Airway contraction and cytokine release in isolated rat lungs induced by wear particles from the road and tire interface and road vehicle brakes.

The dominant road traffic particle sources are wear particles from the road and tire interface, and from vehicle brake pads. The aim of this work was to investigate the effect of road and brake wear particles on pulmonary function and biomarkers in isolated perfused rat lungs. Particles were sampled from the studded tire wear of three road pavements containing different rock materials in a road simulator; and from the wear of two brake pad materials using a pin-on-disk machine. Isolated rat lungs inhaled the coarse and fine fractions of the sampled particles resulting in an estimated total particle lung dose of 50 µg. The tidal volume (TV) was measured during the particle exposure and the following 50 min. Perfusate and BALF were analyzed for the cytokines TNF, CXCL1 and CCL3. The TV of lungs exposed to rock materials was significantly reduced after 25 min of exposure compared to the controls, for quartzite already after 4 min. The particles of the heavy-duty brake pads had no effect on the TV. Brake particles resulted in a significant elevation of CXCL1 in the perfusate. Brake particles showed significant elevations of all three measured cytokines, and quartzite showed a significant elevation of TNF in BALF. The study shows that the toxic effect on lungs exposed to airborne particles can be investigated using measurements of tidal volume. Furthermore, the study shows that the choice of rock material in road pavements has the potential to affect the toxicity of road wear PM10.

Occupational exposure and health surveys at metal additive manufacturing facilities.

Introduction: Additive manufacturing is a novel state-of-the art technology with significant economic and practical advantages, including the ability to produce complex structures on demand while reducing the need of stocking materials and products. Additive manufacturing is a technology that is here to stay; however, new technologies bring new challenges, not only technical but also from an occupational health and safety perspective. Herein, leading Swedish companies using metal additive manufacturing were studied with the aim of investigating occupational exposure and the utility of chosen exposure- and clinical markers as predictors of potential exposure-related health risks. Methods: Exposure levels were investigated by analysis of airborne dust and metals, alongside particle counting instruments measuring airborne particles in the range of 10 nm-10 µm to identify dusty work tasks. Health examinations were performed on a total of 48 additive manufacturing workers and 39 controls. All participants completed a questionnaire, underwent spirometry, and blood and urine sampling. A subset underwent further lung function tests. Results: Exposure to inhalable dust and metals were low, but particle counting instruments identified specific work tasks with high particle emissions. Examined health parameters were well within reference values on a group level. However, statistical analysis implied an impact on workers kidney function and possible airway inflammation. Conclusion: The methodology was successful for investigating exposure-related health risks in additive manufacturing. However, most participants have been working <5 years. Therefore, long-term studies are needed before we can conclusively accept or reject the observed effects on health.

Health hazards of particles in additive manufacturing: a cross-disciplinary study on reactivity, toxicity and occupational exposure to two nickel-based alloys.

The increasing use of additive manufacturing (AM) techniques (e.g., 3D-printing) offers many advantages but at the same time presents some challenges. One concern is the possible exposure and health risk related to metal containing particles of different sizes. Using the nickel-based alloys Hastelloy X (HX) and Inconel 939 (IN939) as a case, the aim of this cross-disciplinary study was to increase the understanding on possible health hazards and exposure. This was done by performing in-depth characterization of virgin, reused and condensate powders, testing in vitro toxicity (cytotoxicity, genotoxicity, oxidative stress), and measuring occupational airborne exposure. The results showed limited metal release from both HX and IN939, and slightly different surface composition of reused compared to virgin powders. No or small effects on the cultured lung cells were observed when tested up to 100 µg/mL. Particle background levels in the printing facilities were generally low, but high transient peaks were observed in relation to sieving. Furthermore, during post processing with grinding, high levels of nanoparticles (> 100,000 particles/cm3) were noted. Urine metal levels in AM operators did not exceed biomonitoring action limits. Future studies should focus on understanding the toxicity of the nanoparticles formed during printing and post-processing.

An explorative study on respiratory health among operators working in polymer additive manufacturing.

Additive manufacturing (AM), or 3D printing, is a growing industry involving a wide range of different techniques and materials. The potential toxicological effects of emissions produced in the process, involving both ultrafine particles and volatile organic compounds (VOCs), are unclear, and there are concerns regarding possible health implications among AM operators. The objective of this study was to screen the presence of respiratory health effects among people working with liquid, powdered, or filament plastic materials in AM. Methods: In total, 18 subjects working with different additive manufacturing techniques and production of filament with polymer feedstock and 20 controls participated in the study. Study subjects filled out a questionnaire and underwent blood and urine sampling, spirometry, impulse oscillometry (IOS), exhaled NO test (FeNO), and collection of particles in exhaled air (PEx), and the exposure was assessed. Analysis of exhaled particles included lung surfactant components such as surfactant protein A (SP-A) and phosphatidylcholines. SP-A and albumin were determined using ELISA. Using reversed-phase liquid chromatography and targeted mass spectrometry, the relative abundance of 15 species of phosphatidylcholine (PC) was determined in exhaled particles. The results were evaluated by univariate and multivariate statistical analyses (principal component analysis). Results: Exposure and emission measurements in AM settings revealed a large variation in particle and VOC concentrations as well as the composition of VOCs, depending on the AM technique and feedstock. Levels of FeNO, IOS, and spirometry parameters were within clinical reference values for all AM operators. There was a difference in the relative abundance of saturated, notably dipalmitoylphosphatidylcholine (PC16:0_16:0), and unsaturated lung surfactant lipids in exhaled particles between controls and AM operators. Conclusion: There were no statistically significant differences between AM operators and controls for the different health examinations, which may be due to the low number of participants. However, the observed difference in the PC lipid profile in exhaled particles indicates a possible impact of the exposure and could be used as possible early biomarkers of adverse effects in the airways.

Temporal risk assessment - 20th century Pb emissions to air and exposure via inhalation in the Swedish glass district.

The objective of the present study was to assess historical emissions of Pb to air around a number of glassworks sites in southeastern Sweden, and the possible implications for human exposure. To do so, a four-step method was applied. First, emissions of Pb to air around 10 glassworks were modelled for the 20th century. Second, an assessment of the resulting exposure was made for a number of scenarios. Third, the number of people potentially exposed at different times was estimated, and fourth, measurements of "current" Pb concentrations in PM10 material from four sites were conducted in 2019. The results show that the highest emissions, and exposures, occurred from 1970 to1980. It coincides with the time period when the highest number of people resided in the villages. At this time, the average Pb concentration in air around the six largest factories was about 2.4 µg Pb/m3, i.e. 16 times the present US national ambient air quality standard (NAAQS) of 0.15 µg Pb/m3. By year 2000 the modelled average concentration had dropped to 0.05 µg Pb/m3, a level that is normal for urban regions today. The PM10 measurements from 2019 indicate a further decline, now with a mean value of about 0.02 µg Pb/m3. Over the entire study period, inhalation hazard quotients (HQs) exceeded the dietary HQ by many orders of magnitude, indicating that inhalation has been the most prevalent exposure pathway in the past. At present, both pathways are judged to be associated with low exposures. Even if only roughly approximated, a picture of the historical exposure can increase our understanding of the connection between exposure and disease, and can be valuable when risks are to be communicated to residents near contaminated areas.

Effect of N-3 Polyunsaturated Fatty Acids on Lipid Composition in Familial Hypercholesterolemia: A Randomized Crossover Trial.

Individuals with familial hypercholesterolemia (FH) have an increased risk of cardiovascular disease. Treatment is mainly low-density lipoprotein cholesterol (LDL-C) reduction. How omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplements affect lipoproteins in FH subjects is unknown. We hypothesized that a high-dose n-3 PUFA supplement would reduce atherogenic lipoproteins and influence the high-density lipoprotein cholesterol (HDL-C) function. We performed a randomized, double-blinded crossover study with 34 genetically verified FH individuals (18−75 years, clinically stable, statin treatment > 12 months). Treatment was 4 g n-3 PUFAs (1840 mg eicosapentaenoic acid and 1520 mg docosahexaenoic acid daily) or four capsules of olive oil for three months in a crossover design with a washout period of three months. The defined outcomes were changes in triglycerides, lipoproteins, lipoprotein subfractions, apolipoproteins, and HDL-C function. After treatment with n-3 PUFAs, total cholesterol, LDL-C, and triglycerides were reduced compared to placebo (p ≤ 0.01 for all). Total HDL-C levels were unchanged, but the subfraction of large HDL-C was higher (p ≤ 0.0001) after n-3 PUFAs than after placebo, and intermediate HDL-C and small HDL-C were reduced after n-3 PUFAs compared to placebo (p = 0.02 and p ≤ 0.001, respectively). No changes were found in apolipoproteins and HDL-C function. N-3 PUFAs supplements reduced atherogenic lipoproteins in FH subjects, leaving HDL-C function unaffected.

Particle Safety Assessment in Additive Manufacturing: From Exposure Risks to Advanced Toxicology Testing.

Additive manufacturing (AM) or industrial three-dimensional (3D) printing drives a new spectrum of design and production possibilities; pushing the boundaries both in the application by production of sophisticated products as well as the development of next-generation materials. AM technologies apply a diversity of feedstocks, including plastic, metallic, and ceramic particle powders with distinct size, shape, and surface chemistry. In addition, powders are often reused, which may change the particles' physicochemical properties and by that alter their toxic potential. The AM production technology commonly relies on a laser or electron beam to selectively melt or sinter particle powders. Large energy input on feedstock powders generates several byproducts, including varying amounts of virgin microparticles, nanoparticles, spatter, and volatile chemicals that are emitted in the working environment; throughout the production and processing phases. The micro and nanoscale size may enable particles to interact with and to cross biological barriers, which could, in turn, give rise to unexpected adverse outcomes, including inflammation, oxidative stress, activation of signaling pathways, genotoxicity, and carcinogenicity. Another important aspect of AM-associated risks is emission/leakage of mono- and oligomers due to polymer breakdown and high temperature transformation of chemicals from polymeric particles, both during production, use, and in vivo, including in target cells. These chemicals are potential inducers of direct toxicity, genotoxicity, and endocrine disruption. Nevertheless, understanding whether AM particle powders and their byproducts may exert adverse effects in humans is largely lacking and urges comprehensive safety assessment across the entire AM lifecycle-spanning from virgin and reused to airborne particles. Therefore, this review will detail: 1) brief overview of the AM feedstock powders, impact of reuse on particle physicochemical properties, main exposure pathways and protective measures in AM industry, 2) role of particle biological identity and key toxicological endpoints in the particle safety assessment, and 3) next-generation toxicology approaches in nanosafety for safety assessment in AM. Altogether, the proposed testing approach will enable a deeper understanding of existing and emerging particle and chemical safety challenges and provide a strategy for the development of cutting-edge methodologies for hazard identification and risk assessment in the AM industry.

Protein interaction, monocyte toxicity and immunogenic properties of cerium oxide crystals with 5% or 14% gadolinium, cobalt oxide and iron oxide nanoparticles - an interdisciplinary approach.

Metal oxide nanoparticles are widely used in both consumer products and medical applications, but the knowledge regarding exposure-related health effects is limited. However, it is challenging to investigate nanoparticle interaction processes with biological systems. The overall aim of this project was to improve the possibility to predict exposure-related health effects of metal oxide nanoparticles through interdisciplinary collaboration by combining workflows from the pharmaceutical industry, nanomaterial sciences, and occupational medicine. Specific aims were to investigate nanoparticle-protein interactions and possible adverse immune reactions. Four different metal oxide nanoparticles; CeOx nanocrystals with 5% or 14% Gd, Co3O4, and Fe2O3, were characterized by dynamic light scattering and high-resolution transmission electron microscopy. Nanoparticle-binding proteins were identified and screened for HLA-binding peptides in silico. Monocyte interaction with nanoparticle-protein complexes was assessed in vitro. Herein, for the first time, immunogenic properties of nanoparticle-binding proteins have been characterized. The present study indicates that especially Co3O4-protein complexes can induce both 'danger signals', verified by the production of inflammatory cytokines and simultaneously bind autologous proteins, which can be presented as immunogenic epitopes by MHC class II. The clinical relevance of these findings should be further evaluated to investigate the role of metal oxide nanoparticles in the development of autoimmune disease. The general workflow identified experimental difficulties, such as nanoparticle aggregate formation and a lack of protein-free buffers suitable for particle characterization, protein analyses, as well as for cell studies. This confirms the importance of future interdisciplinary collaborations.

Sphingolipids in HDL - Potential markers for adaptation to pregnancy?

Plasma high density lipoprotein (HDL) exhibits many functions that render it an effective endothelial protective agent and may underlie its potential role in protecting the maternal vascular endothelium during pregnancy. In non-pregnant individuals, the HDL lipidome is altered in metabolic disease compared to healthy individuals and is linked to reduced cholesterol efflux, an effect that can be reversed by lifestyle management. Specific sphingolipids such as sphingosine-1-phosphate (S1P) have been shown to mediate the vaso-dilatory effects of plasma HDL via interaction with the endothelial nitric oxide synthase pathway. This review describes the relationship between plasma HDL and vascular function during healthy pregnancy and details how this is lost in pre-eclampsia, a disorder of pregnancy associated with widespread endothelial dysfunction. Evidence of a role for HDL sphingolipids, in particular S1P and ceramide, in cardiovascular disease and in healthy pregnancy and pre-eclampsia is discussed. Available data suggest that HDL-S1P and HDL-ceramide can mediate vascular protection in healthy pregnancy but not in preeclampsia. HDL sphingolipids thus are of potential importance in the healthy maternal adaptation to pregnancy.

Metal additive manufacturing and possible clinical markers for the monitoring of exposure-related health effects.

Additive manufacturing (AM) includes a series of techniques used to create products, in several different materials, such as metal, polymer or ceramics, with digital models. The main advantage of AM is that it allows the creation of complex structures, but AM promises several additional advantages including the possibility to manufacture on demand or replacing smaller worn parts by directly building on an existing piece. Therefore, the interest for and establishment of AM is rapidly expanding, which is positive, however it is important to be aware that new techniques may also result in new challenges regarding health and safety issues. Metals in blood and possible clinical effects due to metal exposure were investigated in AM operators at one of the first serial producing AM facilities in the world during two consecutive years with implementation of preventive measures in-between. As comparison, welders and office workers as control group were investigated. Health investigations comprised of surveys, lung function tests, antioxidant activity and vascular inflammation as well as renal- and hepatic function analysis. AM operators had significantly reduced nickel levels in blood (10.8 vs 6.2 nmol/L) as well as improved lung function (80 vs 92% of predicted) from year 1 to year 2. This is in line with previously published results displaying reduced exposure. Blood cobalt and nickel levels correlated with previously reported urinary levels, while blood chromium did not. Multivariate modelling showed that blood cobalt, antioxidant/inflammatory marker serum amyloid A1/serum paraoxonase/arylesterase 1 activity and the hepatic markers aspartate transaminase, alanine transaminase, and alkaline phosphatase were higher in AM operators compared to controls. The study show that the selected clinical analyses could function as a complement to metal analyses in biological fluids when investigating exposure-related health effects in AM operators. However, validation in larger cohorts is necessary before more definite conclusions could be drawn.

High-density lipoprotein's vascular protective functions in metabolic and cardiovascular disease - could extracellular vesicles be at play?

High-density lipoprotein (HDL) is a circulating complex of lipids and proteins known primarily for its role in reverse cholesterol transport and consequent protection from atheroma. In spite of this, therapies aimed at increasing HDL concentration do not reduce the risk of cardiovascular disease (CVD), and as such focus has shifted towards other HDL functions protective of vascular health - including vasodilatory, anti-inflammatory, antioxidant and anti-thrombotic actions. It has been demonstrated that in disease states such as CVD and conditions of insulin resistance such as Type 2 diabetes mellitus (T2DM), HDL function is impaired owing to changes in the abundance and function of HDL-associated lipids and proteins, resulting in reduced vascular protection. However, the gold standard density ultracentrifugation technique used in the isolation of HDL also co-isolates extracellular vesicles (EVs). EVs are ubiquitous cell-derived particles with lipid bilayers that carry a number of lipids, proteins and DNA/RNA/miRNAs involved in cell-to-cell communication. EVs transfer their bioactive load through interaction with cell surface receptors, membrane fusion and endocytic pathways, and have been implicated in both cardiovascular and metabolic diseases - both as protective and pathogenic mediators. Given that studies using density ultracentrifugation to isolate HDL also co-isolate EVs, biological effects attributed to HDL may be confounded by EVs. We hypothesise that some of HDL's vascular protective functions in cardiovascular and metabolic disease may be mediated by EVs. Elucidating the contribution of EVs to HDL functions will provide better understanding of vascular protection and function in conditions of insulin resistance and potentially provide novel therapeutic targets for such diseases.

Exosomes in specific fractions of the boar ejaculate contain CD44: A marker for epididymosomes?

Seminal plasma (SP) is a complex fluid containing proteins, peptides, enzymes, hormones as well as extracellular vesicles (EVs). The SP interacts with spermatozoa and the inner cell lining of the female genital tract, adsorbing proteins and exosomes that modulate sperm functions and female immune responsiveness. In the present study, boar sperm-free SP was studied using flow cytometry (FC) after membrane tetraspanins (CD9, CD63 and CD81) and membrane receptor CD44 marking of non-enriched (whole SP) or gradient fractions enriched through two-step discontinuous KBr-density-gradient ultracentrifugation, in whole ejaculate or in selected ejaculate fractions. The results, evaluated by transmission electron microscopy, confirmed the presence of exosomes in all fractions of the pig SP. Noteworthy, these pig SP-exosomes were CD44-bearing when analysed by FC, with bands detected by western blotting (WB) at the expected 85 kD size. The two-step discontinuous KBr-density-gradient ultracentrifugation enriched the population of exosomes in two specific gradient fractions, indicating exosomes (either prostasomes or epididymosomes) could be separated from low-density lipoprotein (LDL) but they co-sediment with the high-density lipoprotein (HDL)-bearing fraction. The findings pave for the selective isolation of exosomes in functional studies of their function when interacting with spermatozoa, the oocyte and/or the female genitalia, including hyaluronan-CD44 interplay.

Exposure of metals and PAH through local foods and risk of cancer in a historically contaminated glassworks area.

BACKGROUND: Production of crystal glass and colored art glassware have been going on in the south-eastern part of Sweden since the 1700s, at over 100 glassworks and smaller glass blowing facilities, resulting in environmental contamination with mainly arsenic (As), cadmium (Cd), lead (Pb) and polycyclic hydrocarbons (PAH). High levels of metals have been found in soil, and moderately elevated levels in vegetables, mushrooms and berries collected around the glassworks sites compared with reference areas. Food in general, is the major exposure source to metals, such as Cd and Pb, and PAHs. Exposure to these toxic metals and PAH has been associated with a variety of adverse health effects in humans including cancer. OBJECTIVE: The aim of the present study was to evaluate the occurrence of cancer in a cohort from the contaminated glasswork area in relation to long-term dietary intake of locally produced foods, while taking into account residential, occupational and life styles factors. METHODS: The study population was extracted from a population cohort of 34,266 individuals who, at some time between the years 1979-2004, lived within a 2 km radius of a glassworks or glass landfill. Register information on cancer incidence and questionnaire information on consumption of local foods (reflecting 30 years general eating habits), life-time residence in the area, life style factors and occupational exposure was collected. Furthermore, blood (n = 660) and urine (n = 400) samples were collected in a subsample of the population to explore associations between local food consumption frequencies, biomarker concentrations in blood (Cd, Pb, As) and urine (PAH metabolite 1-OHPy) as well as environmental and lifestyle factors. The concurrent exposure to persistent organic pollutants (POPs) from food was also considered. A case-control study was performed for evaluation of associations between intakes of local food and risk of cancer. RESULTS: Despite high environmental levels of Cd, Pb and As at glasswork sites and landfills, current metal exposure in the population living in the surrounding areas was similar or only moderately higher in our study population compared to the general population. Reported high consumption of certain local foods was associated with higher Cd and Pb, but not As, concentrations in blood, and 1-OHPy in urine. An increased risk of cancer was associated with smoking, family history of cancer, obesity, and residence in glasswork area before age 5 years. Also, a long-term high consumption of local foods (reflecting 30 years general eating habits), i.e. fish and meat (game, chicken, lamb), was associated with increased risk of various cancer forms. CONCLUSIONS: The associations between consumption of local food and different types of cancer may reflect a higher contaminant exposure in the past, and thus, if consumption of local food contributes to the risk of acquiring cancer, that contribution is probably lower today than before. Furthermore, it cannot be ruled out that other contaminants in the food contribute to the increased cancer risks observed.

Modified lipoproteins in periodontitis: a link to cardiovascular disease?

There is a strong association between periodontal disease and atherosclerotic cardiovascular disorders. A key event in the development of atherosclerosis is accumulation of modified lipoproteins within the arterial wall. We hypothesise that patients with periodontitis have an altered lipoprotein profile towards an atherogenic form. Therefore, the present study aims at identifying modifications of plasma lipoproteins in periodontitis. Lipoproteins from ten female patients with periodontitis and gender- and age-matched healthy controls were isolated by density-gradient ultracentrifugation. Proteins were separated by 2D gel-electrophoresis and identified by map-matching or by nano-LC followed by MS. Apolipoprotein (Apo) A-I (ApoA-I) methionine oxidation, Oxyblot, total antioxidant capacity and a multiplex of 71 inflammation-related plasma proteins were assessed. Reduced levels of apoJ, phospholipid transfer protein, apoF, complement C3, paraoxonase 3 and increased levels of α-1-antichymotrypsin, apoA-II, apoC-III were found in high-density lipoprotein (HDL) from the patients. In low-density lipoprotein (LDL)/very LDL (VLDL), the levels of apoL-1 and platelet-activating factor acetylhydrolase (PAF-AH) as well as apo-B fragments were increased. Methionine oxidation of apoA-I was increased in HDL and showed a relationship with periodontal parameters. α-1 antitrypsin and α-2-HS glycoprotein were oxidised in LDL/VLDL and antioxidant capacity was increased in the patient group. A total of 17 inflammation-related proteins were important for group separation with the highest discriminating proteins identified as IL-21, Fractalkine, IL-17F, IL-7, IL-1RA and IL-2. Patients with periodontitis have an altered plasma lipoprotein profile, defined by altered protein levels as well as post-translational and other structural modifications towards an atherogenic form, which supports a role of modified plasma lipoproteins as central in the link between periodontal and cardiovascular disease (CVD).

Biomonitoring of Metal Exposure During Additive Manufacturing (3D Printing).

BACKGROUND: Additive manufacturing (AM) is a rapidly expanding new technology involving challenges to occupational health. Here, metal exposure in an AM facility with large-scale metallic component production was investigated during two consecutive years with preventive actions in between. METHODS: Gravimetric analyzes measured airborne particle concentrations, and filters were analyzed for metal content. In addition, concentrations of airborne particles <300 nm were investigated. Particles from recycled powder were characterized. Biomonitoring of urine and dermal contamination among AM operators, office personnel, and welders was performed. RESULTS: Total and inhalable dust levels were almost all below occupational exposure limits, but inductively coupled plasma mass spectrometry showed that AM operators had a significant increase in cobalt exposure compared with welders. Airborne particle concentrations (<300 nm) showed transient peaks in the AM facility but were lower than those of the welding facility. Particle characterization of recycled powder showed fragmentation and condensates enriched in volatile metals. Biomonitoring showed a nonsignificant increase in the level of metals in urine in AM operators. Dermal cobalt and a trend for increasing urine metals during Workweek Year 1, but not in Year 2, indicated reduced exposure after preventive actions. CONCLUSION: Gravimetric analyses showed low total and inhalable dust exposure in AM operators. However, transient emission of smaller particles constitutes exposure risks. Preventive actions implemented by the company reduced the workers' metal exposure despite unchanged emissions of particles, indicating a need for careful design and regulation of the AM environments. It also emphasizes the need for relevant exposure markers and biomonitoring of health risks.

Comprehensive proteome analysis of nasal lavage samples after controlled exposure to welding nanoparticles shows an induced acute phase and a nuclear receptor, LXR/RXR, activation that influence the status of the extracellular matrix.

BACKGROUND: Epidemiological studies have shown that many welders experience respiratory symptoms. During the welding process a large number of airborne nanosized particles are generated, which might be inhaled and deposited in the respiratory tract. Knowledge of the underlying mechanisms behind observed symptoms is still partly lacking, although inflammation is suggested to play a central role. The aim of this study was to investigate the effects of welding fume particle exposure on the proteome expression level in welders suffering from respiratory symptoms, and changes in protein mediators in nasal lavage samples were analyzed. Such mediators will be helpful to clarify the pathomechanisms behind welding fume particle-induced effects. METHODS: In an exposure chamber, 11 welders with work-related symptoms in the lower airways during the last month were exposed to mild-steel welding fume particles (1 mg/m3) and to filtered air, respectively, in a double-blind manner. Nasal lavage samples were collected before, immediately after, and the day after exposure. The proteins in the nasal lavage were analyzed with two different mass spectrometry approaches, label-free discovery shotgun LC-MS/MS and a targeted selected reaction monitoring LC-MS/MS analyzing 130 proteins and four in vivo peptide degradation products. RESULTS: The analysis revealed 30 significantly changed proteins that were associated with two main pathways; activation of acute phase response signaling and activation of LXR/RXR, which is a nuclear receptor family involved in lipid signaling. Connective tissue proteins and proteins controlling the degradation of such tissues, including two different matrix metalloprotease proteins, MMP8 and MMP9, were among the significantly changed enzymes and were identified as important key players in the pathways. CONCLUSION: Exposure to mild-steel welding fume particles causes measurable changes on the proteome level in nasal lavage matrix in exposed welders, although no clinical symptoms were manifested. The results suggested that the exposure causes an immediate effect on the proteome level involving acute phase proteins and mediators regulating lipid signaling. Proteases involved in maintaining the balance between the formation and degradation of extracellular matrix proteins are important key proteins in the induced effects.

Lipoprotein apheresis affects lipoprotein particle subclasses more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study.

Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are last therapeutic resorts in patients with familial hypercholesterolemia (FH). We explored changes in lipoprotein subclasses and high-density lipoprotein (HDL) function when changing treatment from lipoprotein apheresis to PCSK9 inhibition. We measured the levels of low-density lipoprotein (LDL) and HDL particle subclasses, serum amyloid A1 (SAA1), paraoxonase-1 (PON1) activity and cholesterol efflux capacity (CEC) in three heterozygous FH patients. Concentrations of all LDL particle subclasses were reduced during apheresis (large 68.0 ±â€¯17.5 to 16.3 ±â€¯2.1 mg/dL, (p = 0.03), intermediate 38.3 ±â€¯0.6 to 5.0 ±â€¯3.5 mg/dL (p = 0.004) and small 5.0 ±â€¯2.6 to 0.2 ±â€¯0.1 mg/dL (p = 0.08)). There were non-significant reductions in the LDL subclasses during evolocumab treatment. There were non-significant reductions in subclasses of HDL particles during apheresis, and no changes during evolocumab treatment. CEC was unchanged throughout the study, while the SAA1/PON1 ratio was unchanged during apheresis but decreased during evolocumab treatment. In conclusion, there were significant reductions in large and intermediate size LDL particles during apheresis, and a non-significant reduction in small LDL particles. There were only non-significant reductions in the LDL subclasses during evolocumab treatment.

Bariatric surgery improves lipoprotein profile in morbidly obese patients by reducing LDL cholesterol, apoB, and SAA/PON1 ratio, increasing HDL cholesterol, but has no effect on cholesterol efflux capacity.

BACKGROUND: Bariatric surgery has been shown to reduce cardiovascular events and cause-specific mortality for coronary artery disease in obese patients. Lipoprotein biomarkers relating to low-density lipoprotein (LDL), high-density lipoprotein (HDL), their subfractions, and macrophage cholesterol efflux have all been hypothesized to be of value in cardiovascular risk assessment. OBJECTIVES: The objective of this study was to examine the effect of a lifestyle intervention followed by bariatric surgery on the lipid profile of morbidly obese patients. METHODS: Thirty-four morbidly obese patients were evaluated before and after lifestyle changes and then 1 year after bariatric surgery. They were compared with 17 lean subjects. Several lipoprotein metrics, serum amyloid A (SAA), serum paraoxonase-1 (PON1), and macrophage cholesterol efflux capacity (CEC) were assessed. RESULTS: Average weight loss after the lifestyle intervention was 10.5% and 1 year after bariatric surgery was 33.9%. The lifestyle intervention significantly decreased triglycerides (TGs; -28.7 mg/dL, P < .05), LDL cholesterol (LDL-C; -32.3 mg/dL, P < .0001), and apolipoprotein B (apoB; -62.9 µg/mL, P < .001). Bariatric surgery further reduced TGs (-36.7 mg/dL, P < .05), increased HDL cholesterol (+12 mg/dL, P < .0001), and reductions in LDL-C and apoB were sustained. Bariatric surgery reduced large, buoyant LDL (P < .0001), but had no effect on the small, dense LDL. The large HDL subfractions increased (P < .0001), but there was no effect on the smaller HDL subfractions. The ratio for SAA/PON1 was reduced after the lifestyle intervention (P < .01) and further reduced after bariatric surgery (P < .0001). Neither the lifestyle intervention nor bariatric surgery had any effect on CEC. CONCLUSIONS: Lifestyle intervention followed by bariatric surgery in 34 morbidly obese patients showed favorable effects on TGs, LDL-C, and apoB. HDL cholesterol and apoA1 was increased, apoB/apoA1 ratio as well as SAA/PON1 ratio reduced, but bariatric surgery did not influence CEC.

Challenges in assessing the health risks of consuming vegetables in metal-contaminated environments.

A great deal of research has been devoted to the characterization of metal exposure due to the consumption of vegetables from urban or industrialized areas. It may seem comforting that concentrations in crops, as well as estimated exposure levels, are often found to be below permissible limits. However, we show that even a moderate increase in metal accumulation in crops may result in a significant increase in exposure. We also highlight the importance of assessing exposure levels in relation to a regional baseline. We have analyzed metal (Pb, Cd, As) concentrations in nearly 700 samples from 23 different vegetables, fruits, berries and mushrooms, collected near 21 highly contaminated industrial sites and from reference sites. Metal concentrations generally complied with permissible levels in commercial food and only Pb showed overall higher concentrations around the contaminated sites. Nevertheless, probabilistic exposure assessments revealed that the exposure to all three metals was significantly higher in the population residing around the contaminated sites, for both low-, median- and high consumers. The exposure was about twice as high for Pb and Cd, and four to six times as high for As. Since vegetable consumption alone did not result in exposure above tolerable intakes, it would have been easy to conclude that there is no risk associated with consuming vegetables grown near the contaminated sites. However, when the increase in exposure is quantified, its potential significance is harder to dismiss - especially when considering that exposure via other routes may be elevated in a similar way.

Exposure to atheroma-relevant 7-oxysterols causes proteomic alterations in cell death, cellular longevity, and lipid metabolism in THP-1 macrophages.

The 7-oxysterols are recognised as strong enhancers of inflammatory processes in foamy macrophages. Atheroma-relevant 7-oxysterol mixtures induce a mixed type of cell death in macrophages, and trigger cellular oxidative stress responses, which mimic oxidative exposures observed in atherosclerotic lesions. However, the macrophage proteome has not previously been determined in the 7-oxysterol treated cell model. The aim of the present study was to determine the specific effects of an atheroma-relevant 7-oxysterol mixture on human macrophage proteome. Human THP-1 macrophages were exposed to an atheroma-relevant mixture of 7ß-hydroxycholesterol and 7-ketocholesterol. Two-dimensional gel electrophoresis and mass spectrometry techniques were used to analyse the alterations in macrophage proteome, which resulted in the identification of 19 proteins with significant differential expression upon oxysterol loading; 8 increased and 11 decreased. The expression patterns of 11 out of 19 identified significant proteins were further confirmed by tandem-mass spectrometry, including further validation of increased histone deacetylase 2 and macrophage scavenger receptor types I and II expressions by western blot analysis. Identified proteins with differential expression in the cell model have been associated with i) signalling imbalance in cell death and cellular longevity; ii) lipid uptake and metabolism in foam cells; and iii) inflammatory proteins. The presented findings highlight a new proteomic platform for further studies into the functional roles of macrophages in atherosclerosis, and present a cell model for future studies to modulate the macrophage proteome by potential anti-atherosclerotic agents.