Toward an “omic” physiopathology of reactive chemicals: Thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds

Abstract

Cancer and degenerative diseases are major causes of morbidity and death, derived from the permanent modification of key biopolymers such as DNA and regulatory proteins by usually smaller, reactive molecules, present in the environment or generated from endogenous and xenobiotic components by the body's own biochemical mechanisms (molecular adducts). In particular, protein adducts with organic electrophiles have been studied for more than 30 [see, e.g., Calleman et al., 1978] years essentially for three purposes: (a) as passive monitors of the mean level of individual exposure to specific chemicals, either endogenously present in the human body or to which the subject is exposed through food or environmental contamination; (b) as quantitative indicators of the mean extent of the individual metabolic processing which converts a non-reactive chemical substance into its toxic products able to damage DNA (en route to cancer induction through genotoxic mechanisms) or key proteins (as in the case of several drugs, pesticides or otherwise biologically active substances); (c) to relate the extent of protein modification to that of biological function impairment (such as enzyme inhibition) finally causing the specific health damage. This review describes the role that contemporary mass spectrometry-based approaches employed in the qualitative and quantitative study of protein-electrophile adducts play in the discovery of the (bio)chemical mechanisms of toxic substances and highlights the future directions of research in this field. A particular emphasis is given to the measurement of often high levels of the protein adducts of several industrial and environmental pollutants in unexposed human populations, a phenomenon which highlights the possibility that a number of small organic molecules are generated in the human organism through minor metabolic processes, the imbalance of which may be the cause of "spontaneous" cases of cancer and of other degenerative diseases of still uncharacterized etiology. With all this in mind, it is foreseen that a holistic description of cellular functions will take advantage of new analytical methods based on time-integrated metabolomic measurements of a new biological compartment, the "adductome," aimed at better understanding integrated organism response to environmental and endogenous stressors.

Implications of the exposome for exposure science

“…Thus, it is important to apply agnostic approaches to detect a larger cross-section of toxic chemicals arising from all sources (Rappaport and Smith, 2010). Fortunately, some ''omics'' methods offer unbiased means for characterizing exposures to several important classes of toxicants, namely, metals (metallomics) (Mounicou et al, 2009), small metabolic products (metabolomics) (Dunn et al, 2008) and reactive electrophiles (adductomics) (Rubino et al, 2009;Li et al, in press). …”

MALDI In-Source Decay, from Sequencing to Imaging

“…The field of biopolymer analysis has evolved considerably over the past 10 years [1]. A major example is the explosion of "omics" techniques.…”

SSPaQ: A Subtractive Segmentation Approach for the Exhaustive Parallel Quantification of the Extent of Protein Modification at Every Possible Site

“…Table 2 shows the five most modified segments to consider at the end of the narrowing process. Four segments contain only one modifiable residue: [2][3], [77], [78][79][80], and [155][156]. The f bound values observed in these areas can thus be attributed to these sites, (i.e., the N-terminal site, Lys77, Lys80, and Lys156), with some level of confidence.…”

“…Induced modifications are usually the result of exposure to stress, infectious agents, food, drugs, lifestyle-derived xenobiotics such as tobacco and alcohol, pollutants, and radiation [1]. Developmental dysfunctions and human disease may arise as a consequence of PTM disorders and/or induced chemical modifications [2].…”