Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Hadžiselimović, Faruk; Hadziselimovic, Nils; Demougin, Philippe; Oakeley, E. J.

doi:10.1159/000323955

Cited by 57 publications

(56 citation statements)

References 129 publications

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“…In addition, there were fundamental differences between the human and model organisms. Although these models contain mutations in INSL3 and its Leu-rich repeat-containing G protein-coupled receptor 8 (LGR8), homeobox A10 (HOXA10), ZNF214, and ZNF215 that have also been discovered in human tissue samples [13][14][15], the effects of these mutations on testis development and fertility need to be investigated in a human research model.…”

Section: Discussionmentioning

confidence: 99%

Generation and Characterization of Human Cryptorchid-Specific Induced Pluripotent Stem Cells from Urine

Zhou

Wang

Zhang

et al. 2013

Stem Cells and Development

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Cryptorchidism is a common congenital birth defect in human beings with the possible complication of infertility. An in vitro model of cryptorchidism might be valuable due to the inaccessibility of human embryos for research purposes. In this study, we reprogrammed urine cells containing genetic variations in insulin-like factor 3, zinc finger (ZNF) 214, and ZNF215 from a cryptorchid patient by introducing human OCT4, SOX2, C-MYC, and KLF4 with lentivirus. The cells were then replated on irradiated mouse embryonic fibroblasts and cultured with the human embryonic stem (ES) cell medium. The compact colonies with well-defined borders were manually picked, and 2 induced pluripotent cell lines were fully characterized. Our results demonstrated that these 2 cell lines were similar to human ES cells in morphological appearance, marker expression, and epigenetic status of the pluripotent cell-specific gene, OCT4. These cells could be differentiated into cells of all 3 germ layers in teratomas and in vitro, including into the VASA-positive germ cell lineage. Both parental urine cells and the reprogrammed cells possessed the normal karyotype and the same short tandem repeat loci, indicating that these 2 cell population share the same genetic identity. This establishment and characterization of human urinederived cryptorchid-specific induced pluripotent stem cells could present a good human genetic system for future studies investigating the molecular mechanism of cryptorchidism.

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Section: Discussionmentioning

confidence: 99%

Generation and Characterization of Human Cryptorchid-Specific Induced Pluripotent Stem Cells from Urine

Zhou

Wang

Zhang

et al. 2013

Stem Cells and Development

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“…Thus, cryptorchidism is one of the main etiologic causes of non-obstructive azoospermia in man [16.] Interestingly enough, in unilateral cryptorchid males, no significant differences in the frequency of azoospermia were observed irrespective of the treatment modalities used (untreated, 12% (16/134); human chorionic gonadotropin (HCG) treated, 12.6% (25/198); surgically treated, 10.3% (198/1,773) [17]. Moreover, more than one third of males in the high-infertility risk group will develop azoospermia (8/21) (10), (20/61) [18] while none (0/50) (p < 0.000001) of the males with identical testicular pathology at surgery who received treatment with luteinizing hormone (LH)-RHa following orchidopexy developed azoospermia.…”

Section: Hormonal Treatment For Descent and Fertilitymentioning

confidence: 99%

Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

Hadžiselimović¹

2016

Urol Int

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The ultimate goal in the treatment of cryptorchidism is to achieve normal fertility. However, in a substantial number of cryptorchid males, early and apparently successful orchidopexy does not improve fertility as it does not address the underlying pathophysiological cause, namely, the impaired transformation of gonocytes into Ad spermatogonia. It is important to realize that over half the patients presenting with unilateral cryptorchidism and the majority of those presenting with bilateral cryptorchidism have abnormal spermiogram which indicates that unilateral cryptorchidism is in fact a bilateral disease and therefore a serious andrological problem. More importantly, only testicular biopsy can nowadays determine which patient should benefit from hormonal therapy. This means that the rationale behind testicular biopsy is both diagnostic and therapeutic, particularly since LH-RHa hormonal therapy is a worthwhile solution to this andrological problem. In boys with a high risk of azoospermia development, adequate treatment with low doses of LH-RHa allowed 86% of subjects to achieve a normal sperm count. This strongly contrasts with the results of the ‘surgery-only' group where not a single patient had a normal spermiogram and 20% suffered from azoospermia. Testicular biopsy is all the more justified that it allowed the detection of in situ carcinoma in 0.6% of all the cryptorchid boys studied. Even if hormonal pre-treatment only achieves successful epididymo-testicular descent in 20% of cases, this treatment should remain the first therapeutic choice because it may avoid resorting to surgery. In addition, it has no adverse effect on fertility and, in unsuccessful cases, facilitates orchidopexy and considerably helps reduce the incidence of post-surgical testicular atrophy, whether unilateral or, and this is a much more serious event, bilateral.

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“…infertility induced by cryptorchidism are predominantly an endocrine disease of impaired mini-puberty rather than being due to a mutation of CDC20, DAZ and DAZL, SCP3, or RBMY genes [Hadziselimovic et al, 2011]. Vast territories of animal genomes are populated by numerous types of transposons (mobile genetic elements) that act predominantly as parasites, without being influenced by the impact on the host [Aravin and Hannon, 2008;Cordaux and Batzer, 2009].…”

mentioning

confidence: 99%

Deficient Expression of Genes Involved in the Endogenous Defense System against Transposons in Cryptorchid Boys with Impaired Mini-Puberty

Hadžiselimović¹,

Hadziselimovic²,

Demougin

et al. 2011

Sex Dev

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Mini-puberty is the period between 30 and 80 days after birth when testosterone and gonadotropin surges occur in male infants to induce the transformation of gonocytes into adult/dark spermatogonia. Cryptorchid boys with impaired mini-puberty develop infertility despite timely and successful surgical treatment. The decreased germ cell count found in this group of boys could be the result of uncontrolled transposon activity inducing genomic instability and germ cell death. A genome-wide analysis of 18 cryptorchid and 4 control testes was performed with Affymetrix chips. We found that 5 of 8 genes that are important for transposon silencing were not expressed in the high azoospermia risk group of cryptorchid boys but were expressed in the low azoospermia risk and control groups. Two genes, CBX3 and DNMT1, were equally expressed in all 3 groups. Impaired expression of the DDX4, MAEL,MOV10L1, PIWIL2, PIWIL4, and TDRD9 genes in the group of cryptorchid boys at high risk of infertility indicates that gene instability induced by impaired expression of transposon silencing genes contribute to the development of azoospermia. Intact mini-puberty appears to be essential for the development of the endogenous defense system mediated by transposon silencing.

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Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Cited by 57 publications

References 129 publications

Generation and Characterization of Human Cryptorchid-Specific Induced Pluripotent Stem Cells from Urine

Generation and Characterization of Human Cryptorchid-Specific Induced Pluripotent Stem Cells from Urine

Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

Deficient Expression of Genes Involved in the Endogenous Defense System against Transposons in Cryptorchid Boys with Impaired Mini-Puberty

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