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Microbiota imbalances are linked to inflammation and disease, as well as neurodevelopmental conditions where they may contribute to behavioral, physiological, and central nervous system dysfunction. By contrast, the role of the microbiota in Fetal Alcohol Spectrum Disorder (FASD), the group of neurodevelopmental conditions that can occur following prenatal alcohol exposure (PAE), has not received similar attention. Here we utilized a rodent model of alcohol consumption during pregnancy to characterize the impact of alcohol on the microbiota of dam-offspring dyads. Overall, bacterial diversity decreased in alcohol-consuming dams and community composition differed from that of controls in alcohol-consuming dams and their offspring. Bacterial taxa and predicted biochemical pathway composition were also altered with alcohol consumption/exposure; however, there was minimal overlap between the changes in dams and offspring. These findings illuminate the potential importance of the microbiota in the pathophysiology of FASD and support investigation into novel microbiota-based interventions.
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Consumo de Bebidas Alcohólicas , Heces , Efectos Tardíos de la Exposición Prenatal , Animales , Embarazo , Femenino , Heces/microbiología , Consumo de Bebidas Alcohólicas/efectos adversos , Efectos Tardíos de la Exposición Prenatal/microbiología , Ratas , Trastornos del Espectro Alcohólico Fetal/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Etanol/efectos adversos , Masculino , Modelos Animales de Enfermedad , Microbiota/efectos de los fármacos , Bacterias/clasificación , Bacterias/efectos de los fármacosRESUMEN
Low desire in women is the most common sexual difficulty, and stress has been identified as a significant predictor of symptoms. We evaluated a mindfulness-based cognitive therapy (MBCT) group treatment versus a sex education comparison group treatment (STEP) on self-reported stress and on the physiological stress response measured via morning-to-evening cortisol slope in 148 women with a diagnosis of sexual interest/arousal disorder (SIAD). Perceived stress decreased following treatment in both groups, and significantly more after MBCT. The cortisol slope was steeper (indicative of better stress system regulation) from pre-treatment to 6-month follow-up, with no differences between the groups. As an exploratory analysis, we found that the reduction in perceived stress predicted increases in sexual desire and decreases in sex-related distress for participants after MBCT only. These findings suggest that group mindfulness targeting women with low sexual desire leads to improvements in self-reported and physiological stress, with improvements in self-reported stress partially accounting for improvements in sexual desire and distress.
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Hidrocortisona , Atención Plena , Educación Sexual , Disfunciones Sexuales Psicológicas , Estrés Psicológico , Humanos , Femenino , Atención Plena/métodos , Estrés Psicológico/terapia , Estrés Psicológico/psicología , Adulto , Hidrocortisona/sangre , Hidrocortisona/análisis , Disfunciones Sexuales Psicológicas/terapia , Disfunciones Sexuales Psicológicas/psicología , Educación Sexual/métodos , Persona de Mediana Edad , Libido/fisiologíaRESUMEN
Prenatal alcohol exposure (PAE) is known to cause a variety of cognitive, behavioral, and neurological changes. Importantly, mental health problems are also overrepresented in individuals with Fetal Alcohol Spectrum Disorder (FASD), the group of neurodevelopmental conditions that can occur following PAE. Approximately 90% of individuals with FASD report experiencing mental health problems over their lifespan, compared to approximately 30% in the overall population. Individuals with FASD also display impairments in coping skills and increased vulnerability to stress. Here, we investigated whether the COVID-19 pandemic would have a differential impact on mental health and inflammation-to-mood associations in adults with FASD, compared to unexposed controls (no PAE). We capitalized on our pre-pandemic study examining health and immune function and invited past-participants to enroll in the current study. Participants completed mental health assessments and COVID-related questionnaires by phone. In addition, blood samples collected at baseline (pre-pandemic) were used to probe for inflammation-to-mood associations. Overall, our results indicate that lower SES was predictive of higher coronavirus anxiety scores, with no differences between adults with FASD and controls. In addition, while there were no differences in depression or anxiety measures at baseline (pre-pandemic) or during the pandemic, examination of inflammation-to-mood associations identified differential relationships in adults with FASD compared to unexposed controls. Specifically, there was a positive association between baseline neutrophil counts and both baseline and pandemic mental health scores in unexposed controls only. In addition, for unexposed controls there was also a negative association between baseline interferon-É£ (IFN-É£) and pandemic mental health scores. By contrast, only adults with FASD showed positive associations between baseline interleukin-12p70 (IL-12p70), IL-8, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) and pandemic mental health scores. Taken together, to our knowledge, this study is the first to examine the impact of the pandemic in adults with FASD. And while it may be too soon to predict the long-term effects of the pandemic on mental health, our data suggest that it will be important that future work also takes into account how immune function may be modulating mental health outcomes in this population.
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Alcohol (ethanol) exposure during pregnancy can adversely affect development, with long-lasting consequences that include neuroimmune, cognitive, and behavioral dysfunction. Alcohol-induced alterations in cytokine levels in the hippocampus may contribute to abnormal cognitive and behavioral outcomes in individuals with fetal alcohol spectrum disorders (FASD). Nutritional intervention with the essential nutrient choline can improve hippocampal-dependent behavioral impairments and may also influence neuroimmune function. Thus, we examined the effects of choline supplementation on hippocampal cytokine levels in adolescent and adult rats exposed to alcohol early in development. From postnatal day (PD) 4-9 (third trimester-equivalent), Sprague-Dawley rat pups received ethanol (5.25 g/kg/day) or sham intubations and were treated with choline chloride (100 mg/kg/day) or saline from PD 10-30; hippocampi were collected at PD 35 or PD 60. Age-specific ethanol-induced increases in interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and keratinocyte chemoattractant/human growth-regulated oncogene (KC/GRO) were identified in adulthood, but not adolescence, whereas persistent ethanol-induced increases of interleukin-6 (IL-6) levels were present at both ages. Interestingly, choline supplementation reduced age-related changes in interleukin-1 beta (IL-1ß) and interleukin-5 (IL-5) as well as mitigating the long-lasting increase in IFN-γ in ethanol-exposed adults. Moreover, choline influenced inflammatory tone by modulating ratios of pro- to -anti-inflammatory cytokines. These results suggest that ethanol-induced changes in hippocampal cytokine levels are more evident during adulthood than adolescence, and that choline can mitigate some effects of ethanol exposure on long-lasting inflammatory tone.
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Trastornos del Espectro Alcohólico Fetal , Humanos , Embarazo , Femenino , Animales , Ratas , Adolescente , Ratas Sprague-Dawley , Animales Recién Nacidos , Citocinas/farmacología , Etanol/farmacología , Colina , Modelos Animales , Hipocampo , Suplementos DietéticosRESUMEN
Prenatal alcohol exposure can disrupt the development of numerous systems, including the immune system. Indeed, alterations in cytokine levels may contribute to the neuropathological, behavioral, and cognitive problems, and other adverse outcomes observed in individuals with fetal alcohol spectrum disorders. Importantly, supplementation with the essential nutrient choline can improve performance in hippocampal-dependent behaviors; thus, the present study examined the effects of choline on plasma and hippocampal cytokines in adult rats exposed to ethanol in early development. From postnatal day (PD) 4-9 (third trimester equivalent), pups received ethanol (5.25 g/kg/day) or Sham intubations. Subjects were treated with choline chloride (100 mg/kg/day) or saline from PD10-30. On PD60, plasma and hippocampal tissue was collected before and after an immune challenge (lipopolysaccharide (LPS); 50 ug/kg). Prior to the immune challenge, ethanol-exposed subjects showed an overall increase in hippocampal pro-inflammatory cytokines, an effect mitigated by choline supplementation. In contrast, in the plasma, choline reduced LPS-related increases in pro-inflammatory markers, particularly in ethanol-exposed subjects. Thus, early choline supplementation may modify both brain and peripheral inflammation. These results suggest that early choline can mitigate some long-term effects of ethanol exposure on hippocampal inflammation, which may contribute to improved hippocampal function, and could also influence peripheral immune responses that may impact overall health.
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Colina , Etanol , Efectos Tardíos de la Exposición Prenatal , Animales , Animales Recién Nacidos , Colina/farmacología , Citocinas , Suplementos Dietéticos , Etanol/efectos adversos , Femenino , Hipocampo , Inmunidad , Inflamación , Lipopolisacáridos , Embarazo , RatasRESUMEN
BACKGROUND: Inflammation has been linked to a variety of mental and physical health outcomes that disproportionately impact women, and which can impair sexual function; thus, there is reason to expect a link between inflammation and women's sexual functioning. AIM: To test the hypothesis that higher concentrations of C-reactive protein (CRP), a general biomarker of inflammation, would predict women's lower sexual desire. METHOD: As 2 independent research teams, we conducted 3 separate studies (total n = 405) that assessed salivary CRP and various measurements of sexual desire in different women populations. OUTCOMES: Female Sexual Function Index, Sexual Desire Inventory-2, Decreased Sexual Desire Screener, and Sexual Interest and Desire Inventory. RESULTS: Regardless of the way sexual desire was measured (e.g., state vs trait; general desire vs. desire functioning) and the population sampled (i.e., healthy vs. clinically diagnosed with sexual dysfunction), all the studies revealed null results. CLINICAL IMPLICATIONS: While exploratory, the convergence of these null results across studies and researchers suggests that if there is an association between inflammation and women's sexual desire, it is likely very subtle. STRENGTHS & LIMITATIONS: Across 2 independent research teams, 3 unrelated studies, and various measurements of sexual desire, results were consistent. These points lend to the generalizability of the results. However, study designs were cross-sectional. CONCLUSIONS: Future research may reveal (i) a non-linear threshold effect, such that inflammation does not begin to impact women's sexual desire until it is at a high level, (ii) inflammatory biomarkers other than CRP might be more sensitive in detecting associations between inflammation and desire, should they exist, or (iii) the mechanisms underlying sexual dysfunction may differ between sexes. Clephane K, et al. Lack of Evidence for a Relationship Between Salivary CRP and Women's Sexual Desire: An Investigation Across Clinical and Healthy Samples. J Sex Med 2022;19:745-760.
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Proteína C-Reactiva , Libido , Disfunciones Sexuales Fisiológicas , Proteína C-Reactiva/análisis , Femenino , Humanos , Inflamación , Saliva/química , Disfunciones Sexuales Fisiológicas/etiología , Encuestas y CuestionariosRESUMEN
BACKGROUND: There are known environmental risk factors associated with rheumatoid arthritis; however, less is known regarding how the prenatal environment impacts later-life risk for rheumatoid arthritis. Based on preliminary clinical data suggesting that individuals with fetal alcohol spectrum disorder (FASD) are at higher risk for autoimmune disorders, this study investigated the modulatory impact of prenatal alcohol exposure (PAE) on the inflammatory disease profile in an adjuvant-induced arthritis rat model. METHODS: Pregnant rats received liquid ethanol or control diet throughout gestation. To model the increased exposure to stressors often experienced by individuals with FASD, adolescent offspring were exposed to chronic mild stress (CMS) or remained undisturbed. In adulthood, experimental arthritis was initiated and rats terminated either at the peak or following resolution from inflammation to assess endocrine, immune, and histopathological outcomes. FINDINGS: PAE rats had an increased incidence and severity of, and impaired recovery from, arthritis. Increased joint damage was observed in PAE animals, even in the face of apparent recovery from the clinical signs of arthritis, while it appeared that oestradiol may have a protective role. Moreover, with the combination of PAE and adolescent stress, increased macrophage density was detected in the synovium of PAE but not control rats. INTERPRETATION: These findings demonstrate that PAE alters the severity and course of arthritis, highlighting the potential immunomodulatory impact of adverse prenatal exposures. In particular, these data have implications for understanding preliminary data that suggest a heightened propensity for autoimmune disorders in individuals with FASD. FUNDING: This work was supported by: National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism [R37 AA007789] and Kids Brain Health Network (KBHN; Canadian Networks of Centres of Excellence) to JW, a Natural Sciences and Engineering Research Council of Canada (NSERC) CGS-D to TSB and NIH/NIAAA R01 AA022460 to JW and TSB.
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Artritis Experimental , Trastornos del Espectro Alcohólico Fetal , Efectos Tardíos de la Exposición Prenatal , Adolescente , Adulto , Animales , Artritis Experimental/etiología , Canadá , Etanol/efectos adversos , Femenino , Trastornos del Espectro Alcohólico Fetal/etiología , Humanos , Embarazo , RatasRESUMEN
BACKGROUND: There is growing evidence that the gut microbiota can be shaped by early-life experiences/exposures, with long-term consequences for brain, behavior, and health. Changes in the gut microbiota have also been identified in neurodevelopmental disorders including Autism Spectrum Disorder and schizophrenia. In contrast, no studies to date have investigated whether the gut microbiota is altered in individuals with Fetal Alcohol Spectrum Disorder (FASD), the neurodevelopmental disorder that results from prenatal alcohol exposure (PAE). The current study was designed to assess the impact of PAE on the fecal microbiota. METHODS: We used a rodent model in which pregnant Sprague-Dawley rats were provided with an EtOH-containing diet or a control diet throughout gestation. Fecal samples were collected from adult male and female animals and 16s rRNA sequencing was performed. RESULTS: Overall, PAE rats showed greater richness of bacterial species, with community structure investigations demonstrating distinct clustering by prenatal treatment. In addition, prenatal treatment and sex-specific alterations were observed for many specific microbes. For example, in males, Bacteroides and Bifidobacterium, and in females, Faecalitalea and Proteus, differed in abundance between PAE and control rats. CONCLUSIONS: Taken together, these results show for the first time that PAE has a long-lasting and sex-specific impact on the fecal microbiota. Further research is needed that considers fetal microbiota in the development of new interventions in FASD.
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Trastorno del Espectro Autista , Trastornos del Espectro Alcohólico Fetal , Microbiota , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Humanos , Masculino , Embarazo , ARN Ribosómico 16S/genética , Ratas , Ratas Sprague-DawleyRESUMEN
Prenatal alcohol exposure can impact virtually all body systems, resulting in a host of structural, neurocognitive, and behavioral abnormalities. Among the adverse impacts associated with prenatal alcohol exposure are alterations in immune function, including an increased incidence of infections and alterations in immune/neuroimmune parameters that last throughout the life-course. Epigenetic patterns are also highly sensitive to prenatal alcohol exposure, with widespread alcohol-related alterations to epigenetic profiles, including changes in DNA methylation, histone modifications, and miRNA expression. Importantly, epigenetic programs are crucial for immune system development, impacting key processes such as immune cell fate, differentiation, and activation. In addition to their role in development, epigenetic mechanisms are emerging as attractive candidates for the biological embedding of environmental factors on immune function and as mediators between early-life exposures and long-term health. Here, following an overview of the impact of prenatal alcohol exposure on immune function and epigenetic patterns, we discuss the potential role for epigenetic mechanisms in reprogramming of immune function and the consequences for health and development. We highlight a range of both clinical and animal studies to provide insights into the array of immune genes impacted by alcohol-related epigenetic reprogramming. Finally, we discuss potential consequences of alcohol-related reprogramming of immune/neuroimmune functions and their effects on the increased susceptibility to mental health disorders. Overall, the collective findings from animal models and clinical studies highlight a compelling relationship between the immune system and epigenetic pathways. These findings have important implications for our understanding of the biological mechanisms underlying the long-term and multisystem effects of prenatal alcohol exposure, laying the groundwork for possible novel interventions and therapeutic strategies to treat individuals prenatally exposed to alcohol.
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Prenatal adversity or stress can have long-term consequences on developmental trajectories and health outcomes. Although the biological mechanisms underlying these effects are poorly understood, epigenetic modifications, such as DNA methylation, have the potential to link early-life environments to alterations in physiological systems, with long-term functional implications. We investigated the consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. As these insults can have sex-specific effects on biological outcomes, we analyzed epigenome-wide DNA methylation patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females. We found sex-dependent and sex-concordant influences of these insults on epigenetic patterns. These alterations occurred in genes and pathways related to brain development and immune function, suggesting that PAE and food-related stress may reprogram neurobiological/physiological systems partly through central epigenetic changes, and may do so in a sex-dependent manner. Such epigenetic changes may reflect the sex-specific effects of prenatal insults on long-term functional and health outcomes and have important implications for understanding possible mechanisms underlying fetal alcohol spectrum disorder and other neurodevelopmental disorders.
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Alcoholes/efectos adversos , Metilación de ADN/efectos de los fármacos , Corteza Prefrontal/química , Efectos Tardíos de la Exposición Prenatal/genética , Análisis de Secuencia de ADN/métodos , Animales , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Función Ejecutiva/efectos de los fármacos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Masculino , Corteza Prefrontal/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Caracteres SexualesRESUMEN
Lithium's efficacy in reducing both symptom severity in bipolar disorder (BD) and suicide risk across clinical populations may reflect its ability to reduce impulsivity. Changes in immune markers are associated with BD and suicidality yet their exact role in symptom expression remains unknown. Evidence also suggests that lithium may decrease levels of pro-inflammatory cytokines in the periphery and central nervous system, and that such changes are related to its therapeutic efficacy. However, issues of cause and effect are hard to infer from clinical data alone. Here, we investigated the effects of chronic dietary lithium treatment on rats' performance of the 5-Choice Serial Reaction Time Task (5CSRTT), a well-validated operant behavioural task measuring aspects of impulsivity, attention and motivation. Male Long-Evans rats received a diet supplemented with 0.3% LiCl (n = 13), or the equivalent control diet (n = 16), during behavioural testing. Blood and brain tissue samples were assayed for a wide range of cytokines once any changes in impulsivity became significant. After 12 weeks, chronic lithium treatment reduced levels of motor impulsivity, as indexed by premature responses in the 5CSRTT; measures of sustained attention and motivation were unaffected. Plasma levels of IL-1ß, IL-10 and RANTES (CCL-5) were reduced in lithium-treated rats at this time point. IL-1ß, IL-6 and RANTES were also reduced selectively within the orbitofrontal cortex of lithium-treated rats, whereas cytokine levels in the medial prefrontal cortex and nucleus accumbens were comparable with control subjects. These results are consistent with the hypothesis that lithium may improve impulse control deficits in clinical populations by minimising the effects of pro-inflammatory signalling on neuronal activity, particularly within the orbitofrontal cortex.
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Citocinas , Litio , Animales , Conducta Impulsiva , Masculino , Corteza Prefrontal , Ratas , Ratas Long-EvansRESUMEN
BACKGROUND: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status. METHODS: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis. RESULTS: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1ß, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-ß, IL-10, and IL-15 was associated with neurodevelopmental delay. CONCLUSIONS: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.
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Depresores del Sistema Nervioso Central/efectos adversos , Discapacidades del Desarrollo/inducido químicamente , Discapacidades del Desarrollo/inmunología , Etanol/efectos adversos , Sistema Inmunológico/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Adulto , Consumo de Bebidas Alcohólicas/efectos adversos , Preescolar , Citocinas/sangre , Discapacidades del Desarrollo/psicología , Femenino , Humanos , Sistema Inmunológico/efectos de los fármacos , Lactante , Recién Nacido , Estudios Longitudinales , Madres , Pruebas Neuropsicológicas , Embarazo , UcraniaRESUMEN
The maternal brain displays considerable plasticity, and motherhood is associated with changes in affective and cognitive function. Motherhood can alter the trajectory of brain aging, including modifications to neuroplasticity and cognition. Here, we investigated the short- and long-term effects of motherhood on hippocampal neurogenesis, microglial density and morphology, and circulating cytokines, domains known to be altered with age and implicated in cognition and mood. Female rats were bred then euthanized during gestation or at various postpartum time points, culminating in middle age, and nulliparous rats served as age-matched controls. Hippocampal neurogenesis was significantly suppressed during gestation and the postpartum period. Interestingly, neurogenesis declined significantly in middle-aged nulliparous rats but increased in primiparous rats across the same period. Transient postpartum adaptations to the neuroimmune environment of the hippocampus were evidenced, as Iba-1-immunoreactive microglia assumed a deramified morphology followed by increased density. Intriguingly, aging-related changes in circulating cytokines were dependent on parity. These adaptations in neurogenic and immune processes may have ramifications for maternal mood and cognition across the peripartum period and beyond.
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Envejecimiento , Citocinas/metabolismo , Hipocampo/fisiología , Microglía/fisiología , Madres , Neurogénesis/fisiología , Afecto , Envejecimiento/inmunología , Envejecimiento/metabolismo , Envejecimiento/patología , Envejecimiento/fisiología , Animales , Proteínas de Unión al Calcio , Recuento de Células , Cognición , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Femenino , Hipocampo/inmunología , Humanos , Masculino , Proteínas de Microfilamentos , Microglía/patología , Proteínas Asociadas a Microtúbulos , Madres/psicología , Neuroinmunomodulación , Neuropéptidos , Periodo Posparto/fisiología , Periodo Posparto/psicología , Embarazo , Ratas Sprague-DawleyRESUMEN
Background: Prenatal alcohol exposure (PAE) can alter the development of neurobiological systems, leading to lasting neuroendocrine, neuroimmune, and neurobehavioral deficits. Although the etiology of this reprogramming remains unknown, emerging evidence suggests DNA methylation as a potential mediator and biomarker for the effects of PAE due to its responsiveness to environmental cues and relative stability over time. Here, we utilized a rat model of PAE to examine the DNA methylation profiles of rat hypothalami and leukocytes at four time points during early development to assess the genome-wide impact of PAE on the epigenome and identify potential biomarkers of PAE. Our model of PAE resulted in blood alcohol levels of ~80-150 mg/dl throughout the equivalent of the first two trimesters of human pregnancy. Hypothalami were analyzed on postnatal days (P) 1, 8, 15, 22 and leukocytes at P22 to compare central and peripheral markers. Genome-wide DNA methylation analysis was performed by methylated DNA immunoprecipitation followed by next-generation sequencing. Results: PAE resulted in lasting changes to DNA methylation profiles across all four ages, with 118 differentially methylated regions (DMRs) displaying persistent alterations across the developmental period at a false-discovery rate (FDR) < 0.05. In addition, 299 DMRs showed the same direction of change in the hypothalamus and leukocytes of P22 pups at an FDR < 0.05, with some genes overlapping with the developmental profile findings. The majority of these DMRs were located in intergenic regions, which contained several computationally-predicted transcription factor binding sites. Differentially methylated genes were generally involved in immune function, epigenetic remodeling, metabolism, and hormonal signaling, as determined by gene ontology analyses. Conclusions: Persistent DNA methylation changes in the hypothalamus may be associated with the long-term physiological and neurobehavioral alterations in observed in PAE. Furthermore, correlations between epigenetic alterations in peripheral tissues and those in the brain will provide a foundation for the development of biomarkers of fetal alcohol spectrum disorder (FASD). Finally, findings from studies of PAE provide important insight into the etiology of neurodevelopmental and mental health disorders, as they share numerous phenotypes and comorbidities.
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Cytokines and chemokines are potent modulators of brain development and as such, dysregulation of the maternal immune system can result in deviations in the fetal cytokine balance, altering the course of typical brain development, and putting the individual on a "pathway to pathology". In the current study, we used a multi-variate approach to evaluate networks of interacting cytokines and investigated whether alterations in the maternal immune milieu could be linked to alcohol-related and alcohol-independent child neurodevelopmental delay. This was achieved through the measurement of 40 cytokines/chemokines from maternal blood samples collected during the second and third trimesters of pregnancy. Importantly, during the second trimester we identified network enrichment in levels of cytokines including IFN-É£, IL-10, TNF-ß, TNF-α, and CRP associated with offspring neurodevelopmental delay. However, as elevations in levels of these cytokines have previously been reported in a wide range of neurodevelopmental disorders including autism spectrum disorder and schizophrenia, we suggest that this cytokine profile is likely not disorder specific, but rather may be an indicator of neurodevelopmental delay in general. By contrast, distinct clusters of activated/inhibited cytokines were identified based on maternal alcohol consumption and child neurodevelopmental outcome. Specifically, cytokines including IL-15, IL-10, MDC, and members of the VEGF sub-family were highest in alcohol-consuming mothers of children with neurodevelopmental delay and were identified in both network analyses and examination of individual cytokines, whereas a differential and unique cytokine profile was identified in the case of alcohol-independent child neurodevelopmental delay. We propose that the current findings could provide a critical step towards the development of early biomarkers and possibly interventions for alcohol-related neurodevelopmental delay. Importantly, the current approach could be informative for understanding mechanisms linking maternal immune system dysfunction and adverse child outcomes in a range of other neurodevelopmental disorders.
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Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Consumo de Bebidas Alcohólicas/fisiopatología , Quimiocinas/análisis , Quimiocinas/sangre , Citocinas/análisis , Citocinas/sangre , Discapacidades del Desarrollo/etiología , Etanol/efectos adversos , Femenino , Humanos , Inmunidad Materno-Adquirida/fisiología , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Madres , Trastornos del Neurodesarrollo/etiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatologíaRESUMEN
The contribution of the early postnatal environment to the pervasive effects of prenatal alcohol exposure (PAE) is poorly understood. Moreover, PAE often carries increased risk of exposure to adversity/stress during early life. Dysregulation of immune function may play a role in how pre- and/or postnatal adversity/stress alters brain development. Here, we combine two animal models to examine whether PAE differentially increases vulnerability to immune dysregulation in response to early-life adversity. PAE and control litters were exposed to either limited bedding (postnatal day [PN] 8-12) to model early-life adversity or normal bedding, and maternal behavior and pup vocalizations were recorded. Peripheral (serum) and central (amygdala) immune (cytokines and C-reactive protein - CRP) responses of PAE animals to early-life adversity were evaluated at PN12. Insufficient bedding increased negative maternal behavior in both groups. Early-life adversity increased vocalization in all animals; however, PAE pups vocalized less than controls. Early-life adversity reduced serum TNF-α, KC/GRO, and IL-10 levels in control but not PAE animals. PAE increased serum CRP, and levels were even higher in pups exposed to adversity. Finally, PAE reduced KC/GRO and increased IL-10 levels in the amygdala. Our results indicate that PAE alters immune system development and both behavioral and immune responses to early-life adversity, which could have subsequent consequences for brain development and later life health.
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Etanol/administración & dosificación , Conducta Materna , Efectos Tardíos de la Exposición Prenatal/inmunología , Amígdala del Cerebelo/inmunología , Amígdala del Cerebelo/metabolismo , Animales , Proteína C-Reactiva/metabolismo , Citocinas/sangre , Femenino , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas Sprague-Dawley , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismo , Vocalización AnimalRESUMEN
Rheumatoid arthritis (RA) is a chronic inflammatory condition with variable clinical presentation and disease progression. Importantly, animal models of RA are widely used to examine disease pathophysiology/treatments. Here, we exploited known vendor colony-based differences in endocrine/immune responses to gain insight into inflammatory modulators in arthritis, utilizing the adjuvant-induced arthritis (AA) model. Our previous study found that Sprague-Dawley (SD) rats from Harlan develop more severe AA, have lower corticosteroid binding globulin, and have different patterns of cytokine activation in the hind paw, compared to SD rats from Charles River. Here, we extend these findings, demonstrating that Harlan rats show reduced hypothalamic cytokine responses to AA, compared to Charles River rats, and identify colony-based differences in cytokine profiles in hippocampus and spleen. To go beyond individual measures, probing for networks of variables underlying differential responses, we combined datasets from this and the previous study and performed constrained principal component analysis (CPCA). CPCA revealed that with AA, Charles River rats show activation of chemokine and central cytokine networks, whereas Harlan rats activate peripheral immune/hypothalamic-pituitary-adrenal networks. These data suggest differential underlying disease mechanism(s), highlighting the power of evaluating multiple disease biomarkers, with potential implications for understanding differential disease profiles in individuals with RA.
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Artritis Reumatoide/etiología , Artritis Reumatoide/metabolismo , Sistema Endocrino/inmunología , Sistema Endocrino/metabolismo , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Animales , Artritis Experimental , Artritis Reumatoide/patología , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hormonas/metabolismo , Especificidad del Huésped , Mediadores de Inflamación/metabolismo , Masculino , Especificidad de Órganos , RatasRESUMEN
BACKGROUND: Reproductive maturation is initiated with the onset of puberty, which activates the hypothalamic-pituitary-gonadal axis and coincidences with increased expression of the hormone kisspeptin within the hypothalamus. Maturational events are sensitive to environmental factors, including alcohol, which is known to delay reproductive development. We hypothesized that, similar to alcohol's adverse effects during reproductive maturation, prenatal alcohol exposure (PAE) would alter pubertal markers, sex hormone profiles, and kisspeptin expression in the hypothalamus. METHODS: Female offspring from control (C), pair-fed (PF), and PAE groups were sacrificed prior to puberty onset (postnatal day [PND] 30), during puberty [PND 35], or in adulthood [PND 65]. Estradiol (E2 ), progesterone (P4 ), prolactin, and luteinizing hormone levels, and Kiss1 mRNA expression were measured in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei of the hypothalamus. Pubertal markers (vaginal opening [VO], uterus/body wt ratio) were assessed. RESULTS: Our findings indicate that (i) PAE inhibits the expected increases in E2 levels with age and delays maturational increases of P4 levels; (ii) PAE and pair feeding have similar adverse effects on VO and uterus/body wt ratio; (iii) differential relationships between PRL and P4 suggest that different mechanisms may underlie delayed maturation in PAE and PF; that is, PF females have low PRL levels and no increase in P4 with age, whereas PAE animals, despite low PRL, show the expected age-related increase in P4 ; and (iv) there is higher mean density of Kiss1 mRNA in the ARC of adult PAE females and altered Kiss1 expression in the AVPV of both PAE and PF females. CONCLUSIONS: PAE and pair feeding have some overlapping but important differential effects on hormonal profiles and Kiss1 mRNA expression during reproductive development. Preadolescent alterations in Kiss1 expression in the AVPV and ARC, which may change the balance of function in these 2 nuclei, may differentially contribute to delayed reproductive maturation in PAE and PF compared to C females.
Asunto(s)
Trastornos del Espectro Alcohólico Fetal/metabolismo , Kisspeptinas/metabolismo , Maduración Sexual/efectos de los fármacos , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Estradiol/sangre , Femenino , Hipotálamo Anterior/metabolismo , Hormona Luteinizante/sangre , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal , Progesterona/sangre , Prolactina/sangre , Ratas Sprague-DawleyRESUMEN
Plasma corticosteroid-binding globulin (CBG) plays a critical role in regulating glucocorticoid bioavailability and is an acute phase 'negative' protein during inflammation. In an adjuvant-induced arthritis model, plasma CBG levels decrease in rats that develop severe inflammation, and we have now determined when and how these reductions in CBG occur. After administering complete Freund's adjuvant or saline intra-dermally at the tail base, blood samples were taken periodically for 16days. In adjuvant-treated rats, decreases in plasma CBG levels matched the severity of inflammation, and decreases were observed 4days before any clinical signs of inflammation. Decreases in CBG levels coincided with an ~5kDa reduction in its apparent size, consistent with proteolytic cleavage, and cleaved CBG lacked steroid-binding activity. At the termination of the experimental period, hepatic Cbg mRNA levels were decreased in rats with severe inflammation. While plasma TNF-α increased in all adjuvant-treated rats, increases in Il-4, IL-6, IL-10, IL-13 and IFN-γ were only observed in rats with cleaved CBG. Rats with cleaved CBG also exhibited increased spleen weights, and strong negative correlations were observed among CBG, IL-6 and spleen weights, respectively. However, there were no differences in hepatic Cbg mRNA levels in relation to the apparent proteolysis of CBG, suggesting that CBG cleavage occurs before changes in hepatic Cbg expression. Our results indicate that the levels and integrity of plasma CBG are biomarkers of the onset and severity of inflammation. Dynamic changes in the levels and function of CBG likely modulate the tissue availability of corticosterone during inflammation.
Asunto(s)
Inflamación/sangre , Transcortina/metabolismo , Animales , Biomarcadores/sangre , Peso Corporal , Citocinas/sangre , Femenino , Hígado/metabolismo , Proteolisis , Ratas Sprague-DawleyRESUMEN
Evidence for immune/neuroimmune disturbances as a possible root cause of a range of disorders, including neurodevelopmental disorders, is growing. Although prenatal alcohol exposure (PAE) impacts immune function, few studies to date have examined immune function in relation to long-term negative health outcomes following PAE, and most have focused on males. To fill this gap, we utilized a rat model to examine the effects of PAE on immune/neuroimmune function during early-life [postnatal day 1 (P1), P8, and P22] in PAE and control females. Due to the extensive interplay between the immune and endocrine systems, we also measured levels of corticosterone and corticosterone binding globulin (CBG). While corticosterone levels were not different among groups, CBG levels were lower in PAE offspring from P1 to P8, suggesting a lower corticosterone reservoir that may underlie susceptibility to inflammation. Spleen weights were increased in PAE rats on P22, a marker of altered immune function. Moreover, we detected a unique cytokine profile in PAE compared to control offspring on P8 - higher levels in the PFC and hippocampus, and lower levels in the hypothalamus and spleen. The finding of a specific immune signature in PAE offspring during a sensitive developmental period has important implications for understanding the basis of long-term immune alterations and health outcomes in children with Fetal Alcohol Spectrum Disorder (FASD). Our findings also highlight the future possibility that immune-based intervention strategies could be considered as an adjunctive novel therapeutic approach for individuals with FASD.