Androgen signaling in male fishes: Examples of anti-androgenic chemicals that cause reproductive disorders

Abstract

Similar to other vertebrates, androgens regulate spermatogenesis in fishes. In teleosts, the main androgen is 11-Ketotestosterone (11-KT), which is oxidized testosterone (T) at the C₁₁ position. Compared to T, 11-KT is a nonaromatizable steroid, and does not convert to 17β-estradiol. However, circulatory levels of both T and 11-KT undergo seasonal variations along with testicular development. Physiological functions of androgens are mediated via androgen receptor (Ar). So far, nuclear Ar and membrane Ar have been identified in fishes. In the present study, we reviewed androgen biosynthesis in fishes, compared molecular structure of nuclear Ar in models of mammals and fishes, and investigated the mechanisms of action of environmental contaminants that differentially disrupt androgen signaling in fish reproduction. In the latter case, the adverse effects of vinclozolin (VZ) and bis(2-ethylhexyl) phthalate (DEHP) are compared. Both VZ and DEHP are capable of decreasing sperm quality in males. Vinclozolin causes an increase in 11-KT production associated with increases in kisspeptin (kiss-1) and salmon gonadotropin-releasing hormone (gnrh3) mRNA levels as well as circulatory levels of luteinizing hormone (Lh). In contrast, DEHP inhibits 11-KT production associated with a decrease in circulatory Lh levels. However, DEHP-inhibited 11-KT production is not associated with changes in kiss-1 and gnrh3 mRNA levels. Studies also show that VZ alters ar mRNA levels, while DEHP is without effect. These suggest that VZ and DEHP act differentially to cause androgen-dependent reproductive disorder in male fishes. Molecular analyses of the nuclear AR show that both DNA and ligand binding domains (DBD and LBD, respectively) are highly conserved within models of mammals and fishes. A phylogeny tree of the AR shows distinct clusters between mammals and fishes. In fishes, subtypes of Arα and Arβ are also separated in distinct clusters. Thus, further studies need to generate ar knockout fish model to better elucidate androgen regulation of reproduction in fishes via Ar.

Keywords: Androgen receptor; Bis(2-ethylhexyl) phthalate; Fertility; Hypothalamus-pituitary-testis axis; Sperm; Vinclozolin.