The influence of gender on hepatocarcinogenesis in Japanese medaka, Oryzias latipes

Although the mechanisms are not yet fully elucidated, endogenous hormones, particularly estradiol, likely play a role in the development of a variety of human and animal neoplasms. Japanese medaka (Oryzias latipes) have been used for the past two decades in hepatocarcinogenesis research. Because the livers of female fish are responsive to estrogen, and because of known proliferative estrogen effects, female medaka may be at higher risk of developing hepatic tumors after carcinogen exposure. Several key factors could be involved in gender differences in tumor occurrence. First, differential growth rates between the sexes could affect tumor incidence. Chapter 2 of this thesis quantifies differences in somatic, hepatic and gonad weights between young female and male medaka under variable stocking density, feeding and photoperiod conditions. Results show that females have consistently higher mean body, liver and gonad weights and that female growth is differentially impacted by certain husbandry conditions.; A second factor in gender-specific tumor occurrence could be differences in DNA adduct formation in the initiation stage of carcinogenesis. In chapter 3, total hepatic DNA adducts were quantified shortly after diethynitrosamine exposure using accelerator mass spectrometry. Adducts rose in a dose-dependent manner after exposures spanning 6 orders of magnitude. Males exhibited more adducts than females at 10 of 11 time points. DNA adducts declined in a time-dependent manner in both sexes, but more dramatically in females.; A third factor could be a promotional effect of estradiol on specific carcinogen-induced lesions. In Chapter 4, mature females had the highest diethylnitrosamine-induced lesion incidence followed by immature females, then males. In-situ hybridization demonstrated a positive correlation between estrogen receptor mRNA expression and lesion histologic grade in females only. Higher estrogen receptor and choriogenin mRNA expression in altered foci, adenomas and carcinomas in females compared to males suggests different mechanisms of growth promotion, dependent upon gender.; Results of these studies support a role for estradiol in the promotional phase of hepatocarcinogenesis, rather than during the early initiation stage. Likely due to effects on hepatic growth, estradiol is important in the formation and progression of altered foci and hepatocellular carcinomas in DEN-exposed female medaka.