Response of the mouse lung transcriptome to welding fume: effects of stainless and mild steel fumes on lung gene expression in A/J and C57BL/6J mice

<p>Abstract</p> <p>Background</p> <p>Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at risk population for the development of lung cancer. Recently, we found that exposure to welding fume caused an acutely greater and prolonged lung inflammatory response in lung tumor susceptible A/J versus resistant C57BL/6J (B6) mice and a trend for increased tumor incidence after stainless steel (SS) fume exposure. Here, our objective was to examine potential strain-dependent differences in the regulation and resolution of the lung inflammatory response induced by carcinogenic (Cr and Ni abundant) or non-carcinogenic (iron abundant) metal-containing welding fumes at the transcriptome level.</p> <p>Methods</p> <p>Mice were exposed four times by pharyngeal aspiration to 5 mg/kg iron abundant gas metal arc-mild steel (GMA-MS), Cr and Ni abundant GMA-SS fume or vehicle and were euthanized 4 and 16 weeks after the last exposure. Whole lung microarray using Illumina Mouse Ref-8 expression beadchips was done.</p> <p>Results</p> <p>Overall, we found that tumor susceptibility was associated with a more marked transcriptional response to both GMA-MS and -SS welding fumes. Also, Ingenuity Pathway Analysis revealed that gene regulation and expression in the top molecular networks differed between the strains at both time points post-exposure. Interestingly, a common finding between the strains was that GMA-MS fume exposure altered behavioral gene networks. In contrast, GMA-SS fume exposure chronically upregulated chemotactic and immunomodulatory genes such as <it>CCL3</it>, <it>CCL4</it>, <it>CXCL2</it>, and <it>MMP12 </it>in the A/J strain. In the GMA-SS-exposed B6 mouse, genes that initially downregulated cellular movement, hematological system development/function and immune response were involved at both time points post-exposure. However, at 16 weeks, a transcriptional switch to an upregulation for neutrophil chemotactic genes was found and included genes such as <it>S100A8</it>, <it>S100A9 </it>and <it>MMP9</it>.</p> <p>Conclusions</p> <p>Collectively, our results demonstrate that lung tumor susceptibility may predispose the A/J strain to a prolonged dysregulation of immunomodulatory genes, thereby delaying the recovery from welding fume-induced lung inflammation. Additionally, our results provide unique insight into strain- and welding fume-dependent genetic factors involved in the lung response to welding fume.</p

Gene expression profiling in the lung tissue of cynomolgus monkeys in response to repeated exposure to welding fumes

Many in the welding industry suffer from bronchitis, lung function changes, metal fume fever, and diseases related to respiratory damage. These phenomena are associated with welding fumes; however, the mechanism behind these findings remains to be elucidated. In this study, the lungs of cynomolgus monkeys were exposed to MMA-SS welding fumes for 229 days and allowed to recover for 153 days. After the exposure and recovery period, gene expression profiles were investigated using the Affymetrix GeneChip® Human U133 plus 2.0. In total, it was confirmed that 1,116 genes were up-or down-regulated (over 2-fold changes, P < 0.01) for the T1 (31.4 ± 2.8 mg/m3) and T2 (62.5 ± 2.7 mg/m3) dose groups. Differentially expressed genes in the exposure and recovery groups were analyzed, based on hierarchical clustering, and were imported into Ingenuity Pathways Analysis to analyze the biological and toxicological functions. Functional analysis identified genes involved in immunological disease in both groups. Additionally, differentially expressed genes in common between monkeys and rats following welding fume exposure were compared using microarray data, and the gene expression of selected genes was verified by real-time PCR. Genes such as CHI3L1, RARRES1, and CTSB were up-regulated and genes such as CYP26B1, ID4, and NRGN were down-regulated in both monkeys and rats following welding fume exposure. This is the first comprehensive gene expression profiling conducted for welding fume exposure in monkeys, and these expressed genes are expected to be useful in helping to understand transcriptional changes in monkey lungs after welding fume exposure

Respiratory Health Effects of Exposure to Welding Fumes

The ability to weld created an industrial "revolution" in the mid 20th century. Metals could be joined faster, cheaper, leaner, and stronger. The welding process is a method for joining pieces of metallic materials when heated to such high temperatures that the pieces merge and unite in pasty condition, often using filler metal or under pressure.Much more than one million workers perform welding as professional workers and many more workers perform the process as a part of their jobs. The equipment is affordable and widely distributed.We know that the welding process produces metal fumes and gases that may be harmful to the operator. The exposure composition is dependent on the welding work piece, the electrode and temperature. The particles formed in the welding process are often "ultra fine size range" (0.01-.10 microns), but they often form chains after the process and before reaching the operators’ respiratory system.There are obvious challenges in the assessment of causality. Health effects can therefore more often be attributed to the effects of exposure from one profession (welding) than from the specific exposures (welding fumes).To assess exposure indirect methods can be used. That is by characterizing type of industry, end product, steel used, application of the end product, time period, training, working conditions in general, other exposures, and other exposed.In Norway, gloves and glasses have in principle always been used. That is because they prevent acute effects.In Norway, before 1970, respiratory protection was in little use.At that time, a growing concern for chronic lung effects, gradually introduced respiratory protection.Appropriate breathing equipment provides significant reduction in corresponding exposure (1:6). The effects of the exposure are depending on the type of smoke or gas, its physical and chemical properties, dose, exposure conditions, and vulnerability for the exposed.Relevant respiratory diseases could be asthma, chronic obstructive pulmonary disease (COPD), metal fever, acute chemical or hypersensitivity pneumonitis, lung edema, infections, emphysema, siderosis, and lung cancer

The health of welders in Her Majesty's Dockyards at Devonport, Portsmouth, Rosyth and Chatham : a review of the literature relating to the sources, nature, control, actual and potential biological effects of particulate and gaseous pollutants arising from welding processes used in HM Dockyards

Summary available: p.

Pharmacol Ther

The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.CC999999/ImCDC/Intramural CDC HHS/United States2021-04-01T00:00:00Z33176178PMC79694419402vault:3675

Occupational exposure to particles in relation to chronic obstructive pulmonary disease and cardiovascular disease

Objective The working life is expanding with increased retirement ages as the population is aging, in Sweden but in also other parts of the world. However, workers with poor health might not cope with working in higher ages. Two of the world’s most common causes of death, chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVDs) are partly due to exposures from work. Exposure to particles increase the risk of incident COPD and CVD. However, more research is needed on the effect of occupational exposure of particles of different origin, and to which extent they contribute to COPD and different types of CVD, including dose-response relationships. The overall aim of this thesis was to investigate occupational particle exposure in relation to COPD and CVD, investigate effects of different particle types, dose-response relationships, and potential differences in effects in men and women. Methods This thesis comprises four studies, two epidemiological studies, one on COPD and one on CVD resulting in two papers, and two field studies on CVD. Study I is a populationbased longitudinal study in which we investigated the smoking-adjusted risk of COPD associated with occupational exposure to 13 particles/groups (inorganic, organic, combustion particles, and welding fumes). We formed a cohort of subjects born in 1965 or earlier who responded to the Stockholm Public Health Survey in 2002, 2006, or 2010 with follow-up surveys in 2007, 2010, and 2014, in total 43,641 subjects. Participants were identified as COPD cases if they had been diagnosed with COPD by a physician during 1990-2014 or were prescribed anticholinergic medication specific for COPD. A job exposure matrix (JEM) was used to estimate occupational particle exposure. Study II and III investigated the association between particle exposure and markers of CVD. They are based on measurements of respirable silica, respirable dust, and dust of PM 0.1-10, and on biological sampling of included participants within construction industry. Study II, based on 65 participants, investigated if occupational particle exposure is affecting common biomarkers for CVD, both cross-sectionally at work and longitudinally before and after vacation. In study III, based on 46 participants, our aim was to study short-term effects on pulse rate and blood pressure associated with rapid varying particle levels at work, but also intermittent noise. Study IV analyzed the association between occupational exposure to 41 different particles and chemicals and first MI adjusted for joint exposures of lack of decision authority, physical workload, noise, and other particles/chemicals. It is based on the Swedish National Cohort on Work and Health (SNOW) and includes all persons who were born between 1930 and 1990 and working in Sweden (6,437,660 subjects), in this study working at any time between 1985-2013. Occupational history was retrieved from the 1980, 1985, and 1990 National censuses and the Occupational register within the Statistic Sweden’s Longitudinal Integrated Database for Health Insurance and Labour Market Studies (LISA). Cases of first MI were identified from the National Patient Register and the National Cause of Death Register. Other registries and cohorts were matched to add additional information of education, smoking, and body mass index (BMI). Four different JEMs were used to estimate the different occupational exposures. Results After adjusting for smoking, men occupationally exposed to any type of inorganic, organic, high levels to any combustion particles, and high levels of welding fumes had increased risk of incident COPD. Specifically, respirable crystalline silica (RCS), gypsum and insulation, diesel exhaust, and high levels of welding fumes were associated with COPD and showed dose-response relationships. There was also a tendency of dose-response relationship among men exposed to particles of asphalt/bitumen. For women there was an increased risk of COPD among those highly exposed to various organic particles from animal, flour, leather, plastic, soil, soot, and textile. The population attributable fractions in all ages were 10 % for men and 3 % for women (study I). The two field studies showed changed levels of markers of CVD. Low to moderate occupational exposure to all types of the particles included (median levels: respirable silica 0.015 mg/m3, respirable dust 0.259 mg/m3, particulate matter (PM) 0.1-10 0.473 mg/m3) was associated with higher homocysteine levels, lower high-density lipoprotein-levels, and higher resting pulse rate. Also, long-term (years) occupational exposure to particles was associated with changes in low-density lipoprotein and homocysteine levels (study II). Furthermore, PM 0.1-10 in levels above 0.480 mg/m3 was significantly associated with elevated pulse rate within the same minute. A significant positive association with pulse rate was also found for noise exposure, and there was an additive effect on pulse rate if simultaneously exposed to particles and noise (study III). With regard to first MI, for the whole population of all ages, significant increased risks were observed with cumulative exposure of particles adjusted for joint occupational exposures for the combustion compounds diesel and gasoline engine exhaust, polycyclic aromatic hydrocarbons (PAH) including benzo(a)pyrene (BAP), and sulfur dioxide (SO2), the gases carbon monoxide (CO) and volatile sulfur compounds, and the metals cadmium (Cd), chromium (Cr), iron (Fe) and lead (Pb), as well as for oil mist, benzene, gasoline, pulp or paper dust, and respirable dust. Near significant associations were seen for welding fumes and quartz dust. There were some differences between sexes. Recent exposure was also significantly associated with MI in the whole study population for diesel engine exhaust, PAH including BAP, SO2, CO, volatile sulfur compounds, Cd, Fe, formaldehyde, welding fumes, asbestos, and flour dust, for most exposures with dose-response relationships (study IV). Conclusions There are several particle types which are associated with COPD and first MI, respectively. Additionally, some particle types show effect on these two outcomes in two or more of the included studies, i.e., diesel engine exhaust, welding fumes, and respirable particles/silica which all are associated with both COPD and MI, even in levels below the OELs for respirable silica, and respirable inorganic particles. Results from the field studies also indicate changes in markers of CVD if occupationally exposed to respirable particles and particles of PM 0.1-10. Preventing poor health by improving work environment, for example by reducing occupational exposure to particles, will increase the likelihood of people remaining longer at work, and would most likely prevent incident COPD and CVD