Agnostic Cys34‐albumin adductomics and DNA methylation: Implication of N‐acetylcysteine in lung carcinogenesis years before diagnosis

Dagnino, Sonia; Bodinier, Barbara; Grigoryan, Hasmik; Rappaport, Stephen M.; Karimi, Maryam; Guida, Florence; Edmands, WIlliam B.; Naccarati, Alessio; Fiorito, Giovanni; Sacerdote, Carlotta; Vermeulen, Roel; Víneis, Paolo; Chadeau‐Hyam, Marc

doi:10.1002/ijc.32680

Cited by 13 publications

(9 citation statements)

References 36 publications

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“…In that study, the BDE adduct was detected in 8/10 of the exposed subjects, but not detected in any of the controls (levels in control participants were imputed with values of the lower limit of detection). This is in line with other studies using the DDA-based Cys 34 adductomics assay, in which the BDE adduct has not been detected in settings without high levels of benzene exposure. ,,,, While the BDE adduct may have been present in sera of subjects from these other reports, it only reached the threshold for DDA analysis in individuals with very high-benzene exposures (>3 ppm). In contrast, using our targeted PRM assay, we detected the BDE adduct in 77 of 78 samples (BDE was not detectable at the baseline in one subject), facilitating longitudinal biomonitoring of exposure to ambient levels of benzene (ppb) and exploration of BDE adduct as a dosimetric biomarker of OAP (+465%, +319%, and +376% per doubling of NO 2 , SO 2 , or PM 10 , respectively).…”

Section: Discussionsupporting

confidence: 90%

Biomonitoring of Ambient Outdoor Air Pollutant Exposure in Humans Using Targeted Serum Albumin Adductomics

Smith

O’Meally

et al. 2021

Chem. Res. Toxicol.

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Outdoor air pollution, a spatially and temporally complex mixture, is a human carcinogen. However, ambient measurements may not reflect subject-level exposures, personal monitors do not assess internal dose, and spot assessments of urinary biomarkers may not recapitulate chronic exposures. Nucleophilic sites in serum albuminparticularly the free thiol at Cys34form adducts with electrophiles. Due to the 4-week lifetime of albumin in circulation, accumulating adducts can serve as intermediate- to long-residence biomarkers of chronic exposure and implicate potential biological effects. Employing nanoflow liquid chromatography-high-resolution mass spectrometry (nLC-HRMS) and parallel reaction monitoring (PRM), we have developed and validated a novel targeted albumin adductomics platform capable of simultaneously monitoring dozens of Cys34 adducts per sample in only 2.5 μL of serum, with on-column limits of detection in the low-femtomolar range. Using this platform, we characterized the magnitude and impact of ambient outdoor air pollution exposures with three repeated measurements over 84 days in n = 26 nonsmoking women (n = 78 total samples) from Qidong, China, an area with a rising burden of lung cancer incidence. In concordance with seasonally rising ambient concentrations of NO2, SO2, and PM10 measured at stationary monitors, we observed elevations in concentrations of Cys34 adducts of benzoquinone (p < 0.05), benzene diol epoxide (BDE; p < 0.05), crotonaldehyde (p < 0.01), and oxidation (p < 0.001). Regression analysis revealed significant elevations in oxidation and BDE adduct concentrations of 300% to nearly 700% per doubling of ambient airborne pollutant levels (p < 0.05). Notably, the ratio of irreversibly oxidized to reduced Cys34 rose more than 3-fold during the 84-day period, revealing a dramatic perturbation of serum redox balance and potentially serving as a portent of increased pollution-related mortality risk. Our targeted albumin adductomics assay represents a novel and flexible approach for sensitive and multiplexed internal dosimetry of environmental exposures, providing a new strategy for personalized biomonitoring and prevention.

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Section: Discussionsupporting

confidence: 90%

Biomonitoring of Ambient Outdoor Air Pollutant Exposure in Humans Using Targeted Serum Albumin Adductomics

Smith

O’Meally

et al. 2021

Chem. Res. Toxicol.

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“…29 In another study of occupational exposure to benzene, a positive association was found for putative benzene metabolite adducts. 30 Furthermore, the Cys34 method has been applied in studies of lung cancer 31 and childhood leukemia. 32 Adducts to the N-terminal amino acid valine in Hb can be analyzed after detachment with a modified Edman degradation.…”

Section: Introductionmentioning

confidence: 99%

Pathways to Identify Electrophiles In Vivo Using Hemoglobin Adducts: Hydroxypropanoic Acid Valine Adduct and Its Possible Precursors

Vryonidis

Karlsson

Aasa

et al. 2022

Chem. Res. Toxicol.

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Analytical methods and tools for the characterization of the human exposome by untargeted mass spectrometry approaches are advancing rapidly. Adductomics methods have been developed for untargeted screening of short-lived electrophiles, in the form of adducts to proteins or DNA, in vivo. The identification of an adduct and its precursor electrophile in the blood is more complex than that of stable chemicals. The present work aims to illustrate procedures for the identification of an adduct to N-terminal valine in hemoglobin detected with adductomics, and pathways for the tracing of its precursor and possible exposure sources. Identification of the adduct proceeded via preparation and characterization of standards of adduct analytes. Possible precursor(s) and exposure sources were investigated by measurements in blood of adduct formation by precursors in vitro and adduct levels in vivo. The adduct was identified as hydroxypropanoic acid valine (HPA-Val) by verification with a synthesized reference. The HPA-Val was measured together with other adducts (from acrylamide, glycidamide, glycidol, and acrylic acid) in human blood (n = 51, schoolchildren). The HPA-Val levels ranged between 6 and 76 pmol/g hemoglobin. The analysis of reference samples from humans and rodents showed that the HPA-Val adduct was observed in all studied samples. No correlation of the HPA-Val level with the other studied adducts was observed in humans, nor was an increase in tobacco smokers observed. A small increase was observed in rodents exposed to glycidol. The formation of the HPA-Val adduct upon incubation of blood with glycidic acid (an epoxide) was shown. The relatively high adduct levels observed in vivo in relation to the measured reactivity of the epoxide, and the fact that the epoxide is not described as naturally occurring, suggest that glycidic acid is not the only precursor of the HPA-Val adduct identified in vivo. Another endogenous electrophile is suspected to contribute to the in vivo HPA-Val adduct level.

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“…In particular, the cysteine residue at position 34 (Cys34) of HSA is an effective target of cellular oxidation, generating a host of covalent modi cations to circulating thiols that act as redox switches in homeostatic processes (7b, 8). An untargeted adductomics approach has been developed and implemented in prior studies to identify Cys34 modi cations associated with exposure to environmental agents and certain chronic diseases, including cancers (6,(8)(9)(10)(11)(12). This approach, thus, has been proposed as a novel method to characterize exposure biomarkers and understand the etiology of oxidative stress-related diseases, including many cancers.…”

Section: Introductionmentioning

confidence: 99%

A nested case-control study of untargeted albumin adductomics and acute myeloid leukemia

Rahman¹,

Bassig²,

Grigoryan

et al. 2022

Preprint

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Environmental exposures often produce reactive electrophiles in vivo, leading to oxidative stress, which plays a major role in carcinogenesis. These electrophiles frequently form adducts with human albumin, which can be measured to assess in vivo oxidative stress. Here, we aimed to examine the associations of albumin adducts with acute myeloid leukemia (AML), the most common adult myeloid leukemia with consistent associations with environmental exposures. We conducted a case-control study of 52 incident AML cases and 103 controls matched on age, sex, and race nested on two prospective cohorts: the CLUE and PLCO studies. We measured 42 untargeted albumin adducts in pre-diagnostic samples using liquid chromatography-high resolution mass spectrometry. Circulatory albumin adducts were associated with AML in conditional logistic regression models. For instance, higher levels of Cys34 disulfide adduct of the S-γ-glutamylcysteine, a precursor of an essential antioxidant, glutathione were associated with a lower risk of AML (odds ratios (95% confidence intervals) for the 1st, 2nd, and 3rd tertiles were 1.0, 0.65(0.31–1.36); and 0.31(0.12–0.80), respectively (p-trend = 0.01). These associations were largely driven by effects present among cases diagnosed ≥ median follow-up year of 5.5 years. Our results support the idea that oxidative stress may play a role in the etiology of AML.

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Agnostic Cys34‐albumin adductomics and DNA methylation: Implication of N‐acetylcysteine in lung carcinogenesis years before diagnosis

Cited by 13 publications

References 36 publications

Biomonitoring of Ambient Outdoor Air Pollutant Exposure in Humans Using Targeted Serum Albumin Adductomics

Biomonitoring of Ambient Outdoor Air Pollutant Exposure in Humans Using Targeted Serum Albumin Adductomics

Pathways to Identify Electrophiles In Vivo Using Hemoglobin Adducts: Hydroxypropanoic Acid Valine Adduct and Its Possible Precursors

A nested case-control study of untargeted albumin adductomics and acute myeloid leukemia

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