Research On The Lung Cancer Promoting Effects And Mechanisms Of Atmospheric Particulate Matter And Its Aerosol Components

With the rapid development of the global economy,different regions of the world have experienced a certain degree of regional haze pollution and China is one of the most affected areas.Atmospheric aerosol particles are the main components of China's severe haze pollution.Secondary organic aerosols and secondary inorganic aerosols have similar contributions to the average mass concentration of atmospheric particulate matter.However,due to the different sources and the complex composition of atmospheric particulate matter,there is still a lack of effective methods to explore the toxicological effects and mechanisms of particulate matter.Epidemiological studies have revealed the increased incidence of respiratory diseases,especially lung cancer,during haze pollution days.Therefore,have a clear understanding about the pollution characteristics of atmospheric particulate matter in China and explore its possible carcinogenic risk and mechanism are instructive for the health risk assessment and the prevention or treatment of haze pollution.This study analyzed the pollution characteristics and carcinogenic risks of atmospheric particulate matters in typical coal-fired cities in northern China,and revealed the possible carcinogenic mechanisms of different effective components.1.There is a close relationship between severe atmospheric particulate matter(PM)exposure and the increased lung cancer mortality.Considering PM is highly heterogeneous,its potential health risks of promoting lung tumor metastasis as well as its physichemical characteristics remain elusive.In this study,PM2.5 and PM10 were collected from a typical coal-fired city in northern China and their physichemical analysis showed that the concentrations of 18 polycyclic aromatic hydrocarbons(PAHs)on PM have a seasonal variation trend,and the concentration of PAHs in winter PM was the highest.We calculated the benzo(a)pyrene-equivalent(Ba Peq)and found that the PAHs-bound PM in winter exhibited higher carcinogenic risk than in other seasons.Following this result,in vitro bioassays demonstrated that PM2.5 and PM10 induced the increase of lung cancer cell migration and invasion,and the mechanism involved reactive oxygen species(ROS)-mediated epithelial-to-mesenchymal transition(EMT)activation and extracellular matrix(ECM)degradation.This study indicates the potential lung tumor metastasis risks of PAHs-bound PM in winter and reveals a mechanistic basis for treating,ameliorating or preventing outcomes in haze polluted environment.2.Atmospheric particles with different particle size have different physicochemical and toxicological properties.PM2.5 and PM10 are not the only monitoring indicators of environmental particulate matter,ultrafine particles with large specific surface area and high quantity concentrations are more likely to adsorb toxic substances such as organic compounds and transition metals,and could show higher health risks.This study analyzed the emission characteristics of quasi-ultrafine particles that collected in a typical coal-burning city during winter,and found the similar components and sources between PM2.5 and quasi-ultrafine particles.The in vitro bioassays revealed that endocytosis of quasi-ultrafine particles stimulated the release of High Mobility Group Box1(HMGB1),induced NF?B-facilitated proinflammatory cytokine production through the interaction of HMGB1 with the receptor for advanced glycation end products(RAGE),and resulted in cancer-endothelial cell adhesion and promoted cancer cell hematogenous metastasis.Based on this result,carbon black particles(Huber990)were used as particle size references.And the researches about Huber990 and quasi-ultrafine particles revealed that composition and particle size have different contributions to the toxicity of PM.These findings remind us of the potential effects of anthropogenic ultrafine particle pollution and provide a theoretical reference for the mitigation of tumorigenesis in a severe particulate matter contaminated environment.3.Secondary inorganic aerosols(SIA)are central constituents of particulate matter aerosols in severe haze days and exert profound impacts on human health;however,our understanding about the mechanisms of which SIA cause malignancy in lung cancer remains incomplete.In this study,the cell exposure model and the nude mouse tumor-bearing model were used to investigate the carcinogenic effects of SIA components.It was found that exposure to SIA,especially sulfate aerosols,significantly induced the invasion and migration of lung epithelial cells in vitro and promoted lung tumor metastasis in vivo.This action was associated with E-cad inhibition that regulated by ROS activated HIF-1?-Snail transcriptional processes.Additionally,hypermethylation in the E-cad promoter Cp G regions partly contributed to the sulfate aerosol-regulated E-cad repression and the tumor metastasis.This study revealed the potential mechanism of sulfate aerosol exposure promoted lung tumor metastasis,and provides an experimental basis for health risk assessment under the inorganic aerosol particulate polluted conditions.4.The effective formation of secondary organic aerosol particles is an important cause of the haze pollution in northern China.Nitro-polycyclic aromatic hydrocarbons(NPAHs)are the key pollutants of secondary organic aerosols.The NPAHs,with lower volatility,are more likely to be absorbed with PM and to pose a threat to health,whereas there is insufficient information about carcinogenesis caused by NPAHs.This study evaluated the pollution characteristics and carcinogenic risks of NPAHs-bound PM in typical coal-fired cities in northern China,and found that 1-nitropyrene(1-NP)showed a higher cancer risk.In addition,the cell model and nude mouse tumor-bearing model were used and found that typical NPAHs could directly induce the inactivation of serine/threonine kinase(MST1/2)and large tumor suppressor(LATS1/2),and result in the nuclear translocation of Yes-associated protein(YAP).The nuclear YAP would then combine with TEA domain transcription factor(TEAD)and profoundly influence the transcription of adhesion genes related to lung cancer hematogenous metastasis.These findings remind us of the possible carcinogenicity of NPAHs absorbed with PM and provide a reference for the prevention and mitigation of tumorigenesis in a heavily polluted environment.In this study,we first analyzed the pollution characteristics of atmospheric PM2.5 and PM10 in northern China and revealed the cancer-promoting risk of PM-attached PAHs and possible mechanism of tumor invasion and metastasis.Then,we evaluated the pollution characteristics of quasi-ultrafine particles with smaller particle size,and analyzed the contribution of components and particle size to the promotion of tumor hematogenous metastasis,and finally declared the related molecular mechanisms.Based on these findings,we explored the carcinogenic effects and possible mechanisms of secondary inorganic aerosol components(sulfate)and secondary organic aerosol components(NPAHs)by using cell exposure model and nude mouse tumor-bearing model.Our study provides an experimental basis for the study of atmospheric aerosol particulate exposure and its health risks in China.