Advancing Synthetic Hydrogels through Nature-Inspired Materials Chemistry.

Synthetic extracellular matrix (ECM) mimics that can recapitulate the complex biochemical and mechanical nature of native tissues are needed for advanced models of development and disease. Biomedical research has heavily relied on the use of animal-derived biomaterials, which is now impeding their translational potential and convoluting the biological insights gleaned from in vitro tissue models. Natural hydrogels have long served as a convenient and effective cell culture tool, but advances in materials chemistry and fabrication techniques now present promising new avenues for creating xenogenic-free ECM substitutes appropriate for organotypic models and microphysiological systems. However, significant challenges remain in creating synthetic matrices that can approximate the structural sophistication, biochemical complexity, and dynamic functionality of native tissues. This review summarizes key properties of the native ECM, and discusses recent approaches used to systematically decouple and tune these properties in synthetic matrices. The importance of dynamic ECM mechanics, such as viscoelasticity and matrix plasticity, is also discussed, particularly within the context of organoid and engineered tissue matrices. Emerging design strategies to mimic these dynamic mechanical properties are reviewed, such as multi-network hydrogels, supramolecular chemistry, and hydrogels assembled from biological monomers.

Convergently evolved placental villi show multiscale structural adaptations to differential placental invasiveness.

Despite having a single evolutionary origin and conserved function, the mammalian placenta exhibits radical structural diversity. The evolutionary drivers and functional consequences of placental structural diversity are poorly understood. Humans and equids both display treelike placental villi, however these villi evolved independently and exhibit starkly different levels of invasiveness into maternal tissue (i.e. the number of maternal tissue layers between placental tissue and maternal blood). The villi in these species therefore serve as a compelling evolutionary case study to explore whether placentas have developed structural adaptations to respond to the challenge of reduced nutrient availability in less invasive placentas. Here, we use three-dimensional X-ray microfocus computed tomography and electron microscopy to quantitatively evaluate key structures involved in exchange in human and equid placental villi. We find that equid villi have a higher surface area to volume ratio and deeper trophoblastic vessel indentation than human villi. Using illustrative computational models, we propose that these structural adaptations have evolved in equids to boost nutrient transfer to compensate for reduced invasiveness into maternal tissue. We discuss these findings in relation to the 'maternal-fetal conflict hypothesis' of placental evolution.

Placental evolution from a three-dimensional and multiscale structural perspective.

The placenta mediates physiological exchange between the mother and the fetus. In placental mammals, all placentas are descended from a single common ancestor and functions are conserved across species; however, the placenta exhibits radical structural diversity. The selective pressures behind this structural diversity are poorly understood. Traditionally, placental structures have largely been investigated by grouping them into qualitative categories. Assessing the placenta on this basis could be problematic when inferring the relative "efficiency" of a placental configuration to transfer nutrients from mother to fetus. We argue that only by considering placentas as three-dimensional (3D) biological structures, integrated across scales, can the evolutionary questions behind their enormous structural diversity be quantitatively determined. We review the current state of placental evolution from a structural perspective, detail where 3D imaging and computational modeling have been used to gain insight into placental function, and outline an experimental roadmap to answer evolutionary questions from a multiscale 3D structural perspective. Our approach aims to shed light on placental evolution, and can be transferred to evolutionary investigations in any organ system.

Harnessing Macromolecular Chemistry to Design Hydrogel Micro- and Macro-Environments.

Cell encapsulation within three-dimensional hydrogels is a promising approach to mimic tissues. However, true biomimicry of the intricate microenvironment, biophysical and biochemical gradients, and the macroscale hierarchical spatial organizations of native tissues is an unmet challenge within tissue engineering. This review provides an overview of the macromolecular chemistries that have been applied toward the design of cell-friendly hydrogels, as well as their application toward controlling biophysical and biochemical bulk and gradient properties of the microenvironment. Furthermore, biofabrication technologies provide the opportunity to simultaneously replicate macroscale features of native tissues. Biofabrication strategies are reviewed in detail with a particular focus on the compatibility of these strategies with the current macromolecular toolkit described for hydrogel design and the challenges associated with their clinical translation. This review identifies that the convergence of the ever-expanding macromolecular toolkit and technological advancements within the field of biofabrication, along with an improved biological understanding, represents a promising strategy toward the successful tissue regeneration.

Depth profiling via nanoindentation for characterisation of the elastic modulus and hydraulic properties of thin hydrogel layers.

The accurate determination of the mechanical properties of hydrogels is of fundamental importance for a range of applications, including in assessing the effect of stiffness on cell behaviour. This is a particular issue when using thin hydrogel layers adherent to stiff substrate supports, as the apparent stiffness can be significantly influenced by the constraint of the underlying impermeable substrate, leading to inaccurate measurements of the elastic modulus and permeability of thin hydrogel layers. This study used depth profiling nanoindentation and a poroelastic model for spherical indentation to identify the elastic moduli and hydraulic conductivity of thin polyacrylamide (PAAm) hydrogel layers (∼27 µm-782 µm thick) on impermeable substrates. The apparent stiffness of thin PAAm layers increased with indentation depth and was significantly greater than those of thicker hydrogels, which showed no influence of indentation depth. The hydraulic conductivity decreased as the geometrical confinement of hydrogels increased, indicating that the fluid became more constrained within the confinement areas. The impact of geometrical confinement on the apparent modulus and hydraulic conductivity of thin PAAm hydrogel layers was then established, and their elastic moduli and intrinsic permeability were determined in relation to this effect. This study offers valuable insights into the mechanical characterisation of thin PAAm hydrogel layers used for the fundamental study of cell mechanobiology.

3D Volumetric Mechanosensation of MCF7 Breast Cancer Spheroids in a Linear Stiffness Gradient GelAGE.

The tumor microenvironment presents spatiotemporal shifts in biomechanical properties with cancer progression. Hydrogel biomaterials like GelAGE offer the stiffness tuneability to recapitulate dynamic changes in tumor tissues by altering photo-energy exposures. Here, a tuneable hydrogel with spatiotemporal control of stiffness and mesh-network is developed. The volume of MCF7 spheroids encapsulated in a linear stiffness gradient demonstrates an inverse relationship with stiffness (p < 0.0001). As spheroids are exposed to increased crosslinking (stiffer) and greater mechanical confinement, spheroid stiffness increases. Protein expression (TRPV4, ß1 integrin, E-cadherin, and F-actin) decreases with increasing stiffness while showing strong correlations to spheroid volume (r2  > 0.9). To further investigate the role of volume, MCF7 spheroids are grown in a soft matrix for 5 days prior to a second polymerisation which presents a stiffness gradient to equally expanded spheroids. Despite being exposed to variable stiffness, these spheroids show even protein expression, confirming volume as a key regulator. Overall, this work showcases the versatility of GelAGE and demonstrates volume expansion as a key regulator of 3D mechanosensation in MCF7 breast cancer spheroids. This platform has the potential to further investigation into the role of stiffness and dimensionality in 3D spheroid culture for other types of cancers and diseases.

Computational Modelling of Paracellular Diffusion and OCT3 Mediated Transport of Metformin in the Perfused Human Placenta.

Metformin is an antidiabetic drug, increasingly prescribed in pregnancy and has been shown to cross the human placenta. The mechanisms underlying placental metformin transfer remain unclear. This study investigated the roles of drug transporters and paracellular diffusion in the bidirectional transfer of metformin across the human placental syncytiotrophoblast using placental perfusion experiments and computational modelling. 14C-metformin transfer was observed in the maternal to fetal and fetal to maternal directions and was not competitively inhibited by 5 mM unlabelled metformin. Computational modelling of the data was consistent with overall placental transfer via paracellular diffusion. Interestingly, the model also predicted a transient peak in fetal 14C-metformin release due to trans-stimulation of OCT3 by unlabelled metformin at the basal membrane. To test this hypothesis a second experiment was designed. OCT3 substrates (5 mM metformin, 5 mM verapamil and 10 mM decynium-22) added to the fetal artery trans-stimulated release of 14C-metformin from the placenta into the fetal circulation, while 5 mM corticosterone did not. This study demonstrated activity of OCT3 transporters on the basal membrane of the human syncytiotrophoblast. However, we did not detect a contribution of either OCT3 or apical membrane transporters to overall materno-fetal transfer, which could be represented adequately by paracellular diffusion in our system.

Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (CPR) restores perfusion and oxygenation in a patient who does not have spontaneous circulation. The evidence with regard to the effect of extracorporeal CPR on survival with a favorable neurologic outcome in refractory out-of-hospital cardiac arrest is inconclusive. METHODS: In this multicenter, randomized, controlled trial conducted in the Netherlands, we assigned patients with an out-of-hospital cardiac arrest to receive extracorporeal CPR or conventional CPR (standard advanced cardiac life support). Eligible patients were between 18 and 70 years of age, had received bystander CPR, had an initial ventricular arrhythmia, and did not have a return of spontaneous circulation within 15 minutes after CPR had been initiated. The primary outcome was survival with a favorable neurologic outcome, defined as a Cerebral Performance Category score of 1 or 2 (range, 1 to 5, with higher scores indicating more severe disability) at 30 days. Analyses were performed on an intention-to-treat basis. RESULTS: Of the 160 patients who underwent randomization, 70 were assigned to receive extracorporeal CPR and 64 to receive conventional CPR; 26 patients who did not meet the inclusion criteria at hospital admission were excluded. At 30 days, 14 patients (20%) in the extracorporeal-CPR group were alive with a favorable neurologic outcome, as compared with 10 patients (16%) in the conventional-CPR group (odds ratio, 1.4; 95% confidence interval, 0.5 to 3.5; P = 0.52). The number of serious adverse events per patient was similar in the two groups. CONCLUSIONS: In patients with refractory out-of-hospital cardiac arrest, extracorporeal CPR and conventional CPR had similar effects on survival with a favorable neurologic outcome. (Funded by the Netherlands Organization for Health Research and Development and Maquet Cardiopulmonary [Getinge]; INCEPTION ClinicalTrials.gov number, NCT03101787.).

In Utero Exposure to Air Pollutants and Mitochondrial Heteroplasmy in Neonates.

Mitochondria are sensitive to oxidative stress, which can be caused by traffic-related air pollution. Placental mitochondrial DNA (mtDNA) mutations have been previously linked with air pollution. However, the relationship between prenatal air pollution and cord-blood mtDNA mutations has been poorly understood. Therefore, we hypothesized that prenatal particulate matter (PM2.5) and NO2 exposures are associated with cord-blood mtDNA heteroplasmy. As part of the ENVIRONAGE cohort, 200 mother-newborn pairs were recruited. Cord-blood mitochondrial single-nucleotide polymorphisms were identified by whole mitochondrial genome sequencing, and heteroplasmy levels were evaluated based on the variant allele frequency (VAF). Outdoor PM2.5 and NO2 concentrations were determined by a high-resolution spatial-temporal interpolation method based on the maternal residential address. Distributed lag linear models were used to determine sensitive time windows for the association between NO2 exposure and cord-blood mtDNA heteroplasmy. A 5 µg/m3 increment in NO2 was linked with MT-D-Loop16311T>C heteroplasmy from gestational weeks 17-25. MT-CYTB14766C>T was negatively associated with NO2 exposure in mid pregnancy, from weeks 14-17, and positively associated in late pregnancy, from weeks 31-36. No significant associations were observed with prenatal PM2.5 exposure. This is the first study to show that prenatal NO2 exposure is associated with cord-blood mitochondrial mutations and suggests two critical windows of exposure in mid-to-late pregnancy.

The association between ambient particulate matter exposure and the telomere-mitochondrial axis of aging in newborns.

BACKGROUND: Particulate matter (PM) is associated with aging markers at birth, including telomeres and mitochondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), are associated with prenatal air pollution and whether there are underlying mechanisms. METHODS: 556 mother-newborn pairs from the ENVIRONAGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1α protein levels were measured using ELISA. Daily ambient PM2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms. RESULTS: A 5 µg/m3 increment in PM2.5 exposure was associated with -11.23 % (95 % CI: -17.36 % to -4.65 %, p = 0.0012) and -7.34 % (95 % CI: -11.56 % to -2.92 %, p = 0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with -12.96 % (95 % CI: -18.84 % to -6.64 %, p < 0.001) lower placental mtDNAc during the third trimester. Furthermore, PM2.5 exposure was associated with a 12.42 % (95 % CI: -1.07 % to 27.74 %, p = 0.059) higher cord plasma p53 protein level and a -3.69 % (95 % CI: -6.97 % to -0.31 %, p = 0.033) lower cord plasma PGC-1α protein level during the third trimester. Placental TL mediated 65 % of the negative and 17 % of the positive association between PM2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively. CONCLUSION: Ambient PM2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context.

3D visualization of trans-syncytial nanopores provides a pathway for paracellular diffusion across the human placental syncytiotrophoblast.

The placental syncytiotrophoblast, a syncytium without cell-cell junctions, is the primary barrier between the mother and the fetus. Despite no apparent anatomical pathway for paracellular diffusion of solutes across the syncytiotrophoblast, size-dependent paracellular diffusion is observed. Here we report data demonstrating that the syncytiotrophoblast is punctuated by trans-syncytial nanopores (TSNs). These membrane-bound TSNs directly connect the maternal and fetal facing sides of the syncytiotrophoblast, providing a pathway for paracellular diffusion between the mother and fetus. Mathematical modeling of TSN permeability based on their 3D geometry suggests that 10-37 million TSNs per cm3 of placental tissue could explain experimentally observed placental paracellular diffusion. TSNs may mediate physiological hydrostatic and osmotic pressure homeostasis between the maternal and fetal circulations but also expose the fetus to pharmaceuticals, environmental pollutants, and nanoparticles.

In utero particulate matter exposure in association with newborn mitochondrial ND4L10550A>G heteroplasmy and its role in overweight during early childhood.

BACKGROUND: Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L10550A>G heteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM2.5 exposure is associated with cord blood MT-ND4L10550A>G heteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L10550A>G heteroplasmy in overweight during early childhood is investigated. METHODS: This study included 386 mother-newborn pairs. Outdoor PM2.5 concentrations were determined at the maternal residential address. Cord blood MT-ND4L10550A>G heteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM2.5 exposure on childhood overweight mediated by cord blood MT-ND4L10550A>G heteroplasmy. RESULTS: Prenatal PM2.5 exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51; p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM2.5 exposure was associated with cord blood MT-ND4L10550A>G heteroplasmy from gestational week 9 - 13. The largest effect was observed in week 10, where a 5 µg/m3 increment in PM2.5 was linked with cord blood MT-ND4L10550A>G heteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L10550A>G heteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50; p = 0.02). The effect of prenatal PM2.5 exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L10550A>G heteroplasmy. CONCLUSIONS: Cord blood MT-ND4L10550A>G heteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM2.5 during the first trimester of pregnancy was associated with cord blood MT-ND4L10550A>G heteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L10550A>G heteroplasmy in the association between PM2.5 exposure and childhood overweight.

The telomere-mitochondrial axis of aging in newborns.

Aging starts at the beginning of life as evidenced by high variability in telomere length (TL) and mitochondrial DNA content (mtDNAc) at birth. Whether p53 and PGC-1α are connected to these age-related markers in early life is unclear. In this study, we hypothesized that these hallmarks of aging are associated at birth. In 613 newborns from the ENVIRONAGE birth cohort, p53 and PGC-1α protein levels were measured in cord plasma, while TL and mtDNAc were measured in both cord blood and placental tissue. Cord blood methylation data of genes corresponding to the measured protein levels were available from the Human MethylationEPIC 850K BeadChip array. Pearson correlations and linear regression models were applied while accounting for selected covariates. In cord, a 10% increase in TL was associated with 5.22% (95% CI: 3.26 to 7.22; p < 0.0001) higher mtDNAc and -2.66% (95% CI: -5.04 to -0.23%; p = 0.032) lower p53 plasma level. In placenta, a 10% increase in TL was associated with 5.46% (95% CI: 3.82 to 7.13%; p < 0.0001) higher mtDNAc and -2.42% (95% CI: -4.29 to -0.52; p = 0.0098) lower p53 plasma level. Methylation level of TP53 was correlated with TL and mtDNAc in cord blood and with cord plasma p53 level. Our study suggests that p53 may be an important factor both at the protein and methylation level for the telomere-mitochondrial axis of aging at birth.

Injection-Free Delivery of MSC-Derived Extracellular Vesicles for Myocardial Infarction Therapeutics.

As emerging therapeutic factors, extracellular vesicles (EVs) offer significant potential for myocardial infarction (MI) treatment. Current delivery approaches for EVs involve either intra-myocardial or intravenous injection, where both have inherent limitations for downstream clinical applications such as secondary tissue injury and low delivery efficiency. Herein, an injection-free approach for delivering EVs onto the heart surface to treat MI is proposed. By spraying a mixture of EVs, gelatin methacryloyl (GelMA) precursors, and photoinitiators followed by visible light irradiation for 30 s, EVs are physically entrapped within the GelMA hydrogel network covering the surface of the heart, resulting in an enhanced retention rate. Moreover, EVs are gradually released from the hydrogel network through a combination of diffusion and/or enzymatic degradation of the hydrogel, and they are effectively taken up by the sprayed tissue area. More importantly, the released EVs further migrate deep into myocardium tissue, which exerts an improved therapeutic effect. In an MI-induced mice model, the group treated with EVs-laden GelMA hydrogels shows significant recovery in cardiac function after 4 weeks. The work demonstrates a new strategy for delivering EVs into cardiac tissues for MI treatment in a localized manner with high retention.

Development and Characterization of Gelatin-Norbornene Bioink to Understand the Interplay between Physical Architecture and Micro-Capillary Formation in Biofabricated Vascularized Constructs.

The principle challenge for engineering viable, cell-laden hydrogel constructs of clinically-relevant size, is rapid vascularization, in order to moderate the finite capacity of passive nutrient diffusion. A multiscale vascular approach, with large open channels and bulk microcapillaries may be an admissible approach to accelerate this process, promoting overall pre-vascularization for long-term viability of constructs. However, the limited availability of bioinks that possess suitable characteristics that support both fabrication of complex architectures and formation of microcapillaries, remains a barrier to advancement in this space. In this study, gelatin-norbornene (Gel-NOR) is investigated as a vascular bioink with tailorable physico-mechanical properties, which promoted the self-assembly of human stromal and endothelial cells into microcapillaries, as well as being compatible with extrusion and lithography-based biofabrication modalities. Gel-NOR constructs containing self-assembled microcapillaries are successfully biofabricated with varying physical architecture (fiber diameter, spacing, and orientation). Both channel sizes and cell types affect the overall structural changes of the printed constructs, where cross-signaling between both human stromal and endothelial cells may be responsible for the reduction in open channel lumen observed over time. Overall, this work highlights an exciting three-way interplay between bioink formulation, construct design, and cell-mediated response that can be exploited towards engineering vascular tissues.

Glyphosate and AMPA exposure in relation to markers of biological aging in an adult population-based study.

BACKGROUND/AIM: Glyphosate, a broad-spectrum herbicide, and its main metabolite aminomethylphosphonic acid (AMPA) are persistent in the environment. Studies showed associations between glyphosate or AMPA exposure and several adverse cellular processes, including metabolic alterations and oxidative stress. OBJECTIVE: To determine the association between glyphosate and AMPA exposure and biomarkers of biological aging. METHODS: We examined glyphosate and AMPA exposure, mtDNA content and leukocyte telomere length in 181 adults, included in the third cycle of the Flemish Environment and Health Study (FLEHSIII). DNA was isolated from leukocytes and the relative mtDNA content and telomere length were determined using qPCR. Urinary glyphosate and AMPA concentrations were measured by Gas Chromatography-Tandem Mass Spectrometry (GC-MS-MS). We used multiple linear regression models to associate mtDNA content and leukocyte telomere length with glyphosate or AMPA exposure while adjusting for confounding variables. RESULTS: A doubling in urinary AMPA concentration was associated with 5.19% (95% CI: 0.49 to 10.11; p = 0.03) longer leukocyte telomere length, while no association was observed with urinary glyphosate concentration. No association between mtDNA content and urinary glyphosate nor AMPA levels was observed. CONCLUSIONS: This study showed that AMPA exposure may be associated with telomere biology in adults.

A scaffold-free approach to cartilage tissue generation using human embryonic stem cells.

Articular cartilage functions as a shock absorber and facilitates the free movement of joints. Currently, there are no therapeutic drugs that promote the healing of damaged articular cartilage. Limitations associated with the two clinically relevant cell populations, human articular chondrocytes and mesenchymal stem cells, necessitate finding an alternative cell source for cartilage repair. Human embryonic stem cells (hESCs) provide a readily accessible population of self-renewing, pluripotent cells with perceived immunoprivileged properties for cartilage generation. We have developed a robust method to generate 3D, scaffold-free, hyaline cartilage tissue constructs from hESCs that are composed of numerous chondrocytes in lacunae, embedded in an extracellular matrix containing Type II collagen, sulphated glycosaminoglycans and Aggrecan. The elastic (Young's) modulus of the hESC-derived cartilage tissue constructs (0.91 ± 0.08 MPa) was comparable to full-thickness human articular cartilage (0.87 ± 0.09 MPa). Moreover, we have successfully scaled up the size of the scaffold-free, 3D hESC-derived cartilage tissue constructs to between 4.5 mm and 6 mm, thus enhancing their suitability for clinical application.

Dynamics of skin microvascular blood flow in 4-6-year-old children in association with pre- and postnatal black carbon and particulate air pollution exposure.

BACKGROUND: A growing body of evidence indicates that cardiovascular health in adulthood, particularly that of the microcirculation, could find its roots during prenatal development. In this study, we investigated the association between pre- and postnatal air pollution exposure on heat-induced skin hyperemia as a dynamic marker of the microvasculature. METHODS: In 139 children between the ages of 4 and 6 who are followed longitudinally within the ENVIRONAGE birth cohort, we measured skin perfusion by Laser Doppler probes using the Periflux6000. Residential black carbon (BC), particulate (PM10 and PM2.5) air pollution, and nitrogen dioxide (NO2) levels were modelled for each participant's home address using a high-resolution spatiotemporal model for multiple time windows. We assessed the association between skin hyperemia and pre- and postnatal air pollution using multiple regression models while adjusting for relevant covariates. RESULTS: Residential BC exposure during the whole pregnancy averaged (IQR) 1.42 (1.22-1.58) µg/m3, PM10 18.88 (16.64 - 21.13) µg/m3, PM2.5 13.67 (11.5 - 15.56) µg/m3 and NO2 18.39 (15.52 - 20.31) µg/m3. An IQR increment in BC exposure during the third trimester of pregnancy was associated with an 11.5 % (95% CI: -20.1 to -1.9; p = 0.020) lower skin hyperemia. Similar effect estimates were retrieved for PM10, PM2.5 and NO2 (respectively 13.9 % [95% CI: -21.9 to -3.0; p = 0.003], 17.0 % [95% CI: -26.7 to -6.1; p = 0.004] and 12.7% [95 % CI: -22.2 to -1.9; p = 0.023] lower skin hyperemia). In multipollutant models, PM2.5 showed the strongest inverse association with skin hyperemia. Postnatal exposure to BC, PM10, PM2.5 or NO2, was not associated with skin hyperemia at the age of 4 to 6, and did not alter the previous reported prenatal associations when taken into account. CONCLUSION: Our findings support that BC, particulate air pollution, and NO2 exposure, even at low concentrations, during prenatal life, can have long-lasting consequences for the microvasculature. This proposes a role of prenatal air pollution exposures over and beyond postnatal exposure in the microvascular alterations which were persistent into childhood.

Glomerular function in relation to fine airborne particulate matter in a representative population sample.

From 1990 until 2017, global air-pollution related mortality increased by 40%. Few studies addressed the renal responses to ultrafine particulate [≤ 2.5 µm (PM2.5)], including black carbon (BC), which penetrate into the blood stream. In a Flemish population study, glomerular filtration estimated from serum creatinine (eGFR) and the urinary albumin-to-creatinine ratio were measured in 2005-2009 in 820 participants (women, 50.7%; age, 51.1 years) with follow-up of 523 after 4.7 years (median). Serum creatinine, eGFR, chronic kidney disease (eGFR < 60 mL/min/1.73 m2) and microalbuminuria (> 3.5/> 2.5 mg per mmol creatinine in women/men) were correlated in individual participants via their residential address with PM2.5 [median 13.1 (range 0.3-2.9) µg/m3] and BC [1.1 (0.3-18) µg/m3], using mixed models accounting for address clusters. Cross-sectional and longitudinally, no renal outcome was associated with PM2.5 or BC in models adjusted for sex and baseline or time varying covariables, including age, blood pressure, heart rate, body mass index, plasma glucose, the total-to-HDL serum cholesterol ratio, alcohol intake, smoking, physical activity, socioeconomic class, and antihypertensive treatment. The subject-level geocorrelations of eGFR change with to BC and PM2.5 were 0.13 and 0.02, respectively (P ≥ 0.68). In conclusion, in a population with moderate exposure, renal function was unrelated to ultrafine particulate.

Placental mobilization of free fatty acids contributes to altered materno-fetal transfer in obesity.

BACKGROUND: Metabolic changes in obese pregnant women, such as changes of plasma lipids beyond physiological levels, may subsequently affect fetal development in utero. These metabolic derangements may remain in the offspring and continue throughout life. The placenta mediates bidirectional exchange of nutrients between mother and fetus. The impact of prepregnancy obesity on placental transfer of lipids is still unknown. OBJECTIVE: We aimed to examine materno-to-fetal free fatty acid (FFA) transfer by a combined experimental and modeling approach. Flux of 13C-labeled FFA was evaluated by ex vivo perfusion of human placentae as a function of prepregnancy obesity. Mathematical modeling complemented ex vivo results by providing FFA kinetic parameters. RESULTS: Obesity was strongly associated with elevated materno-to-fetal transfer of applied 13C-FFA. Clearance of polyunsaturated 13C-docosahexaenoic acid (DHA) was most prominently affected. The use of the mathematical model revealed a lower tissue storage capacity for DHA in obese compared with lean placentae. CONCLUSION: Besides direct materno-to-fetal FFA transfer, placental mobilization accounts for the fetal FA supply. Together, with metabolic changes in the mother and an elevated materno-fetal FFA transfer shown in obesity, these changes suggest that they may be transmitted to the fetus, with yet unknown consequences.