Exposure to genotoxic carcinogens via both external and internal environments increases risks for major human cancers. Such chemicals form covalent adducts with DNA, which are thought to create a complex program of genetic change acting as the initiating event in malignant transformation and contributing to subsequent tumor progression. Adducts can also disrupt formation or maintenance of normal genome modifications, altering gene expression in affected tissues. Factors that influence formation or repair of adducts are thus likely to be important determinants of human susceptibility to environmental carcinogenesis. We propose an approach to elucidate types of DNA damage and cellular processes responsible for genetic changes that transform normal cells to malignant ones. As a tool, our work focuses on aflatoxin B1 (AFB1), an established risk factor for human hepatocellular carcinoma that strongly elevates risk in synergy with hepatitis B virus infection. As in the human HCC incidence pattern, AFB1 is more potent in males than females, and animals of both sexes are more sensitive as juveniles than as adults. The hypothesis underlying our proposed work is that different quantitative features of mutagenesis (mutation frequencies) or qualitative features (mutational patterns) are determinants of the initiation and promotion phases of tum origenesis. The goal of our work is to characterize these quantitative and qualitative features and define their roles in modulating liver carcinogenesis. Experiments designed to test this hypothesis will employ a newly developed Duplex Sequencing protocol that enables the application of Next-generation sequencing platforms for mutational analysis. Mutation frequencies and spectra will be determined in selected genomic DNAs at stages throughout the tumorigenic process in a mouse model of AFB1-induced liver cancer. These analyses will enable us to determine whether a """"""""mutator phenotype"""""""" is acquired during tumor development induced by AFB1, while providing a picture of its variation among different genes. Evidence of mutator phenotypes is seen in many advanced human tumors, and is increasingly considered as a possible source of premature-onset drug or radiation resistance. The types of mutations that we observe will provide hallmarks of the cellular processes that orchestrate the genetic changes during tumorigenesis. Our animal model is well suited to study the time of onset of a mutator phenotype and, of equal importance, for additional studies to investigate interventions that could delay tumor development and drug resistance.

Public Health Relevance

Genetic changes produced by environmental chemicals underlie disease processes that are important to public health. Understanding the fundamental mutagenic mechanisms by which environmental agents drive tumor development will enable us to take measures defined to limit exposures and design interventions for disease prevention. This grant application uses an animal model to identify pathways of genetic change during the development of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016313-07
Application #
8727548
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shreffler, Carol K
Project Start
2008-01-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Fedeles, Bogdan I; Essigmann, John M (2018) Impact of DNA lesion repair, replication and formation on the mutational spectra of environmental carcinogens: Aflatoxin B1 as a case study. DNA Repair (Amst) :
Vartanian, Vladimir; Minko, Irina G; Chawanthayatham, Supawadee et al. (2017) NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice. Proc Natl Acad Sci U S A 114:4207-4212
Sriwattanapong, Kanokwan; Slocum, Stephen L; Chawanthayatham, Supawadee et al. (2017) Editor's Highlight: Pregnancy Alters Aflatoxin B1 Metabolism and Increases DNA Damage in Mouse Liver. Toxicol Sci 160:173-179
Fedeles, Bogdan I; Chawanthayatham, Supawadee; Croy, Robert G et al. (2017) Early detection of the aflatoxin B1 mutational fingerprint: A diagnostic tool for liver cancer. Mol Cell Oncol 4:e1329693
Chawanthayatham, Supawadee; Valentine 3rd, Charles C; Fedeles, Bogdan I et al. (2017) Mutational spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma. Proc Natl Acad Sci U S A 114:E3101-E3109
Techapiesancharoenkij, Nirachara; Fiala, Jeannette L A; Navasumrit, Panida et al. (2015) Sulforaphane, a cancer chemopreventive agent, induces pathways associated with membrane biosynthesis in response to tissue damage by aflatoxin B1. Toxicol Appl Pharmacol 282:52-60
Chawanthayatham, Supawadee; Thiantanawat, Apinya; Egner, Patricia A et al. (2015) Prenatal exposure of mice to the human liver carcinogen aflatoxin B1 reveals a critical window of susceptibility to genetic change. Int J Cancer 136:1254-62
Wattanawaraporn, Roongtiwa; Woo, Leslie L; Belanger, Crystal et al. (2012) A single neonatal exposure to aflatoxin b1 induces prolonged genetic damage in two loci of mouse liver. Toxicol Sci 128:326-33
Wattanawaraporn, Roongtiwa; Kim, Min Young; Adams, Jillian et al. (2012) AFB(1) -induced mutagenesis of the gpt gene in AS52 cells. Environ Mol Mutagen 53:567-73
Fiala, Jeannette L A; Egner, Patricia A; Wiriyachan, Nirachara et al. (2011) Sulforaphane-mediated reduction of aflatoxin B?-N?-guanine in rat liver DNA: impacts of strain and sex. Toxicol Sci 121:57-62

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