E-Poster Presentation ESA-SRB-ANZBMS 2021

Blockage of the classical and backdoor androgen production pathways indicates a third pathway in mice (#528)

Ben M. Lawrence 1 , Lee B. Smith 1 , Diane Rebourcet 1
  1. Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW, Australia

Androgens are essential for male sexual development, virilisation, spermatogenesis and general health and wellbeing. Androgen deficiency can lead to multiple pathologies including disorders of sexual development, infertility and increased risk of cardiovascular disease and diabetes. Active androgens mainly produced in the testis by Leydig cells include testosterone and the more potent dihydrotestosterone (DHT). Two androgen production pathways have been identified: the classical pathway using testosterone as a precursor to DHT, and the backdoor pathway bypassing the need for testosterone. Both pathways are essential for males, however, it is unknown how they function together, and the importance of each at androgen-responsive endpoints during sexual development and in later life.

Using a knockout (KO) mouse model involving HSD17B3 (classical pathway) and SRD5A1 (backdoor pathway), we are dissecting the roles and interactions between the classical and backdoor androgen pathways (Figure).

Following validation of the model (genotyping, transcript, and hormone levels), we have demonstrated that the double KO of HSD17B3 and SRD5A1 had normal development at birth and adulthood. Testis development at both ages appears normal compared to littermate controls. Epididymal coiling remained present in double KO mice and contained sperm in adulthood. Interestingly, double KO males remain fertile.

Unaltered sexual development and remaining fertile suggest the existence of a compensatory mechanism or a third, unknown, androgen production pathway in mice. We recently identified that HSD17B12 may be involved in this process [1]. Whilst human HSD17B12 is specific to estrogens, mouse HSD17B12 can convert androstenedione to testosterone.

Preliminary observations demonstrate that androgen production is not fully understood. Further investigation is required into deciphering the roles of each pathway in development, reproduction and androgen-related pathologies affecting male health.

611da394c5655-Figure+pathways.png

Figure. Schematic representation of the double knockout mouse model. HSD17B3 and SRD5A1 are critical for the classical and backdoor pathways, respectively. X = Knockout of the enzyme.

  1. Rebourcet, D., et al., Ablation of the canonical testosterone production pathway via knockout of the steroidogenic enzyme HSD17B3, reveals a novel mechanism of testicular testosterone production. Faseb j, 2020. 34(8): p. 10373-10386.