Molecular epidemiology of aflatoxin exposures: Validation of aflatoxin-N7-guanine levels in urine as a biomarker in experimental rat models and humans

J. D. Groopman, C. P. Wild, J. Hasler, C. Junshi, G. N. Wogan, T. W. Kensler

Research output: Contribution to journalArticlepeer-review

Abstract

Human epidemiology and experimental animal data have provided the statistical association and biological information necessary to propose that aflatoxins are risk factors for human liver cancer. As liver cancer causes at least 200,000 deaths per year, prevention measures must be developed to ameliorate this nearly always fatal disease. Preventive strategies will be facilitated by the identification of individuals at high risk. It is the goal of the molecular dosimetry field to provide facile and accurate biomarkers to identify people at high risk for carcinogen exposure and consequent adverse health effects. We have developed methods to detect the major aflatoxin DNA adduct, aflatoxin N7-guanine (AFB-N7-guanine), in urine, examined the dose-response characteristics in people living in China and The Gambia, and have found an excellent association of this biomarker with exposure. In addition to exposure studies in people, our laboratories have monitored AFB-N7-guanine excretion in the urine of rats whose risk for developing cancer has been modulated with dietary chemoprotective agents such that independent groups of animals receiving the same dosage of aflatoxin B1 were at either high or low risk for tumorigenesis. The production of DNA damage by aflatoxins is not the exclusive mechanism for liver cancer. Many other factors, including hepatitis B vu-us, cell proliferation, and nutritional status, can exert strong modification effects in human disease. Thus, molecular epidemiological investigations that examine only one biomarker may greatly underestimate or overestimate the risk for an individual. In our experimental studies, we have found the need to measure specific, biologically relevant metabolites in a urine sample. Our data show that the levels of the daily urinary excretion of total aflatoxin metabolites are unrelated to risk of aflatoxin-induced disease. Similar analyses using the human urine samples from China also revealed that total aflatoxin metabolites in urine do not reflect appropriate exposure assessments. In the rat model, AFB-N7-guanine is a minor, but biologically relevant, metabolite representing less than 1% of the excreted material in urine, which does reflect exposure in experimental models. Thus, the composite human and experimental data generated from our research indicates that a cautious interpretation of the relationship between any biomarker and tumor outcome must be employed. However, both experimental rat data and human studies have also found that the AFB-N7-guanine adduct in urine is a good, noninvasive, short-term biomarker for determining both aflatoxin exposure and risk of genetic damage in target organs.

Original languageEnglish (US)
Pages (from-to)107-113
Number of pages7
JournalEnvironmental health perspectives
Volume99
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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