Title

Elucidating the mechanisms of action of tributyltin and dibutyltin in zebrafish, Danio rerio

Date of Completion

January 2011

Keywords

Health Sciences, Toxicology|Biology, Endocrinology|Biology, Physiology

Degree

Ph.D.

Abstract

Tributyltin (TBT) is an endocrine disrupting chemical (EDC), which has been implicated in the masculinization of female gastropods. Female TBT-exposed gastropods have been characterized with superimposed male genitalia (imposex). While it is generally accepted that TBT is responsible for this condition in mollusks, little information is known about TBT's effect on fish. The goal of this thesis research was to further elucidate the mechanisms of action of TBT and its metabolite dibutyltin (DBT) in fish. The zebrafish was chosen as an ideal model system for studying these mechanisms due to their sensitivity to endocrine disrupting chemicals (EDCs) and the similarity between zebrafish and human genomes. ^ TBT was used as a marine antifouling agent until 2008 when it was completely banned, because of its potential role as an endocrine disruptor; however, the endocrine disrupting mechanism is poorly understood. The data presented in this thesis shows that TBT acts in a complex way with both masculinization and feminization effects. Previous studies have shown that TBT directly inhibits aromatase activity, which is responsible for the conversion of testosterone to estrogen; however, the present research revealed no evidence for this in vitro or in vivo. ^ In addition to identifying TBT's mechanism of action, another goal of the present study was to examine DBT's endocrine disrupting mechanism of action. There is no previous work that investigates DBT as an endocrine disrupter. This thesis research demonstrates that DBT is indeed an endocrine disruptor; however, its actions promote feminization. ^ The final goal of this thesis was to identify genes involved in the sexual differentiation. Currently, the zebrafish sexual differentiation pathway is not known and this thesis investigates the role of Sox9 following long-term treatment of TBT. The findings suggest that Sox9 is a major player in the pathway. ^