The Pathway And Cellular Mechanism Of Aneuploidy Induction In Asbestos Exposure Induced Tumorigenesis

Natural mineral fiber asbestos,a well-known occupational carcinogen,causes types of human malignancies and aneuploidy during the early stages of neoplastic development,which is a significant hallmark of tumors.However,the cellular mechanism by which asbestos induces aneuploidy formation remains elusive.To examine the origins of asbestos-induced aneuploidy,we performed long-term live cell imaging and fluorescence in situ hybridization(FISH)analysis in HBEC(human bronchial epithelial cell)and MeT5A(human mesothelial cell)cell lines and demonstrated that asbestos induces aneuploidy formation via binucleated intermediate cells from cytokinesis failures following elongated cytoplasmic bridge stages.The binucleated cells contributed to aneuploidy induction by both bipolar(47.83%in HBEC and 23.08%in MeT5A)and multipolar mitosis(52.17%in HBEC and 76.92%in MeT5A),while cytochalasinB induced binucleated cells produced aneuploidy all from multipolar mitosis(100%in HBEC and MeT5A).Furthermore,chromosome loss via asbestos induced micronuclei was not the main pathway to contribute to aneuploidy formation(0%in HBEC or MeT5A).In vivo studies in a mesothelioma mice model showed a significant increase of binucleated intermediates during the asbestos exposure induced tumorigenesis by intraperitoneal injection.Our results for the first time explicitly clarified the cellular origins of asbestos induced aneuploidy and explored the significant role of binucleated cells during the development of asbestos related aneuploidy and tumorigenesis.We discovered the direct effect of asbestos on increasing missegregations of binucleated intermediate cells,which is the first reported carcinogen that could directly interfere with the accurate chromosome segregations of tetraploids to our knowledge.