Sex-Specific Pathways From Prenatal Maternal Inflammation to Adolescent Depressive Symptoms.

Importance: Prenatal maternal inflammation has been associated with major depressive disorder in offspring in adulthood as well as with internalizing and externalizing symptoms in childhood; however, the association between prenatal inflammation and offspring depression in adolescence has yet to be examined. Objective: To determine whether maternal levels of inflammatory biomarkers during pregnancy are associated with depressive symptomatology in adolescent-aged offspring and to examine how gestational timing, offspring sex, and childhood psychiatric symptoms impact these associations. Design, Setting, and Participants: This was an observational study of a population-based birth cohort from the Child Health and Development Studies (CHDS), which recruited almost all mothers receiving obstetric care from the Kaiser Foundation Health Plan (KFHP) in Alameda County, California, between June 1959 and September 1966. Pregnancy data and blood sera were collected from mothers, and offspring psychiatric symptom data were collected in childhood (ages 9-11 years) and adolescence (ages 15-17 years). Mother-offspring dyads with available maternal prenatal inflammatory biomarkers during first and/or second trimesters and offspring depressive symptom data at adolescent follow-up were included. Data analyses took place between March 2020 and June 2023. Exposures: Levels of inflammatory biomarkers (interleukin 6 [IL-6], IL-8, IL-1 receptor antagonist [IL-1RA], and soluble tumor necrosis factor receptor-II) assayed from maternal sera in the first and second trimesters of pregnancy. Main Outcomes and Measures: Self-reported depressive symptoms at adolescent follow-up. Results: A total of 674 mothers (mean [SD] age, 28.1 [5.9] years) and their offspring (350 male and 325 female) were included in this study. Higher second trimester IL-6 was significantly associated with greater depressive symptoms in offspring during adolescence (b, 0.57; SE, 0.26); P = .03). Moderated mediation analyses showed that childhood externalizing symptoms significantly mediated the association between first trimester IL-6 and adolescent depressive symptoms in male offspring (b, 0.18; 95% CI, 0.02-0.47), while childhood internalizing symptoms mediated the association between second trimester IL-1RA and adolescent depressive symptoms in female offspring (b, 0.80; 95% CI, 0.19-1.75). Conclusions and Relevance: In this study, prenatal maternal inflammation was associated with depressive symptoms in adolescent-aged offspring. The findings of the study suggest that pathways to adolescent depressive symptomatology from prenatal risk factors may differ based on both the timing of exposure to prenatal inflammation and offspring sex.

Association between a Mixture of Per- and Polyfluoroalkyl Substances (PFAS) and Inflammatory Biomarkers in the Atlanta African American Maternal-Child Cohort.

Per- and polyfluoroalkyl substances (PFAS) have been identified as environmental contributors to adverse birth outcomes. One potential mechanistic pathway could be through PFAS-related inflammation and cytokine production. Here, we examined associations between a PFAS mixture and inflammatory biomarkers during early and late pregnancy from participants enrolled in the Atlanta African American Maternal-Child Cohort (N = 425). Serum concentrations of multiple PFAS were detected in >90% samples at 8-14 weeks gestation. Serum concentrations of interferon-γ (IFN-γ), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured at up to two time points (8-14 weeks and 24-30 weeks gestation). The effect of the PFAS mixture on each inflammatory biomarker was examined using quantile g-computation, Bayesian kernel machine regression (BKMR), Bayesian Weighted Sums (BWS), and weighted quantile sum (WQS) regression. Across all models, the PFAS mixture was associated with increased IFN-γ, IL-10, and TNF-α at both time points, with the strongest effects being observed at 24-30 weeks. Using quantile g-computation, increasing concentrations of a PFAS mixture were associated with a 29% (95% confidence interval = 18.0%, 40.7%) increase in TNF-α at 24-30 weeks. Similarly, using BWS, the PFAS mixture was associated with increased TNF-α at 24-30 weeks (summed effect = 0.29, 95% highest posterior density = 0.17, 0.41). The PFAS mixture was also positively associated with TNF-α at 24-30 weeks using BKMR [75th vs 50th percentile: 17.1% (95% credible interval = 7.7%, 27.4%)]. Meanwhile, PFOS was consistently the main drivers of overall mixture effect across four methods. Our findings indicated an increase in prenatal PFAS exposure is associated with an increase in multiple pro-inflammatory cytokines, potentially contributing to adverse pregnancy outcomes.

Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk.

Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

Cigarette Smoke Condensate Exposure Induces Receptor for Advanced Glycation End-Products (RAGE)-Dependent Sterile Inflammation in Amniotic Epithelial Cells.

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor for advanced glycation end-products (RAGE) and its ligands can result in cigarette-dependent inflammation. FM explants and amniotic epithelial cells (AECs) were treated with cigarette smoke condensate (CSC), combined or not with RAGE antagonist peptide (RAP), an inhibitor of RAGE. Cell suffering was evaluated by measuring lactate dehydrogenase (LDH) medium-release. Extracellular HMGB1 (a RAGE ligand) release by amnion and choriodecidua explants were checked by western blot. NF-κB pathway induction was determined by a luciferase gene reporter assay, and inflammation was evaluated by cytokine RT-qPCR and protein quantification. Gelatinase activity was assessed using a specific assay. CSC induced cell suffering and HMGB1 secretion only in the amnion, which is directly associated with a RAGE-dependent response. CSC also affected AECs by inducing inflammation (cytokine release and NFκB activation) and gelatinase activity through RAGE engagement, which was linked to an increase in extracellular matrix degradation. This RAGE dependent CSC-induced inflammation associated with an increase of gelatinase activity could explain a pathological FM weakening directly linked to pPROM.

Immune Responses Following BCG Immunization of Infants in Uganda and United Kingdom Are Similar for Purified Protein Derivative but Differ for Secretory Proteins of Mycobacterium tuberculosis.

Introduction: The immunogenicity of BCG vaccination in infants differs between populations. We hypothesized that prenatal exposure to mycobacterial antigens might explain the differences in immune responses to BCG seen in other studies of infants in Africa and the United Kingdom (UK) and we explored this in birth cohorts in Uganda and the UK. Materials and Methods: Blood samples were obtained from BCG-immunized infants of mothers with (n = 110) and without (n = 121) latent Mycobacterium tuberculosis infection (LTBI) in Uganda and BCG-immunized infants of mothers without LTBI (n = 25) in the UK at 10 and 52 weeks after birth. Cytokine and chemokine responses to PPD were measured to assess responses to BCG immunization, and to ESAT6/CFP10 to assess exposure to or infection with M. tuberculosis or non-tuberculous mycobacteria (NTM) in 6-day whole blood culture supernatants by a 17-plex Luminex assay. Median responses were compared between Ugandan infants (together, and separated by maternal LTBI status) and UK infants. Results: The IFN-γ response to BCG vaccination was similar between Ugandan and UK infants at 10 and 52 weeks. At week 52, TNF production was marginally higher in Ugandan infants, but after adjusting for multiple comparisons this difference was not significant. At weeks 10 and 52, stimulation of blood with ESAT6/CFP10 produced significantly higher IFN-γ, TNF, IL-12p40, IL-1α, IL-1ß, IL-1Ra, IP-10, MIP-1α, MIP-1ß, and GM-CSF in Ugandan compared to UK infants. Stimulation of blood with ESAT6/CFP10 produced significantly higher amounts of IL-8 (p = 0.0001), IL-10 (p = 0.0022), and IL-13 (p = 0.0020) in the UK than in Ugandan infants of mothers without LTBI at week 10, but not at week 52. Conclusions: Immune responses to mycobacterial antigens following BCG immunization are similar for PPD, but differ for ESAT6/CFP10, between infants in Uganda and the UK. Neither maternal LTBI nor infant exposure to or infection with mycobacteria impacts the response to BCG. The observed global differences in immune response to BCG immunization are likely to be due to other causes.

Maternal Vitamin C and Iron Intake during Pregnancy and the Risk of Islet Autoimmunity and Type 1 Diabetes in Children: A Birth Cohort Study.

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

Prenatal and Postnatal Cigarette Smoke Exposure Is Associated With Increased Risk of Exacerbated Allergic Airway Immune Responses: A Preclinical Mouse Model.

Increased exposure to household air pollution and ambient air pollution has become one of the world's major environmental health threats. In developing and developed countries, environmental cigarette smoke (CS) exposure is one of the main sources of household air pollution (HAP). Moreover, results from different epidemiological and experimental studies indicate that there is a strong association between HAP, specifically CS exposure, and the development of allergic diseases that often persists into later life. Here, we investigated the impact of prenatal and postnatal CS exposure on offspring susceptibility to the development of allergic airway responses by using a preclinical mouse model. Pregnant BALB/c mice were exposed to either CS or air during pregnancy and lactation and in order to induce allergic asthma the offspring were sensitized and challenged with house dust mite (HDM). Decreased lung function parameters, like dynamic compliance and pleural pressure, were observed in PBS-treated offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. Maternal CS exposure significantly increased the HDM-induced airway eosinophilia and neutrophilia in the offspring. Prenatal and postnatal CS exposure increased the frequency of Th2 cells in the lungs of HDM-treated offspring compared to offspring born to air-exposed mothers. Offspring born to CS-exposed mothers showed increased levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid compared to offspring from air-exposed mothers. Ex-vivo restimulation of lung cells isolated from HDM-treated offspring born to CS-exposed mothers also resulted in increased IL-4 production. Finally, serum immunoglobulins levels of HDM-specific IgE and HDM-specific IgG1 were significantly increased upon a HDM challenge in offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. In summary, our results reveal a biological plausibility for the epidemiological studies indicating that prenatal and postnatal CS exposure increases the susceptibility of offspring to allergic immune responses.

Maternal Sodium Valproate Exposure Alters Neuroendocrine-Cytokines and Oxido-inflammatory Axes in Neonatal Albino Rats.

OBJECTIVE: The aim of the study was to determine the influence of maternal sodium valproate (SVP) on neonatal neuroendocrine (hypothalamic-pituitary-adrenal; HPA)-cytokines and oxido-inflammatory axes. METHODS: Pregnant rats (Rattus norvegicus) were orally administered (by gavage) SVP (50 mg/kg) from gestation day (GD) 8 to lactation day (LD) 21. RESULTS: The elevation in serum corticotropin-releasing hormone (CRH), corticosterone, and adrenocorticotropic hormone (ACTH) levels was highly significant at postnatal days (PNDs) 14 and 21 in both dams and neonates of the maternal SVP-treated group relative to those in the control group. However, hypercortisolism (cortisolemia) was highly significant in neonates at both PNDs 14 and 21, while in dams, it was not significantly increased at LD 14 but was at LD 21. This disruption caused adverse effects on maternal food consumption and maternal/neonatal body weight. The maternal SVP treatment resulted in higher levels of neonatal serum adrenaline, noradrenaline, neuropeptide Y (NPY), tumor necrosis factor-alpha (TNF-α), leptin, interleukins (IL-1ß, IL-17, IL-4, IL-6 & IL-2), transforming growth factor-beta (TGF-ß), and prostaglandin E2 (PGE2), and lower levels of neonatal serum growth hormone (GH), insulin growth factor-1 (IGF-1) and adiponectin at both PNDs. This administration also induced the oxidative stress in neonatal cerebrum and cerebellum at both tested PNDs via the production of free radicals (malondialdehyde; MDA & nitric oxide; NO) and reduction of antioxidant parameters (glutathione; GSH, superoxide dismutase; SOD & catalase; CAT). CONCLUSION: Maternal SVP treatment stimulated the neonatal stress-brain (HPA) axis, resulted in an oxido-inflammatory state, and disrupted the neuroendocrine-cytokines axis, and generally neonatal health.

Dysfunctional Immune System Reconstitution After Rituximab Exposure In Utero.

Rituximab is an antibody that binds to B-lymphocytes and is increasingly used during pregnancy. As an immunoglobulin G, it will transfer across the placenta. Previous case reports describe a diversity of clinical presentations in neonates born following rituximab exposure in utero. Our case is the first to offer the long-term experience in the care of an infant with severe neutropenia and prolonged profound hypogammaglobulinemia and class-switching B cell defect after in utero rituximab exposure.

Longitudinal Changes in Fecal Calprotectin Levels Among Pregnant Women With and Without Inflammatory Bowel Disease and Their Babies.

BACKGROUND & AIMS: The effect of pregnancy on inflammatory bowel disease (IBD) remains poorly understood. We aimed to monitor intestinal inflammation using fecal calprotectin (FC) in pregnant women and their babies during early life. METHODS: Pregnant women with or without IBD and their infants were prospectively enrolled. FC levels were measured at each trimester of pregnancy and in babies throughout the first 3 years of life. Repeated-measures analysis was applied to investigate changes in FC levels while adjusting for confounders. The FC levels were correlated with the bacterial abundance in both mothers and babies. RESULTS: Six hundred and fourteen fecal samples from 358 mothers (98 with IBD) and 1005 fecal samples from 289 infants (76 born to IBD mothers) were analyzed. Pregnant Patients with IBD maintained higher FC levels through pregnancy compared with controls (P = 7.5 × 10-54). FC gradually increased in controls and declined in Patients with IBD throughout pregnancy (P for interaction = 5.8 × 10-7). Babies born to mothers with IBD presented with significantly higher FC levels than those born to controls up to 3 years of age, after adjusting for sex, delivery mode, feeding behavior, and antibiotics exposure (2 weeks to 3 months of age, P = .015; 12-36 months of age, P = .00003). Subdoligranulum, Roseburia, Fusicatenibacter, and Alistipes negatively correlated, and Streptococcus, Prevotella, Escherichia-Shigella, and Bifidobacterium positively correlated with maternal FC levels at T3. Faecalibacterium, Bifidobacterium, and Alistipes showed negative correlations, and Streptococcus were positively correlated with FC levels within 3 months of birth. CONCLUSIONS: Pregnancy is associated with decreased inflammatory activity in mothers with IBD. Higher FC levels in babies born to mothers with IBD suggest subclinical inflammation in early life, the long-term consequences of which are uncertain.

Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child. METHODS: Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest. RESULTS: Among 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51). CONCLUSIONS: Biologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.

Brain changes in NF-κB1 and epidermal growth factor system markers at peri-pubescence in the spiny mouse following maternal immune activation.

Environmental risk factors that operate at foetal or neonatal levels increase the vulnerability to schizophrenia, plausibly via stress-immune activation that perturbs the epidermal growth factor (EGF) system, a system critical for neurodevelopment. We investigated potential associations between environmental insults and immune and EGF system changes through a maternal immune activation (MIA) model, using the precocial spiny mice (Acomys cahirinus). After mid-gestation MIA prepubescent offspring showed elevated NF-κB1 protein in nucleus accumbens, decreased EGFR in caudate putamen and a trend for increased PI3K-110δ in ventral hippocampus. Thus, prenatal stress may cause a heightened NF-κB1-mediated immune attenuation of EGF system signalling.

Cord Blood Levels of EPA, a Marker of Fish Intake, Correlate with Infants' T- and B-Lymphocyte Phenotypes and Risk for Allergic Disease.

Maternal fish intake during pregnancy has been associated with reduced allergy development in the offspring and here, we hypothesized that components of fish stimulate fetal immune maturation. The aim of this study was to investigate how maternal fish intake during pregnancy and levels of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in the infant's cord serum correlated with different subsets of B- and T-cells in cord blood and B-cell activating factor (BAFF) in cord plasma, and with doctor-diagnosed allergy at 3 and 8 years of age in the FARMFLORA birth-cohort consisting of 65 families. Principal component analysis showed that infant allergies at 3 or 8 years of age were negatively associated with the proportions of n-3 LCPUFAs (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) in infant cord serum, which, in turn correlated positively with maternal fish intake during pregnancy. Both maternal fish intake and cord serum n-3 LCPUFAs correlated negatively to CD5+ B cells and the FOXP3+CD25high of the CD4+ T cell subsets in cord blood, but not to BAFF in cord plasma. Our observational study suggests that fish might contain components that promote maturation of the infant's immune system in a manner that protects against allergy development.

Prenatal programming of the immune response induced by maternal periodontitis: Effects on the development of acute lung injury in rat pups.

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

Factors associated with immunosenescence during early adulthood in HIV-infected patients after durable efficient combination antiretroviral therapy.

Perinatally HIV-infected patients face the consequences of both chronic infection effects per se and long-term combination antiretroviral therapy (cART) on immunosenescence. Aims of our study were to evaluate which factors independently contribute to immunosenescence in HIV-infected young adults with a very different HIV infection duration (perinatally HIV-infected young individuals -pHIVy- and age-matched non perinatally HIV-infected youths -npHIVy), after durable  efficient cART. We considered low thymic and bone marrow output, respectively evaluated by quantifying T-cell receptor excision circles (TRECs), K-deleting recombination excision circles (KRECs), and shorter telomeres lenght (TL) as surrogate biomarkers of immunosenescence. Twenty-one pHIVy and 19 npHIVy (with a mean HIV duration of 3-8 years) were included; mean age was 27 years for both groups. Immunosenescence biomarkers were comparable between pHIVy and npHIVy (despite longer HIV-infection, higher frequency of AIDS events, past cART-free periods and concomitant chronic viral infections in pHIVy). At the multivariate analysis, CD4+ was the only variable independently associated with TRECs and TL. Our data suggest that a good level of thymic activity can compensate the deleterious effects of past periods without cART, if HIV replication is suppressed for a sufficient time.

Induction of inducible nitric oxide synthase expression in activated microglia and astrocytes following pre- and postnatal immune challenge in an animal model of schizophrenia.

In the central nervous system, activated microglia and astrocytes produce proinflammatory mediators such as inducible nitric oxide (iNOS) and cytokines. Uncontrolled release of these mediators induced by immune challenge can lead to increased vulnerability to complex brain disorders such as schizophrenia. In this study, BALB/c mice were injected intraperitoneally (i.p) with the viral mimetic polyriboinosinic-polyribocytidilic acid (poly(I:C)) or saline. At postnatal day 30 (PND0), the animals were sacrificed and the hippocampus, corpus callosum, striatum, cortex, fimbria and ventricle were immunostained for Iba-1, a microglial marker, glial fibrillary acidic protein (GFAP), an astrocyte marker, and iNOS, an activation marker for NO. Additionally, serum cytokine profiling (Interleukin-2 (IL-2), IL- 4, IL-6, interferon gamma (IFN-γ), tumour necrosis factor (TNF), IL-17A and IL-10) was determined using serum samples from poly(I:C)-treated and control mice. Our results demonstrated that poly(I:C) induced overactivation of differential proinflammatory responses in microglia and astrocytes, which could be strongly enhanced by a postnatal poly(I:C) administration before PND 30 in one part of the animals investigated. Specifically, there was significant iNOS upregulation in hippocampus, cortex and corpus callosum of poly(I:C)-affected off-springs. These inflammatory alterations were accompanied by increased circulating levels of the proinflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). This study provides insight into the role of microglia and astrocytes in an animal model of schizophrenia and an understanding of the regulation of iNOS expression in glial cells and cytokine networks. This knowledge could help identify novel targets for anti-oxidative and anti-inflammatory therapeutic schizophrenia intervention.

Dietary intake of glucoraphanin during pregnancy and lactation prevents the behavioral abnormalities in the offspring after maternal immune activation.

AIM: Epidemiological data suggest that maternal immune activation (MIA) plays a role in the etiology of neuropsychiatric disorders including autism spectrum disorder (ASD) and schizophrenia. However, there is no prophylactic nutrition that can prevent the onset of neurodevelopmental disorders in offspring after MIA. The aim of this study was undertaken to examine whether dietary intake of glucoraphanin (GF: the precursor of a natural anti-inflammatory compound sulforaphane) can prevent the onset of behavioral abnormalities in offspring after MIA. METHODS: One percent of GF food pellet or normal food pellet was given into female mice during pregnancy and lactation (from E5 to P21). Saline (5 mL/kg/d) or poly(I:C) (5 mg/kg/d) was injected into pregnant mice from E12 to E17. Behavioral tests and immunohistochemistry of parvalbumin (PV) were performed in male offspring. RESULTS: Dietary intake of GF during pregnancy and lactation prevented cognitive deficits and social interaction deficits in the juvenile offspring after MIA. Furthermore, dietary intake of GF during pregnancy and lactation prevented cognitive deficits in the adult offspring after MIA. Moreover, dietary intake of GF prevented the reduction of PV immunoreactivity in the medial prefrontal cortex of adult offspring after MIA. CONCLUSION: These data suggest that dietary intake of GF during pregnancy and lactation could prevent behavioral abnormalities in offspring after MIA.

Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols.

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

A prenatally disrupted airway epithelium orchestrates the fetal origin of asthma in mice.

BACKGROUND: Prenatal challenges such as maternal stress perception increase the risk and severity of asthma during childhood. However, insights into the trajectories and targets underlying the pathogenesis of prenatally triggered asthma are largely unknown. The developing lung and immune system may constitute such targets. OBJECTIVE: Here we have aimed to identify the differential sex-specific effects of prenatal challenges on lung function, immune response, and asthma severity in mice. METHODS: We generated bone marrow chimeric (BMC) mice harboring either prenatally stress-exposed lungs or a prenatally stress-exposed immune (hematopoietic) system and induced allergic asthma via ovalbumin. Next-generation sequencing (RNA sequencing) of lungs and assessment of airway epithelial barrier function in ovalbumin-sensitized control and prenatally stressed offspring was also performed. RESULTS: Profoundly enhanced airway hyperresponsiveness, inflammation, and fibrosis were exclusively present in female BMC mice with prenatally stress-exposed lungs. These effects were significantly perpetuated if both the lungs and the immune system had been exposed to prenatal stress. A prenatally stress-exposed immune system alone did not suffice to increase the severity of these asthma features. RNA sequencing analysis of lungs from prenatally stressed, non-BMC, ovalbumin-sensitized females unveiled a deregulated expression of genes involved in asthma pathogenesis, tissue remodeling, and tight junction formation. It was also possible to independently confirm a tight junction disruption. In line with this, we identified an altered perinatal and/or postnatal expression of genes involved in lung development along with an impaired alveolarization in female prenatally stressed mice. CONCLUSION: Here we have shown that the fetal origin of asthma is orchestrated by a disrupted airway epithelium and further perpetuated by a predisposed immune system.

Sex-specific effects of developmental exposure to polychlorinated biphenyls on neuroimmune and dopaminergic endpoints in adolescent rats.

Exposure to environmental contaminants early in life can have long lasting consequences for physiological function. Polychlorinated biphenyls (PCBs) are a group of ubiquitous contaminants that perturb endocrine signaling and have been associated with altered immune function in children. In this study, we examined the effects of developmental exposure to PCBs on neuroimmune responses to an inflammatory challenge during adolescence. Sprague Dawley rat dams were exposed to a PCB mixture (Aroclor 1242, 1248, 1254, 1:1:1, 20 µg/kg/day) or oil control throughout pregnancy, and adolescent male and female offspring were injected with lipopolysaccharide (LPS, 50 µg/kg, ip) or saline control prior to euthanasia. Gene expression profiling was conducted in the hypothalamus, prefrontal cortex, striatum, and midbrain. In the hypothalamus, PCBs increased expression of genes involved in neuroimmune function, including those within the nuclear factor kappa b (NF-κB) complex, independent of LPS challenge. PCB exposure also increased expression of receptors for dopamine, serotonin, and estrogen in this region. In contrast, in the prefrontal cortex, PCB exposure blunted or induced irregular neuroimmune gene expression responses to LPS challenge. Moreover, neither PCB nor LPS exposure altered expression of neurotransmitter receptors throughout the mesocorticolimbic circuit. Almost all effects were present in males but not females, in agreement with the idea that male neuroimmune cells are more sensitive to perturbation and emphasizing the importance of studying both male and female subjects. Given that altered neuroimmune signaling has been implicated in mental health and substance abuse disorders that often begin during adolescence, these results highlight neuroimmune processes as another mechanism by which early life PCBs can alter brain function later in life.