RNA epitranscriptomics dysregulation: A major determinant for significantly increased risk of ASD pathogenesis.

Autism spectrum disorders (ASDs) are perhaps the most severe, intractable and challenging child psychiatric disorders. They are complex, pervasive and highly heterogeneous and depend on multifactorial neurodevelopmental conditions. Although the pathogenesis of autism remains unclear, it revolves around altered neurodevelopmental patterns and their implications for brain function, although these cannot be specifically linked to symptoms. While these affect neuronal migration and connectivity, little is known about the processes that lead to the disruption of specific laminar excitatory and inhibitory cortical circuits, a key feature of ASD. It is evident that ASD has multiple underlying causes and this multigenic condition has been considered to also dependent on epigenetic effects, although the exact nature of the factors that could be involved remains unclear. However, besides the possibility for differential epigenetic markings directly affecting the relative expression levels of individual genes or groups of genes, there are at least three mRNA epitranscriptomic mechanisms, which function cooperatively and could, in association with both genotypes and environmental conditions, alter spatiotemporal proteins expression patterns during brain development, at both quantitative and qualitative levels, in a tissue-specific, and context-dependent manner. As we have already postulated, sudden changes in environmental conditions, such as those conferred by maternal inflammation/immune activation, influence RNA epitranscriptomic mechanisms, with the combination of these processes altering fetal brain development. Herein, we explore the postulate whereby, in ASD pathogenesis, RNA epitranscriptomics might take precedence over epigenetic modifications. RNA epitranscriptomics affects real-time differential expression of receptor and channel proteins isoforms, playing a prominent role in central nervous system (CNS) development and functions, but also RNAi which, in turn, impact the spatiotemporal expression of receptors, channels and regulatory proteins irrespective of isoforms. Slight dysregulations in few early components of brain development, could, depending upon their extent, snowball into a huge variety of pathological cerebral alterations a few years after birth. This may very well explain the enormous genetic, neuropathological and symptomatic heterogeneities that are systematically associated with ASD and psychiatric disorders at large.

Cardiovascular risk in the postnatal life of children born to women with systemic lupus erythematous / Riesgo cardiovascular en la vida posnatal de hijos de mujeres con lupus eritematoso sistémico

Abstract Systemic lupus erythematous (SLE) is an autoimmune disease with clinical manifestations in multiple organs, primarily striking women of reproductive age. Women with SLE can became pregnant such as any other healthy woman and carrier their pregnancy to term due to the improvement of health systems, but their specific inflammatory conditions could affect the microenvironment in which the fetus grows, and influence the development of placenta and the fetal heart. Until now, there is very little evidence of any increased risk of postnatal cardiovascular disease (CVD) in the apparently healthy children from women with SLE, but it is this great variability in the effects of lupus on pregnant products is related to.

Resumen El lupus eritematoso sistémico (LES) es una enfermedad autoinmune que presenta diversas manifestaciones clínicas en múltiples órganos, y afecta principalmente a mujeres en edad reproductiva. Las mujeres con LES se pueden embarazar y llevar a término su embarazo, sin embargo, las condiciones inflamatorias específicas de la madre pueden modificar el microambiente en el que el embrión y el feto se desarrollan y afectar la formación y desarrollo de la placenta y el corazón fetal. Hasta ahora hay muy poca evidencia de que haya un mayor riesgo de enfermedad cardiovascular (ECV) en hijos aparentemente sanos de madres con LES, a pesar de que se sabe que hay un mayor riesgo de alteraciones cognitivas y neuronales, así como de desarrollar enfermedades autoinmunes en esos niños. El objetivo de esta revisión fue realizar una búsqueda bibliografía cruzando palabras clave acerca la enfermedad cardiovascular en hijos sanos de mujeres con LES. La evidencia mostró que la autoinmunidad materna puede favorecer la predisposición para el desarrollo de ECV en sus hijos, por medio de la modificación de señales que alteran el microambiente durante la gestación, lo que puede afectar la respuesta inmunitaria y cambios epigenéticos durante la vida posnatal.

Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring.

The prevalence of obesity is increasingly common in the United States, with ~25% of women of reproductive age being overweight or obese. Metaflammation, a chronic low grade inflammatory state caused by altered metabolism, is often present in pregnancies complicated by obesity. As a result, the fetuses of mothers who are obese are exposed to an in-utero environment that has altered nutrients and cytokines. Notably, both human and preclinical studies have shown that children born to mothers with obesity have higher risks of developing chronic illnesses affecting various organ systems. In this review, the authors sought to present the role of cytokines and inflammation during healthy pregnancy and determine how maternal obesity changes the inflammatory landscape of the mother, leading to fetal reprogramming. Next, the negative long-term impact on offspring's health in numerous disease contexts, including offspring's risk of developing neuropsychiatric disorders (autism, attention deficit and hyperactive disorder), metabolic diseases (obesity, type 2 diabetes), atopy, and malignancies will be discussed along with the potential of altered immune/inflammatory status in offspring as a contributor of these diseases. Finally, the authors will list critical knowledge gaps in the field of developmental programming of health and diseases in the context of offspring of mothers with obesity, particularly the understudied role of hematopoietic stem and progenitor cells.

Iron nitrosyl complexes are formed from nitrite in the human placenta.

Placental nitric oxide (NO) is critical for maintaining perfusion in the maternal-fetal-placental circulation during normal pregnancy. NO and its many metabolites are also increased in pregnancies complicated by maternal inflammation such as preeclampsia, fetal growth restriction, gestational diabetes, and bacterial infection. However, it is unclear how increased levels of NO or its metabolites affect placental function or how the placenta deals with excessive levels of NO or its metabolites. Since there is uncertainty over the direction of change in plasma levels of NO metabolites in preeclampsia, we measured the levels of these metabolites at the placental tissue level. We found that NO metabolites are increased in placentas from patients with preeclampsia compared to healthy controls. We also discovered by ozone-based chemiluminescence and electron paramagnetic resonance that nitrite is efficiently converted into iron nitrosyl complexes (FeNOs) within the human placenta and also observed the existence of endogenous FeNOs within placentas from sheep and rats. We show these nitrite-derived FeNOs are relatively short-lived, predominantly protein-bound, heme-FeNOs. The efficient formation of FeNOs from nitrite in the human placenta hints toward the importance of both nitrite and FeNOs in placental physiology or pathology. As iron nitrosylation is an important posttranslational modification that affects the activity of multiple iron-containing proteins such as those in the electron transport chain, or those involved in epigenetic regulation, we conclude that FeNOs merit increased study in pregnancy complications.

Maternal Progesterone Treatment Reduces Maternal Inflammation-Induced Fetal Brain Injury in a Mouse Model of Preterm Birth.

Maternal natural vaginal progesterone (nVP) administration has been shown to reduce the risk of preterm birth (PTB). The largest randomized trial of nVP for PTB (OPPTIMUM) noted a sonographic reduction in neonatal brain injury following nVP treatment. We investigated the neuroinflammatory protective effect of maternal nVP in a mouse model for maternal inflammation. Pregnant mice (n = 24) were randomized to nVP (1 mg/day) or vehicle from days 13-16 of gestation. At days 15 and 16, lipopolysaccharide (30 µg) or saline were administered. Mice were sacrificed 4 h following the last injection. Fetal brains and placentas were collected. Levels of NF-κB, nNOS, IL-6, and TNFα were determined by Western blot. Maternal lipopolysaccharide significantly increased fetal brain levels of IL-6 (0.33 ± 0.02 vs. 0.11 ± 0.01 u), TNFα (0.3 ± 0.02 vs. 0.10 ± 0.01 u), NF-κB (0.32 ± 0.01 vs. 0.17 ± 0.01 u), and nNOS (0.24 ± 0.04 vs. 0.08 ± 0.01 u), and reduced the total glutathione levels (0.014 ± 0.001 vs. 0.026 ± 0.001 pmol/µl; p < 0.01) compared with control. Maternal nVP significantly reduced fetal brain levels of IL-6 (0.14 ± 0.01 vs. 0.33 ± 0.02 u), TNFα (0.2 ± 0.06 vs. 0.3 ± 0.02 u), NF-κB (0.16 ± 0.01 vs 0.32 ± 0.01 u), and nNOS (0.14 ± 0.01 vs 0.24 ± 0.04 u), and prevented the reduction of fetal brain total glutathione levels (0.022 ± 0.001 vs. 0.014 ± 0.001 pmol/µl; p < 0.01) to levels similar to controls. A similar pattern was demonstrated in the placenta. Maternal nVP for PTB may protect the fetal brain from inflammation-induced brain injury by inhibiting specific inflammatory and oxidative pathways in both brain and placenta.

Studies on Haloperidol and Adjunctive α-Mangostin or Raw Garcinia mangostana Linn Pericarp on Bio-Behavioral Markers in an Immune-Inflammatory Model of Schizophrenia in Male Rats.

Schizophrenia is a severe brain disorder that is associated with neurodevelopmental insults, such as prenatal inflammation, that introduce redox-immune-inflammatory alterations and risk for psychotic symptoms later in life. Nutraceuticals may offer useful adjunctive benefits. The aim of this study was to examine the therapeutic effects of Garcinia mangostana Linn (GML) and one of its active constituents, α-mangostin (AM), alone and as adjunctive treatment with haloperidol (HAL) on schizophrenia related bio-behavioral alterations in a maternal immune-activation (MIA) model. Sprague-Dawley dams were exposed to lipopolysaccharide (LPS) (n = 18) or vehicle (n = 3) on gestational days 15 and 16. Male offspring (n = 72) were treated from PND 52-66 with either vehicle, HAL (2 mg/kg), GML (50 mg/kg), HAL + GML, AM (20 mg/kg), or HAL + AM. Control dams and control offspring were treated with vehicle. In order to cover the mood-psychosis continuum, prepulse inhibition (PPI) of startle, open field test (locomotor activity), and the forced swim test (depressive-like behavior) were assessed on PND's 64-65, followed by assay of frontal-cortical lipid peroxidation and plasma pro-inflammatory cytokines, viz. interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). MIA-induced deficits in sensorimotor gating were reversed by HAL and HAL + GML, but not GML and AM alone. MIA-induced depressive-like behavior was reversed by AM and GML alone and both in combination with HAL, with the combinations more effective than HAL. MIA-induced cortical lipid peroxidation was reversed by HAL and AM, with elevated IL-6 levels restored by GML, AM, HAL, and HAL + GML. Elevated TNF-α was only reversed by GML and HAL + GML. Concluding, prenatal LPS-induced psychotic- and depressive-like bio-behavioral alterations in offspring are variably responsive to HAL, GML, and AM, with depressive (but not psychosis-like) manifestations responding to GML, AM, and combinations with HAL. AM may be a more effective antioxidant than GML in vivo, although this does not imply an improved therapeutic response, for which trials are required.

Maternal inflammation leads to different mTORC1 activity varied by anatomic locations in mouse placenta†.

Maternal inflammation (MI) is associated with many adverse perinatal outcomes. The placenta plays a vital role in mediating maternal-fetal resource allocation. Studies have shown that MI contributes to placental dysfunction, which then leads to adverse birth outcomes and high health risks throughout childhood. Placental mammalian target of rapamycin complex 1 (mTORC1) signaling pathway links maternal nutrient availability to fetal growth; however, the impact of MI on mTORC1 signaling in the placenta remains unclear. In this study, we sought to explore the changes of mTORC1 signaling in the mouse placenta at late gestation by using two models of MI employing lipopolysaccharide (LPS) and interleukin-1ß (IL-1ß) to mimic acute (aMI) and sub-chronic (cMI) inflammatory states, respectively. We determined placental mTORC1 activity by measuring the activity of mTORC1 downstream molecules, including S6k, 4Ebp1, and rpS6. In the aMI model, we found that mTORC1 activity was significantly decreased in the placental decidual and junctional zone at 2 and 6 h after LPS surgery, respectively; however, mTORC1 activity was significantly increased in the placental labyrinth zone at 2, 6, and 24 h after LPS treatment, respectively. In the cMI model, we observed that mTORC1 activity was increased only in the placental labyrinth zone after consecutive IL-1ß exposure. Our study reveals that different parts of the mouse placenta react differently to MI, leading to variable mTORC1 activity throughout the placenta. This suggests that different downstream molecules of mTORC1 from different parts of the mouse placenta may be used in clinical research to monitor the fetal well-being during MI.

Maternal inflammation during pregnancy and offspring psychiatric symptoms in childhood: Timing and sex matter.

OBJECTIVE: Maternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship. METHOD: Participants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9-11, mothers completed a questionnaire assessing psychological symptoms. RESULTS: Multivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only. CONCLUSION: These findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work.

Maternal pomegranate juice attenuates maternal inflammation-induced fetal brain injury by inhibition of apoptosis, neuronal nitric oxide synthase, and NF-κB in a rat model.

BACKGROUND: Maternal inflammation is a risk factor for neonatal brain injury and future neurological deficits. Pomegranates have been shown to exhibit anti-inflammatory, anti-apoptotic and anti-oxidant activities. OBJECTIVE: We hypothesized that pomegranate juice (POM) may attenuate fetal brain injury in a rat model of maternal inflammation. STUDY DESIGN: Pregnant rats (24 total) were randomized for intraperitoneal lipopolysaccharide (100 µg/kg) or saline at time 0 at 18 days of gestation. From day 11 of gestation, 12 dams were provided ad libitum access to drinking water, and 12 dams were provided ad libitum access to drinking water with pomegranate juice (5 mL per day), resulting in 4 groups of 6 dams (saline/saline, pomegranate juice/saline, saline/lipopolysaccharide, pomegranate juice/lipopolysaccharide). All dams were sacrificed 4 hours following the injection and maternal blood and fetal brains were collected from the 4 treatment groups. Maternal interleukin-6 serum levels and fetal brain caspase 3 active form, nuclear factor-κB p65, neuronal nitric oxide synthase (phosphoneuronal nitric oxide synthase), and proinflammatory cytokine levels were determined by enzyme-linked immunosorbent assay and Western blot. RESULTS: Maternal lipopolysaccharide significantly increased maternal serum interleukin-6 levels (6039 ± 1039 vs 66 ± 46 pg/mL; P < .05) and fetal brain caspase 3 active form, nuclear factor-κB p65, phosphoneuronal nitric oxide synthase, and the proinflammatory cytokines compared to the control group (caspase 3 active form 0.26 ± 0.01 vs 0.20 ± 0.01 U; nuclear factor-κB p65 0.24 ± 0.01 vs 0.1 ± 0.01 U; phosphoneuronal nitric oxide synthase 0.23 ± 0.01 vs 0.11 ± 0.01 U; interleukin-6 0.25 ± 0.01 vs 0.09 ± 0.01 U; tumor necrosis factor-α 0.26 ± 0.01 vs 0.12 ± 0.01 U; chemokine (C-C motif) ligand 2 0.23 ± 0.01 vs 0.1 ± 0.01 U). Maternal supplementation of pomegranate juice to lipopolysaccharide-exposed dams (pomegranate juice/lipopolysaccharide) significantly reduced maternal serum interleukin-6 levels (3059 ± 1121 pg/mL, fetal brain: caspase 3 active form (0.2 ± 0.01 U), nuclear factor-κB p65 (0.22 ± 0.01 U), phosphoneuronal nitric oxide synthase (0.19 ± 0.01 U) as well as the brain proinflammatory cytokines (interleukin-6, tumor necrosis factor-α and chemokine [C-C motif] ligand 2) compared to lipopolysaccharide group. CONCLUSION: Maternal pomegranate juice supplementation may attenuate maternal inflammation-induced fetal brain injury. Pomegranate juice neuroprotective effects might be secondary to the suppression of both the maternal inflammatory response and inhibition of fetal brain apoptosis, neuronal nitric oxide synthase, and nuclear factor-κB activation.

Maternal IL-17A in autism.

Although autism spectrum disorder (ASD) has a strong genetic basis, its etiology is complex, with several genetic factors likely to be involved as well as environmental factors. Immune dysregulation has gained significant attention as a causal mechanism in ASD pathogenesis. ASD has been associated with immune abnormalities in the brain and periphery, including inflammatory disorders and autoimmunity in not only the affected individuals but also their mothers. Prenatal exposure to maternal immune activation (MIA) has been implicated as an environmental risk factor for ASD. In support of this notion, animal models have shown that MIA results in offspring with behavioral, neurological, and immunological abnormalities similar to those observed in ASD. This raises the question of how MIA exposure can lead to ASD in susceptible individuals. Recent evidence points to a potential inflammation pathway linking MIA-associated ASD with the activity of T helper 17 (Th17) lymphocytes and their effector cytokine interleukin-17A (IL-17A). IL-17A has been implicated from human studies and elevated IL-17A levels in the blood have been found to correlate with phenotypic severity in a subset of ASD individuals. In MIA model mice, elevated IL-17A levels also have been observed. Additionally, antibody blockade to inhibit IL-17A signaling was found to prevent ASD-like behaviors in offspring exposed to MIA. Therefore, IL-17A dysregulation may play a causal role in the development of ASD. The source of increased IL-17A in the MIA mouse model was attributed to maternal Th17 cells because genetic removal of the transcription factor RORγt to selectively inhibit Th17 differentiation in pregnant mice was able to prevent ASD-like behaviors in the offspring. Similar to ASD individuals, the MIA-exposed offspring also displayed cortical dysplasia which could be prevented by inhibition of IL-17A signaling in pregnant mice. This finding reveals one possible cellular mechanism through which ASD-related cognitive and behavioral deficits may emerge following maternal inflammation. IL-17A can exert strong effects on cell survival and differentiation and the activity of signal transduction cascades, which can have important consequences during cortical development on neural function. This review examines IL-17A signaling pathways in the context of both immunity and neural function that may contribute to the development of ASD associated with MIA.

Maternal inflammation induces immune activation of fetal microglia and leads to disrupted microglia immune responses, behavior, and learning performance in adulthood.

Maternal inflammation during pregnancy can have detrimental effects on embryonic development that persist during adulthood. However, the underlying mechanisms and insights in the responsible cell types are still largely unknown. Here we report the effect of maternal inflammation on fetal microglia, the innate immune cells of the central nervous system (CNS). In mice, a challenge with LPS during late gestation stages (days 15-16-17) induced a pro-inflammatory response in fetal microglia. Adult whole brain microglia of mice that were exposed to LPS during embryonic development displayed a persistent reduction in pro-inflammatory activation in response to a re-challenge with LPS. In contrast, hippocampal microglia of these mice displayed an increased inflammatory response to an LPS re-challenge. In addition, a reduced expression of brain-derived neurotrophic factor (BDNF) was observed in hippocampal microglia of LPS-offspring. Microglia-derived BDNF has been shown to be important for learning and memory processes. In line with these observations, behavioral- and learning tasks with mice that were exposed to maternal inflammation revealed reduced home cage activity, reduced anxiety and reduced learning performance in a T-maze. These data show that exposure to maternal inflammation during late gestation results in long term changes in microglia responsiveness during adulthood, which is different in nature in hippocampus compared to total brain microglia.

miR-29b supplementation decreases expression of matrix proteins and improves alveolarization in mice exposed to maternal inflammation and neonatal hyperoxia.

Even with advances in the care of preterm infants, chronic lung disease or bronchopulmonary dysplasia (BPD) continues to be a significant pulmonary complication. Among those diagnosed with BPD, a subset of infants develop severe BPD with disproportionate pulmonary morbidities. In addition to decreased alveolarization, these infants develop obstructive and/or restrictive lung function due to increases in or dysregulation of extracellular matrix proteins. Analyses of plasma obtained from preterm infants during the first week of life indicate that circulating miR-29b is suppressed in infants that subsequently develop BPD and that decreased circulating miR-29b is inversely correlated with BPD severity. Our mouse model mimics the pathophysiology observed in infants with severe BPD, and we have previously reported decreased pulmonary miR-29b expression in this model. The current studies tested the hypothesis that adeno-associated 9 (AAV9)-mediated restoration of miR-29b in the developing lung will improve lung alveolarization and minimize the deleterious changes in matrix deposition. Pregnant C3H/HeN mice received an intraperitoneal LPS injection on embryonic day 16 and newborn pups were exposed to 85% oxygen from birth to 14 days of life. On postnatal day 3, AAV9-miR-29b or AAV9-control was administered intranasally. Mouse lung tissues were then analyzed for changes in miR-29 expression, alveolarization, and matrix protein levels and localization. Although only modest improvements in alveolarization were detected in the AAV9-miR29b-treated mice at postnatal day 28, treatment completely attenuated defects in matrix protein expression and localization. Our data suggest that miR-29b restoration may be one component of a novel therapeutic strategy to treat or prevent severe BPD in prematurely born infants.

Fetal sex is associated with maternal stimulated cytokine production, but not serum cytokine levels, in human pregnancy.

Some studies suggest that fetal sex plays a role in maternal physiological processes during pregnancy including glycemic control, blood pressure, and cortisol regulation. However, data examining fetal sex-specific differences in maternal immune parameters is lacking. In the current study, serum levels of interleukin(IL)-6, IL-8, and tumor necrosis factor(TNF)-α as well as LPS-stimulated production of IL-6, IL-8, TNF-α, and IL-1ß by PBMCs incubated for 24h were assessed in early, mid, and late pregnancy among 80 women (46 with male and 34 with female fetuses). Linear mixed models showed that women carrying females versus males exhibited greater stimulated production of IL-6 at each timepoint (ps⩽0.03), TNF-α in early pregnancy (p=0.04), and IL-1ß in mid- and late pregnancy (ps⩽0.05). Despite changes in serum levels of IL-8 (p=0.002) and TNF-α (p<0.0001) across pregnancy, no differences in any serum cytokines were observed in relation to fetal sex (ps>0.85). In conclusion, in pregnant women, those carrying female versus male fetuses exhibited greater stimulated cytokine production across pregnancy. Differential inflammatory responses could affect maternal health and fetal development. Fetal sex should be considered as a factor in studies of maternal inflammation. These findings have relevance both clinically and conceptually. For example, maternal asthma is exacerbated among women carrying female versus male fetuses. In addition, data on associations between fetal sex and maternal immune function among women with health conditions (e.g., preeclampsia) and adverse pregnancy outcomes (e.g., preterm birth) would be informative.

DHA suppresses chronic apoptosis in the lung caused by perinatal inflammation.

We have previously shown that an adverse perinatal environment significantly alters lung growth and development and results in persistently altered cardiopulmonary physiology in adulthood. Our model of maternal LPS treatment followed by 14 days of neonatal hyperoxia exposure causes severe pulmonary disease characterized by permanent decreases in alveolarization and diffuse interstitial fibrosis. The current investigations tested the hypothesis that dysregulation of Notch signaling pathways contributes to the permanently altered lung phenotype in our model and that the improvements we have observed previously with maternal docosahexaenoic acid (DHA) supplementation are mediated through normalization of Notch-related protein expression. Results indicated that inflammation (IL-6 levels) and oxidation (F2a-isoprostanes) persisted through 8 wk of life in mice exposed to LPS/O2 perinatally. These changes were attenuated by maternal DHA supplementation. Modest but inconsistent differences were observed in Notch-pathway proteins Jagged 1, DLL 1, PEN2, and presenilin-2. We detected substantial increases in markers of apoptosis including PARP-1, APAF-1, caspase-9, BCL2, and HMGB1, and these increases were attenuated in mice that were nursed by DHA-supplemented dams during the perinatal period. Although Notch signaling is not significantly altered at 8 wk of age in mice with perinatal exposure to LPS/O2, our findings indicate that persistent apoptosis continues to occur at 8 wk of age. We speculate that ongoing apoptosis may contribute to persistently altered lung development and may further enhance susceptibility to additional pulmonary disease. Finally, we found that maternal DHA supplementation prevented sustained inflammation, oxidation, and apoptosis in our model.

Prenatal maternal immune activation increases anxiety- and depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is thought to result from a combination of genetics and environmental factors. Several lines of evidence indicate that significant prevalence of anxiety and depression-related disorders in MS patients can influence the progression of the disease. Although we and others have already reported the consequences of prenatal maternal immune activation on anxiety and depression, less is known about the interplay between maternal inflammation, MS and gender. We here investigated the effects of maternal immune activation with Poly I:C during mid-gestation on the progression of clinical symptoms of experimental autoimmune encephalomyelitis (EAE; a mouse model of MS), and then anxiety- and depressive-like behaviors in non-EAE and EAE-induced offspring were evaluated. Stress-induced corticosterone and tumor necrosis factor-alpha (TNF-α) levels in EAE-induced offspring were also measured. Maternal immune activation increased anxiety and depression in male offspring, but not in females. This immune challenge also resulted in an earlier onset of the EAE clinical signs in male offspring and enhanced the severity of the disease in both male and female offspring. Interestingly, the severity of the disease was associated with increased anxiety/depressive-like behaviors and elevated corticosterone or TNF-α levels in both sexes. Overall, these data suggest that maternal immune activation with Poly I:C during mid-pregnancy increases anxiety- and depressive-like behaviors, and the clinical symptoms of EAE in a sex-dependent manner in non-EAE or EAE-induced offspring. Finally, the progression of EAE in offspring seems to be linked to maternal immune activation-induced dysregulation in neuro-immune-endocrine system.

Prenatal inflammatory risk factors for development of bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a serious, chronic lung disease affecting preterm infants. OBJECTIVE: To identify prenatal risk factors for BPD, focusing on inflammation. METHODS: Observational cohort study including 106,339 preterm infants, live born before gestational week 37 + 0, from 1988 to 2009 in Sweden. A total of 2,115 infants were diagnosed with BPD, of which 1,393 were born extremely preterm, before gestational week 28 + 0. Information on risk factors was obtained from national health registers and included maternal chronic inflammatory diseases, pregnancy related diseases, and drugs related to treatment of inflammation or infection during pregnancy. Adjusted odds ratios (OR) were calculated in multivariable logistic regression models and are presented with 95% confidence intervals [95% CI]. RESULTS: Preeclampsia was the strongest risk factor for BPD [adjusted OR 2.04, 95% CI 1.83, 2.29]. For extremely preterm infants the adjusted OR was 1.33 [95% CI 1.08, 1.64]. Chorioamnionitis was associated with an increased risk of BPD, but only when including all infants in the analyses [OR 1.33, 95% CI 1.19, 1.48]. No apparent associations were found between maternal chronic inflammatory disease or use of anti-inflammatory drugs and the risk of BPD. Maternal diabetes mellitus, gestational diabetes and maternal use of antibiotics were associated with reduced risks of BPD. CONCLUSION: Preeclampsia related disorders increased the risk and maternal diabetes mellitus and gestational diabetes reduced the risk for BPD. As angiogenic factors play a role in preeclampsia and diabetes our findings suggest that an impaired angiogenesis may contribute to BPD development.