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Experimental Cryptorchidism Causes Chronic Inflammation and a Progressive Decline in Sertoli Cell and Leydig Cell Function in the Adult Rat Testis

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Abstract

Cryptorchidism causes spermatogenic failure and reduced serum androgen levels, as well as testicular oedema and fibrosis, which are hallmarks of inflammation. However, the role of inflammation and the effects of cryptorchidism on Sertoli cell and Leydig cell function at the molecular level remain ill-defined. Bilateral cryptorchidism was surgically induced in adult rats for 7 and 14 weeks. Testis weights decreased to 40% of normal within 7 weeks, due to loss of all developing spermatogenic cells except spermatogonia, but did not decrease further at 14 weeks. Serum FSH and LH were increased at both time points, consistent with a loss of feedback by inhibin and testosterone. This damage was accompanied by progressive accumulation of interstitial fluid and peritubular fibrosis, and a progressive decline of several critical Sertoli cell genes (Sox9, Inha (inhbin α-subunit), Cldn11 (claudin 11), Gja1 (connexin 43), and Il1a (interleukin-1α)) and the Leydig cell steroidogenic enzymes, Cyp11a1, Hsd3b1, and Hs17b3. Activin B and the activin-binding protein, follistatin, also declined, but the intratesticular concentration of activin A, which is a regulator of inflammatory responses, was largely unaffected at either time point. Expression of genes involved in inflammation (Tnf, Il10, Il1b, Mcp1) and fibrosis (Acta2, Col1a1) were considerably elevated at both time points. These data indicate that induction of experimental cryptorchidism, which causes complete failure of spermatogenesis in the adult rat, also induces chronic testicular inflammation, manifesting in oedema and fibrosis, and a progressive decline of Sertoli and Leydig cell gene expression and function.

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Acknowledgements

We thank Oxford Brookes University for kindly supplying the antibody reagents E4 and 46 A/F used in the activin A and B assays, Adnan Sali and Julie Muir for assistance in animal procedures, and Susan Hayward for her expert immunoassay skills and assistance. Furthermore, the authors thank the MHTP Medical Genomics Facility at Monash Medical Centre for assistance with the Fluidigm analysis.

Funding

This research was supported by funding provided by Imam Abdulrahman Bin Faisal University in Saudi Arabia, the National Health and Medical Research Council of Australia, and the Victorian State Government Operational Infrastructure Support Programme.

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Authors and Affiliations

  1. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia

    Rashid A. Aldahhan, Peter G. Stanton, David M. de Kretser & Mark P. Hedger

  2. Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia

    Rashid A. Aldahhan, Peter G. Stanton, David M. de Kretser & Mark P. Hedger

  3. Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, P.O. Box 2114, Dammam, 31541, Saudi Arabia

    Rashid A. Aldahhan

  4. Oxford Brookes University, Oxford, UK

    Helen Ludlow

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Contributions

Conceived and designed the experiments: DDK, MPH, RA

Performed the experiments: RA, MPH

Reagents/activin A and B assay techniques: HL

Analysed the data: RA, MPH

Critical discussion of data: RA, MPH, DDK, PGS

Wrote the manuscript: RA, MPH

Critical review of manuscript: all authors

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Correspondence to Rashid A. Aldahhan.

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Aldahhan, R.A., Stanton, P.G., Ludlow, H. et al. Experimental Cryptorchidism Causes Chronic Inflammation and a Progressive Decline in Sertoli Cell and Leydig Cell Function in the Adult Rat Testis. Reprod. Sci. 28, 2916–2928 (2021). https://doi.org/10.1007/s43032-021-00616-0

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