The endogenous exposome

Abstract

The concept of the Exposome is a compilation of diseases and one's lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or occupational exposures; or endogenous chemicals that are formed from normal metabolism, inflammation, oxidative stress, lipid peroxidation, infections, and other natural metabolic processes such as alteration of the gut microbiome. In this review, we have focused on the endogenous exposome, the DNA damage that arises from the production of endogenous electrophilic molecules in our cells. It provides quantitative data on endogenous DNA damage and its relationship to mutagenesis, with emphasis on when exogenous chemical exposures that produce identical DNA adducts to those arising from normal metabolism cause significant increases in total identical DNA adducts. We have utilized stable isotope labeled chemical exposures of animals and cells, so that accurate relationships between endogenous and exogenous exposures can be determined. Advances in mass spectrometry have vastly increased both the sensitivity and accuracy of such studies. Furthermore, we have clear evidence of which sources of exposure drive low dose biology that results in mutations and disease. These data provide much needed information to impact quantitative risk assessments, in the hope of moving towards the use of science, rather than default assumptions.

Keywords: DNA damage; Endogenous exposome; Mutagenesis; Risk assessment; Stable isotopes.

Figure 1

Dose-response relationships of H₂O₂ (30 min exposure) in TK6 cells with respect to (A) 8-oxodG adducts (B) Mutation frequency (MF) in TK forward mutation assay (MF). Data represent Mean +/− SD * p<0.05; one-way analysis of variance (ANOVA) with Dunnet’s test were employed to test for doses statistically significant from control.

Figure 2

Endogenous versus exogenous adducts in AHH-1 cells exposed to [D₃]-Methylnitrosourea (0.0075uM to 2.5uM) for 1h. The endogenous and exogenous O⁶-me-dG and N7-me-G adducts at each exposure concentration are plotted on a log versus log scale. Exogenous adducts from samples with no detectable amounts are not shown. Data represent Mean +/− SD. Statistical comparison between the sum of adducts and the endogenous mean was conducted using a t-test (*p<0.05) to determine doses when the amount of total adducts become significantly higher than the identical average endogenous adducts. This dose was ≥ 0.75uM for N7-me-G and ≥0.025uM for O⁶-me-dG.

Figure 3

Approach for stable isotope versus endogenous N²-HOMedG

Figure 4

When do exogenous DNA adducts result in a total endogenous plus exogenous adducts that is significantly greater and mutations are significantly greater than controls. Adapted from Moeller, et al., Toxicol. Sci. 133: 1–12, 2013