Research progress on mechanism of epithelial mesenchymal transition induced by chrysotile exposure / 环境与职业医学

As a mineral material widely used in life, chrysotile is a public health concern for its fibrogenicity and carcinogenicity. Currently, more than 50 countries have completely banned the import and use of chrysotile, but China is still the world's largest consumer and second largest producer of chrysotile, with a large occupationally exposed population. Investigations have shown that chrysotile miners are significantly more likely to develop pulmonary fibrosis, lung cancer, and mesothelioma than workers in other occupations. Chrysotile-induced cancers generally have a decades-long latency period and are difficult to diagnose and treat in a timely manner. Therefore, the cancer fatality due to chrysotile exposure is significant and is a leading contributor to occupational cancer death. Epithelial mesenchymal transition is a key step in the biological processes of chronic inflammation, fibrosis, carcinogenesis, and cancer metastasis in tissues and organs, also plays an important role in pulmonary fibrosis, lung cancer, and other diseases due to chrysotile exposure. This paper summarized the mechanisms of chrysotile inducing epithelial interstitial transition from dynamics of inflammatory factors, mitogen-activated protein kinase pathways, oxidative stress, and other biological pathways, and proposed possible research directions for further study on chrysotile-induced epithelial mesenchymal transition, aiming to provide a reliable basis and reference for in-depth research on pulmonary fibrosis, lung cancer, and other diseases due to chrysotile exposure.

Effect of exposure to chrysotile on ribosomal DNA copy number variation and DNA damage response / 预防医学

Objective@#To investigate the effect of chrysotile exposure on ribosomal DNA (rDNA) copy number and DNA damage response, so as to provide insights into the mechanism of asbestos-induced carcinogenesis. @*Methods@#Human pleural mesothelial MeT-5A cells were treated with chrysotile suspensions at doses of 1.25, 2.5 and 5 μg/cm2 (low-, medium-, high-dose group), while PBS served as controls. MeT-5A cells were harvested 6, 24, 48 and 72 h post-treatment, and the rDNA copy numbers and the BIRC5, HRAS, GINS4 and RRM2 mRNA expression were determined using a quantitative real-time PCR (qPCR) assay. The apoptosis of MeT-5A cells and DNA damage were detected using Muse cell analyzer. The rDNA copy numbers, DNA damage responses and BIRC5, HRAS, GINS4 and RRM2 mRNA expression were compared in MeT-5A cells treated with different doses of chrysotile suspensions.@*Results@#There were significant differences in 45S rDNA copy numbers among low-, medium-, high-dose groups and the control groups 6, 48 and 72 h post-treatment with chrysotile suspensions, and significantly lower 45S rDNA copy numbers were measured in low-, medium- and high-dose groups than in the control group 6 h post-treatment, while significantly higher 45S rDNA copy numbers were found in the high-dose group than in low- and medium-dose groups 48 and 72 h post-treatment (all P<0.05). There were significant differences in 5S rDNA copy numbers among low-, medium-, high-dose groups and the control groups 24, 48 and 72 h post-treatment with chrysotile suspensions, and significantly lower 5S rDNA copy numbers were measured in medium- and high-dose groups than in the control group 24 and 48 h post-treatment, while significantly lower 5S rDNA copy numbers were found in medium- and high-dose groups than in the low-dose group 24, 72 h post-treatment (all P<0.05). There were significant differences in the overall apoptotic rate of MeT-5A cells among groups at different time points, and the overall apoptotic rate of MeT-5A cells were significantly higher in medium- and high-dose groups than in the control group (all P<0.05), with late-stage apoptosis predominantly detected. There were significant differences in the rates of ATM activation and DNA double-strand break in MeT-5A cells among groups 72 h post-treatment, and higher rates of ATM activation and DNA double-strand break were measured in medium- and high-dose groups than in the control group (all P<0.05). In addition, there were significant differences in the relative mRNA expression of BIRC5, HRAS, GINS4 and RRM2 genes among groups 24 and 48 h post-treatment, and significantly lower BIRC5, HRAS, GINS4 and RRM2 mRNA expression was quantified in medium- and high-dose groups than in the control group (all P<0.05).@*Conclusion@#Exposure to chrysotile may induce rDNA copy number variations and altered expression of nucleolar proteins in human pleural mesothelial cells, which may be involved in the regulation of DNA damage responses.

The change of gene expression in chrysotile asbestos-induced malignanttransformation of bronchial epithelial cells / 中国职业医学

@#Abstract:Objective - ToinvestigatetheeffectofchrysotileasbestosongeneexpressioninhumanbronchialepithelialBEAS 2B Methods - cells. BEAS 2B cells were randomly divided into two groups. The cells in the chrysotile malignant transformation- groupweretreatedwith 20μg/cm²chrysotiletoestablishthechrysotileinducedmalignanttransformationBEAS 2Bcellmodel, andthecellsinthecontrolgroupweretreatedwiththesamevolumeofphosphatesaltbuffersolution.ThetotalRNAinthecells--wasextractedandthecDNAwassynthesizedbyreversetranscription.Cy5dCTPandCy3dCTPfluoresceinwereusedtolabel the two groups to prepare probes for chip scanning. LuxScan 3.0 image analysis software was used to analyze the fluorescence signal of labeled DNA, and the differentially expressed genes were screened. The Kyoto Encyclopedia of Genes and Genomes Results (KEGG) signaling pathway analysis and Gene Ontology (GO) enrichment analysis were carried out. There were 642 - - differentiallyexpressedgenes(193up regulatedand449down regulated)inchrysotilemalignanttransformationgroupcompared with the control group. The KEGG signaling pathway analysis and GO enrichment analysis showed that the differentially - expressed genes in the malignant transformed BEAS 2B cells induced by chrysotile asbestos were mainly involved in P53 - signaling pathway, histone H3 K9 methylation and methylenetetrahydrofolate reductase deficiency pathway, phosphoinositide binding protein 3 activated protein kinase B signaling pathway, nucleoside phosphate metabolism process and the expression Conclusion inhibitionofhistocompatibilitycomplexⅡantigenpresentation. Chrysotileasbestoscaninducethechangeofgene - - expression profile in BEAS 2B cells. The P53 signaling pathway, histone H3 K9 methylation and other related pathways are

Adverse health effects of asbestos: solving mysteries regarding asbestos carcinogenicity based on follow-up survey of a Chinese factory

The present review summarizes the results of several follow-up studies assessing an asbestos product manufacturing plant in Chongqing, China, and discusses three controversial issues related to the carcinogenicity of asbestos. The first issue is the amphibole hypothesis, which asserts that the carcinogenicity of asbestos is limited to amphiboles, such as crocidolite, but not serpentines, such as chrysotile. However, considering the possible multiple component of asbestos carcinogenicity in the presence of tobacco smoke or other carcinogens, chrysotile cannot be regarded as non-carcinogenic. Additionally, in a practical sense, it is not possible to assume "pure" chrysotile due to its ubiquitous contamination with tremolite, which is a type of amphibole. Thus, as the International Agency for Research on Cancer (IARC) assessed, all forms of asbestos including chrysotile should be regarded carcinogenic to humans (Group 1). The second issue is the chrysotile/tremolite paradox, which is a phenomenon involving predominant levels of tremolite in the lung tissues of individuals who worked in locations with negligible levels of tremolite due to the exclusive use of chrysotile. Four possible mechanisms to explain this paradox have been proposed but this phenomenon does not support the claim that amphibole is inert. The final issue discussed is the textile mystery, i.e., the higher incidence of cancer in asbestos textile plants compared to asbestos mines where the same asbestos was produced and the exposure levels were comparable. This phenomenon was first reported in North America followed by UK and then in the present observations from China. Previously, levels of fiber exposure were calculated using a universal converting coefficient to estimate the mass concentration versus fiber concentration. However, parallel measurements of fiber and mass concentrations in the workplace and exposed air indicated that there are wide variations in the fiber/mass ratio, which unjustifies the universal conversion. It is possible that contamination by airborne non-fibrous particles in mines with mass fiber conversion led to the overestimation of fiber concentrations and resulted in the textile mystery. Although the use and manufacturing of asbestos has been banned in Japan, more than 10 million tons of asbestos had been imported and the majority remains in existing buildings. Thus, efforts to control asbestos exposure should be continued.

Asbestosis y mesotelioma pleural maligno / Asbestosis and malignant pleural mesothelioma

Trabajo de revisión sobre los aspectos clínicos de la asbestosis y el mesotelioma pleural en el contexto de una posible epidemia de mesotelioma pleural en los próximos 50 años. Estas enfermedades tienen como agente etiológico común a las fibras de asbesto. Se describe la historia del asbesto desde que los cipriotas lo usaron para hacer vestidos hace 5,000 años hasta su participación industrial en la década de 1870 y su prohibición al descubrirlo como causante de la asbestosis, el cáncer pulmonar y el mesotelioma pleural. Se describen las diferencias de la estructura, la química y las propiedades biológicas de los asbestos. En México se utiliza el crisotilo en un 90% para fabricar productos de fibrocemento destinados a la construcción y componentes destinados a piezas de rozamiento, de calefacción y textiles. Se analizan los aspectos clínicos, radiológicos, histológicos y funcionales de la asbestosis y el mesotelioma pleural, así como su tratamiento y prevención. Se refieren los diagnósticos diferenciales de estas enfermedades con otros padecimientos respiratorios. El periodo de latencia tanto de la asbestosis como del mesotelioma pleural varía de 20 a 40 años, por lo cual nos enfrentamos en México a una epidemia de mesotelioma pleural en los próximos 50 años. La única prevención efectiva de la asbestosis y el mesotelioma pleural maligno es la prohibición de las industrias que utilizan el asbesto.

Review article considering clinical issues of asbestosis and pleural mesothelioma in the context of a potential pleural mesothelioma outbreak in Mexico in the next 50 years. The common etiologic agent of asbestosis and pleural mesothelioma are asbestos fibers. The history of asbestos dates from 5 000 years ago when Cypriots used it to make their garments, until its industrial usage in the 1870s and its prohibition in some countries after finding its direct relationship with asbestosis, lung cancer, and pleural mesothelioma. The main structural characteristics, chemical profile, and biological properties of asbestos are described here. In Mexico, chrysotile, or white asbestos, is used in 90% of the production of fibercements for the building industry, as well as in components of friction pieces, heating and textile industries. This article analyses the clinical, radiological, histological, and functional issues of asbestosis and pleural mesothelioma; as well as their treatment and prevention. The differential diagnoses for this disease in relation to other respiratory illnesses are described. Since the latent period for both asbestosis and pleural mesothelioma is between 20 and 40 years, an outbreak of pleural mesothelioma can be expected in Mexico in the next 50 years. The only effective way to prevent asbestosis and malignant pleural mesothelioma is banning asbestos-related industries.

Analysis of Mortality in Chrysotile Asbestos Miners in China / 华中科技大学学报（医学）（英德文版）

In order to investigate the mortality of a cohort of chrysotile asbestos miners in China and evaluate its association with exposure to chrysotile,a fixed cohort of 1932 workers in chrysotile asbestos mine was established in 1981 and followed till June 1,2010.Information on vital status,cause of death and smoking habits was collected.The workers were divided into two groups according to their exposure status.The exposed group was composed of frontline workers who worked directly on mining or processing asbestos products.The control group consisted of those who were not directly exposed to asbestos in their work.Standardized mortality ratio (SMR) was calculated according to Chinese national death rates.Cox proportional hazards model was applied to estimate the adjusted relative risks of deaths from major causes in exposed and control groups:The results of this study showed that main causes of mortality were malignant neoplasm,cardiovascular disease,cerebrovascular disease and respiratory disease for chrysotile miners.The mortality rate was 939.20 per 100 000 person-years for workers.The SMR for all causes of death was 1.46 in the cohort.Statistically significant mortality excesses were found for lung cancer (SMR=1.51),pulmonary heart disease (SMR=2.70),respiratory disease (SMR=1.93),asbestosis (SMR=9.62),and accident (SMR=l.59).The mortalities from malignant neoplasm,lungcancer,cerebrovascular disease and digestive disease in the exposed group were significantly higher than those in the control group.The findings indicate that chrysotile exposure is a risk factor for lung cancer,respiratory disease,cerebrovascular disease and digestive disease.

Mesotelioma maligno: experiencia clínico-patológica de 247 casos / Malignant mesothelioma: clinical and pathological features from 247 cases

Objective: This study describes the frequency, occupational, clinical, and pathological features in a large cohort of cases of Malignant Mesothelioma (MM) from the National Institute of Respiratory Diseases (INER), in México. Methods: A retrospective and transversal study was carried out in medical records of patients diagnosed with MM between the years 1991 to 2007. Results: Of the 247 patients, 184 were male and 63 were female with an average age of 51-60 years. Dyspnea and chest pain were the presenting symptoms in most of the patients. Exposure to asbestos was referred only in 34 percent of cases but direct exposition only was documented in five of them. Clinical features of MM patients were similar in asbestos related and non-asbestos related malignant mesothelioma. Conclusion: Although a growing tendency is observed in, the number of cases with MM, in many of them was not possible to establish the source of asbestos exposure.

Objetivo: Este estudio describe la frecuencia, características patológicas, ocupación y exposición a asbesto en una cohorte grande de casos de mesotelioma maligno (MM) admitidos en el Instituto Nacional de Enfermedades Respiratorias (INER), en México. Método: Se llevó a cabo un estudio retrospectivo y transversal en los registros médicos de pacientes diagnosticados con MM entre los años 1991-2007. Resultados: De los 247pacientes, 184 fueron hombres y 63 fueron mujeres con un promedio de edad de 51 y 60 años. Disnea y dolor torácico fueron los principales síntomas observados. Exposición a fibras de asbesto fue referida sólo en 34 por ciento) de los casos, aunque una exposición directa sólo puedo ser documentada en cinco de ellos. Las características clínicas de los pacientes con MM fueron similares en aquellos con y sin exposición a asbesto reconocida. Conclusión: Aunque se observa una tendencia creciente en el número de casos con MM, en muchos de ellos no fue posible establecer una fuente de exposición a asbesto como la causa de contaminación para el desarrollo de la enfermedad.

In Vitro Assessment of Cytotoxicity and Mutagenicity of Rock Wool Fibers / 예방의학회지

This study was carried out to evaluate the cytotoxicity of rock wool fibers(RWFs) such as cell division disturbance, chromosomal and DNA damage, and mutagenicity using cultured cells. RWFs were the man made mineral fibers. In order to find the correlation between the cytotoxicity of RWFs and the phagocytic capacity of cells, the phagocytic processes were observed using scanning electron microscope. Cell division disturbance by RWFs was evaluated by the formation of multinucleated giant cells. The chromosomal damage was evaluated by the micronucleus formation. For the evaluation of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine (8-OH-dG) formation was measured utilizing calf thymus DNA. Mutagenicity was determined by the point mutation of HGPRT and the effect of RWFs on cell transformation was also observed. 1. Compared with the results of chrysotile, RWFs were no or little effect on the cell growth according to the results done by the tests of cell proliferation inhibition and relative plating efficiency. 2. The frequency of multinucleated giant cell formation was increased by the treatment of RWFs and it was dose-dependent. However, the effect of RWFs was weaker than that of chrysotile. 3. The number of micronuclei formed in the RWFs treated cells was between those of cells treated with chrysotile and those of untreated cells. 4. The 2 fold increase in the formation of 8-OH-dG in calf thymus DNA was observed in the cells treated with RWFs in the presence of H2O2. On the other hand, chrysotile had no effect on the 8-OH-dG formation. 5. RWFs had no effect on the HGPRT point mutation and cell transformation. These results showed that RWFs could induce chromosomal damage, cell division disturbance and oxidative DNA damage in the RWFs treated cells.