The studies of Dr. Hinton and colleagues have established that the medaka (Oryzias latipes), a small aquarium teleost fish, is a highly valuable vertebrate model for hepatocarcinogenesis because of its small size, ease of maintenance, rapid tumor onset, and immense potential as a bioassay subject. Their recent studies revealed that when medaka were exposed to the initiating carcinogen diethylnitrosamine (DEN) at an early age (21 days after hatching), females were more sensitive than males to development of hepatic neoplasms. The process of maturation in preparation for formation of mature oocytes (10 weeks of age) is accompanied by an earlier doubling of the number of hepatocytes (seen at 7 weeks or earlier). The investigators hypothesize that increased gender sensitivity to hepatocarcinogenesis, exemplified by female medaka, is due to the existence of increased growth effects, likely mediated by estrogen, and/or to increased genotoxic insult, due to greater differences in carcinogen metabolism or in DNA adduction and repair. To test their hypothesis, they will perform experiments with the following specific aims: 1A) serially define features of normal hepatic growth in medaka correlating them with gender-specific effects of estrogen and estrogen receptor levels, and vitellogenin (VG) gene expression.During DEN-induced hepatocarcinogenesis, address gender effects on number and volume of specific foci of cellular alteration, and their fate (reversion, coalescence, growth, alteration) and, predict their relationship to eventual hepatic neoplasms using stochastic modeling; 1B) Determine modulatory effects of estradiol (E2) or antiestrogen (AE) on incidence of DEN-induced hepatic neoplasms in male and female medaka, respectively; and 2) establish if gender and/or age effects on procarcinogen metabolism, DNA adduct formation and DNA repair are related to eventual hepatic neoplasms in medaka. This project is a highly integrated effort among three laboratories, with particular expertise in cellular pathology of hepatocarcinogenesis, aquatic biochemical toxicology, and risk assessment. Understanding the gender sensitivity of medaka to hepatocarcinogenesis may provide valuable information about gender effects on cancer formation in other vertebrates and will further characterize the medaka model.
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