The endogenous exposome

Nakamura, Jun; Mutlu, Esra; Sharma, Vyom; Collins, Leonard B.; Bodnar, Wanda M.; Yu, Rui; Lai, Yongquan; Moeller, Benjamin C.; Lü, Kun; Swenberg, James A.

doi:10.1016/j.dnarep.2014.03.031

Cited by 90 publications

(79 citation statements)

References 128 publications

(152 reference statements)

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“…Moreover, endogenous DNA adducts are now recognized to be ubiquitously present at quantifiable levels in all living tissues. This new perception of the background exposome is shifting perspective on what is normal vs. adaptive vs. adverse [7, 8]. This review discusses the current understanding of biological, mechanistic processes that explain these PoDs, specifically DNA repair and DNA damage response, and complex interactions between these pathways.…”

Section: Introductionmentioning

confidence: 99%

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Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

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From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.

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Section: Introductionmentioning

confidence: 99%

“…Recent work has begun addressing the potential role of endogenous/background DNA damage in background mutagenesis [5, 6, 8, 16-19]. The Engelward laboratory developed a sensitive mouse model in which HR events at an integrated Fluorescent Yellow Direct Repeat (FYDR) transgene give rise to a fluorescent signal.…”

Section: Introductionmentioning

confidence: 99%

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

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“…The ratio of naïve versus suicide MGMT decreased with increasing concentrations of MNU treatment with almost no active MGMT left at the highest MNU concentration (not shown). Interestingly, without MNU treatment, protease V8 cutting is still detected supporting formation of endogenous alkylating DNA adducts as a part of normal cellular metabolism in these cells (1,42), although the assay specificity for detecting suicide MGMT may not be perfect due to its potential binding to other proteins. The ratio of naïve versus suicide MGMT was higher in control HBECs compared to UBR1 KD lines (0.95 vs 0.71, paired ttest p=0.037, Figure 1b) with the largest difference seen in HBEC26 (0.36, Figure 1c), suggesting accumulation of suicide MGMT in UBR1 KD lines.…”

Section: Resultsmentioning

confidence: 99%

Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung

Leng

Collins

et al. 2015

Cancer Research

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O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells (HBEC), while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells.

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“…The environment with which genes interact is known as the exposome [8,9]. The exposome includes nutrients, noise, occupation, psychosocial environment, social economic status and education as well as pollutant chemicals, microorganisms, drugs, food, and additives [9].…”

Section: Introductionmentioning

confidence: 99%

Social Determinants of Health and Epigenetics: A New Tool for Health Policy

Sehgal¹,

Toscano²

2017

Preprint

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Globally, humans are struggling with the double threat of communicable and noncommunicable diseases, which are presenting new challenges to public health. Public health problems are generally studied and addressed at primary, secondary and tertiary levels. Most effective results are seen with primary interventions. Public health is becoming more aware of the importance of environment-gene interactions in the ontology of health and disease using epigenetics. Epigenetics is the study of altered gene expression without change in base pairs. Be it physical, social, behavioral, or economic factors; they all influence quality of life and health of individuals and populations. That environments are changing the human health phenotype and these changed phenotypes are heritable is of concern for the future of the human race. Knowing the causes of non-communicable human diseases using epigenetics will contribute to the development of new policies to encourage prevention using primary public health initiatives. Research and application of epigenetics shows great promise for improving population health. Continued advances in epigenetics will enhance how we understand and address the way environments are affecting the human health phenotype. For some time, health systems have been and continue to be tertiary in nature. Epigenetic changes can provide information necessary to better understand how social determinants of health can be used to build societies focused on equitable health for all people, rather than continuing to focus on treatment of diseases in the tertiary phase that leads to health disparities. Understanding mechanisms of social determinants of disease, will allow society to evolve in a health-oriented rather than a disease-oriented world. For this reason, we must enhance and apply epigenetics (physical, social, behavioral, economic) research to policy development. We will discuss how bringing social determinants together with biology can be used as new tools for public health policy.

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The endogenous exposome

Cited by 90 publications

References 128 publications

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung

Social Determinants of Health and Epigenetics: A New Tool for Health Policy

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