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Asian Journal of Andrology 2011年第4期13卷 620-621页

作者： douglas t carrell Andrology and IVF Laboratories Departments of Surgery （Urology） Obstetrics and Gynecology and Physiology University of Utah School of Medicine Salt Lake City UT 84108 USA

Human sperm chromatin, and the sperm of most mammals, undergoes extensive remodeling during spermiogenesis during which 85%-95% of the histones are removed and replaced with protamines. the replacement of most histones with protamines facilitates a tighter packaging of the chromatin that is necessary for normal sperm function, and may help protect sperm DNA from damage during transport.

关键词： Epigenetic fertilization

Analysis of the methylation pattern of six gene promoters in sperm of men with abnormal protamination

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Asian Journal of Andrology 2011年第2期13卷 342-346页

作者： Laszlo Nanassy douglas t carrell Andrology and IVF Laboratories Department of Surgery University of Utah School of Medicine Salt Lake City UT 84108 USA Department of Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City UT 84208 USA Department of Physiology University of Utah School of Medicine Salt Lake City UT 84108 USA

It has recently been shown that alteration of the methylation pattern of imprinted genes is associated with different types of male infertility. the objective of our study was to investigate the methylation pattern of selected gene promoters in sperm of patients with abnormal protamine replacement. the promoters of OCt4, SOX2, NANOG, HOXC11, miR-17and CREMwere analyzed using bisulfite sequencing and the percentage of DNA methylation was compared between patients with an abnormal protamine l/protamine 2 （P1/ P2） ratio and normozoospermic controls. No significant quantitative differences were found between groups of patients with either an abnormally high or low P1/P2 ratio compared to normal controls. However, two individual samples from infertile subjects （2/20, 10%） showed an altered methylation pattern for the CREMgene promoter that was not found in control samples. these two samples had a significantly higher （P〈0.05） promoter methylation （5.58 and 4.23%, respectively） compared to the control group （0.46%）. In conclusion, in our pilot study, extreme methylations defects were not seen broadly in severely infertile men. However, two patients exhibited altered methylation of the CREMgene, which may be either causative or a result of abnormal protmaine replacement.

关键词： Epigenetic gene promoter male infertility methylation protamine

the paternal epigenome and embryogenesis： poising mechanisms for development

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Asian Journal of Andrology 2011年第1期13卷 76-80页

作者： timothy G Jenkins douglas t carrell Andrology and IVF Laboratories Department of Surgery University of Utah Salt Lake City UT 84108 USA Department of Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City UT 84108 USA Department of Physiology University of Utah School of Medicine Salt Lake City UT 84108 USA

the scope of paternal contributions during early embryonic development has long been considered limited. Dramatic changes in chromatin structure throughout spermatogenesis have been thought to leave the sperm void of complex layers of epigenetic regulation over the DNA blueprint, thus leaving the balance of that regulation to the oocyte. However, recent work in the fields of epigenetics and male factor infertility has placed this long-held, and now controversial dogma, in a new light. Elegant studies investigating chromatin and epigenetic modifications in the developing sperm cell have provided new insights that may establish a more critical role for the paternal epigenome in the developing embryo. DNA methylation, histone tail modifications, targeted histone retention and protamine incorporation into the chromatin have great influence in the developing sperm cell. Perturbations in the establishment and/or maintenance of any of these epigenetic marks have been demonstrated to affect fertility status, ranging in severity from mild to catastrophic. Sperm require this myriad of chromatin structural changes not only to serve a protective role to DNA throughout spermatogenesis and future delivery to the egg, but also, it appears, to contribute to the developmental program of the future embryo. this review will focus on our current understanding of the epigenetics of sperm. We will discuss sperm-specific chromatin modifications that result in genes essential to development being poised for activation early in embryonic development, the disruption of which may result in reduced fecundity.

关键词： chromatin DNA methylation embryogenesis epigenetics histone modification male infertility

Animal models of genetic causes of male infertility

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Asian Journal of Andrology 2002年第3期4卷 213-219页

作者： Greg L. Christensen douglas t. carrell Andrology Department University of Utah School of Medicine Salt Lake City Utah 84132 USAAndrology Department University of Utah School of Medicine Salt Lake City Utah 84132 USA

Introduction In the past 10 years, more than 100 different genetically engineered mice have been developed with an abnormality in spermatogenesis. More than half of these male infertility animal models have been reported in the past three years alone. Spermatogenic defects in these models vary considerably, ranging from the inappropriate migration of primordial germ cells to the inability of mature spermatozoa to bind the zona pellucida. Many of

关键词： animal models genes genetics knockout male infertility

A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome

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Asian Journal of Andrology 2017年第1期19卷 80-90页

作者： Luke Simon Armand Zini Alina Dyachenko Antonio Ciampi douglas t carrell Department of Surgery (Urology) University of Utah School of Medicine Salt Lake City UT USA Division of Urology Department of Surgery St. Mary's Hospital Center St. Mary's Hospital 3830 Lacombe Avenue Montreal Quebec H3T 1M5 Canada Department of Human Genetics University of Utah School of Medicine Salt Lake City UT USA Department of Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City UT USA.

Sperm DNA damage is prevalent among infertile men and is known to influence natural reproduction. However, the impact of sperm DNA damage on assisted reproduction outcomes remains controversial. Here, we conducted a meta-analysis of studies on sperm DNA damage （assessed by SCSA, tUNEL, SCD, or Comet assay） and clinical pregnancy after IVF and/or ICSI treatment from MEDLINE, EMBASE, and PUBMED database searches for this analysis. We identified 41 articles （with a total of 56 studies） including 16 IVF studies, 24 ICSI studies, and 16 mixed （IVF ＋ ICSI） studies. these studies measured DNA damage （by one of four assays： 23 SCSA, 18 tUNEL, 8 SCD, and 7 Comet） and included a total of 8068 treatment cycles （3734 IVF, 2282 ICSI, and 2052 mixed IVF ＋ ICSI）. the combined OR of 1.68 （95% Ch 1.49-1.89; P 〈 0.0001） indicates that sperm DNA damage affects clinical pregnancy following IVF and/or ICSI treatment. In addition, the combined OR estimates of IVF （16 estimates, OR = 1.65; 95% CI： 1.34-2.04; P 〈 0.0001）, ICSI （24 estimates, OR = 1.31; 95% Ch 1.08-1.59; P = 0.0068）, and mixed IVF ＋ ICSI studies （16 estimates, OR = 2.37; 95% Ch 1.89-2.97; P〈 0.0001） were also statistically significant. there is sufficient evidence in the existing literature suggesting that sperm DNA damage has a negative effect on clinical pregnancy following IVF and/or ICSI treatment.

关键词： assisted reproductive technology outcomes clinical pregnancy meta-analysis sperm DNA damage systematic review

Human protamines and the developing spermatid: their structure, function, expression and relationshipwith male infertility

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Asian Journal of Andrology 2003年第4期5卷 315-324页

作者： Vincent W. Aoki douglas t. carrell Andrology and IVF Laboratories University of Utah School of Medicine Salt Lake City UT 84108 USAAndrology and IVF Laboratories University of Utah School of Medicine Salt Lake City UT 84108 USA

During spermiogenesis, the protamine proteins play an integral role in spermatid chromatin compaction. Recent research has focused on many facets of protamine biology, including protamine gene and protein structure/ f... 详细信息

tract>During spermiogenesis, the protamine proteins play an integral role in spermatid chromatin compaction. Recent research has focused on many facets of protamine biology, including protamine gene and protein structure/ function relationships, mechanisms of protamine expression regulation and involvement of the protamines in male fertility. In this paper, we review our current understanding of the structure and function of the protamine-1 (P1) and protamine-2 (P2) proteins and genes, the expression and regulation of these genes and the relationship between the protamines and male fertility. In addition, we offer a brief outlook on future investigation into protamine proteins.

关键词： protamines spermatids male infertility spermatid transition proteins

the hamster egg penetration test may decrease intracytoplasmic sperm injection utilization while maintaining high conventional fertilization rates

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Asian Journal of Andrology 2021年第1期23卷 11-15页

作者： Yetunde Ibrahim Brett Einerson douglas t carrell Benjamin R Emery Erica Johnstone Division of Reproductive Endocrinology and Infertility Department of Obstetrics and GynecologyUniversity of UtahSchool of MedicineSalt Lake CityUT 84132USA Division of Maternal-Fetal Medicine Department of Obstetrics and GynecologyUniversity of UtahSchool of MedicineSalt Lake CityUT 84132USA Division of Urology Department of SurgeryUniversity of UtahSchool of MedicineSalt Lake CityUT 84132USA Department of Human Genetics University of UtahSchool of MedicineSalt Lake CityUT 84132USA

this was a cohort study of in vitro fertilization(IVF)subjects at the University of Utah,Salt Lake City(Ut,USA)utilizing partner sperm.Cycles where both the hamster egg penetration test(HEPt)and semen analysis were performed within 2 years prior to IVF cycles were stratified into four groups based on a normal or an abnormal HEPt and morphology.the mean conventional and intracytoplasmic sperm injection(ICSI)fertilization rates were calculated in each group.We performed a univariate analysis on the primary outcome comparing clinically interesting subjects.We performed a cost-effectiveness analysis of a policy of HEPt versus universal ICSI in couples with an abnormal morphology.Among patients with a normal HEPt,there was no difference in the mean conventional fertilization rates between those with a normal and an abnormal morphology.there was no difference in the mean conventional fertilization rates between subjects with a normal morphology without a hamster test and those with a normal HEPt without a morphology assessment.In 1000 simulated cycles with an abnormal morphology,a policy of HEPt was cost saving compared to universal ICSI,yet produced similar fertilization rates.the HEPt is similar to the World Health Organization edition 5(WHO-5)morphology in predicting successful conventional fertilization while allowing decreased utilization of ICSI.A policy of HEPt for males with abnormal morphology saves cost in selecting couples for a fertilization method.

关键词： conventional fertilization hamster egg penetration test intracytoplasmic sperm injection semen analysis sperm penetration assay

Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters

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Asian Journal of Andrology 2012年第6期14卷 855-859页

作者： Ahmad O Hammoud A Wayne Meikle C Matthew Peterson Joseph Stanford Mark Gibson douglas t carrell Division of Reproductive Endocrinology and Infertility University of Utah Salt Lake City UT 84108 USA Division of Endocrinology Metabolism and Diabetes Department of Internal Medicine University of Utah School of Medicine Salt Lake City UT 84108 USA ARUP Institute for Clinical and Experimental Pathology Salt Lake City UT 84108 USA Department of Preventive and Family Medicine University of Utah Salt Lake City UT 84108 USA Department of Surgery (Urology) and Physiology Andrology and IVF Laboratories University of Utah Salt Lake City UT 84108 USA

Vitamin D levels have been linked to various health outcomes including reproductive disorders. the purpose of this study was to explore the association between serum vitamin D level （25-hydroxy-vitamin D, or 250HD） and semen and hormonal parameters. this is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. the main measures were hormonal （total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone） and semen parameters, adjusted （n= 147） for age, body mass index （BMI）, season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined apriori. the mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m-2. the mean 250HD was 34.1± 15.06 ng m1-1. BMI showed a negative association with 250HD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with ‘250HD ≥ 50 ng ml-1＇ when compared to men with‘20 ng ml-1 ≤ 250H D〈 50 ng ml-1,. total sperm count and total progressive motile sperm count were lower in men with ‘250HD〈20 ng ml-1＇ when compared to men with‘20 ng ml-1≤250HD〈50 ng ml-1＇. the adjusted means of various hormonal parameters did not show statistical difference in the different categories of 250HD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.

关键词： low semen count obesity semen parameters vitamin D

Novel UBE2B-associated polymorphisms in an azoospermic / oligozoospermic population

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Asian Journal of Andrology 2008年第3期10卷 461-466页

作者： Ivan Huang Benjamin R. Emery Greg L. Christensen Jeanine Griffin C. Matthew Peterson douglas t. carrell Division of Reproductive Endocrinology University of Utah Health Sciences Salt LakeCity Utah 84106 USA Andrology and IVF Laboratories University of Utah Health Sciences Salt LakeCity Utah 84106 USA

Aim： to assess whether abnormalities exist in the UBE2B gene in a population of infertile human males, and to establish biologic plausibility of any discovered mutations. Methods： We carried out polymerase chain reaction （PCR） amplification and sequence analysis of the 5＇-untranslated region and six exons of the UBE2B gene, including flanking intronic regions, in a group of fertile and infertile men. Following the identification of a putative promoter region that contained single or dual triplet deletions within a 10-CGG repeat island, we evaluated the binding affinity of these identified polymorphisms as compared to the wild-type sequence to transcription factor SP1 using a DNA-protein gel shift assay. Results： there was a novel exonic single nucleotide polymorphism （SNP） noted in exon 4 in 5% of infertile men. In silico 3D modeling of the altered protein showed an innocuous isoleucine for valine substitution. there were no mutations noted within any of the other exons. three novel intronic SNPs were identified within the fertile group, and seven novel intronic SNPs identified in the infertile group. the DNA-protein gel shift assay noted that both single CGG deletion and double CGG deletion bands had approximately twice the binding affinity compared to the wild-type for SP1. the negative control confirmed no non-specific protein binding. Conclusion- By themselves, a single or double CGG deletion is unlikely to pose biologic significance. However, such deletions in this suspected promoter region are associated with increased binding affinity for SP1, and might represent one of several factors required for alteration of UBE2B gene expression.

关键词： UBE2B SP1 spermatogenesis male infertility single nucleotide polymorphism

Prospects for clinically relevant epigenetic tests in the andrology laboratory

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Asian Journal of Andrology 2014年第5期16卷 782-782页

作者： Kenneth I Aston douglas t carrell Department of Surgery University of Utah School of Medicine Salt Lake City Utah USA Department of Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City Utah USA Department of Human Genetics University of Utah School of Medicine Salt Lake City Utah USA

the review published by K1aver and Gromoll is a timely reminder of the ever-changing landscape of the clinical andrology laboratory as well as the limitations of current approaches to properly diagnose and treat male infertility. In a variety of disciplines, the clinical relevance of epigenetic status is becoming increasingly apparent. In this paper, the authors review the various studies that have evaluated the epigenetics （primarily DNA methylation） of sperm in the context of infertility, and they discuss the potential value of sperm epigenetic analysis in the workup of idiopathic male infertility.

关键词： Prospects clinically relevant