Our mission has been to largely characterize responses to carcinogenic inorganics to elucidate mechanisms. A major focus is on arsenic with a smaller cadmium (Cd) and lead (Pb) sub-projects. Inorganic carcinogens are major human hazards and characterizing their mechanisms is key to defining risk and designing methods of intervention. The development of rodent cancer models for arsenic is a recent advent and we have played a major role. We also use in vitro models with relevant cells. Cd is a well defined human and rodent carcinogen, so cell models were used to define mechanisms in recently established or suspected human targets. The further development of our mouse transplacental (TPL) carcinogenesis model has shown fetal arsenic exposure causes oncogenic lesions at multiple sites, including known human targets1-3, and fortifies emerging human data concerning early life exposure and arsenic carcinogenesis5,6. We now have also greatly lowered dose by using whole life (WL) exposure, which much more reasonably duplicates human environmental exposure. Tumor sites are unaltered but tumor incidence often increases, indicating fetal exposure dictates target tissues, pointing towards fetal stem cells (SCs) as target populations. Prenatal arsenic, which results or predisposes to mouse lung, skin and kidney tumors in adults, also causes an over-abundance cancer SCs (CSCs) in these same tumors. We also find superior innate and acquired arsenic resistance in human prostate and rodent kidney SC lines, involving general and arsenic-specific adaptation genes. Malignant transformation of a heterogenous mature prostate line with arsenic causes a stunning CSC overproduction. A major question now is how arsenic targets SCs. Cells adapt to arsenic and arsenic-transformed skin keratinocytes adapt via diminished oxidative stress response. Once adapted, cells are cross-adapted to ultraviolet (UV) irradiation, but still show UV-induced oxidative DNA damage (ODD) at a level higher than control due to apoptotic by-pass, likely a basis of skin co-carcinogenesis with arsenic and UV. Arsenic biomethylation (BML) was thought to be adaptive but many target cells do not BML arsenic. The role of arsenic BML in ODD and transformation has been tested. When a BML-capable liver line and a BML-deficient prostate line were exposed to transforming arsenic levels, ODD occurred in BML-capable cells prior to transformation but BML-deficient cells showed no ODD despite exposure past transformation. Thus, arsenic BML is obligatory for ODD, and hastens acquired cancer phenotype, but cells can acquire a cancer phenotype without ODD indicating arsenic has multiple mechanisms. We can now test methylated arsenicals for ODD and linkage to transformation and look at epigenetic mechanisms of arsenic that may not involve ODD. The prostate is a potential human target of Cd. In contrast to arsenic, which selects for SC accumulation, Cd early on selectively kills SCs. Cd caused 95% cytolethality in our prostate SC line exposed to a non-toxic, but transforming, level for the heterogeneous parental mature line. Though depleted, remaining SCs rapidly undergo transformation, consistent with Cd as a single dose carcinogen. We will determine if Cd has transformed these SCs and observe the mature cell line for selection of hyper-resistant SCs. The pancreas is another potential human target of Cd. Human pancreatic epithelial cells are transformed by Cd, and then become highly enriched in CSCs. At early stages Cd also selectively kills pancreatic SCs but those that survive may be transformed. We are comparing Cd in other systems for this early bottleneck event.
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