Crosstalk between the Thyroid Hormone and Androgen Axes Throughout the Lifecycle of Silurana Tropicalis

Abstract

It is widely accepted that thyroid hormones (THs) influence gonadal development and functioning; however, our understanding of the molecular mechanisms underlying TH-induced effects with regard to reproduction is limited. There is increasing evidence that TH actions are mediated via androgenic mechanisms in gonadal tissues. I first investigated the degree to which induced hypothyroid conditions affect molecular mechanisms underlying crosstalk between the TH and reproductive axes. To do this, frogs were chronically exposed to low concentrations of potassium perchlorate (KClO4) for one year. KClO4 altered TH- and androgen-related gene expression in tissues of both developing and sexually mature Silurana tropicalis frogs; female growth (e.g., body mass, snout vent length, and hind limb length) was reduced and male-biased traits such as plasma androgen content and sperm motility were also negatively impacted. THs (triiodothyronine (T3) and thyroxine (T4)) as well as the deiodinase inhibitor iopanoic acid (IOP) were used as model compounds to further assess the consequences of TH status on select stages in frog development. I also incorporated the use of androgens (testosterone (T), 5α-dihydrotestosterone (5α-DHT), and 5β-dihydrotestosterone (5β-DHT)) to elucidate potential reciprocal mechanisms of crosstalk between the androgen and TH axes. Ex vivo exposures using male and female juvenile reproductive tissues were performed to examine mechanisms of crosstalk sans hypophyseal feedback as well as investigate possible sex-specific molecular responses to THs and androgens. Ex vivo exposures provided (i) evidence that TH-related gene expression can be directly regulated by androgens and (ii) demonstrated for the first time the sex-specific transcriptional effects of TH and androgen mediated actions on gonadal tissues of frogs. Lastly, I established sex-determining gene transcript profiles during S. tropicalis early development and investigated the putative role of THs in determining gonadal fate. Elevated TH levels increased the expression of gonadal differentiating genes in larval S. tropicalis and in silico analysis identified TH binding motifs in the putative promoter regions further supporting TH-mediated regulation. This doctoral research provides not only novel mechanistic and developmental insight into the bidirectional crosstalk between the TH and androgen axes, but also elaborates upon the putative role of THs throughout the reproductive lifecycle of frogs.