Over the past decade it has become clear that chemicals contrived and dispersed by humans are present in substantial quantities throughout the environment, and these same chemicals act as endocrine disruptors. The challenge for the future is to develop model systems that will allow us to identify the mechanisms by which these substances negatively impact the reproductive potential of animals, including humans. We propose to test the hypothesis that exogenous steroids and methoxychlor, an endocrine disruptor that binds to the estrogen receptor, will modify the development of the forebrain reproductive centers in the zebrafish (Danio rerio) by altering the expression of key neuropeptides that control reproductive behavior and/or physiology. The forebrain reproductive centers are 1) the primary pathway for regulating reproductive function in all vertebrates, 2) developmentally regulated via the early action of gonadal steroids, and 3) potentially modified as a result of exposure to environmental compounds that act as endocrine disruptors. Endocrine disruption of reproductive function is currently being examined in several fish species and in other vertebrates, but there is a great potential benefit in conducting these studies in a genetic model such as the zebrafish, particularly in order to understand the mechanisms of action of these compounds. We will ultimately be able to examine the regulation of gene expression in the developing brain and determine the specific mechanisms whereby methoxychlor and steroids disrupt normal brain development. In order to establish zebrafish as a model system for determining the mechanisms of action of endocrine disruption, we must first provide a basic characterization of the structures within the brain that are likely to be affected by these compounds and whose alteration is likely to affect reproductive function. We will then examine how exposure to exogenous steroids and methoxychlor modify this basic pattern during development and in adults.
| Stokes, Elizabeth A; Lonergan, William; Weber, Lynn P et al. (2004) Decreased apoptosis in the forebrain of adult male medaka (Oryzias latipes) after aqueous exposure to ethinylestradiol. Comp Biochem Physiol C Toxicol Pharmacol 138:163-7 |
