Chem Res Toxicol. 2020 May 11.
The cellular outcomes of chemical exposure are as much about the cellular response to the chemical as it is an effect of the chemical. We are growing in our understanding of the genotoxic interaction between chemistry and biology. For example, recent data has revealed the biological basis for mutation induction curves for a methylating chemical, which has been shown to be dependent on the repair capacity of the cells. However, this is just one endpoint in the toxicity pathway from chemical exposure to cell death. Much remains to be known in order for us to predict how cells will respond to a certain dose. Methylating agents, a subset of alkylating agents, are of particular interest because of the variety of adverse genetic endpoints that can result, not only at increasing doses but also, over time. For instance, methylating agents are mutagenic, their potency for this endpoint, is determined by the cellular repair capacity of an enzyme called methylguanine DNA-methyltransferase (MGMT), for example. However, the adducts can become clastogenic. Erroneous biological processing will convert mutagenic adducts into clastogenic events in the form of double strand breaks (DSBs). How the cell responds to DSBs, via a cascade of protein kinases, called the DNA damage response (DDR), will determine if the damage is repaired effectively, via homologous recombination, or with errors, via non-homologous end joining. Alternatively, the cell dies via apoptosis, or enters senescence. The fate of cells may be determined by the extent of damage and the resulting strength of DDR signalling. Therefore, thresholds of damage may exist that determine cell fate. Such thresholds would be dependent on each of the repair and response mechanisms that these methyl adducts stimulate. The molecular mechanism of how methyl adducts kill cells is still to be fully resolved. If we are able to quantify each of these thresholds of damage, then we can ascertain; of the many adducts that are induced, what proportion of them are mutagenic, what proportion are clastogenic and how many of these clastogenic events are toxic. This review examines the possibility of dose and damage thresholds for an SN1-type methylating agent, from the perspective of the underlying evolutionary mechanisms that may be accountable.