Time‐Dependent transcriptional profiles of genes of the hypothalamic‐pituitary‐gonadal axis in medaka (Oryzias latipes) exposed to fadrozole and 17β‐trenbolone

Abstract

Abstract-Both the anabolic androgen 17␤-trenbolone (TRB) and the aromatase inhibitor fadrozole (FAD) can cause decreased plasma concentrations of estrogen (E2) and reduce fecundity of fish. However, the underlying mechanisms and the molecular pathways involved are largely unknown. The present study was designed to assess time-dependent effects of FAD and TRB on the transcriptional responses of the hypothalamic-pituitary-gonadal (HPG) axis of Japanese medaka (Oryzias latipes). Fourteen-weekold Japanese medaka were exposed to 50 g FAD/L or 2 g TRB/L in a 7-d static renewal test, and the expression profiles of 36 HPG axis genes were measured by means of a medaka HPG real-time reverse-transcription polymerase chain reaction array after 8 h, 32 h, or 7 d of exposure. Exposure to TRB or FAD caused lesser fecundity of Japanese medaka and down-regulated transcription of vitellogenin and choriogenin (CHG) gene expression in the liver of females. Exposure to FAD for 8 h resulted in an 8-fold and 71-fold down-regulation of expression of estrogen receptor ␣ and choriogenin L (CHG L), respectively, in female liver. 17␤-Trenbolone caused similar down-regulation of these genes, but the effects were not observed until 32 h of exposure. These results support the hypothesis that FAD reduces plasma E2 more quickly by inhibiting aromatase enzyme activity than does TRB, which inhibits the production of the E2 precursor testosterone. Exposure to FAD and TRB resulted in rapid (after 8 h) down-regulation of luteinizing hormone receptor and low-density-lipoprotein receptor in the testis to compensate for excessive androgen levels. Overall, the molecular responses observed in the present study differentiate the mechanisms of the reduced fecundity by TRB and FAD.

Inhibition of Aromatase Induces Partial Sex Change in a Cichlid Fish: Distinct Functions for Sex Steroids in Brains and Gonads

“…In contrast, cyp19a1b expression was significantly downregulated compared to both control groups, which in addition to the inhibition on the protein level could probably account for the increase in androgen levels. Similar effects on the expression of the brain aromatase cyp19a1b are observed in female medaka [Zhang et al, 2008], goldfish [Zhang et al, 2009], and fathead minnow [Ankley et al, 2002], where cyp19a1b levels significantly decrease in the brain in response to fadrozole treatment. In Melanotaenia fluviatilis fadrozole leads to a decrease in cyp19a1b brain expression in females and to an increase in males [Shanthanagouda et al, 2014].…”

Profiling neuroendocrine gene expression changes following fadrozole-induced estrogen decline in the female goldfish

“…However, the associated gene expression changes caused by fadrozoleinduced E2 decline in neuroendocrine systems are still largely unknown. Several studies have utilized real-time PCR analysis of selected genes (61,72) and low-density microarrays (60) to profile fadrozole-induced changes in gene expression. Recently, the zebrafish (Danio rerio) model was used to identify the relationship of the global transcriptomic changes between brain, testis, and ovary after fadrozole treatments (62).…”

Toxicology of Water

“…For example, both the anabolic androgen 17b-trenbolone (TRB) and the aromatase inhibitor fadrozole (FAD) can cause decreased plasma concentrations of 17b-estradiol (E2) and reduce fecundity of fish. The mechanisms of the reduced fecundity by TRB and FAD were differentiated by a time-course exposure study aided with the Japanese medaka HPG-PCR array [57]. Both TRB and FAD caused lesser mRNA expression of vitellogenin and choriogenin (CHG) in the liver of females.…”