Protamine Levels Vary Between Individual Sperm Cells of Infertile Human Males and Correlate With Viability and DNA Integrity

Aoki, Vincent W.; Emery, Benjamin R.; Liu, Lihua; Carrell, Douglas T.

doi:10.2164/jandrol.106.000703

Cited by 208 publications

(128 citation statements)

References 27 publications

(50 reference statements)

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“…The indirect association between abnormal protamine expression and severely altered spermatogenesis may not be intuitively obvious, but animal studies have also shown that spermatogenesis is severely altered when protamine expression is experimentally reduced [Zhong et al 1999;Aoki et al 2005]. In contrast to human data, haploinsufficient mice show a homogenous population of severely affected sperm, while infertile male patients with protamine deregulation exhibit a truly heterogenous population of sperm [Cho et al 2001;Aoki et al 2005;Aoki et al 2006b;Zhang et al 2006]. This may be due to focal disruptions in the tubular structure of the testis or disruption of upstream regulators with an incomplete phenotypic penetrance.…”

Section: Discussionmentioning

confidence: 99%

Identification of Genetic Variation in the 5′ and 3′ Non-coding Regions of the Protamine Genes in Patients with Protamine Deregulation

Hammoud

Emery

Aoki

et al. 2007

Archives of Andrology

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Deregulation of sperm nuclear protamine ratio (P1=P2) has been shown to correlate with male factor infertility in humans, but the cause of this abnormal protein expression has yet to be identified. Recent studies have shown that there is little genetic variability in the coding regions of either of the protamine gene sequences. However, these studies did not investigate the 5 0 or 3 0 non-coding regions of these genes for mutations that might account for changes in the transcriptional or translational regulation of the protamines.In an effort to determine if genetic variation in these non-coding regions may account for aberrant protamine expression, we have sequenced the 5 0 and 3 0 untranslated regions (UTRs) of both protamine 1 (P1) and protamine 2 (P2) genes in a population of infertile men with protamine deregulation, men presenting for infertility work-up with normal protamine ratios, and a population of unrelated, fertile men from the Utah Genetic Reference Project (UGRP). This analysis has identified 14 single nucleotide polymorphisms (SNPs), of which 13 were novel SNPs in the UTRs of P1 and P2, and verified the existence of a variable length repeat (VLR), GA n , in the P2 5 0 region. The SNP frequencies and VLR allelic frequencies did not achieve statistical significance between the populations, however, one of the SNPs identified in the 3 0 UTR of protamine 2 was found at a low frequency in the abnormal protamine patients, but was completely absent in men with verified normal protamine ratio and donors of known fertility.In conclusion, a number of SNPs have been reported in the protamine genes and the untranslated regions, however, these gene variants do not appear to be responsible for protamine deficiency. Hence, the underlying cause for aberrant protamine expression may possibly be due to abnormalities in candidate spermatogenic transcriptional=translational regulators, post-translational modifiers, or as-of-yet unidentified factors affecting the testicular environment.

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Section: Discussionmentioning

confidence: 99%

Identification of Genetic Variation in the 5′ and 3′ Non-coding Regions of the Protamine Genes in Patients with Protamine Deregulation

Hammoud

Emery

Aoki

et al. 2007

Archives of Andrology

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“…Mutations in the PRM1 and PRM2 genes have been identified in infertile men [Aoki et al 2006b;Ravel et al 2007]. Lower expression of one or both genes is associated with severe male infertility and also DNA damage in spermatozoa as evidenced by acridine orange staining [Aoki et al 2006a;Cho et al 2003]. Defects in the regulation of expression of protamines have been observed in infertile men as premature expression or retention of mRNA leads to infertility [Aoki et al 2006b;Lee et al 1995].…”

Section: Protaminesmentioning

confidence: 99%

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

Leduc¹,

Nkoma²,

Boissonneault³

2008

Systems Biology in Reproductive Medicine

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This paper reviews the possible origin of sperm DNA fragmentation and focuses on the nuclear events associated with spermiogenesis as a potential source of genetic instability and reduced fertilizing potential of the mature male gamete. Recent findings suggest a programmed DNA fragmentation and DNA damage response during the chromatin remodeling steps in spermatids. We also discuss the spermatid DNA repair mechanisms and the possible involvement of condensing proteins, such as transition proteins and protamines, in the process, as this DNA fragmentation is normally not found in late spermatids. We propose that alterations in the chromatin remodeling steps or DNA repair in elongating spermatids may lead to persistent DNA breaks. This vulnerable step of spermiogenesis may provide a clue to the etiology of sperm DNA fragmentation associated with infertility in humans. This vulnerability is further emphasized given the haploid character of spermatids that must resolve programmed double-stranded breaks by an error-prone DNA repair mechanism. Therefore, spermiogenesis has probably been overlooked as an important source of genetic instability.

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“…gonadotoxins, hyperthermia, oxidants, endocrine abnormalities) [2][3][4][5][6][7][8][9][10]. Investigators have suggested that protamine deficiency (with aberrant chromatin remodeling), reactive oxygen species (ROS) and abortive apoptosis may cause sperm DNA damage [11][12][13][14][15][16][17][18]. De Iuliis et al, have proposed a two-step model to explain the origin of sperm DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Which isolated sperm abnormality is most related to sperm DNA damage in men presenting for infertility evaluation

Belloc¹,

Benkhalifa²,

Cohen-Bacrie³

et al. 2014

J Assist Reprod Genet

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Background Sperm DNA damage is common in infertile men and is associated with poor semen parameters but the impact of an isolated sperm abnormality on sperm DNA damage has not been studied. Objective To evaluate sperm DNA damage in a large cohort of infertile men with isolated sperm defects. Design, setting and participants Retrospective study of 1084 consecutive, non-azoospermic infertile men with an isolated sperm defect: isolated oligozoospermia (iOligo), isolated asthenozoospermia (iAstheno) or isolated teratozoospermia (iTerato). Outcome measurements and statistical analysis We examined and compared clinical parameters, conventional semen parameters and %sperm DNA fragmentation (%SDF, assessed by flow cytometry-based Terminal deoxynucleotidyl transferase-mediated dUTP Nick End-Labeling assay) in the three groups of men. Results and limitations The mean (±SD) %SDF was significantly higher in the iAstheno compared to the iOligo and iTerato groups (25.0±14.0 vs. 19.2±11.6 and 20.7±12.1 %, respectively, P<0.0001). Similarly, the proportion of men with high %SDF (>30 %) was significantly higher in the iAstheno compared to the iOligo and iTerato groups (31 % vs. 18 % and 19 %, respectively, P<0.0001). In the group of 713 men with iAstheno, %SDF was positively correlated with paternal age (r=0.20, P<0.0001) and inversely correlated with %progressive motility (r=−0.18, P<0.0001). In the subset of 218 men with iTerato, %SDF was also positively correlated with paternal age (r=0.15, P=0.018) and inversely correlated with %progressive motility (r=−0.26, P=0.0001). Conclusions In this large cohort of infertile men with isolated sperm abnormalities, we have found that the sperm DNA fragmentation level is highest in the men with sperm motility defects and that 31 % of these men have high levels of sperm DNA fragmentation. The data indicate that poor motility is the sperm parameter abnormality most closely related to sperm DNA damage.

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Protamine Levels Vary Between Individual Sperm Cells of Infertile Human Males and Correlate With Viability and DNA Integrity

Cited by 208 publications

References 27 publications

Identification of Genetic Variation in the 5′ and 3′ Non-coding Regions of the Protamine Genes in Patients with Protamine Deregulation

Identification of Genetic Variation in the 5′ and 3′ Non-coding Regions of the Protamine Genes in Patients with Protamine Deregulation

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

Which isolated sperm abnormality is most related to sperm DNA damage in men presenting for infertility evaluation

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