Oregon Health & Science University
Endocrine disrupting chemicals (EDCs) are known to affect reproduction through interacting with the hypothalamic-pituitary-gonadal (HPG) axis in fish. EDCs can mimic or block the functions of key elements (e.g. estrogen receptors and androgen receptors) of the HPG axis, and result in altered endocrine signals. The EDCs studied in this dissertation include estrogenic compounds such as 17Î²-estradiol (E2) and 17Î±-ethynylestradiol (EE2), and androgenic EDCs such as 17Î²-trenbolone (TB). E2 is a predominant estrogen naturally present in females. EE2 is a synthetic estrogen used in birth control pills. Both E2 and EE2 are discharged from wastewater treatment plants into water bodies throughout the United States. TB is a relatively stable metabolite of trenbolone acetate, a synthetic androgen used as a growth promoter for cattle. TB enters the environment mainly through runoff from cattle feedlots. In the first part of this dissertation, a physiologically-based computational model was developed of the HPG axis in unexposed male fathead minnows (FHMs, Pimephales promelas) and male FHMs exposed to EE2 and E2. The second part of this dissertation describes a physiologically-based computational model of the HPG axis in unexposed female FHMs and female FHMs exposed to EE2 and TB. For both models, apical reproductive endpoints include plasma concentrations of steroid hormones and vitellogenin. Using Markov chain Monte Carlo simulation, the models were calibrated with data from unexposed FHMs and FHMs exposed to the selected EDCs, respectively. Independent experimental data sets were used to evaluate model predictions. Good agreement was found between model predictions and a variety of measured reproductive endpoints. The conclusion is that the two models provide robust representations of the HPG axis in male and female FHMs, respectively. In the third part of this dissertation, a computational model of oocyte growth dynamics has been developed. The model provides a quantitative link between oocyte growth dynamics and biochemical processes in FHMs through the absorption of vitellogenin into oocytes, which contributes significantly to oocyte growth in fish. Model-predicted clutch sizes, spawning intervals, and average fecundity in unexposed FHMs and FHMs exposed to TB matched the experimental data well. The third model meets an urgent need in ecotoxicological studies to link the effects of endocrine disrupting chemicals at a biochemical level to adverse effects upon reproduction in individual fish and, subsequently, populations. Since oocyte growth and maturation are part of female reproduction, the third model could be integrated with the second one as a future work. The models described in this dissertation can serve as a basis for government to develop cost-effective predictive tools to test and monitor EDCs.
Div. of Environmental and Biomolecular Systems
School of Medicine
Li, Zhenhong, "Physiologically based computational modeling of the hypothalmic-pituitary-gonadal axis in fathead minnows" (2010). Scholar Archive. 368.