Most carcinogens form covalent products, or adducts, with DNA. Adducts are believed to drive the genetic changes that convert normal cells into cancer cells, which then outgrow into a tumor. Factors that influence the formation or removal of adducts, therefore, are likely to be important determinants of human susceptibility to carcinogenesis. Moreover, agents that damage DNA can modify targets not directly relevant to cancer;directly or indirectly, DNA damaging agents may play important roles in initiating or promoting a host of other diseases. The work described below is an effort to understand how DNA adduction integrates with other biochemical factors, determinable by modern analytical tools, to define the differences in sensitivity to environmental agents that are associated with age and gender. The main focus of the work deals with aflatoxin B1 (AFB1), an important human liver carcinogen that is associated with most cases of hepatocellular carcinoma, especially when toxin works in concert with hepatitis viruses. Our work will address four gaps in knowledge. First, we shall provide a high resolution map of the biological networks of both genders of the B6C3F1 mouse at specific time points from fetus through infancy and adulthood and determine how those networks respond to AFB1. Second, the gene network data we produce will be anchored to sensitive detection of DNA adducts, using a tool that will even detect adducts in the fetus of an exposed mother. Accelerator Mass Spectrometry (AMS) will be used to examine the formation and fate of DNA adducts at sensitive and resistant stages of life. Third, we shall administer to mice a chemo-interventive agent, sulphoraphane, that we expect will alter metabolic networks in a manner that will protect pre- born, infant and adult animals from this environmental insult. Finally, our experiments with AFB1 will be coupled with a more limited investigation of the genotoxic effects of four compounds from the NTP data set. These additional agents include4-aminobiphenyl (ABP), 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), acrylamide and 17?-estradiol (E2). An important goal of this research is the development of a host of new biomarkers that can be applied to the mouse model, and later other models that are used to predict the impact of environmental agents on humans.

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National Institute of Environmental Health Sciences (NIEHS)
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Cancer Etiology Study Section (CE)
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Shreffler, Carol K
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Massachusetts Institute of Technology
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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
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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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