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Download Prenatal Exposure of Mice to the Human Liver Carcinogen Aflatoxin
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Prenatal Exposure of Mice to Aflatoxin B1 Reveals a Susceptibility to Genetic Change Supawadee Chawanthayatham, Ph.D. Department of Biological Engineering and Center for Environmental Health Sciences, MIT October 26-29, 2014 Boston, MA 1 Acknowledgements Essigmann / Wogan Group MIT John M. Essigmann Gerald N. Wogan Robert G. Croy Leslie Woo Crystal R. Belanger Johns Hopkins Funding John D. Groopman Patricia A. Egner 2 Aflatoxins are environmental health problem • Discovered ~1960 in moldy animal feed – also present in human food – Secondary metabolites produced by Aspergillus flavus (A. flavus toxin = Aflatoxin) • AFB1 is predominant and is the most potently toxic and carcinogenic • 2.5 billion people in the developing world have chronic exposure through diet which leads to a high risk of developing liver cancer – Aflatoxin exposure has also been associated with childhood stunting and impaired neurological development AFB1 A. flavus on 3 Environmental AFB1 -- Relevance to liver cancer • Geographically specific -- sub-Saharan Africa, Southeast Asia and China • Liver cancer incidence is greatly elevated by concurrent exposure to both aflatoxin and hepatitis B infection • Early life exposure to aflatoxin could underlie elevated risk of liver cancer Age-specific incidence of HCC in male 45-50 yr 70 yr International Variation in Age-standardized Liver Cancer Incidence Rates, Global cancer, 2008 Kensler T W et al. Toxicol. Sci. 2011;120:S28-S48 4 Aflatoxin adducts are biomarkers H that predict cell death, mutations AFB1 and cancer H Blood Liver Cell DNA Adducts Protein Adducts AFB1-Lysine Albumin AFB1-N7-Gua H O AFB1 Phase II Enzymes O2 Phase I Enzymes HH (Dialdehyde) H O AFB1-FAPY H Reactive Intermediates (Epoxide) O * * * * H Polar Species Cell Replication AFB1-DNA adducts are functional biomarkers that predict 5 Cellcancer; Death protein adducts are Mutations Cancer liver stable and?easier to measure Serum albumin adducts reveal significant exposure to AFB1 Clear evidence of early life exposure Serum, Cord Blood, 2-Year Old 6 Groopman et al, Food Chem. Toxicol, 2014 Objective Quantify the risk of developing liver cancer from in utero exposure to AFB1 by measuring AFB1-DNA adducts and characterizing the subsequent frequency and spectrum of mutations in the gpt transgenic mouse 7 Log Total Adducts (AFB1-N7-Gua + AFB1-FAPY)/106 nts DNA adduct levels in maternal and fetal (GD14) livers Snapshot of DNA damage 6 h after dosing with aflatoxin B1 100 10 100 X 1 0.1 Fetus Mother • Total adducts (N7-Gua + FAPY) in fetal livers were 100-fold lower than in maternal livers Increased mutation frequency in the gpt gene of 10 week old mice after in utero exposure to AFB1 • The predominant mutations found in the liver of AFB1 treatment group were G:C T:A transversions 9 A DNA adduct in a fetus is 20 times more likely to cause mutations than the same adduct in adult Fetus Adult 0.62 63.5 10 wk gpt MF (x10 ) 6.5 30 gpt MF/ DNA adducts 10 0.5 Relative risk of mutation1 20 1 80 <1 AFB1-DNA adducts 6 (adducts/10 bases) -6 Mitotic Index (liver) 2 1 Mutation risk relative to adult liver = [gpt MF/DNA adducts] / [gpt MF/DNA adducts]adult 2 Determined by Ki67 cell proliferation marker staining 10 Summary • A DNA adduct in the liver of a fetus is 20 time more likely to cause mutations than the same adduct in the mother. • Early life measurement of albumin and DNA adduct biomarkers can predict the risk of developing diseases resulting from aflatoxin exposure. • Young animals have increased sensitivity to aflatoxin (infant is not like a small adult). • Reduction of early life exposure can have a major protective effect on cancer outcomes later in life. 11 Thank you 12