Date of Award
Level of Access Assigned by Author
Doctor of Philosophy (PhD)
Biochemistry and Molecular Biology
John P. Wise, Sr.
Second Committee Member
Third Committee Member
Stephen C. Pelsue
Hexavalent chromium (Cr(VI)) compounds are well-known human lung carcinogens. Solubility plays an essential role in Cr(VI)-induced carcinogenesis, with the particulate form being the most potent. The carcinogenic mechanism of particulate Cr(VI) is poorly understood. The most plausible mechanistic model for particulate Cr(VI)- induced lung cancer appears to be one that involves genomic instability. We found that chronic exposure to two different particulate Cr(VI) compounds induced a concentration- and time-dependent increase in numerical chromosome instability in the form of aneuploidy. Furthermore, we found that aneuploidy is a permanent phenotypic change.
Defects in sister chromatid cohesion is a mechanism that leads to chromosome instability. Consistent with this mechanism, chronic exposure to two different particulate Cr(VI) compounds induced a concentration-dependent increase in sister chromatid cohesion defect that correlates with aneuploidy. Additionally, we found that the cohesion defect phenotype is also a permanent phenotypic change after chromate exposure. This suggests that defects in sister chromatid cohesion may play a role in particulate Cr(VI)- induced carcinogenesis.Additionally for this study, we focused on investigating the potential mechanism of particulate Cr(VI)-induced cohesion defect phenotype. We found that exposure to particulate Cr(VI) disrupted vital proteins that are involved in maintaining sister chromatid cohesion and a decrease in histone methylation. In particular we found that chronic exposure to chromate disrupted the protein levels and localization of Shugoshin1 (Sgo1) in G2 cells, and that this disruption is a permanent change in human lung fibroblast cells.
We propose that chronic exposure to particulate Cr(VI) decreases histone methylation which facilitates in disrupting Sgo1 localization, which prompts premature sister chromatid separation, leading to a cohesion defect phenotype and numerical chromosome instability.
Falank, Carolyne, "Sister Chromatid Cohesion Disruption: A Potential Role in Particulate Hexavalent Chromium-Induced Carcinogenesis" (2015). Electronic Theses and Dissertations. 2358.