5 minute lightning oral presentation (and poster) ESA-SRB 2023 in conjunction with ENSA

Identifying alternative hydroxysteroid dehydrogenases capable of testosterone biosynthesis in Hsd17b3-deficient mice (#210)

Ben M Lawrence 1 , Liza O'Donnell 2 , Anne-Louise Gannon 1 , Imogen Abbott 1 , Diane Rebourcet 1 , Lee B Smith 1 2
  1. The University of Newcastle, Callaghan, NSW, Australia
  2. Griffith University, Southport, QLD, Australia

Testosterone regulates androgen-dependent functions including male sexual development and spermatogenesis. In the adult testis, Leydig cells synthesise testosterone via the canonical androgen biosynthesis pathway, where the HSD17B3 enzyme catalyses the conversion of the androgen precursor androstenedione into testosterone. Consequently, loss of function mutations in human HSD17B3 results in a disorder of sexual development. 46,XY HSD17B3-deficient individuals retain internal Wolffian structures however genitalia is undermasculinised, appearing as female or ambiguous.

Two independent research groups have generated Hsd17b3-deficient mice [1, 2]. Surprisingly, in contrast to human cases of HSD17B3-deficiency, male Hsd17b3 knockout mice are masculinised from birth and fertile in adulthood. Although Hsd17b3 knockout mice exhibit high androstenedione/testosterone ratios (indicative of HSD17B3 dysfunction), intratesticular testosterone is normal. This suggests the existence of alternative testosterone biosynthetic enzymes in mice. We aimed to identify hydroxysteroid dehydrogenase (HSD) enzymes that may be responsible for continued testosterone biosynthesis in Hsd17b3 knockout mice.

We have identified mouse HSD enzymes that can convert androstenedione into testosterone. We have demonstrated that a key amino acid in a particular HSD allows it to synthesise testosterone, in contrast to the human enzyme which has a different amino acid and is unable to produce testosterone. To model human androgen production in mice, we developed a transgenic mouse line expressing the HSD that is altered to express the human amino acid and is thus unable to produce testosterone. We are cross breeding this humanised HSD mouse line with Hsd17b3 knockout mice to identify whether the mutated HSD is unable to compensate for the lack of Hsd17b3. The validity of the mouse model has been established and the phenotype is currently being characterised. In conclusion, we are generating mouse models that can be used to better understand human disorders of androgen biosynthesis and can be exploited to identify novel therapies for androgen deficiency.

 

  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.
  2. Sipilä, P., et al., The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency. Faseb j, 2020. 34(5): p. 6111-6128.