Contaminant effects on vitellogenesis and oogenesis in zebrafish (danio rerio) and killifish (fundulus heteroclitus) from the chemically impacted Newark Bay, NJ

Vitellogenins are large glycolipoprotein precursors to yolk–proteins that act as vital biomolecules and growth substrate in developing oocytes of teleosts and are synthesized exclusively in the liver. The studies in this Dissertation tested the general hypothesis that aryl hydrocarbon receptor agonist contaminants in Newark Bay, NJ down–regulate hepatic vitellogenin synthesis, resulting in inhibition of oogenesis and reproductive dysfunction. This hypothesis was examined using a variety of studies with a field population of killifish (Fundulus heteroclitus) from the contaminated Newark Bay and relatively clean Tuckerton, NJ, and using lab studies with zebrafish (Danio rerio) as a model teleost. In killifish native to Newark Bay, inhibition of oocyte yolk–development resulted in decreased egg production, decreased embryo mass and reduced yolk–volume. The cause of these effects was shown to be the down–regulation of vitellogenesis in the liver. Decreased vitellogenin expression during spawning was demonstrated to be due to deficient levels of circulating 17β–estradiol, and a decreased sensitivity of the vitellogenin pathway to induction (protein and mRNA levels) by physiological doses of 17β–estradiol. In the Newark Bay population, vitellogenin expression was inversely correlated with CYP1A, a biomarker for aryl hydrocarbon receptor 2 (AhR2) activity. I therefore propose that the down–regulation of the vitellogenin pathway is phenotypic of aryl hydrocarbon receptor mediated cross–talk inhibition of the estrogen receptor (ER). The role of AhR2 in mediating AhR–ER cross–talk inhibition of vitellogenin was examined using the zebrafish as a model teleost. The potent AhR agonists 2,3,7,8–tetrachlorodibenzo–p–dioxin and 1,2,3,7,8–pentachlorodibenzo–p–dioxin were found to inhibit the induction of vitellogenins 1, 2 and 3 by 17α–ethynylestradiol in zebrafish. Transient knock–down of AhR2 levels showed that the AhR2 mediates inhibition of vitellogenesis by 2,3,7,8–tetrachlorodibenzo–p–dioxin, demonstrating that AhR2 activation plays a role in AhR–ER cross–talk. Taken together, these studies demonstrated that the contaminant induced down–regulation of vitellogenesis in the liver can cause reproductive dysfunction in the ovary and that the mechanism for these effects is mediated through AhR2–ER signaling pathways.Ph. D.Includes bibliographical referencesby Sean Michael Buge