RESUMO
Glucocorticoids (GCs) are steroid hormones fundamental to the body's normal physiological functions and are pivotal in fetal growth and development. During gestation, the mother's cortisol concentration (active GCs) escalates to accommodate the requirements of fetal organ development and maturation. A natural placental GCs barrier, primarily facilitated by 11ß hydroxysteroid dehydrogenase 2, exists between the mother and fetus. This enzyme transforms biologically active cortisol into biologically inactive corticosterone, thereby mitigating fetal GCs exposure. However, during pregnancy, the mother may be vulnerable to adverse factor exposures such as stress, hypoxia, caffeine, and synthetic GCs use. In these instances, maternal serum GCs levels may surge beyond the protective capacity of the placental GCs barrier. Moreover, these adverse factors could directly compromise the placental GCs barrier, resulting in excessive fetal exposure to GCs. It is well-documented that prenatal GCs exposure can detrimentally impact the offspring's cardiovascular system, particularly in relation to blood pressure, vascular function, and heart function. In this review, we succinctly delineate the alterations in GCs levels during pregnancy and the potential mechanisms driving these changes, and also analyze the possible causes of prenatal GCs exposure. Furthermore, we summarize the current advancements in understanding the adverse effects and mechanisms of prenatal GCs exposure on the offspring's cardiovascular system.
Assuntos
Glucocorticoides , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Feminino , Glucocorticoides/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Desenvolvimento Fetal/efeitos dos fármacos , Placenta/metabolismo , Placenta/efeitos dos fármacosRESUMO
Increasing evidence indicates that prenatal cocaine exposure may result in many developmental and long-lasting neurological and behavioral effects. The behaviors of female animals are strongly associated with the estrous cycle. Estrogen receptors and oxytocin are important neuroendocrine factors that regulate social behavior and are of special relevance to females. However, whether prenatal cocaine exposure induces estrous cycle changes in offspring and whether neurobehavioral changes in estrus and diestrus offspring differ remains unclear. On gestational day 12, mice were administered cocaine once daily for seven consecutive days, then the estrous cycle was examined in adult female offspring, as well as locomotion, anxiety level, and social behaviors, and the expression of estrogen receptor alpha-immunoreactive and oxytocin-immunoreactive neurons were compared between estrus and diestrus offspring. Prenatal cocaine exposure resulted in the shortening of proestrus and estrus in the offspring. During estrus and diestrus, prenatally cocaine-exposed offspring showed increased anxiety levels and changed partial social behaviors; their motility showed no significant differences in estrus, but declined in diestrus. Prenatal cocaine exposure reduced estrogen receptor alpha-immunoreactive expression in the medial preoptic area, ventromedial hypothalamic nucleus, and arcuate nucleus and oxytocin-immunoreactive expression in the paraventricular nucleus in estrus and diestrus offspring. These results suggest that prenatal cocaine exposure induces changes in the offspring's estrous cycle and expression of estrogen receptor alpha and oxytocin in a brain region-specific manner and that prenatal cocaine exposure and the estrous cycle interactively change motility and partial social behavior. Estrogen receptor alpha and oxytocin signaling are likely to play important concerted roles in mediating the effects of prenatal cocaine exposure on the offspring.
Assuntos
Cocaína , Diestro , Receptor alfa de Estrogênio , Ciclo Estral , Estro , Ocitocina , Efeitos Tardios da Exposição Pré-Natal , Comportamento Social , Animais , Ocitocina/metabolismo , Feminino , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Gravidez , Receptor alfa de Estrogênio/metabolismo , Cocaína/farmacologia , Camundongos , Ciclo Estral/efeitos dos fármacos , Estro/efeitos dos fármacos , Diestro/efeitos dos fármacos , Diestro/metabolismo , Comportamento Animal/efeitos dos fármacos , Ansiedade/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/efeitos dos fármacosRESUMO
Maternal immune activation (MIA) is reported to increase the risk of psychiatric disorders in the offspring. However, the underlying mechanism remains unclear. Methods: We constructed a MIA mouse model by intraperitoneal injection of LPS into pregnant mice and evaluated the behaviors and gene expression profiles in the brains of the female and male offspring, respectively. Results: We found that the MIA female offspring exhibited increased anxiety and a large number of differentially expressed genes (DEGs) in the brain, which were enriched with candidate gene sets of psychiatric disorders and immune functions. In contrast, the MIA male offspring exhibited no significant abnormal behaviors and only a small number of DEGs that were not enriched with disease genes and immune functions. Therefore, we further pursued the downstream study on the molecular mechanism underlying the increased anxiety in the female offspring. We identified the lncRNA AU020206-IRFs-STAT1-cytokine axis by integrating lncRNA-protein interaction data and TF-promoter interaction data, and verified the axis in vitro and in vivo. Conclusion: This study illustrates that MIA upregulates the AU020206-IRFs-STAT1 axis in controlling the brain immunity linked to abnormal behaviors, providing a basis for understanding the role of MIA in psychiatric disorders.
Assuntos
Encéfalo , Citocinas , Modelos Animais de Doenças , Fator de Transcrição STAT1 , Animais , Feminino , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Camundongos , Encéfalo/metabolismo , Encéfalo/imunologia , Gravidez , Citocinas/metabolismo , Masculino , Regulação para Cima , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores Reguladores de Interferon/metabolismo , Fatores Reguladores de Interferon/genética , Lipopolissacarídeos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ansiedade/imunologia , Ansiedade/metabolismo , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
OBJECTIVE: To probe into the protective effect of different dose of secoisolariciresinol diglucoside(SDG) on brain of offspring of mice anainst oxidative damage and inflammatory reaction induced by maternal exposure to trans fatty acids(TFA) during gestation, and observe the the changes of regulating Nrf2/Keap1 pathway in the course. METHODS: 30 healthy female mice(C57BL/6) were divided into 5 groups randomly, they are respectively control group, TFA-exposed group, and three SDG-intervention groups(low-(TFA+LSDG), medium-(TFA+MSDG) and high-(TFA+HSDG)). The pregnancy mice of control group and TFA group were treated with distilled water and 60 mg/kg·d TFA by gavage, in the same time, the mice of three SDG-intervention groups were treated with 60 mg/kg·d TFA by gavage and fed with feed included SDG(10, 20 and 30 mg/kg). The treatment to pregnancy mice continued to birth of offspring. After 21 days of lactation, the offspring were killed under anesthesia and the experiment was ended. The coefficient of brain was calculated. The levels of superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), malondialdehyde(MDA), tumor necrosis factor-α(TNF-α), interferon-γ(IFN-γ) and amyloid-ß(Aß)of brain were detected. RT-PCR and Western Blot was used to detected gene expression and protein levels of nuclear factor erythroid-2 related factor 2(Nrf2), kelch-like ECH-associated protein 1(Keap1), quinone oxidoreductase 1(NQO1) and hemeoxygenase-l(HO-1). RESULTS: Compared with control group, the brain coefficient and Aß1-40 of offspring of TFA-group had no significant changes(P>0.05), the activity of SOD and GSH-Px reduced, the content of MDA, IFN-γ, TNF-α and Aß1-42 increased, the level of mRNA and protein expression of Nrf2, NQO1 and HO-1 decreased and the level of mRNA and protein expression of Keap1 increase because of the exposion to TFA during gestation and all the differences were statistically significant(P<0.05). Compared with TFA-group, the brain coefficient, Aß1-40 and the level of NQO1 mRNA of offspring of three SDG-intervention groups had no significant changes(P>0.05), the activity of SOD(the middle and high dose SDG intervention groups) and GSH-Px(three SDG-intervention groups) increased, the content of MDA(the middle and high dose SDG intervention groups), IFN-γ(the middle and high dose SDG intervention groups), TNF-α(three SDG-intervention groups) and Aß1-42(the middle and high dose SDG intervention groups) decreased, the mRNA expression of Nrf2 and HO-1(the middle and high dose SDG intervention groups) was up-regulated, the mRNA expression of Keap1(the middle and high dose SDG intervention group) decreased, proteic expression of Nrf2, NQO1 and HO-1 of three SDG-intervention groups increase and the level of protein of Keap1 decreased because of the intervention of SDG during gestation(P<0.05). CONCLUSION: These result suggest that maternal TFA exposure during gestation can result in oxidative stress and inflammation to brain of offspring in a way. SDG can protect brain of mice of offspring from TFA-induced oxidative injury by up-regulating the expression of mRNA and protein of Nrf2, down-regulating the expression of Keap1, accelerating expression of protein of NQO1 and HO-1 which are antioxidant protein lying downstream of pathway of Nrf2/Keap1.
Assuntos
Encéfalo , Butileno Glicóis , Glucosídeos , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ácidos Graxos trans , Animais , Feminino , Camundongos , Glucosídeos/farmacologia , Gravidez , Fator 2 Relacionado a NF-E2/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Estresse Oxidativo/efeitos dos fármacos , Butileno Glicóis/farmacologia , Ácidos Graxos trans/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Inflamação/metabolismo , Inflamação/induzido quimicamente , Exposição Materna/efeitos adversos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Malondialdeído/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD(P)H Desidrogenase (Quinona)/genéticaRESUMO
Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in the blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. When offspring were 3 months of age, ischemic stroke was induced. One and a half months later, blood and brain tissue were collected. We measured levels of matrix metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and reported reduced levels of MMP-2 in ChDD male offspring in both tissue types. No changes were observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.
Assuntos
Encéfalo , Colina , Metaloproteinase 2 da Matriz , Animais , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/sangue , Feminino , Encéfalo/metabolismo , Masculino , Camundongos , Gravidez , Colina/metabolismo , Camundongos Endogâmicos C57BL , Dieta , Ácido Fólico/metabolismo , Ácido Fólico/sangue , Metaloproteinase 9 da Matriz/metabolismo , Deficiência de Colina , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/sangueRESUMO
Maternal stress experienced during prenatal development is recognized as a significant risk factor for neurodevelopmental and neuropsychiatric disorders across the offspring's lifespan. The placental barrier serves a crucial function in safeguarding the fetus from detrimental exposures during gestation. However, previous investigations have not yet comprehensively elucidated the extensive connections between prenatal stress and the expression of placental proteins. In this study, we used iTRAQ-based quantitative proteomics to elucidate the placental adaptive mechanisms of pregnant rats in response to fear-induced stress. Our results showed that during pregnancy, exposure to fear-induced stress led to a pathological hypercoagulable state in the mother's body. Placental circulation was also disrupted, significantly reducing placental efficiency and blood oxygen saturation in newborn rats. Proteomic analyses showed that most of the DEPs were annotated to the PI3K-Akt and ECM-receptor interaction signaling pathway. In addition, the expressions of CDC37, HSP90ß, AKT, p-AKT and p-mTOR were down-regulated significantly in the placenta. Our results demonstrated that prenatal fear-induced stress led to inhibition of the cellular signal transduction of placental PI3K/AKT/mTOR, which affected biological processes such as rRNA processing, translation, protein folding, protein stability, and oxygen transport in the placenta. These abnormalities in biological functions could potentially damage the barrier function of the placenta and thereby result in abnormal development in the offspring.
Assuntos
Placenta , Proteômica , Gravidez , Animais , Feminino , Proteômica/métodos , Placenta/metabolismo , Ratos , Fosfatidilinositol 3-Quinases/metabolismo , Estresse Psicológico/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteoma/metabolismoRESUMO
Maternal nutrition and metabolic health status during pregnancy are critical factors that shape the life-long health trajectory of offspring. Altered nutrition during specific times of development in utero can lead to functional changes in tissues such as the pancreatic ß-cells, predisposing those tissues to metabolic diseases and Type 2 diabetes that manifest later in life. This chapter will focus on the role of pregnancy complications with altered nutrition during gestation in the maladaptive programming of ß-cell mass and function in the offspring.
Assuntos
Células Secretoras de Insulina , Feminino , Gravidez , Células Secretoras de Insulina/metabolismo , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Animais , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estado Nutricional , Complicações na Gravidez , Diabetes Mellitus Tipo 2/metabolismoRESUMO
More than two-thirds of women during childbearing years (20-39 years old) are overweight or obese in the United States, with protein intake among 20-49-year-old women being 1.6 times higher than recommended (75.4 g/day versus 46 g/day) that can be considered as a relatively high-protein diet (HPD). Both gestational obesity and HPDs during gestation adversely affect offspring health. This study investigates the impact of HPDs fed during gestation and lactation on obese mothers and their offspring in Wistar rats. Dams randomized to either a normal-protein diet (NPD) or HPD (n = 12/group). Pups from each maternal group were weaned to either NPD or HPD for 17 weeks (n = 12/group). No effect of maternal or weaning diet on food intake, body weight, or body fat/weight ratio was observed. However, NPD dams exhibited higher glucose area under the curve compared with HPD dams (p < 0.03). At weaning, offspring born to NPD dams showed higher fasting plasma glucose (P < 0.03) and insulin/glucose ratio (P = 0.05) than those born to HPD dams. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was higher in offspring born to NPD dams (P < 0.04) and weaned to NPD (P < 0.05) at week 17. These findings underscore the role of high-protein maternal and weaning diets in pregnancy outcomes for obese mothers, particularly in glucose homeostasis, although gestational obesity may overshadow other parameters. Further research is needed to fully understand the impact on both maternal and offspring health and their underlying mechanisms in this context.
Assuntos
Dieta Rica em Proteínas , Ratos Wistar , Animais , Feminino , Gravidez , Ratos , Masculino , Dieta Rica em Proteínas/efeitos adversos , Dieta Rica em Proteínas/métodos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/etiologia , Peso Corporal , Fenômenos Fisiológicos da Nutrição Materna , Ingestão de Alimentos/fisiologia , Obesidade/metabolismo , Obesidade/etiologia , Obesidade Materna/metabolismo , Composição Corporal , Proteínas Alimentares/administração & dosagem , Glucose/metabolismo , Glicemia/metabolismo , Glicemia/análiseRESUMO
Early nutritional and growth experiences can impact development, metabolic function, and reproductive outcomes in adulthood, influencing health trajectories in the next generation. The insulin-like growth factor (IGF) axis regulates growth, metabolism, and energetic investment, but whether it plays a role in the pathway linking maternal experience with offspring prenatal development is unclear. To test this, we investigated patterns of maternal developmental weight gain (a proxy of early nutrition), young adult energy stores, age, and parity as predictors of biomarkers of the pregnancy IGF axis (n = 36) using data from the Cebu Longitudinal Health and Nutrition Survey in Metro Cebu, Philippines. We analyzed maternal conditional weight measures at 2, 8, and 22 years of age and leptin at age 22 (a marker of body fat/energy stores) in relation to free IGF-1 and IGFBP-3 in mid/late pregnancy (mean age = 27). Maternal IGF axis measures were also assessed as predictors of offspring fetal growth. Maternal age, parity, and age 22 leptin were associated with pregnancy free IGF-1, offspring birth weight, and offspring skinfold thickness. We find that free IGF-1 levels in pregnancy are more closely related to nutritional status in early adulthood than to preadult developmental nutrition and demonstrate significant effects of young adult leptin on offspring fetal fat mass deposition. We suggest that the previously documented finding that maternal developmental nutrition predicts offspring birth size likely operates through pathways other than the maternal IGF axis, which reflects more recent energy status.
Assuntos
Fator de Crescimento Insulin-Like I , Feminino , Humanos , Gravidez , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Adulto Jovem , Criança , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Pré-Escolar , Estudos Longitudinais , Masculino , Filipinas , Desenvolvimento Fetal/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Leptina/metabolismo , Peso ao Nascer/fisiologia , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
Obesity, a complex condition that involves genetic, environmental, and behavioral factors, is a non-infectious pandemic that affects over 650 million adults worldwide with a rapidly growing prevalence. A major contributor is the consumption of high-fat diets, an increasingly common feature of modern diets. Maternal obesity results in an increased risk of offspring developing obesity and related health problems; however, the impact of maternal diet on the adipose tissue composition of offspring has not been evaluated. Here, we designed a generational diet-induced obesity study in female C57BL/6 mice that included maternal cohorts and their female offspring fed either a control diet (10% fat) or a high-fat diet (45% fat) and examined the visceral adipose proteome. Solubilizing proteins from adipose tissue is challenging due to the need for high concentrations of detergents; however, the use of a detergent-compatible sample preparation strategy based on suspension trapping (S-Trap) enabled label-free quantitative bottom-up analysis of the adipose proteome. We identified differentially expressed proteins related to lipid metabolism, inflammatory disease, immune response, and cancer, providing valuable molecular-level insight into how maternal obesity impacts the health of offspring. Data are available via ProteomeXchange with the identifier PXD042092.
Assuntos
Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Obesidade , Proteoma , Animais , Feminino , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Obesidade/etiologia , Camundongos , Gravidez , Omento/metabolismo , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Tecido Adiposo/metabolismo , Metabolismo dos Lipídeos , Proteômica/métodos , Gordura Intra-Abdominal/metabolismoRESUMO
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction, communication, repetitive behaviors, and narrow interests. This study aimed to investigate the impact of the Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor (PX-478) on ASD-like behaviors in rat offspring exposed to prenatal hypoxia (PH). METHODS: Pregnant rats were randomly assigned to control or PH groups, with the latter experiencing six hours of hypoxia on the 17th day of gestation. Offspring were further treated with PX-478 treatment initiated at one week (+1 w) or three weeks (+3 w) after birth. Hippocampal histology was assessed using hematoxylin and eosin (HE) staining, while protein levels of HIF-1α and phosphatase and tensin homolog (PTEN) were analyzed via western blotting. The concentration of vascular endothelial growth factor (VEGF) was measured using an Enzyme-Linked Immunosorbent Assay (ELISA) kit. RESULTS: PX-478 treatment significantly improved spatial memory, learning, and social ability, while reducing anxiety-like behavior in PH-exposed offspring rats. HE staining revealed that PX-478 treatment decreased the number of hippocampal neurons necrosis in offspring. However, PX-478 treatment at one week post-birth led to decreased body weight and elevated levels of alkaline phosphatase (ALP) and Alanine aminotransferase (ALT) in offspring rats, whereas no significant effect was observed after three weeks of treatment. Additionally, PX-478 treatment resulted in reduced HIF-1α protein levels in the hippocampus and VEGF concentration in the serum of PH-exposed offspring rats, along with elevated PTEN protein levels. CONCLUSIONS: The findings suggest that PX-478 treatment attenuated autism-like behavior in offspring. HIF-1α might play an important role in autism-like behavior induced by prenatal hypoxia, which may be realized by inhibiting PTEN activity.
Assuntos
Transtorno do Espectro Autista , Subunidade alfa do Fator 1 Induzível por Hipóxia , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Animais , Gravidez , Feminino , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Masculino , Hipóxia/complicações , Progressão da Doença , Fator A de Crescimento do Endotélio Vascular/metabolismo , Comportamento SocialRESUMO
In mammals, DNA methylation (DNAme) erasure and reinstatement during embryo development and germline establishment are sensitive to the intrauterine environment. Maternal intake of a high-fat diet (HFD), associated with excessive gestational weight gain, has transgenerational effects on offspring health, which may be mediated by changes in DNAme in the germline. Here, we tested the impact of a maternal HFD on embryonic germline DNAme erasure using a rat strain that expresses green fluorescent protein specifically in germ cells. DNAme was analysed by methyl-seq capture in germ cells collected from male and female F1 gonads at gestational day 16. Our data show that although HFD induced global hypomethylation in both sexes, DNAme erasure in female germ cells was more advanced compared to male germ cells. The delay in DNAme erasure in males and the greater impact of HFD suggest that male germ cells are more vulnerable to alterations by exogenous factors.
Assuntos
Metilação de DNA , Dieta Hiperlipídica , Células Germinativas , Animais , Feminino , Dieta Hiperlipídica/efeitos adversos , Masculino , Ratos , Gravidez , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Prenatal stress (PS) affects the development and functioning of the central nervous system, but the exact mechanisms underpinning this effect have not been pinpointed yet. A promising model of PS is one based on chronic exposure of pregnant rodents to variable-frequency ultrasound (US PS), as it mimics the PS with a psychic nature that most adequately captures the human stressors in modern society. The aim of this study was to investigate the effects of US PS on the brain neurotransmitter, neuropeptide, and neurotrophic systems of newborn Wistar rats. We determined the concentration of neurotransmitters and their metabolites (serotonin, HIAA, dopamine, DOPAC, and norepinephrine), neuropeptides (α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P), and the neurotrophin brain-derived neurotrophic factor (BDNF) in rat brain tissues by HPLC-ED, ELISA, and multiplex ELISA. Correlation analysis and principal component analysis (PCA) were used to get a sense of the relationship between the biochemical parameters of the brain. The results demonstrated that US PS increases the concentration of serotonin (p=0.004) and DOPAC (p=0.04) in the hippocampus has no effect on the neurotransmitter systems of the frontal cortex, reduces the concentration of BDNF in the entirety of the brain of males (p=0.008), and increases the neuropeptides α-MSH (p=0.02), ß-endorphin (p=0.01), oxytocin (p=0.008), and substance P (p < 0.001) in the entire brain. A degree of complexity in the neurotransmitter system network in the frontal cortex and network change in the hippocampus after exposure to US PS have been observed. PCA revealed a similar pattern of neurotransmitter system interactions in the frontal cortex and hippocampus in males and females after exposure to US PS. We suggest that US PS can alter neurodevelopment, which is mediated by changes in the studied neurochemical systems that thus affect the behavioral phenotype in animals.
Assuntos
Animais Recém-Nascidos , Encéfalo , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Animais , Feminino , Gravidez , Masculino , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neurotransmissores/metabolismo , Estresse Psicológico/metabolismo , Ondas Ultrassônicas , Neuropeptídeos/metabolismoRESUMO
The developmental origins of healthy and disease (DOHaD) concept has demonstrated a higher rate of chronic diseases in the adult population of individuals whose mothers experienced severe maternal protein restriction (MPR). Using proteomic and in silico analyses, we investigated the lung proteomic profile of young and aged rats exposed to MPR during pregnancy and lactation. Our results demonstrated that MPR lead to structural and immune system pathways changes, and this outcome is coupled with a rise in the PI3k-AKT-mTOR signaling pathway, with increased MMP-2 activity, and CD8 expression in the early life, with long-term effects with aging. This led to the identification of commonly or inversely differentially expressed targets in early life and aging, revealing dysregulated pathways related to the immune system, stress, muscle contraction, tight junctions, and hemostasis. We identified three miRNAs (miR-378a-3p, miR-378a-5p, let-7a-5p) that regulate four proteins (ACTN4, PPIA, HSPA5, CALM1) as probable epigenetic lung marks generated by MPR. In conclusion, MPR impacts the lungs early in life, increasing the possibility of long-lasting negative outcomes for respiratory disorders in the offspring.
Assuntos
Pulmão , MicroRNAs , Proteômica , Animais , Feminino , Pulmão/metabolismo , Masculino , Proteômica/métodos , Gravidez , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/genética , Dieta com Restrição de Proteínas , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Longevidade/genética , Ratos Wistar , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteoma/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Envelhecimento/metabolismo , Envelhecimento/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genéticaRESUMO
Nicotine is developmentally toxic. Prenatal nicotine exposure (PNE) affects the development of multiple fetal organs and causes susceptibility to a variety of diseases in offspring. In this study, we aimed to investigate the effect of PNE on cartilage development and osteoarthritis susceptibility in female offspring rats. Wistar rats were orally gavaged with nicotine on days 9-20 of pregnancy. The articular cartilage was obtained at gestational day (GD) 20 and postnatal week (PW) 24, respectively. Further, the effect of nicotine on chondrogenic differentiation was explored by the chondrogenic differentiation model in human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs). The PNE group showed significantly shallower Safranin O staining and lower Collagen 2a1 content of articular cartilage in female offspring rats. Further, we found that PNE activated pyroptosis in the articular cartilage at GD20 and PW24. In vitro experiments revealed that nicotine inhibited chondrogenic differentiation and activated pyroptosis. After interfering with nod-like receptors3 (NLRP3) expression by SiRNA, it was found that pyroptosis mediated the chondrogenic differentiation inhibition of WJ-MSCs induced by nicotine. In addition, we found that α7-nAChR antagonist α-BTX reversed nicotine-induced NLRP3 and P300 high expression. And, P300 SiRNA reversed the increase of NLRP3 mRNA expression and histone acetylation level in its promoter region induced by nicotine. In conclusion, PNE caused chondrodysplasia and poor articular cartilage quality in female offspring rats. PNE increased the histone acetylation level of NLRP3 promoter region by α7-nAChR/P300, which resulting in the high expression of NLRP3. Further, NLRP3 mediated the inhibition of chondrogenic differentiation by activating pyroptosis.
Assuntos
Cartilagem Articular , Células-Tronco Mesenquimais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nicotina , Efeitos Tardios da Exposição Pré-Natal , Piroptose , Ratos Wistar , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Nicotina/farmacologia , Nicotina/toxicidade , Feminino , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gravidez , Piroptose/efeitos dos fármacos , Ratos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Condrogênese/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Humanos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/citologiaRESUMO
Autism spectrum disorder (ASD) is known as a group of neurodevelopmental conditions including stereotyped and repetitive behaviors, besides social and sensorimotor deficits. Anatomical and functional evidence indicates atypical maturation of the striatum. Astrocytes regulate the maturation and plasticity of synaptic circuits, and impaired calcium signaling is associated with repetitive behaviors and atypical social interaction. Spontaneous calcium transients (SCT) recorded in the striatal astrocytes of the rat were investigated in the preclinical model of ASD by prenatal exposure to valproic acid (VPA). Our results showed sensorimotor delay, augmented glial fibrillary acidic protein -a typical intermediate filament protein expressed by astrocytes- and diminished expression of GABAA-ρ3 through development, and increased frequency of SCT with a reduced latency that resulted in a diminished amplitude in the VPA model. The convulsant picrotoxin, a GABAA (γ-aminobutyric acid type A) receptor antagonist, reduced the frequency of SCT in both experimental groups but rescued this parameter to control levels in the preclinical ASD model. The amplitude and latency of SCT were decreased by picrotoxin in both experimental groups. Nipecotic acid, a GABA uptake inhibitor, reduced the mean amplitude only for the control group. Nevertheless, nipecotic acid increased the frequency but diminished the latency in both experimental groups. Thus, we conclude that striatal astrocytes exhibit SCT modulated by GABAA-mediated signaling, and prenatal exposure to VPA disturbs this tuning.
Assuntos
Astrócitos , Corpo Estriado , Animais , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Feminino , Gravidez , Ratos , Ácido Valproico/farmacologia , Ratos Wistar , Picrotoxina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Modelos Animais de Doenças , Masculino , Cálcio/metabolismo , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Maternal high-fat diet intake has profound effects on the long-term health of offspring, predisposing them to a higher susceptibility to obesity and metabolic dysfunction-associated steatotic liver disease. However, the detailed mechanisms underlying the role of a maternal high-fat diet in hepatic lipid accumulation in offspring, especially at the weaning age, remain largely unclear. In this study, female C57BL/6J mice were randomly assigned to either a high-fat diet or a control diet, and lipid metabolism parameters were assessed in male offspring at weaning. Gut microbiota analysis and targeted metabolomics of short-chain fatty acids (SCFAs) in these offspring were further performed. Both in vivo and in vitro studies were conducted to explore the role of butyrate in hepatic cholesterol excretion in the liver and HepG2 cells. Our results showed that maternal high-fat feeding led to obesity and dyslipidemia, and exacerbated hepatic lipid accumulation in the livers of offspring at weaning. We observed significant decreases in the abundance of the Firmicutes phylum and the Allobaculum genus, known as producers of SCFAs, particularly butyrate, in the offspring of dams fed a high-fat diet. Additionally, maternal high-fat diet feeding markedly decreased serum butyrate levels and down-regulated ATP-binding cassette transporters G5 (ABCG5) in the liver, accompanied by decreased phosphorylated AMP-activated protein kinase (AMPK) and histone deacetylase 5 (HADC5) expressions. Subsequent in vitro studies revealed that butyrate could induce ABCG5 activation and alleviate lipid accumulation via the AMPK-pHDAC5 pathway in HepG2 cells. Moreover, knockdown of HDAC5 up-regulated ABCG5 expression and promoted cholesterol excretion in HepG2 cells. In conclusion, our study provides novel insights into how maternal high-fat diet feeding inhibits hepatic cholesterol excretion and down-regulates ABCG5 through the butyrate-AMPK-pHDAC5 pathway in offspring at weaning.
Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Butiratos , Colesterol , Dieta Hiperlipídica , Microbioma Gastrointestinal , Fígado , Camundongos Endogâmicos C57BL , Animais , Feminino , Humanos , Masculino , Camundongos , Gravidez , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Butiratos/metabolismo , Colesterol/metabolismo , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/metabolismo , Dislipidemias/microbiologia , Dislipidemias/etiologia , Células Hep G2 , Metabolismo dos Lipídeos , Lipoproteínas , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/metabolismo , Obesidade/microbiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Recent research highlights the pivotal role of the maternal gut microbiome during pregnancy in shaping offspring neurodevelopment. In this study, we investigated the impact of maternal intake of a multispecies probiotic formulation during a critical prenatal window (from gestational day 6 until birth) on neurodevelopmental trajectories in mice. Our findings demonstrate significant and persistent benefits in emotional behavior, gut microbiota composition, and expression of tight junction-related genes, particularly in male offspring, who exhibited heightened sensitivity to the probiotic intervention compared to females. Additionally, we observed elevated gene expression levels of the anti-inflammatory cytokine IL-10 and the oxytocin receptor (Oxtr) in the prefrontal cortex (PFC) of exposed juvenile offspring; however, these changes persisted only in the adult male offspring. Furthermore, the sustained increase in the expression of the proton-coupled oligopeptide transporter 1 (PepT1), which is involved in the transport of bacterial peptidoglycan motifs, in the PFC of exposed male offspring suggests a potential mechanistic pathway underlying the observed sex-dependent effects on behavior and gene expression. These results underscore the potential of prenatal multispecies probiotic interventions to promote long-term neurodevelopmental outcomes, with implications for precision microbial reconstitution aimed at promoting healthy neurodevelopment and behavior.
Assuntos
Microbioma Gastrointestinal , Probióticos , Receptores de Ocitocina , Animais , Feminino , Probióticos/administração & dosagem , Gravidez , Microbioma Gastrointestinal/fisiologia , Masculino , Camundongos , Receptores de Ocitocina/metabolismo , Receptores de Ocitocina/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Córtex Pré-Frontal/metabolismo , Camundongos Endogâmicos C57BL , Interleucina-10/metabolismoRESUMO
Developmental exposure to nonylphenol (NP) results in irreversible impairments of the central nervous system (CNS). The neural precursor cell (NPC) pool located in the subgranular zone (SGZ), a substructure of the hippocampal dentate gyrus, is critical for the development of hippocampal circuits and some hippocampal functions such as learning and memory. However, the effects of developmental exposure to NP on this pool remain unclear. Thus, our aim was to clarify the impacts of developmental exposure to NP on this pool and to explore the potential mechanisms. Animal models of developmental exposure to NP were created by treating Wistar rats with NP during pregnancy and lactation. Our data showed that developmental exposure to NP decreased Sox2-and Ki67-positive cells in the SGZ of offspring. Inhibited activation of Shh signaling and decreased levels of its downstream mediators, E2F1 and cyclins, were also observed in pups developmentally exposed to NP. Moreover, we established the in vitro model in the NE-4C cells, a neural precursor cell line, to further investigate the effect of NP exposure on NPCs and the underlying mechanisms. Purmorphamine, a small purine-derived hedgehog agonist, was used to specifically modulate the Shh signaling. Consistent with the in vivo results, exposure to NP reduced cell proliferation by inhibiting the Shh signaling in NE-4C cells, and purmorphamine alleviated this reduction in cell proliferation by restoring this signaling. Altogether, our findings support the idea that developmental exposure to NP leads to inhibition of the NPC proliferation and the NPC pool depletion in the SGZ located in the dentate gyrus. Furthermore, we also provided the evidence that suppressed activation of Shh signaling may contribute to the effects of developmental exposure to NP on the NPC pool.
Assuntos
Proliferação de Células , Giro Denteado , Proteínas Hedgehog , Células-Tronco Neurais , Fenóis , Ratos Wistar , Transdução de Sinais , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Proteínas Hedgehog/metabolismo , Fenóis/farmacologia , Fenóis/toxicidade , Feminino , Gravidez , Ratos , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Purinas/farmacologia , Morfolinas/farmacologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Masculino , Fatores de Transcrição SOXB1/metabolismo , Linhagem CelularRESUMO
Prenatal stress (PNS) profoundly impacts maternal and offspring health, with enduring effects including microbiome alterations, neuroinflammation, and behavioral disturbances such as reductions in social behavior. Converging lines of evidence from preclinical and clinical studies suggest that PNS disrupts tryptophan (Trp) metabolic pathways and reduces gut Bifidobacteria, a known beneficial bacterial genus that metabolizes Trp. Specifically, previous work from our lab demonstrated that human prenatal mood disorders in mothers are associated with reduced Bifidobacterium dentium in infants at 13 months. Given that Bifidobacterium has been positively associated with neurodevelopmental and other health benefits and is depleted by PNS, we hypothesized that supplementing PNS-exposed pregnant dams with B. dentium would ameliorate PNS-induced health deficits. We measured inflammatory outputs, Trp metabolite levels and enzymatic gene expression in dams and fetal offspring, and social behavior in adult offspring. We determined that B. dentium reduced maternal systemic inflammation and fetal offspring neuroinflammation, while modulating tryptophan metabolism and increasing kynurenic acid and indole-3-propionic acid intergenerationally. Additional health benefits were demonstrated by the abrogation of PNS-induced reductions in litter weight. Finally, offspring of the B. dentium cohort demonstrated increased sociability in males primarily and increased social novelty primarily in females. Together these data illustrate that B. dentium can orchestrate interrelated host immune, metabolic and behavioral outcomes during and after gestation for both dam and offspring and may be a candidate for prevention of the negative sequelae of stress.