Genotoxic thresholds, DNA repair, and susceptibility in human populations

Abstract

It has been long assumed that DNA damage is induced in a linear manner with respect to the dose of a direct acting genotoxin. Thus, it is implied that direct acting genotoxic agents induce DNA damage at even the lowest of concentrations and that no "safe" dose range exists. The linear (non-threshold) paradigm has led to the one-hit model being developed. This "one hit" scenario can be interpreted such that a single DNA damaging event in a cell has the capability to induce a single point mutation in that cell which could (if positioned in a key growth controlling gene) lead to increased proliferation, leading ultimately to the formation of a tumour. There are many groups (including our own) who, for a decade or more, have argued, that low dose exposures to direct acting genotoxins may be tolerated by cells through homeostatic mechanisms such as DNA repair. This argument stems from the existence of evolutionary adaptive mechanisms that allow organisms to adapt to low levels of exogenous sources of genotoxins. We have been particularly interested in the genotoxic effects of known mutagens at low dose exposures in human cells and have identified for the first time, in vitro genotoxic thresholds for several mutagenic alkylating agents (Doak et al., 2007). Our working hypothesis is that DNA repair is primarily responsible for these thresholded effects at low doses by removing low levels of DNA damage but becoming saturated at higher doses. We are currently assessing the roles of base excision repair (BER) and methylguanine-DNA methyltransferase (MGMT) for roles in the identified thresholds (Doak et al., 2008). This research area is currently important as it assesses whether "safe" exposure levels to mutagenic chemicals can exist and allows risk assessment using appropriate safety factors to define such exposure levels. Given human variation, the mechanistic basis for genotoxic thresholds (e.g. DNA repair) has to be well defined in order that susceptible individuals are considered. In terms of industrial exposures to known mutagens, knowing the dose relationships and protective mechanisms involved, offers the possibility of screening workers for susceptibility to mutation through examining DNA repair gene polymorphisms. Hence, thresholds may exist for certain mutagens, but there will undoubtedly be human subpopulations who are more at risk from low dose exposures than others and who should not be exposed, if possible. By studying polymorphisms in DNA repair genes, susceptible individuals may be identified, and additional safety factors appropriately targeted to these populations.

Consequences and Repair of Oxidative DNA Damage

“…319 This is primarily due to the fact that very high levels of cellular oxidative DNA damage are produced endogenously. 32 The argument has been that if you add a small increment of damage onto an already high level of damage, the consequences of doing so are going to be insignificant.…”

Estudio de interacciones genotóxicas de mutágenos en mezclas binarias a través del ensayo cometa alcalino en linfocitos humanos

“…Los sistemas de reparación del ADN requieren más de una para iniciar o detectar el daño. Sin embargo, es posible que la expresión basal de las enzimas de reparación sea suficiente para reparar las lesiones ocasionadas por el MX sin S9 (33), puesto que los otros tres mutágenos requieren activación metabólica y los linfocitos no expresan los citocromos suficientes para su inducción (33,47).…”

“…Sin embargo, como se observa en las figuras 1 y 2, en algunas el LOAEL presentado en las mezclas es más bajo que el compuesto puro, pero presentan umbral genotóxico, es decir, se puede encontrar la máxima dosis en la cual no se observa efecto adverso (NOAEL). El hallazgo de esta dosis es el inicio para detectar dosis permisibles de exposición en las mezclas que contengan estos mutágenos a estas concentraciones (33,47,50,54). El antagonismo que se presentó se debe a que hay modulación en la inducción enzimática que lleva a que uno de los mutágenos individuales pueda ser un potente agonista de los receptores o la mezcla afecta la capacidad de inducción de los citocromos, evitando así la activación de los mutágenos indirectos (55).…”

DNA Repair Capacity and the Risk of Head and Neck Cancer

“…However, the early results concerning a high level of DNA lesions and chromosome aberrations in cancer subjects posed a fundamental question concerning a role of former exposure to carcinogens confronted with an impaired DNA repair. Although some papers ignored an impact of DNA repair, their authors brought into light a differentiation between active and passive smoking as a source of carcinogens (Phillips, 2002), location of an organ exposed (Hainaut, Olivier, & Pfeifer, 2001) or exposure threshold (Jenkins et al, 2010).…”