Vulnerable Time Window Research Articles

Associations of prenatal exposure to PM2.5 and its components with offsprings' neurodevelopmental and behavioral problems: A prospective cohort study from China

Prenatal exposure to fine particulate matter (PM2.5) has been linked with increased neurodevelopmental disorders. However, the most detrimental component of PM2.5 and the most vulnerable exposure time windows remain undetermined, especially in areas with high PM2.5 levels. In a prospective cohort study involving 4494 mother-child dyads, we examined the associations of prenatal exposure to PM2.5 and its four main components with children's neurodevelopmental and behavioral problems (NBPs), separately in three pregnancy trimesters. Poisson regression and generalized additive models were used to depict the linear and nonlinear associations, respectively. Weighted quantile sum and Bayesian kernel machine regression models were applied to examine the effects of exposure to both mixed and individual components. Results showed that exposure to PM2.5 and its components throughout the three trimesters increased the risk of children's NBPs (Risk ratio for PM2.5: 1.16, 95 % confidence interval 1.14–1.18 per μg/m3 in the first trimester; 1.15, 1.12–1.17 in the second trimester; 1.06, 1.04–1.08 in the third trimester), with associations gradually diminishing as pregnancy progressed (P values for trends < 0.05). Among the four main components of PM2.5, exposure to SO42- posed the highest risks on children's NBPs, while organic matter contributed the largest proportion to the overall impacts of PM2.5 exposure. These results underscore the significance of mitigating PM2.5 exposure in pregnant women to reduce the risk of neurodevelopmental disorders in offspring. Our findings would inform risk assessment of PM2.5 exposure and facilitate the development of precision preventive strategies targeting specific components of PM2.5 in similar areas with high levels of exposure.

Electrophysiological effects of stretch-activated ion channels: a systematic computational characterization.

Cardiac electrophysiology and mechanics are strongly interconnected. Their interaction is, among others, mediated by mechano-electric feedback through stretch-activated ion channels (SACs). The electrophysiological changes induced by SACs may contribute to arrhythmogenesis, but the precise SAC-induced electrophysiological changes remain incompletely understood. Here, we provide a systematic characterization of stretch effects through three distinguished SACs on cardiac electrophysiology using computational modelling. We implemented potassium-selective, calcium-selective and non-selective SACs in the Tomek-Rodriguez-O'Hara-Rudy model of human ventricular electrophysiology. The model was calibrated to experimental data from isolated cardiomyocytes undergoing stretch, considering inter-species differences, and disease-related remodelling of SACs. SAC-mediated effects on the action potential (AP) were analysed by varying stretch amplitude, application timing and/or duration. Afterdepolarizations of different amplitudes were observed with transient 10-ms stretch stimuli of 15-18% applied during phase 4, while stretch ≥18% during phase 4 elicited triggered APs. Longer stimuli shifted the threshold of AP trigger during phase 4 to lower amplitudes, while shorter stimuli increased it. Continuous stretch provoked electrophysiological remodelling. Furthermore, stretch shortened duration or changed morphology of a subsequent electrically evoked AP, and, if applied during a vulnerable time window with sufficient amplitude, prevented its occurrence because of stretch-induced modulation of sodium and L-type calcium channel gating. These effects were more pronounced with disease-related SAC remodelling due to increased stretch sensitivity of diseased hearts. We showed that SACs may induce afterdepolarizations and triggered activities, and prevent subsequent AP generation or change its morphology. These effects depend on cardiomyocyte stretch characteristics and disease-related SACs remodelling and may contribute to cardiac arrhythmogenesis. KEY POINTS: The interplay between cardiac electrophysiology and mechanics is mediated by mechano-electric feedback through stretch-activated ion channels (SACs). These channels may be pro-arrhythmic, but their precise effect on electrophysiology remains unclear. Here we present a systematic in silico characterization of stretch effects through three SACs by implementing inter-species differences as well as disease-related remodelling of SACs in a novel computational model of human ventricular cardiomyocyte electrophysiology. Our simulations showed that, at the cellular level, SACs may provoke electrophysiological remodelling, afterdepolarizations, triggered activities, change the morphology or shorten subsequent electrically evoked action potentials. The model further suggests that a vulnerable window exists in which stretch prevents the following electrically triggered beat occurrence. The pro-arrhythmic effects of stretch strongly depend on disease-related SAC remodelling as well as on stretch characteristics, such as amplitude, time of application and duration. Our study helps in understanding the role of stretch in cardiac arrhythmogenesis and revealing the underlying cellular mechanisms.

Estimated exposure to perfluoroalkyl substances during infancy and serum-adipokine concentrations in later childhood

BackgroundPerfluoroalkyl substances (PFASs) are transferred through human milk and may cause elevated exposure during infancy. Given the lack of early postnatal blood samples, PFAS concentrations can be estimated to serve as predictors of subsequent metabolic toxicity.MethodsA total of 298 children from a prospective birth cohort were followed up through to age 9 years. Serum-PFAS was measured at birth and 18 months of age, while exposures during infancy were estimated by structural equations. Adiponectin, resistin, leptin, and the leptin receptor were measured in serum at age 9. Adjusted regression coefficients for estimated serum-PFAS concentrations were calculated, with additional consideration of the duration of breastfeeding and potential effect modification by sex.ResultsA doubling in estimated serum-PFAS concentrations, particularly at ages 6 and 12 months, was associated with a loss of about 10–15% in age 9 resistin concentrations, while other associations were much weaker. Sex dependence of the associations was not observed, and neither did the duration of breastfeeding affect outcomes at age 9.ConclusionLowered serum-resistin concentrations at age 9 years were most strongly associated with early postnatal PFAS exposures. These findings suggest that infancy may represent a vulnerable time window for some aspects of metabolic programming that may be affected by PFAS exposure.ImpactSerum-PFAS concentrations during infancy can be estimated in the absence of blood samples.Adipokine concentrations were measured at age 9 years as metabolic biomarkers.Resistin was significantly lower in children with elevated PFAS exposures in infancy.The findings suggest that early postnatal PFAS exposures may affect subsequent metabolic health.Assessment of infancy vulnerability to PFAS can be explored using estimated serum-PFAS concentrations.

Prenatal and postnatal exposure to PM2 .5 and the risk of tic disorders.

Tic disorders are common neurodevelopmental disorders during childhood. Whether prenatal and postnatal exposure to particulate matter with an aerodynamic diameter less than 2.5μm (PM2.5 ) plays a role in the development of tic disorders remains unexplored. To investigate the association of exposure between PM2.5 during the pregnancy and infancy periods and the risk of tic disorders. This birth cohort study recruited singleton live births at term gestations in central Taiwan from the Taiwan Maternal and Child Health Database between 2004 and 2012 and followed up to the end of 2017. New cases of tic disorders were defined using the ICD-9-CM (307.2) and ICD-10-CM (F95), which include all tic spectrum disorders. We assigned daily PM2.5 concentrations derived from a satellite-based model to individuals based on maternal residential addresses at delivery. We fit Cox proportional hazard model and distributed lag non-linear model to estimate the associations between PM2.5 and tic disorders, with hazard ratio (HR) with 95% confidence interval (CI) as the effect measure. Of the 309,376 singleton live births at term gestations, we identified 5902 (1.9%) tic disorder cases. The HR of tic disorders was positively associated with a 10μg/m3 increase in PM2.5 : during pregnancy HR 1.09, 95% CI 1.04, 1.15 and during infancy HR 1.12, 95% CI 1.06, 1.18. The vulnerable time window for infants with increased risk of tic disorders was 6-52 weeks after birth. We observed a nonlinear relationship between PM2.5 and the risk of tic disorders, with exposure to PM2.5 between 16 and 64 μg/m3 being associated with the risk of tic disorders. The association was restricted to Tourette's disorder group. Infant sex did not modify these associations. Infants delivered at term and exposed to PM2.5 are associated with an increased risk of tic disorders (6-52 weeks). Further studies are needed to confirm these associations.

Sevoflurane-Induced Apoptosis in the Mouse Cerebral Cortex Follows Similar Characteristics of Physiological Apoptosis.

General anesthetics are capable of inducing neuronal apoptosis during the rapid synaptogenesis of immature mammalian brains. In this vulnerable time window, physiological apoptosis also occurs to eliminate excess and inappropriately integrated neurons. We previously showed that physiological and ketamine-induced apoptosis in mouse primary somatosensory cortex (S1) followed similar developmental patterns. However, since sevoflurane is more widely used in pediatric anesthesia, and targets mainly on different receptors, as compared with ketamine, it is important to determine whether sevoflurane-induced apoptosis also follows similar developmental patterns as physiological apoptosis or not. Mice at postnatal days 5 (P5) and P9 were anesthetized with 1.5% sevoflurane for 4 h, and the apoptotic neurons in S1 were quantitated by immunohistochemistry. The results showed that sevoflurane raised the levels of apoptosis in S1 without interfering with the developmental patterns of physiological apoptosis. The cells more vulnerable to both physiological and sevoflurane-induced apoptosis shifted from layer V pyramidal neurons at P5 to layers II–IV GABAergic neurons by P9. The magnitude of both sevoflurane-induced and physiological apoptosis was more attenuated at P9 than P5. To determine whether the Akt-FoxO1-PUMA pathway contributes to the developmental decrease in magnitude of both physiological and sevoflurane-induced apoptosis, Western blot was used to measure the levels of related proteins in S1 of P5 and P9 mice. We observed higher levels of antiapoptotic phosphorylated Akt (p-Akt) and phosphorylated FoxO1 (p-FoxO1), and lower levels of the downstream proapoptotic factor PUMA in control and anesthetized mice at P9 than P5. In addition, the Akt-FoxO1-PUMA pathway may also be responsible for sevoflurane-induced apoptosis. Together, these results suggest that magnitude, lamination pattern and cell-type specificity to sevoflurane-induced apoptosis are age-dependent and follow physiological apoptosis pattern. Moreover, The Akt-FoxO1-PUMA pathway may mediate the developmental decreases in magnitude of both physiological and sevoflurane-induced apoptosis in neonatal mouse S1.

Influence of perinatal deltamethrin exposure at distinct developmental stages on motor activity, learning and memory

BackgroundPerinatal exposure to deltamethrin (DM) causes attention-deficit/ hyperactivity disorder-like behaviors. However, the vulnerable time window to DM exposure and the possible mechanism are obscure. We aimed to identify the critical window(s) at perinatal stages for DM exposure and the possible mechanism. MethodPregnant mice were exposed to DM (0.5 mg/kg) at three different prenatal stages [gestational day (GD) 0–5, 6–15 and 16-birth (16-B)] and early postnatal stage (PD 0–10). Locomotor activity, learning and memory were evaluated using open field and Y-maze test, respectively. Nissl staining and western blots were used to examine the neuronal loss and the protein expression, respectively. ResultsPerinatal exposures to DM had no effect on reproductive and growth index of offspring. However, mice receiving DM exposure during GD 16-B displayed significantly higher mortality suggesting GD 16-B is the most vulnerable time window to DM exposure. Prenatal but not early postnatal DM exposure impaired locomotor activity, learning and memory, and caused neuron loss in the dentate gyrus of male offspring. However, neither prenatal nor postnatal DM exposure affected mouse behavior of female offspring. Prenatal DM exposures decreased the protein levels of NR2A and NR2B in both hippocampi and cerebral cortices of male offspring. However, female mice receiving DM exposure at GD 16-B but not other stages displayed increased expression levels of NR2A and NR2B in hippocampi. ConclusionPrenatal but not early postnatal DM exposure impairs the neuron development in male but not female mice. Altered NMDA receptor expression may correlate to DM-induced behavioral deficits.

G-Computation to Causal Mediation Analysis With Sequential Multiple Mediators-Investigating the Vulnerable Time Window of HBV Activity for the Mechanism of HCV Induced Hepatocellular Carcinoma.

Regression-based approaches are widely used in causal mediation analysis. The presence of multiple mediators, however, increases the complexity and difficulty of mediation analysis. In such cases, regression-based approaches cannot efficiently address estimation issues. Hence, a flexible approach to mediation analysis is needed. Therefore, we developed a method for using g-computation algorithm to conduct causal mediation analysis in the presence of multiple ordered mediators. Compared to regression-based approaches, the proposed simulation-based approach increases flexibility in the choice of models and increases the range of the outcome scale. The Taiwanese Cohort Study dataset was used to evaluate the efficacy of the proposed approach for investigating the mediating role of early and late HBV viral load in the effect of HCV infection on hepatocellular carcinoma (HCC) in HBV seropositive patients (n = 2,878; HCV carrier n = 123). Our results indicated that early HBV viral load had a negative mediating role in HCV-induced HCC. Additionally, early exposure to a low HBV viral load affected HCC through a lag effect on HCC incidence [OR = 0.873, 95% CI = (0.853, 0.893)], and the effect of early exposure to a low HBV viral load on HCC incidence was slightly larger than that of a persistently low viral load on HCC incidence [OR = 0.918, 95% CI = (0.896, 0.941)].

Slow oscillations open susceptible time windows for epileptic discharges.

ObjectiveIn patients with epilepsy, interictal epileptic discharges are a diagnostic hallmark of epilepsy and represent abnormal, so‐called “irritative” activity that disrupts normal cognitive functions. Despite their clinical relevance, their mechanisms of generation remain poorly understood. It is assumed that brain activity switches abruptly, unpredictably, and supposedly randomly to these epileptic transients. We aim to study the period preceding these epileptic discharges, to extract potential proepileptogenic mechanisms supporting their expression.MethodsWe used multisite intracortical recordings from patients who underwent intracranial monitoring for refractory epilepsy, the majority of whom had a mesial temporal lobe seizure onset zone. Our objective was to evaluate the existence of proepileptogenic windows before interictal epileptic discharges. We tested whether the amplitude and phase synchronization of slow oscillations (.5–4 Hz and 4–7 Hz) increase before epileptic discharges and whether the latter are phase‐locked to slow oscillations. Then, we tested whether the phase‐locking of neuronal activity (assessed by high‐gamma activity, 60–160 Hz) to slow oscillations increases before epileptic discharges to provide a potential mechanism linking slow oscillations to interictal activities.ResultsChanges in widespread slow oscillations anticipate upcoming epileptic discharges. The network extends beyond the irritative zone, but the increase in amplitude and phase synchronization is rather specific to the irritative zone. In contrast, epileptic discharges are phase‐locked to widespread slow oscillations and the degree of phase‐locking tends to be higher outside the irritative zone. Then, within the irritative zone only, we observe an increased coupling between slow oscillations and neuronal discharges before epileptic discharges.SignificanceOur results show that epileptic discharges occur during vulnerable time windows set up by a specific phase of slow oscillations. The specificity of these permissive windows is further reinforced by the increased coupling of neuronal activity to slow oscillations. These findings contribute to our understanding of epilepsy as a distributed oscillopathy and open avenues for future neuromodulation strategies aiming at disrupting proepileptic mechanisms.

Associations between exposure to perfluoroalkyl substances and body fat evaluated by DXA and MRI in 109 adolescent boys

BackgroundExposure to perfluoroalkyl substances (PFASs) has been associated with changes in body mass index and adiposity, but evidence is inconsistent as study design, population age, follow-up periods and exposure levels vary between studies. We investigated associations between PFAS exposure and body fat in a cross-sectional study of healthy boys.MethodsIn 109 boys (10–14 years old), magnetic resonance imaging and dual-energy X-ray absorptiometry were performed to evaluate abdominal, visceral fat, total body, android, gynoid, android/gynoid ratio, and total fat percentage standard deviation score. Serum was analysed for perfluorooctanoic acid, perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid, perfluorononanoic acid, and perfluorodecanoic acid using liquid chromatography and triple quadrupole mass spectrometry. Data were analysed by multivariate linear regression.ResultsSerum concentrations of PFASs were low. Generally, no clear associations between PFAS exposure and body fat measures were found; however, PFOS was negatively associated with abdominal fat (β = -0.18, P = 0.046), android fat (β = -0.34, P = 0.022), android/gynoid ratio (β = -0.21, P = 0.004), as well as total body fat (β = -0.21, P = 0.079) when adjusting for Tanner stage.ConclusionsOverall, we found no consistent associations between PFAS exposure and body fat. This could be due to our cross-sectional study design. Furthermore, we assessed PFAS exposure in adolescence and not in utero, which is considered a more vulnerable time window of exposure.

Effect of exposure to fine particulate matter during pregnancy and infancy on paediatric allergic rhinitis

BackgroundThe effect of prenatal and postnatal exposure to fine particulate matter (PM2.5) on the development of allergic rhinitis (AR) is poorly understood. We further identified the vulnerable period for AR...

Maternal exposure to sulfur dioxide and the risk of oral clefts in Liaoning Province, China: a population-based case-control study.

There is limited and equivocal epidemiological evidence relating to the association between maternal sulfur dioxide (SO2) exposure and the risk of oral clefts (OCs) in offspring. We performed a population-based case-control study in Liaoning province to evaluate aforementioned relationship during 3 months before conception, the first trimester of pregnancy, and their single months. The study involved 3086 patients with OCs and 7950 controls. Data relating to SO2 concentration was acquired from air monitoring stations throughout the study period. We used a multivariable logistic regression model to evaluate the association between exposure to SO2 and the risk of OCs during the exposure windows. Maternal SO2 exposure was positively related to OCs during the 3 months before conception (odds ratio = 1.38, 95% confidence interval: 1.15-1.65; P for trend < 0.01). Positive relationships were obtained from the first and second months before conception and the first month of pregnancy. Thus, our research reflects a relationship between SO2 exposure and the risk of OCs. Future studies are now required to verify the association between SO2 exposure and OCs during pregnancy and indicate the most relevant vulnerable exposure time windows.

Wood emissions and asthma development: Results from an experimental mouse model and a prospective cohort study

BackgroundIncreased use of renewable resources like sustainably produced wood in construction or for all sorts of long-lived products is considered to contribute to reducing society's carbon footprint. However, as a natural, biological material, wood and wood products emit specific volatile organic compounds (VOCs). Therefore, the evaluation of possible health effects due to wood emissions is of major interest. ObjectivesWe investigated the effects of an exposure to multiple wood-related VOCs on asthma development. MethodsA murine asthma model was used to evaluate possible allergic and inflammatory effects on the lung after short- or long-term and perinatal exposure to pinewood or oriented strand board (OSB). In addition, wood-related VOCs were measured within the German prospective mother–child cohort LINA and their joint effect on early wheezing or asthma development in children until the age of 10 was estimated by Bayesian kernel machine regression (BKMR) stratifying also for family history of atopy (FHA). ResultsOur experimental data show that neither pinewood nor OSB emissions even at high total VOC levels and a long-lasting exposure period induce significant inflammatory or asthma-promoting effects in sensitized or non-sensitized mice. Moreover, an exposure during the vulnerable time window around birth was also without effect. Consistently, in our mother–child cohort LINA, an exposure to multiple wood-related VOCs during pregnancy or the first year of life was not associated with early wheezing or asthma development in children independent from their FHA. ConclusionOur findings indicate that emissions from wood and wood products at levels commonly occurring in the living environment do not exert adverse effects concerning wheezing or asthma development.

A lifestyle pattern during adolescence is associated with cardiovascular risk markers in young adults: results from the DONALD cohort study.

Lifestyle score approaches combining individual lifestyle factors, e.g. favourable diet, physical activity or normal body weight, showed inverse associations with cardiovascular disease (CVD) risk. However, research mainly focussed on adult behaviour and is scarce for vulnerable time windows for adult health like adolescence. We investigated associations between an adolescent lifestyle score and CVD risk markers in young adulthood. Overall, we analysed 270 participants of the open DONALD cohort study with 1-6 complete measurements of five lifestyle factors (healthy diet, moderate-to-vigorous physical activity, sedentary behaviour, sleep duration and BMI standard deviation score) during adolescence (females: 8⋅5-15⋅5 years and males: 9⋅5-16⋅5 years). Multivariable linear regression models were used to investigate the prospective association between the adolescent lifestyle score (0-5 points) and CVD risk markers in young adulthood (18-30 years). On average, participants obtained a mean adolescent lifestyle score of 2⋅9 (0-5) points. Inverse associations between the adolescent lifestyle score and waist circumference, waist-to-height ratio and percentage of body fat were observed (4⋅1, 4⋅1 and 9⋅2 % decrease per 1 point increase in adolescent lifestyle score, respectively, P < 0⋅05). For the remaining CVD risk markers (glucose, blood lipids, blood pressure and a proinflammatory score), no associations were observed. A healthy adolescent lifestyle is particularly associated with CVD risk-related favourable anthropometric markers in adulthood. A more comprehensive understanding of lifestyle patterns in the life course might enable earlier, targeted preventive measures to assist vulnerable groups in prevention of chronic diseases.

Possible Impact of Early-Life Exposure to Perfluoroalkyl Substances on Later Childhood Adipokine Concentrations in Serum

Background: Early-life exposure to perfluoroalkyl substances (PFASs) has been linked to metabolic health changes during later childhood, and a role of adipokines is suspected. Aims: We examined the relative impact of PFAS exposure prenatally and during infancy on childhood adipokine concentrations in serum. Subjects: All children belonged to a prospective birth cohort born in the Faroe Islands in 2007-2009 and followed up through to age 9 years. Study design: Adipokine concentrations in serum were measured at birth and age 9 years. Developmental PFAS exposure was determined from serum concentrations of the five major PFASs at birth and 18 months. Infancy PFAS exposures were estimated by structural equations. Outcome measures: Adipokines measured in serum included adiponectin, leptin, leptin receptor, and resistin. The adjusted regression coefficients for the estimated infancy-age PFAS exposures were compared with those obtained for measured PFAS concentrations at birth and age 18 months, with consideration of potential effect modification by sex. Results: Negative associations were found for resistin at age 9 years in regard to infancy PFAS exposures, and weak, positive associations for infancy exposures were observed for adiponectin. These associations tended to be stronger than prenatal exposures. Sex-dependence of the associations were not observed. Conclusions: Lowered serum-resistin concentrations at age 9 years were most strongly associated with early postnatal PFAS exposures. These findings suggest that infancy may represent a vulnerable time window for PFAS-associated metabolic programming.

Postnatal alcohol exposure and adolescent exercise have opposite effects on cerebellar microglia in rat.

Developmental alcohol exposure results in altered neuroimmune function in both humans and rodents. Given the critical role for the principle neuroimmune cell, microglia, in maintaining synaptic form and function, microglial dysfunction in the cerebellum may be an important mechanism underlying the aberrant cerebellar connectivity observed in rodent models of fetal alcohol spectrum disorders. Using an established rodent model of alcohol exposure during human third-trimester fetal development, we examine the cerebellum of male and female Long Evans rats to determine the impact of early postnatal alcohol exposure on cerebellar microglia, and the potential therapeutic effects of an adolescent intervention consisting of voluntary exercise (running). All cerebelli were examined at postnatal day 42 (i.e., late adolescence), and microglia were labeled with Iba1, a microglia-specific protein. Early postnatal alcohol exposure caused an increase in microglial density throughout cerebellum and a reduction in cerebellar volume, and a reduction in the proportion of fully ramified (often called "resting state") microglia selective to lobules 1-4. In contrast, adolescent exercise decreased microglial density throughout cerebellum and increased cerebellar volume, while activating microglia (as indicated by increases in amoeboid microglia, and reductions in fully and partially ramified microglia) selectively in lobules 1-4. These results suggest that adolescent exercise may be a suitable intervention to ameliorate alcohol-induced neuroimmune dysfunction as it alters microglia density and cerebellar volume in opposite to the effects of developmental alcohol exposure. Importantly, exercise intervention can be flexibly implemented well after the time window of vulnerability to alcohol.

Exposure Timing and Method Affect Beauveria bassiana (Hypocreales: Cordycipitaceae) Efficacy Against House Fly (Diptera: Muscidae) Larvae.

House flies, Musca domestica L., are widely recognized for their ability to develop resistance to chemical insecticides so alternative control strategies are desired. The use of entomopathogenic fungi such as Beauveria bassiana (Balsamo) Vuillemin to manage house fly populations has shown promising results; however, the success of using this fungus against larval house flies varies widely. The overall objective of this study was to examine factors that may influence efficacy of B. bassiana treatments against larvae. When a high concentration (4 × 1011 conidia/ml) was applied to first- and second-instar larvae in rearing medium, there was a significant reduction in pupation and adult emergence rates. Treating third-instar larvae at the same concentration did not result in a significant reduction of pupation or adult emergence. Temperature (22 versus 32°C) and media composition (diets with- and without propionic acid) did not affect the B. bassiana treatment efficacy against house fly larvae. The narrow time window of vulnerability of larvae and the high doses required to infect them indicate that B. bassiana has little potential as an operational biocontrol agent for house fly larvae.

Functional Connectome of the Fetal Brain.

Large-scale functional connectome formation and reorganization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated before birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules, and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function.SIGNIFICANCE STATEMENT The fetal to neonatal period is well known as a critical stage in brain development. Rapid neurodevelopmental processes establish key functional neural circuits of the human brain. Prenatal risk factors may interfere with early trajectories of connectome formation and thereby shape future health outcomes. Recent advances in MRI have made it possible to examine fetal brain functional connectivity. In this study, we evaluate the network topography of normative functional network development during connectome genesis in utero Understanding the developmental trajectory of brain connectivity provides a basis for understanding how the prenatal period shapes future brain function and disease dysfunction.

Early Life Represents a Vulnerable Time Window for IL-33-Induced Peripheral Lung Pathology.

IL-33, an IL-1 family cytokine, is constitutively expressed in mucosal tissues and other organs in healthy humans and animals, and expression levels increase in inflammatory conditions. Although IL-33-mediated promotion of type 2 immune responses has been well established, a gap in our knowledge regarding the functional diversity of this pleiotropic cytokine remains. To address this gap, we developed a new IL-33 transgenic mouse model in which overexpression of full-length IL-33 is induced in lung epithelial cells under conditional control. In adult mice, an ∼3-fold increase in the steady-state IL-33 levels produced no pathologic effects in the lungs. When exposed to airborne allergens, adult transgenic mice released more IL-33 extracellularly and exhibited robust type 2 immune responses. In neonatal transgenic mice, up to postnatal day 14, a similar increase in steady-state IL-33 levels resulted in increased mortality, enlarged alveolar spaces resembling bronchopulmonary dysplasia, and altered expression of genes associated with tissue morphogenesis. Processed 25-kDa IL-33 protein was detected in bronchoalveolar lavage fluids without any exogenous stimuli, and pathologic changes were abolished in mice deficient in the IL-33 receptor ST2. These findings suggest that adult lungs are relatively resistant to IL-33 overexpression unless they encounter environmental insults, whereas developing lungs are highly susceptible, with IL-33 overexpression resulting in detrimental and pathologic outcomes.

Maternal thyroid function during pregnancy and child brain morphology: a time window-specific analysis of a prospective cohort

Adequate thyroid hormone availability during pregnancy is necessary for optimal fetal brain development. During the first 18-20 weeks of gestation, fetal thyroid hormone availability largely depends on the placental transfer of maternal thyroxine. Although various studies have shown that maternal thyroid dysfunction is associated with suboptimal child neurodevelopmental outcomes, the most vulnerable time window remains to be identified. The aim of this study is to examine the association of maternal thyroid function with child brain morphology and to study whether any association depends on the timing of thyroid assessment. This prospective cohort study was part of the Generation R Study in Rotterdam, Netherlands, with a prospective population-based birth cohort. Pregnant women living in Rotterdam with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible. Other inclusion criteria were maternal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) measurement in early or mid-pregnancy (≤18 weeks) and available brain MRI data for child at age 10 years. Exclusion criteria were pre-existing thyroid disorder, thyroid disorder treatment, twin pregnancy, in-vitro fertilisation-induced pregnancy, and suboptimal-quality MRI data or major incidental finding on MRI. The main outcome was the association between maternal TSH and FT4 concentrations with brain MRI outcomes of children. Regression analyses accounted for gestational age at blood sampling, maternal age, ethnicity, education level, smoking, thyroid peroxidase antibody positivity, child sex, age at MRI, and total intracranial volume. Effect modification by gestational age at blood sampling was also investigated. Between Dec 1, 2001, and June 30, 2005, 7069 women were enrolled during early or mid-pregnancy (≤18 weeks of gestation), of whom 5088 were not included because they did not have available data on maternal serum TSH or FT4 concentrations (n=1175), their child did not have brain MRI done (n=3377), or they met exclusion criteria (n=536). Thus, 1981 mother-child pairs were included in the study, with TSH and FT4 concentrations measured during pregnancy at a median of 13·1 weeks of gestation (IQR 12·1-14·5) and offspring brain morphology assessed by MRI at a median age of 9·9 years (9·7-10·2). Maternal TSH had an inverted U-shaped association with offspring total grey matter volume (p=0·007) and with cortical grey matter volume (p=0·022). The association of maternal TSH with child total grey matter volume (pinteraction=0·053) and cortical volume (pinteraction=0·086) differed by the duration of gestation. Analyses stratified for gestational age at blood sampling showed an inverted U-shaped association of maternal TSH with child total grey matter volume and cortical grey matter volume, which was most evident at 8 weeks gestation. After about 14 weeks of gestation, TSH was no longer associated with child brain morphology. Maternal FT4 concentrations were not associated with child total grey matter volume after adjusting for total intracranial volume (p=0·75). Here, we show that both low and high maternal thyroid function are associated with smaller child total grey matter and cortical volume. To the best of our knowledge, this study is the first to show that an association with a neurodevelopmental outcome is most evident when maternal thyroid function is measured early in pregnancy. These novel findings suggest that embryonic brain development is particularly vulnerable to altered maternal thyroid function. Netherlands Organisation for Health Research and Development and the Sophia Children's Hospital Foundation.

Fine particulate matter exposure during pregnancy and infancy and incident asthma

Lung development is a multistage process from conception to the postnatal period, disruption of which by air pollutants can trigger later respiratory morbidity. We sought to evaluate the effects of weekly average fine particulate matter (particulate matter with an aerodynamic diameter less than 2.5μm [PM2.5]) exposure during pregnancy and infancy on asthma and identify vulnerable times to help elucidate possible mechanisms of the effects of PM2.5 on asthma symptoms. A birth cohort study including 184,604 children born during 2004-2011 in Taichung City was retrieved from the Taiwan Maternal and Child Health Database and followed until 2014. Adaily satellite-based hybrid model was applied to estimate PM2.5 exposure for each subject. ACox proportional hazard model combined with a distributed lag nonlinear model was used to evaluate the associations of asthma with PM2.5 exposure during pregnancy and infancy. The birth cohort contained 34,336 asthmatic patients, and the mean age of children given a diagnosis of asthma was 3.39±1.78years. Increased exposure to PM2.5 during gestational weeks 6 to 22 and 9 to 46weeks after birth were significantly associated with an increased incidence of asthma. The exposure-response relationship indicated that the hazard ratio (HR) of asthma increased steeply at PM2.5 exposure of greater than 93μg/m3 during pregnancy. Additionally, the HRs remained significant with postnatal exposure to PM2.5 between 26 and 72μg/m3 (range, 1.01-1.07μg/m3), followed by a sharp increase in HRs at PM2.5 exposure of greater than 73μg/m3. Both prenatal and postnatal exposures to PM2.5 were associated with later development of asthma. The vulnerable time windows might be within early gestation and midgestation and infancy.