiltrate, a higher proportion of mucus-producing cells, and increased IL-4 and IL-5 levels in BAL were detected compared to control mice. These effects were more profound in females than males. Moreover, only females from stressed dams showed an increase in IgE levels. CONCLUSIONS: Increased litter susceptibility to develop allergic lung inflammation induced by maternal stress persists after puberty and is more potent in females than in male mice.
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Asma , Hipersensibilidade , Pneumonia , Gravidez , Masculino , Feminino , Animais , Camundongos , Asma/etiologia , Eosinófilos , Lavagem Broncoalveolar/efeitos adversos , Pneumonia/complicações , Camundongos Endogâmicos BALB C , Pulmão , Modelos Animais de Doenças , Ovalbumina , Líquido da Lavagem BroncoalveolarRESUMO
PURPOSE: Associations between prenatal earthquake exposure and children's mental health remain unclear. Moreover, there is a paucity of research using quasi-experimental statistical techniques to diminish potential selection bias. Thus, this study aimed to explore the impact of prenatal exposure to the Chilean earthquake of 2010 on children's behavioural and emotional problems between 1½ and 3 years old using propensity score matching. METHODS: Participants included 1549 families from the Encuesta Longitudinal de la Primera Infancia cohort in Chile. Maternal reports using the Child Behaviour Checklist (CBCL) were used to assess behavioural and emotional problems between 1½ and 3 years old. Information on prenatal earthquake exposure was collected via maternal report. The Kernel matching estimator was used to compare the average treatment effects of children who were exposed to the earthquake compared to those who were not. RESULTS: Five of the seven CBCL outcomes were statistically significant after matching and adjustment for multiple testing, suggesting greater difficulties for exposed children which included emotional reactivity, anxious/depressed, sleep problems, attention problems, and aggression (mean difference of 0.69, 0.87, 0.73, 0.85, 3.51, respectively). The magnitude of the effect was small to medium. CONCLUSION: Findings contribute to the potential causal inferences between prenatal earthquake exposure and increased behavioural and emotional problems in early childhood. Results suggest that in utero experiences may have long-term consequences for infants' well-being, supporting the need for specific interventions in pregnancy after natural disasters.
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Transtornos do Comportamento Infantil , Terremotos , Lactente , Feminino , Gravidez , Criança , Humanos , Pré-Escolar , Chile , Ansiedade , Transtornos do Comportamento Infantil/psicologia , AgressãoRESUMO
This study aimed to evaluate the effects of maternal exercise on alterations induced by prenatal stress in markers of the inflammatory process and the hypothalamic-pituitary-adrenal axis in the brain and lungs of neonatal mice. Female Balb/c mice were divided into three groups: control, prenatal restraint stress, prenatal restraint stress and physical exercise before and during the gestational period. On day 0 (PND0) and 10 (PND10), mice were euthanized for brain and lung analyses. The gene expression of GR, MR, IL-6, IL-10, and TNF in the brain and lungs and the protein expression of MMP-2 in the lungs were analyzed. Maternal exercise reduced IL-6 and IL-10 gene expression in the brain of PND0 mice. Prenatal stress and maternal exercise decreased GR, MR, IL-6, and TNF gene expression in the lungs of PND0 mice. In the hippocampus of PND10 females, exercise inhibited the effects of prenatal stress on the expression of MR, IL-6, and IL-10. In the lungs of PND10 females, exercise prevented the decrease in GR expression caused by prenatal stress. In the hippocampus and lungs of PND10 males, prenatal stress decreased GR gene expression. Our findings confirm the effects induced by prenatal stress and demonstrate that physical exercise before and during the gestational period may have a protective role on inflammatory changes.
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Sistema Hipófise-Suprarrenal , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Masculino , Animais , Feminino , Camundongos , Humanos , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Interleucina-10/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Animais Recém-Nascidos , Interleucina-6/metabolismo , Estresse Psicológico/metabolismo , Encéfalo/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos BALB C , Corticosterona , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Restrição Física/efeitos adversosRESUMO
Maternal stress during pregnancy results in increased risk of developing psychiatric disorders in the offspring including anxiety, depression, schizophrenia, and autism. However, the mechanisms underlying this disease susceptibility remain largely to be determined. In this study, the involvement of the serotonin (5-HT) and kynurenine (KYN) pathways of tryptophan metabolism on the behavioral deficits induced by maternal stress during the late phase of gestation in mice was investigated. Adult offspring born to control or restraint-stressed dams were exposed to the elevated plus-maze and tail suspension tests. Metabolites of the KYN and 5-HT pathways were measured in the hippocampus and brainstem by ultra-performance liquid chromatography tandem mass spectrometry. Female, but not male, prenatally stressed (PNS) offspring displayed a depressive-like phenotype, mainly when in proestrus/diestrus, along with reduced hippocampal 5-HT levels and high 5-HT turnover rate in the hippocampus and brainstem. In contrast, male PNS mice showed enhanced anxiety-like behaviors and higher hippocampal and brainstem quinolinic acid levels compared to male offspring born to nonstressed dams. These results indicate that maternal stress affects the behavior and brain metabolism of tryptophan in the offspring in a sex-dependent manner and suggest that alterations in both the 5-HT and KYN pathways may underlie the emotional dysfunctions observed in individuals exposed to stress during in utero development.
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Cinurenina , Triptofano , Gravidez , Camundongos , Animais , Feminino , Cinurenina/metabolismo , Triptofano/metabolismo , Serotonina/metabolismo , Ansiedade/metabolismo , Comportamento AnimalRESUMO
RESUMEN: El cuerpo calloso (CC), es la mayor comisura de sustancia blanca del encéfalo de los mamíferos placentados, constituida por numerosos haces de fibras transversales que conectan áreas corticales de ambos hemisferios cerebrales. Por otro lado, el estrés se define como una respuesta general del organismo ante demandas externas o internas, inicialmente amenazantes, que consiste en movilizar recursos fisiológicos y psicológicos para poderlas afrontar. Dada la importancia del cuerpo calloso en las conexiones cortico-corticales, el objetivo del presente estudio, fue evaluar el efecto en ratas, de un estrés prenatal crónico por inmovilización, sobre la anatomía macroscópica del CC. Se utilizaron seis ratas preñadas de la cepa Wistar de 250 g, de las cuales tres fueron sometidas, a partir del octavo día postconcepción, a una restricción de movimiento por diez días (2h/día). Posteriormente, las madres prosiguieron su gestación, parto y lactancia. Al nacimiento, las camadas fueron ajustadas a seis crías machos por madre (n=36), destetadas a los 21 días y sacrificadas a los 45-52 días de edad. Los encéfalos fueron seccionados a través de la cisura interhemisférica y ambos hemisferios fotografiados por su cara medial. Las imágenes fueron digitalizadas y analizadas mediante el programa Scion Image®, para la medición del área total, parciales (tercio anterior, medio, posterior y quinto posterior) y perímetro callosal. Es así como, el estrés prenatal por inmovilización, afectó significativamente (p<0,01), la morfología macroscópica del cuerpo calloso. Evidenciándose una disminución del área total, áreas parciales y perímetro callosal, en los animales sometidos a restricción prenatal. Estableciendo una relación directa entre número de axones y área callosal e inversa entre diámetro y densidad axonal; lo observado podría tener incidencia en la transferencia interhemisférica.
SUMMARY: The Corpus Callosum (CC) is the largest white matter commissure in the brain of placental mammals, consisting of numerous transverse fiber bundles that connect cortical areas of both cerebral hemispheres. On the other hand, stress is defined as a general response of the organism to external or internal demands, initially threatening, which consists of mobilizing physiological and psychological resources to be able to face them. Given the importance of CC in cortico-cortical connections, the aim of the present study, was to evaluate the effect of chronic pre-natal immobilization stress on the macroscopic anatomy of CC in rats. Six 250g pregnant rats of the Wistar strain were used, of which three were subjected, starting on the eighth post-conception day, to movement restriction for ten days (2h/day). Subsequently, the mothers continued their gestation, delivery and lactation. At birth, litters were adjusted to six male offspring per mother (n=36), which were weaned at 21 days and slaughtered at 45-52 days of age. The brains were fixed, and later sectioned through the interhemispheric fissure and both hemispheres photographed by their medial aspect. The images were digitized and analyzed using the Scion Image® program, for the measurement of the total area, partial area (ante- rior, middle and posterior thirds, as well as posterior fifth) and callosal perimeter. Thus, prenatal stress due to immobilization significantly affected (p<0.01), the macroscopic morphology of the CC. Evidence shows a decrease in the total area, partial areas and callosal perimeter in the animals subjected to prenatal restraint, as compared to normal animals. Establishing a direct relationship between number of axons and callosal area and an inverse relationship between diameter and axonal density, what was observed may have an impact on interhemispheric transfer.
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Animais , Masculino , Feminino , Gravidez , Ratos , Estresse Fisiológico , Estresse Psicológico , Corpo Caloso/anatomia & histologia , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , ImobilizaçãoRESUMO
Pregnancy is considered a period of big variation to the maternal organism. Besides, the mother is due to stressing influences from the external environment that might intervene in health and mother-fetal wellbeing. Thus, mating in the experimental facility may avoid stress from handling and transporting pregnancy females, assuring full observation over pre and post gestational periods. However, to obtain pregnancy females can avoid loss of animals that cannot get pregnant and prevent acquiring males. This study aimed to determine if there are behavior changings caused by handling and transporting females obtained already pregnant by observing pre and postnatal periods: gestation, lactation, soundness of neonates and their development after weaning verifying alterations that could cause injury for litter growth. Animals were evaluated through neurobehavior tests and results were compared to those previously obtained in studies whose mating was performed in the experimental animal facility. In the handgrip reflex test, an increase in the experimental group of males and females was observed on the 4th day of observation and a decrease on the 8th day, in females. When comparing postural reflex, results didn’t show significant differences. In the results for negative geotaxia, no significant difference was observed among groups, as well as locomotion movement and general activity. Mother’s body weight during pregnancy didn’t present any significative difference for the experimental group related to control group. These results, put together, cannot allow stating significant influence in transporting females in the first stages of pregnancy in Wistar rats.
A gestação é considerada um período de grandes variações no organismo materno. Além disso, a mãe está sujeita às influências estressantes provindas do ambiente externo que podem interferir na saúde e no bem-estar materno-fetal. Assim, o acasalamento feito no próprio biotério de experimentação pode evitar o estresse da manipulação e do transporte da fêmea gestante, garantindo o acompanhamento total do período pré e pós-gestacional. Porém, adquirir fêmeas prenhes pode evitar perdas decorrentes de animais que não conseguem emprenhar e evitar a solicitação de machos. Este estudo buscou determinar se existem alterações comportamentais causadas pela manipulação e transporte em fêmeas adquiridas prenhez a partir do acompanhamento dos períodos pré e pós-natal: gestação, lactação, sanidade dos neonatos e seu desenvolvimento após o desmame para verificação de alterações que possam causar prejuízo no desenvolvimento dos filhotes. Os animais foram avaliados através da realização de testes neurocomportamentais e comparados a resultados obtidos anteriormente em estudos cujo acasalamento fora feito no próprio biotério de experimentação. No teste de reflexo de preensão palmar foi observado um aumento no tempo de realização no grupo experimental em machos e fêmeas no PN4 e diminuição no PN8 em fêmeas. Na comparação dos grupos no reflexo postural os resultados não demonstraram diferença significativa. Os resultados da geotaxia negativa, na comparação dos grupos, não evidenciou nenhuma diferença significativa, tampouco houve diferenças significativas para movimentos de locomoção e na atividade geral. O peso das mães durante o tempo de gestação não apresentou nenhuma diferença significativa do grupo experimental em relação ao grupo controle. Estes resultados, avaliados em conjunto, não nos permitem afirmar que houve uma influência significativa do transporte das fêmeas no estágio inicial da gestação de ratas Wistar.
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During gestation, stress exposure increases the risk of developing cognitive and physiological alterations in either the long or short term. Among them, metabolic alterations have been described. Adipose tissue is responsible for the secretion of several factors involved in controlling body weight and energy expenditure, the regulation of insulin sensitivity, and the development of inflammation, among others. Moreover, the liver regulates glucose homeostasis and lipid metabolism, playing an essential role in developing insulin resistance. In this work, we analyzed if prenatal stress leads to alterations in metabolism and the relationship between these alterations and gene expression in the adipose tissue and the liver. Prenatal stress-exposed animals developed disturbances in the glucose and insulin response curve, showing in both tests higher glycemia than the control group. However, they did not exhibit increased body weight. At the same time, in the adipose tissue, we observed an increase in mRNA expression of Leptin and Resistin and a decrease in Adiponectin. In the liver, we observed a lower mRNA expression of several genes involved in glucose metabolism and fatty acid oxidation, such as Sirt1, Pgc1α, Pparα, among others. In both tissues, we observed a lower expression of inflammatory genes. These results suggest that prenatal stress exposure produces insulin resistance at both physiological and molecular levels without pro-inflammatory signaling or obesity.
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Resistência à Insulina , Tecido Adiposo/metabolismo , Animais , Feminino , Inflamação/metabolismo , Insulina , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Gravidez , Estresse PsicológicoRESUMO
Prenatal stress affects brain functionality and sexual behavior. The medial prefrontal cortex (mPFC) participates in the integration and processing of sexual stimuli. Electroencephalographic (EEG) theta activity has been associated with attention as well as rewarding and sexually motivated states. Considering that the induction of sexual motivation requires attention to, and the adequate processing of, sexual stimuli, this study aimed to evaluate the effects of exposure to stress during the prenatal period on EEG activity in the mPFC during nose pokes in adulthood, actions which are indicators of attention to a receptive female. Eighteen sexually experienced male rats were used, nine stressed prenatally by immobilization during days 14-21 of gestation (stress-exposed group). The other nine formed the control group. All rats were implanted bilaterally in the mPFC (specifically in prelimbic areas) and were allowed one intromission with a receptive female to induce a sexually motivated state before the experimental session. During this session, both nose pokes and non-contact erections in the male rats were evaluated in the presence of an inaccessible receptive female. EEGs were recorded only during nose pokes. The stress-exposed group presented lower nose poke duration, fewer non-contact erections, and lower relative power of the theta band (4-7 Hz) in both prefrontal areas. Considering that the prevalence of this band is associated with attention and motivational processes, these data confirm the deleterious effect of prenatal stress on attention and sexual activation to sexually relevant stimuli in male rats during adulthood.
Lay summariesPrenatal stress diminishes attention and activation behaviors in receptive females.Prenatal stress decreases prefrontal activation in the presence of receptive females.Prenatal stress decreases prefrontal theta rhythms in male rats.
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Efeitos Tardios da Exposição Pré-Natal , Comportamento Sexual Animal , Animais , Eletroencefalografia , Feminino , Masculino , Motivação , Córtex Pré-Frontal , Gravidez , Ratos , Comportamento Sexual Animal/fisiologia , Estresse PsicológicoRESUMO
Prenatal stress (PS) is a major risk factor for the development of emotional disorders in adulthood that may be mediated by an altered hypothalamic-pituitary-adrenal axis response to stress. Although the early onset of stress-related disorders is recognized as a major public health problem, to date, there are relatively few studies that have examined the incidence of early-life stressors in younger individuals. In this study, we assessed PS impact on the stress-coping response of juvenile offspring in behavioral tests and in the induced molecular changes in the hippocampus. Furthermore, we assessed if pregnancy stress could be driving changes in patterns of maternal behavior during early lactation. We found that PS modified stress-coping abilities of both sex offspring. In the hippocampus, PS increased the expression of bdnf-IV and crfr1 and induced sex difference changes on glucocorticoids and BDNF mRNA receptor levels. PS changed the hippocampal epigenetic landscape mainly in male offspring. Stress during pregnancy enhanced pup-directed behavior of stressed dams. Our study indicates that exposure to PS, in addition to enhanced maternal behavior, induces dynamic neurobehavioral variations at juvenile ages of the offspring that should be considered adaptive or maladaptive, depending on the characteristics of the confronting environment. Our present results highlight the importance to further explore risk factors that appear early in life that will be important to allow timely prevention strategies to later vulnerability to stress-related disorders.
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Adaptação Psicológica , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Restrição Física , Estresse Fisiológico , Estresse Psicológico , Animais , Feminino , Masculino , Gravidez , Ratos , Ansiedade/etiologia , Ansiedade/genética , Ansiedade/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Corticosterona/sangue , Hormônio Liberador da Corticotropina/biossíntese , Hormônio Liberador da Corticotropina/genética , Teste de Labirinto em Cruz Elevado , Regulação da Expressão Gênica , Glucocorticoides/biossíntese , Glucocorticoides/genética , Hipocampo/embriologia , Hipocampo/fisiologia , Sistema Hipotálamo-Hipofisário/embriologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lactação/fisiologia , Lactação/psicologia , Comportamento Materno , Sistema Hipófise-Suprarrenal/embriologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/psicologia , Ratos Wistar , Receptor trkB/biossíntese , Receptor trkB/genética , Receptores de Hormônio Liberador da Corticotropina/biossíntese , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Glucocorticoides/biossíntese , Receptores de Glucocorticoides/genética , Restrição Física/efeitos adversos , Caracteres Sexuais , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , NataçãoRESUMO
BACKGROUND: Studies on the health effects of metal mixtures typically utilize biomarkers measured in a single biological medium, such as blood or urine. However, the ability to evaluate mixture effects are limited by the uncertainty whether a unified medium can fully capture exposure for each metal. Therefore, it is important to compare and assess metal mixtures measured in different media in epidemiology studies. OBJECTIVES: The aim of this study was to examine the mixture predictive performance of urine and blood metal biomarkers and integrated multi-media biomarkers in association with birth outcomes. METHODS: In our analysis of 847 women from the Puerto Rico PROTECT Cohort, we measured 10 essential and non-essential metals in repeated and paired samples of urine and blood during pregnancy. For each metal, we integrated exposure estimates from paired urine and blood biomarkers into multi-media biomarkers (MMBs), using intraclass-correlation coefficient (ICC) and weighted quantile sum (WQS) approaches. Using Ridge regressions, four separate Environmental risk scores (ERSs) for metals in urine, blood, MMBICC, and MMBWQS were computed as a weighted sum of the 10 metal concentrations. We then examined associations between urine, blood, and multi-media biomarker ERSs and birth outcomes using linear and logistic regressions, adjusting for maternal age, maternal education, pre-pregnancy body mass index (BMI), and second-hand smoke exposure. The performance of each ERS was evaluated with continuous and tertile estimates and 95% confidence intervals of the odds ratio of preterm birth using area under the curve (AUC). RESULTS: Pb was the most important contributor of blood ERS as well as the two integrated multi-media biomarker ERSs. Individuals with high ERS (3rd tertile) showed increased odds of preterm birth compared to individuals with low ERS (1st tertile), with 2.8-fold (95% CI, 1.49 to 5.40) for urine (specific gravity corrected); 3.2- fold (95% CI, 1.68 to 6.25) for blood; 3.9-fold (95% CI, 1.72 to 8.66) for multi-media biomarkers composed using ICC; and 5.2-fold (95% CI, 2.34 to 11.42) for multi-media biomarkers composed using WQS. The four ERSs had comparable predictive performances (AUC ranging from 0.64 to 0.68) when urine is examined with specific gravity corrected concentrations. CONCLUSIONS: Within a practical metal panel, measuring metals in either urine or blood may be an equally good approach to evaluate the metals as a mixture. Applications in practical study design require validation of these methods with other cohorts, larger panels of metals and within the context of other adverse health effects of interest.