Abstract
Background
Androgens control rodent inguinoscrotal testicular descent during a “programming window” (E12–17). It is proposed that androgen masculinises the genitofemoral nerve, but the mechanism remains unknown. We investigate androgen receptor (AR)-containing target organs: inguinal fat pad (IFP) and mammary bud (MB), supplied by the genitofemoral nerve, hypothesizing that neurotrophic factors may retrogradely masculinise the GFN.
Methods
The IFP, MB and bulbocavernosus (BC) muscle were collected at E12.5/E17.5 from androgen receptor knockout (ARKO) mice and wild-type (WT) littermates. Immunofluorescence and gene expression (RT-qPCR; n = 8/group) for Bdnf, active (TrkB) and inactive (truncated TrkB) receptors, Cntf and Cntf receptor were performed.
Results
In the IFP at E12.5, ARKO TrkB mRNA expression was significantly downregulated compared to WT males (p < 0.0026). By E17.5, there was increased Bdnf expression (p < 0.0233). The MB had no differences at E12.5 and had regressed in WT males by E17.5. The BC had no differences at E12.5, but at E17.5 had significant upregulation of Bdnf expression in ARKO, compared to WT males. There were no differences in CNTF or CNTF receptor expression.
Conclusions
Androgen alters active TrkB and Bdnf expression in the IFP. IFP Bdnf signalling may regulate “masculinisation” of the GFN sensory nerves to indirectly control inguinoscrotal testicular descent.
Impact
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Androgen mediates neurotrophin release in the inguinal fat pad in mice, which may facilitate normal testicular descent by masculinising the GFN by peripheral uptake of neurotrophin.
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This is the first study to examine the role of neurotrophins in testicular descent.
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This suggests novel steps in the mechanical process of normal testicular descent that may be abnormal in some children with undescended testes.
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Acknowledgements
We would like to thank Dr. Amanda Vannitamby and Dr. Ruili Li from Surgical Research Laboratory for their assistance with animal breeding and processing; Desai from Andrology Laboratory, ANZAC Research Institute, Sydney, NSW, Australia for assistance in hormone analysis; Ms. Louise O’Connor and Dr. Trevelyan Menheniott from GRIP Laboratory, MCRI for advice on qPCR; and Shirley D’Cruz for assistance in preparation of the manuscript. The authors gratefully acknowledge the help of Mark Jimenez and Reena. This research was supported by NHMRC Grant 1049014 and the Victorian Government’s Operational Infrastructure Support Program. Financial support was provided by the Australian National Health and Medical Research Council (Grant Number APP1144752).
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All listed authors contributed substantially to conception and design of this study. J.V., G.S. and L.O. contributed to the acquisition of data and analysis of data. J.V., G.S. and J.M.H. contributed to the interpretation of data, drafting the initial article and subsequent revisions. All listed authors contributed to the revision of the article and critical appraisal of content, as well as approving the final version to be published.
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Vikraman, J., Sarila, G., O’Conner, L. et al. BDNF is upregulated by androgen in the inguinal fat pad of immature mice and may regulate inguinoscrotal testicular descent. Pediatr Res 91, 846–852 (2022). https://doi.org/10.1038/s41390-021-01458-x
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DOI: https://doi.org/10.1038/s41390-021-01458-x
