Genomic and Physiological Mechanisms of Androgen Signaling: Steroid 5-Reductase Knockout Investigation in Frogs

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With the increased presence of environmental contaminants acting as endocrine disruptors to animals, including in humans, there is a critical need to assess how male hormones (androgens) are regulated and produced in order to understand the health consequences of the alteration of androgen biosynthesis. Using one of the best aquatic models for endocrine disruptor testing, the Western clawed frog, I have produced unique lines of frog mutants to mimic androgen disruption. With their metamorphosing ability, frogs represent a unique animal model featuring large externally developing embryos to study all aspects of developmental physiology (as compared to any mammalian models). These mutant frogs do not possess the functional enzymes, called steroid 5-reductases, capable of producing one of the most powerful androgens. Investigating a series of morphological and physiological endpoints paired with state-of-the-art gene knock-out and sequencing technologies, as well as transcriptomics and epigenetics analysis, this research program will move the field of frog androgen signaling forward. I will be testing the hypothesis that steroid 5-reductases have several roles in frog reproduction, but also physiological functions aside from reproduction. My overarching research objective is to characterize how steroid 5-reductases regulate development and reproduction. More specifically, I will investigate the roles of steroid 5-reductases during frog development using my unique lines of frog mutants. In addition, using these mutant frogs, I will study their reproductive function, the roles of a novel androgen I have discovered to be active in frogs, and the effects of the thyroid hormones on these mutants. Lastly, I will assess the reproductive deficiencies of another category of mutants, i.e., frogs lacking the thyroid hormone receptors. The proposed research will contribute directly to international efforts to understand the fundamental aspects of androgen signaling. On a more practical scale, this research may have applications for targeting environmental contamination that would act through the activation or deactivation of androgen production in aquatic and semi-terrestrial species. Fundamental discoveries in frogs have high relevance for understanding reproductive function in all vertebrates. Altogether, from international collaborations to local lab teamwork, my training philosophy will offer my HQP all the resources they need to acquire exceptional professional training to pursuing a successful research career in molecular endocrinology and comparative endocrinology.