Proper reprogramming of parental DNA methylomes is essential for mammalian embryonic development. However, it is unknown whether abnormal methylome reprogramming occurs and is associated with the failure of embryonic ...Proper reprogramming of parental DNA methylomes is essential for mammalian embryonic development. However, it is unknown whether abnormal methylome reprogramming occurs and is associated with the failure of embryonic development. Here we analyzed the DNA methylomes of 57 blastocysts and 29 trophectoderm samples with different morphological grades during assisted reproductive technology （ART） practices. Our data reveal that the global methylation levels of high-quality blastocysts are similar （0.30 ± 0.02, mean ± SD）, while the methylation levels of low-quality blastocysts are divergent and away from those of high-quality blastocysts. The proportion of blastocysts with a methylation level falling within the range of 0.30± 0.02 in different grades correlates with the live birth rate for that grade. Moreover, abnormal methylated regions are associated with the failure of embryonic development. Furthermore, we can use the methylation data of cells biopsied from trophectoderm to predict the blastocyst methylation level as well as to detect the aneuploidy of the blastocysts. Our data indicate that global abnormal methylome reprogramming often occurs in human embryos, and suggest that DNA methylome is a potential biomarker in blastocyst selection in ART.展开更多
Testosterone(T)plays a crucial role in spermatogenesis because extremely low levels of intratesticular T lead to correspondingly low serum levels of total T(tT),severe disorders of spermatogenesis,and male sterility.H...Testosterone(T)plays a crucial role in spermatogenesis because extremely low levels of intratesticular T lead to correspondingly low serum levels of total T(tT),severe disorders of spermatogenesis,and male sterility.However,there is little consensus on the lower limits of serum tT in proven fertile men undergoing assisted reproductive technology treatments in Chinese or other Asian populations.We aimed to establish the reference range of serum tT based on a population of 868 fertile Chinese men undergoing in vitro fertilization or intracytoplasmic sperm injection and embryo transfer(IVF/ICSI-ET)treatments.We defined a fertile man as having had a live baby with his partner as recorded in our IVF registration system.The lower limits of serum tT were established using a Siemens IMMULITE 2000 chemiluminescent system.The 1st,2.5th,and 5th percentiles and their 95%confidence intervals(CIs)were 3.6(95%CI:2.7–4.1)nmol l−1,4.3(95%CI:4.1–5.0)nmol l−1,and 5.6(95%CI:4.8–5.8)nmol l−1,respectively.Using the linear correlation of serum tT between the Siemens platform and a liquid chromatography–tandem mass spectrometry platform,the calculated lower limits of serum tT were also established for fertile Chinese men undergoing IVF/ICSI-ET treatments,which will benefit the clinical diagnosis and treatment of male infertility during such procedures.展开更多
Anti-Mullerian hormone(AMH)is a functional marker of fetal Sertoli cells.The germ cell number in adults depends on the number of Sertoli cells produced duri ng peri natal development.Rece ntly,AMH has received increas...Anti-Mullerian hormone(AMH)is a functional marker of fetal Sertoli cells.The germ cell number in adults depends on the number of Sertoli cells produced duri ng peri natal development.Rece ntly,AMH has received increasi ng attenti on in research of disorders related to male fertility.This paper reviews and summarizes the articles on the regulation of AMH in males and the serum levels of AMH in male fertility-related disorders.We have determined that follicle-stimulating hormone(FSH)promotes AMH transcription in the absenee of androgen signaling.Testosterone inhibits the transcriptional activation of AMH.The undetectable levels of serum AMH and testosterone levels indicate a lack of functional testicular tissue,for example,that in patients with anorchia or severe Klinefelter syndrome suffering from impaired spermatogenesis.The normal serum testosterone level and undetectable AMH are highly suggestive of persistent Mullerian duct syndrome(PMDS),combined with clinical manifestations.The levels of both AMH and testosterone are always subnormal in patients with mixed disorders of sex development(DSD).Mixed DSD is an early-onset complete type of disorder with fetal hypogonadism resulting from the dysfunction of both Leydig and Sertoli cells.Serum AMH levels are varying in patients with male fertility-related disorders,in cludi ng pubertal delay,severe con genital hypog on adotropic hypogonadism,nonobstructive azoospermia,Klinefelter syndrome,varicocele,McCune-Albright syndrome,and male senescence.展开更多
Conventional PCR methods combined with linkage analysis based on short tandem repeats （STRs） or Karyomapping with single nucleotide polymorphism （SNP） arrays, have been applied to preimplantation genetic diagnosis...Conventional PCR methods combined with linkage analysis based on short tandem repeats （STRs） or Karyomapping with single nucleotide polymorphism （SNP） arrays, have been applied to preimplantation genetic diagnosis （PGD） for spinal muscular atrophy （SMA）, an autosome recessive disorder. However, it has limitations in SMA diagnosis by Karyomapping, and these methods are unable to distinguish wild- type embryos with carriers effectively. Mutated allele revealed by sequencing with aneuploidy and linkage analyses （MARSALA） is a new method allowing embryo selection by a one-step next-generation sequencing （NGS） procedure, which has been applied in PGD for both autosome dominant and X-linked diseases in our group previously. In this study, we carried out PGD based on MARSALA for two carrier families with SMA affected children. As a result, one of the couples has given birth to a healthy baby free of mutations in SMA-causing gene. It is the first time that MARSALA was applied to PGD for SMA, and we can distinguish the embryos with heterozygous deletion （carriers） from the wild-type （normal） ones accurately through this NGS-based method. In addition, direct mutation detection allows us to identify the affected embryos （homozygous deletion）, which can be regarded as probands for linkage analysis, in case that the affected family member is absent, In the future, the NGS-based MARSALA method is expected to be used in PGD for all monogenetic disorders with known pathogenic gene mutation.展开更多
Vasoepididymostomy （VE）, as the most challenging procedure in microsurgeries, is often carried out with a double-armed two-suture technique. In this study, we evaluated the efficacy and safety of the single-armed tw...Vasoepididymostomy （VE）, as the most challenging procedure in microsurgeries, is often carried out with a double-armed two-suture technique. In this study, we evaluated the efficacy and safety of the single-armed two-suture VEs on humans and studied the factors that could possibly affect the patency rates. From July 2012 to July 2013, we reviewed 81 patients with consecutive primary epididymal obstruction who underwent single-armed two-suture longitudinal intussusception microsurgical VEs by a single surgeon, Kai Hong （KH）. At the same time, we analyzed seven factors that possibly related to the patency rates. With the single-armed technique, a total of 81 men underwent the microsurgical VEs. Data on 62 patients were completely recorded. 19 patients were lost to follow-up. Mean age was 31 years old. Mean follow-up time was 8.8 （2-17） months. The patency rate was 66.1% （41/62）. Natural pregnancy rate was 34.1% （14/41）. Overall pregnancy rate was 22.6% （14/62）. No severe surgical complications were noted. With logistic regression test analysis, there were two factors related to a higher patency rate： anastomosis sites （P = 0.035） and motile sperm found in the epididymal fluid （P = 0.006）. Motile sperm found in the epididymal fluid were associated with a higher patency rate （OR = 11.80, 95% CI = 1.79, 77.65）. The single-armed two-suture longitudinal VE technique is feasible for microsurgical practice. The patency and pregnancy rates are comparable to the doubled-armed technique. Anastomosis sites and motile sperm found in the epididymal fluid were the most two important factors related to higher patency.展开更多
Marfan syndrome (MFS)(OMIM 154700) is a relatively common autosomal dominant genetic disease that causes skeletal, ocular, and cardiovascular defects and was first described by a French pediatrician in 1896 (Bitterman...Marfan syndrome (MFS)(OMIM 154700) is a relatively common autosomal dominant genetic disease that causes skeletal, ocular, and cardiovascular defects and was first described by a French pediatrician in 1896 (Bitterman and Sponseller, 2017). Its prevalence rate is 1/3000—1/5000, and more than 25% of cases are sporadic (Chiu et al., 2014). Studies have shown that about 90% of MFS is caused by variants in the fibrillin-1 gene (FBN1, OMIM 134797). FBN1, located on chromosome 15q21.1, encodes a macromolecular glycoprotein-fibrin 1, which aggregates to form microfibers in the extracellular matrix and distributes in various human connective tissues, such as periosteum, vessel wall, and crystal suspensor ligament. Variants in FNB1 have been reported in 65 exons, but the relationship between genotype and phenotype remains rather unclear (Sakai et al., 2016). Studies have also shown that patients with MFS and similar diseases may have variants in other related genes such as members of the transforming growth factor beta receptor (TGFBR) family (Mizuguchi et al., 2004;Sakai et al., 2006;Bolar et al., 2012;De Cario et al., 2018). For better prevention and treatment of MFS as well as for suspected MFS patients, there is a strong need for efficient genetic testing for early diagnosis and differential diagnoses of patients with related phenotypes (Aubart et al., 2018).展开更多
The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Who...The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.展开更多
Abstract： With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture （EA） and transcutan...Abstract： With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture （EA） and transcutaneous electrical acupoint stimulation （TEAS）, become more popular world-wide. Increasing evidence has demonstrated that EA and TEAS are effective in treating gynecological disorders, especially infertility. This present paper describes how to select acupoints for the treatment of infertility from the view of theories of traditional Chinese medicine and how to determine critical parameters of electric pulses of ENTEAS based on results from animal and clinical studies. It summarizes the principles of clinical application of EA/rEAS in treating various kinds of reproductive disorders, such as polycystic ovary syndrome （PCOS）, pain induced by oocyte retrieval, diminished ovarian reserve, embryo transfer, and oligosperrnia/ asthenospermia. The possible underlying mechanisms mediating the therapeutic effects of EA/TEAS in reproductive medicine are also examined.展开更多
Objective The study is to identify the carrier rate of common deafness mutation in Chinese pregnant women via detecting deafness gene mutations with gene chip. Methods The pregnant women in obstetric clinic without he...Objective The study is to identify the carrier rate of common deafness mutation in Chinese pregnant women via detecting deafness gene mutations with gene chip. Methods The pregnant women in obstetric clinic without hearing impairment and hearing disorders family history were selected. The informed consent was signed. Peripheral blood was taken to extract genom- ic DNA. Application of genetic deafness gene chip for detecting 9 mutational hot spot of the most common 4 Chinese deafness genes, namely GJB2 （35delG, 176del16bp, 235delC, 299delAT）, GJB3 （C538T） ,SLC26A4 （ IVS72A〉G, A2168G） and mito- chondrial DNA 12S rRNA （A1555G, C1494T） . Further genetic testing were provided to the spouses and newborns of the screened carriers. Results Peripheral blood of 430 pregnant women were detected, detection of deafness gene mutation carri- ers in 24 cases（4.2%）, including 13 cases of the GJB2 heterozygous mutation, 3 cases of SLC26A4 heterozygous mutation, 1 cases of GJB3 heterozygous mutation, and 1 case of mitochondrial 12S rRNA mutation. 18 spouses and 17 newborns took further genetic tests, and 6 newborns inherited the mutation from their mother. Conclusion The common deafness genes muta- tion has a high carrier rate in pregnant women group, 235delC and IVS7-2A〉G heterozygous mutations are common.展开更多
Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presenc...Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presence of NOA in some patients,a proportion of NOA patients remain to be addressed.This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing.Whole-exome sequencing was performed in 46 male patients diagnosed with NOA.First,screening was performed for 119 genes known to be related to male infertility.Next,further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls.Finally,risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed.The frequency of cystic fibrosis transmembrane conductance regulator(CFTR)gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls.Potential risk genes that may be causes of NOA were identified,including seven genes that were highly/specifically expressed in the testes.Four risk genes previously reported to be involved in spermatogenesis(MutS homolog 5[MSH5],cilia-and flagella-associated protein 54[CFAP54],MAP7 domain containing 3[MAP7D3],and coiled-coil domain containing 33[CCDC33])and three novel risk genes(coiled-coil domain containing 168[CCDC168],chromosome 16 open reading frame 96[C16orf96],and serine protease 48[PRSS48])were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls.This study on clinical NOA patients provides further evidence for the four previously reported risk genes.The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.展开更多
Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into sper...Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into spermatids in mammalian testis. SSCs are previously regarded as the unipotent stem cells since they can only give rise to sperm within the seminiferous tubules. However, this concept has recently been challenged because numerous studies have demonstrated that SSCs cultured with growth factors can acquire pluripotency to become embryonic stem-like cells. The in vivo and in vitro studies from peers and us have clearly revealed that SSCs can directly transdifferentiate into morphologic, phenotypic, and functional cells of other lineages. Direct conversion to the cells of other tissues has important significance for regenerative medicine. SSCs from azoospermia patients could be induced to differentiate into spermatids with fertilization and developmental potentials. As such, SSCs could have significant applications in both reproductive and regenerative medicine due to their unique and great potentials. In this review, we address the important plasticity of SSCs, with focuses on their self-renewal, differentiation, dedifferentiation, transdifferentiation, and translational medicine studies.展开更多
Objective To compare the roles of fluorescence in situ hybridization （FISH） and karyotype analysis on chorionic villus in spontaneous abortion. Methods A total of 201 cases were included in this study and were rando...Objective To compare the roles of fluorescence in situ hybridization （FISH） and karyotype analysis on chorionic villus in spontaneous abortion. Methods A total of 201 cases were included in this study and were randomly divided into 2 groups by the same gestational age. The villi from 100 cases （group A） were cultured and used for karyotype analysis, while the uncultured villi from 101 women （group B） were used for FISH. A case was randomly selected from pregnant patients of 6-11 weeks at each gestational week in each group, 6 cases from each group and a total of 12 cases were analyzed by FISH and karyotype at the same time. Results The successful karyotype analysis rate was 66. 0%, and the abnormality karyotype rate was 30.3%; FISH success analysis rate was 100%, and the abnormality rate was 46. 5%; there were significant differences between FISH and karyotype analysis （P=0.036）. Conclusion There were obvious differences between the two techniques. FISH was more successfully analyzed, and was used to more precisely determine fetal chromo- some number. It is an effective way to determine abnormal chromosome by integrating FISH and karyotype analysis in spontaneous abortion.展开更多
Objective The study aimed to investigate the impact of rare earth elements(REEs)exposure on pregnancy outcomes of in vitro fertilization-embryo transfer(IVF-ET)by analyzing samples from spouses.Methods A total of 141 ...Objective The study aimed to investigate the impact of rare earth elements(REEs)exposure on pregnancy outcomes of in vitro fertilization-embryo transfer(IVF-ET)by analyzing samples from spouses.Methods A total of 141 couples were included.Blood and follicular fluid from the wives and semen plasma from the husbands,were analyzed for REEs using inductively coupled plasma mass spectrometry(ICP-MS).Spearman's correlation coefficients and the Mann–Whitney U test were used to assess correlations and compare REE concentrations among three types of samples,respectively.Logistic models were utilized to estimate the individual REE effect on IVF-ET outcomes,while BKMR and WQS models explored the mixture of REE interaction effects on IVF-ET outcomes.Results Higher La concentration in semen(median 0.089 ng/mL,P=0.03)was associated with a lower fertilization rate.However,this effect was not observed after artificial selection intervention through intracytoplasmic sperm injection(ICSI)(P=0.27).In semen,the REEs mixture did not exhibit any significant association with clinical pregnancy.Conclusion Our study revealed a potential association between high La exposure in semen and a decline in fertilization rate,but not clinical pregnancy rate.This is the first to report REEs concentrations in follicular fluid with La,Ce,Pr,and Nd found at significantly lower concentrations than in serum,suggesting that these four REEs may not accumulate in the female reproductive system.However,at the current exposure levels,mixed REEs exposure did not exhibit reproductive toxicity.展开更多
Objective To determine if ARHGEF10 has a haploinsufficient effect and provide evidence to evaluate the severity,if any,during prenatal consultation.Methods Zebrafish was used as a model for generating mutant.The patte...Objective To determine if ARHGEF10 has a haploinsufficient effect and provide evidence to evaluate the severity,if any,during prenatal consultation.Methods Zebrafish was used as a model for generating mutant.The pattern of arhgef10 expression in the early stages of zebrafish development was observed using whole-mount in situ hybridization(WISH).CRISPR/Cas9 was applied to generate a zebrafish model with a single-copy or homozygous arhgef10 deletion.Activity and light/dark tests were performed in arhgef10^(−/−),arhgef10^(+/−),and wild-type zebrafish larvae.ARHGEF10 was knocked down using small interferon RNA(siRNA)in the SH-SY5Y cell line,and cell proliferation and apoptosis were determined using the CCK-8 assay and Annexin V/PI staining,respectively.Results WISH showed that during zebrafish embryonic development arhgef10 was expressed in the midbrain and hindbrain at 36-72 h post-fertilization(hpf)and in the hemopoietic system at 36-48 hpf.The zebrafish larvae with single-copy and homozygous arhgef10 deletions had lower exercise capacity and poorer responses to environmental changes compared to wild-type zebrafish larvae.Moreover,arhgef10^(−/−) zebrafish had more severe symptoms than arhgef10^(+/-) zebrafish.Knockdown of ARHGEF10 in human neuroblastoma cells led to decreased cell proliferation and increased cell apoptosis.Conclusion Based on our findings,ARHGEF10 appeared to have a haploinsufficiency effect.展开更多
This study aimed to investigate the associations between the post-wash total progressively motile sperm count(TPMSC)in the first intrauterine insemination(IUI)cycle and pregnancy outcomes of the second IUI cycle.Data ...This study aimed to investigate the associations between the post-wash total progressively motile sperm count(TPMSC)in the first intrauterine insemination(IUI)cycle and pregnancy outcomes of the second IUI cycle.Data were retrieved from the clinical database at the Reproductive Center of Peking University Third Hospital(Beijing,China)between January 2011 and December 2022.Couples were included in this retrospective cohort study if they had unexplained or mild male factor infertility and were treated with IUI for two consecutive cycles using the same protocol.A total of 8290 couples were included in the analysis.The mean±standard deviation(s.d.)age of women was 32.0±3.5 years.We categorized groups based on the post-wash TPMSC(×10^(6))levels in the first IUI cycle:group 1(0<TPMSC<1,n=1290),group 2(1≤TPMSC<2,n=863),group 3(2≤TPMSC<3,n=800),group 4(3≤TPMSC<4,n=783),group 5(4≤TPMSC<5,n=1541),group 6(5≤TPMSC<6,n=522),group 7(6≤TPMSC<7,n=547),group 8(7≤TPMSC<8,n=175),group 9(8≤TPMSC<9,n=556),group 10(9≤TPMSC<10,n=192),and group 11(TPMSC≥10,n=1021).The primary outcome was live birth rate of the second IUI cycle.Live birth rates were 7.9%,5.8%,7.6%,7.4%,7.3%,8.4%,7.5%,7.4%,8.8%,8.9%,and 7.6%in each group,respectively.There were no statistically significant differences in clinical pregnancy rates or live birth rates between any groups and those with the post-wash TPMSC<1×10^(6).In an IUI program for unexplained and mild male factor infertility,the post-wash TPMSC in the first IUI cycle was not significantly associated with the live birth rate in the second IUI cycle.展开更多
Reciprocal translocation is a chromosomal structural abnormal- ity that arises when two non-homologous chromosomes rearrange and attach with each other, an incidence that occurs in about 1/500 to 1/625 newborns （Mack...Reciprocal translocation is a chromosomal structural abnormal- ity that arises when two non-homologous chromosomes rearrange and attach with each other, an incidence that occurs in about 1/500 to 1/625 newborns （Mackie and Scriven, 2002）. This event typically does not lead to any significant loss of genetic material, thus recip- rocal translocation carriers do not exhibit any severe abnormal phenotypes （Scriven et al., 1998; Zhang et al., 2016）.展开更多
In the present study, we evaluated the impact of sperm origins and concentration on the clinical outcomes of intracytoplasmic sperm injection （ICSI） cycles. A total of 1201 IC51 cycles were retrospectively analyzed ...In the present study, we evaluated the impact of sperm origins and concentration on the clinical outcomes of intracytoplasmic sperm injection （ICSI） cycles. A total of 1201 IC51 cycles were retrospectively analyzed for male azoospermia or oligozoospermia between January 2015 and December 2015 in the Peking University Third Hospital. Patients were divided into three groups （Group 1 vs Group 2/3; surgically extracted sperm vs ejaculated sperms）： Group 1 included 343 ICSI cycles and Group 2 analyzed 388 cycles on semen with sperm concentration 〈5 × 10^6 m1-1 （severe oligozoospermia group）. Group 3 included 470 cycles with sperm concentration between 5×10^6 m1-1 and 15 × 10^6 m1-1 （mild oligozoospermia group）. Fertilization rates, clinical pregnancy rates, and live birth rates were analyzed and compared among groups of different semen origins and concentrations on the oocyte retrieval day. Group 2 showed a lower fertilization rate than Group 3 （62.9%± 21.6% vs 66.8% ± 22.1%, P 〈 0.05）. There were no statistically significant differences in clinical pregnancy rate per transfer （51.3%, 46.7%, and 50.0%, respectively）, live birth rate per transfer （44.4%, 40.9%, and 41.4%, respectively）, accumulative live birth rate （58.3%, 51.0%, and 52.1%, respectively）, twin birth rate （18.4%, 10.6%, and 12.6%, respectively）, and birth defects rate （0, 0.3%, and 0.2%, respectively） among three groups. The results of this study indicated that sperm origins and concentration do not imDact the clinical outcomes in ICSI cycles.展开更多
Congenital contractural arachnodactyly(CCA,OMIM:121050),also known as Beals syndrome,belongs to a group of rare autosomal dominant(AD)diseases of connective tissue(Maslen et al.,1997).People with CCA share many distin...Congenital contractural arachnodactyly(CCA,OMIM:121050),also known as Beals syndrome,belongs to a group of rare autosomal dominant(AD)diseases of connective tissue(Maslen et al.,1997).People with CCA share many distinguishing features,such as arachnodactyly,camp tod actyly,multiple joint contractures(especially finger,elbow,and knee joints),crumpled ears,scoliosis,pectus deformities,and muscular hypoplasia(Jurko et al.,2013).It exhibits no specific geographic or ethnic predilection(Frederic et al.,2009).展开更多
The worldwide infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)impacts human health and life on multiple levels.People infected with SARS-CoV-2 suffer from physical disorders and psychological d...The worldwide infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)impacts human health and life on multiple levels.People infected with SARS-CoV-2 suffer from physical disorders and psychological distress.At present,no direct evidence indicates that SARS-CoV-2 negatively influences human reproduction,and the possibility that gametes and embryos are affected requires further investigation.To evaluate the potential effects of SARS-CoV-2 infection on human reproduction and fetal health,this review summarizes the basic and clinical research of SARS-CoV-2 on reproduction up to date,hoping to offer guidance and advice to people at reproductive age and provide dues for the prevention and treatment of associated diseases.展开更多
基金supported by grants from the CAS Strategic Priority Research Program (XDB13040000)the National Program on Key Basic Research Project (2014CB943203,2015CB856200,2011CB510101 and 2011CB944504)+2 种基金the National Natural Science Foundation of China(Nos.91219104,31425015,31200958,31371521,31230047 and 81370766)the Beijing Nova Program (xxjh2015011)the Zhujiang Science and Technology Star Project of Guangzhou(2012J2200006)
文摘Proper reprogramming of parental DNA methylomes is essential for mammalian embryonic development. However, it is unknown whether abnormal methylome reprogramming occurs and is associated with the failure of embryonic development. Here we analyzed the DNA methylomes of 57 blastocysts and 29 trophectoderm samples with different morphological grades during assisted reproductive technology （ART） practices. Our data reveal that the global methylation levels of high-quality blastocysts are similar （0.30 ± 0.02, mean ± SD）, while the methylation levels of low-quality blastocysts are divergent and away from those of high-quality blastocysts. The proportion of blastocysts with a methylation level falling within the range of 0.30± 0.02 in different grades correlates with the live birth rate for that grade. Moreover, abnormal methylated regions are associated with the failure of embryonic development. Furthermore, we can use the methylation data of cells biopsied from trophectoderm to predict the blastocyst methylation level as well as to detect the aneuploidy of the blastocysts. Our data indicate that global abnormal methylome reprogramming often occurs in human embryos, and suggest that DNA methylome is a potential biomarker in blastocyst selection in ART.
基金the National Key Research and Development Program of China(No.2016YFC1000201,No.2018YFC1002104,No.2018YFC1002106,and No.2016YFC1000302)the National Natural Science Foundation of China(No.81300373,and No.81771650)+2 种基金the Capital Health Research and Development of Special Projects(No.2018-1-4091)the Program for Innovative Research Team of Yunnan,China(No.2017HC009)the Major National R&D Projects of China(No.2017ZX09304012-012).
文摘Testosterone(T)plays a crucial role in spermatogenesis because extremely low levels of intratesticular T lead to correspondingly low serum levels of total T(tT),severe disorders of spermatogenesis,and male sterility.However,there is little consensus on the lower limits of serum tT in proven fertile men undergoing assisted reproductive technology treatments in Chinese or other Asian populations.We aimed to establish the reference range of serum tT based on a population of 868 fertile Chinese men undergoing in vitro fertilization or intracytoplasmic sperm injection and embryo transfer(IVF/ICSI-ET)treatments.We defined a fertile man as having had a live baby with his partner as recorded in our IVF registration system.The lower limits of serum tT were established using a Siemens IMMULITE 2000 chemiluminescent system.The 1st,2.5th,and 5th percentiles and their 95%confidence intervals(CIs)were 3.6(95%CI:2.7–4.1)nmol l−1,4.3(95%CI:4.1–5.0)nmol l−1,and 5.6(95%CI:4.8–5.8)nmol l−1,respectively.Using the linear correlation of serum tT between the Siemens platform and a liquid chromatography–tandem mass spectrometry platform,the calculated lower limits of serum tT were also established for fertile Chinese men undergoing IVF/ICSI-ET treatments,which will benefit the clinical diagnosis and treatment of male infertility during such procedures.
文摘Anti-Mullerian hormone(AMH)is a functional marker of fetal Sertoli cells.The germ cell number in adults depends on the number of Sertoli cells produced duri ng peri natal development.Rece ntly,AMH has received increasi ng attenti on in research of disorders related to male fertility.This paper reviews and summarizes the articles on the regulation of AMH in males and the serum levels of AMH in male fertility-related disorders.We have determined that follicle-stimulating hormone(FSH)promotes AMH transcription in the absenee of androgen signaling.Testosterone inhibits the transcriptional activation of AMH.The undetectable levels of serum AMH and testosterone levels indicate a lack of functional testicular tissue,for example,that in patients with anorchia or severe Klinefelter syndrome suffering from impaired spermatogenesis.The normal serum testosterone level and undetectable AMH are highly suggestive of persistent Mullerian duct syndrome(PMDS),combined with clinical manifestations.The levels of both AMH and testosterone are always subnormal in patients with mixed disorders of sex development(DSD).Mixed DSD is an early-onset complete type of disorder with fetal hypogonadism resulting from the dysfunction of both Leydig and Sertoli cells.Serum AMH levels are varying in patients with male fertility-related disorders,in cludi ng pubertal delay,severe con genital hypog on adotropic hypogonadism,nonobstructive azoospermia,Klinefelter syndrome,varicocele,McCune-Albright syndrome,and male senescence.
基金supported by the National Natural Science Foundation of China (Nos. 31522034, 31571544 and 31230047)the National High Technology Research and Development Program (No. 2015AA020407)+1 种基金Beijing Municipal Science and Technology Commission (No. D151100002415004)Research Fund of National Health and Family Planning Commission of China (No. 201402004)
文摘Conventional PCR methods combined with linkage analysis based on short tandem repeats （STRs） or Karyomapping with single nucleotide polymorphism （SNP） arrays, have been applied to preimplantation genetic diagnosis （PGD） for spinal muscular atrophy （SMA）, an autosome recessive disorder. However, it has limitations in SMA diagnosis by Karyomapping, and these methods are unable to distinguish wild- type embryos with carriers effectively. Mutated allele revealed by sequencing with aneuploidy and linkage analyses （MARSALA） is a new method allowing embryo selection by a one-step next-generation sequencing （NGS） procedure, which has been applied in PGD for both autosome dominant and X-linked diseases in our group previously. In this study, we carried out PGD based on MARSALA for two carrier families with SMA affected children. As a result, one of the couples has given birth to a healthy baby free of mutations in SMA-causing gene. It is the first time that MARSALA was applied to PGD for SMA, and we can distinguish the embryos with heterozygous deletion （carriers） from the wild-type （normal） ones accurately through this NGS-based method. In addition, direct mutation detection allows us to identify the affected embryos （homozygous deletion）, which can be regarded as probands for linkage analysis, in case that the affected family member is absent, In the future, the NGS-based MARSALA method is expected to be used in PGD for all monogenetic disorders with known pathogenic gene mutation.
文摘Vasoepididymostomy （VE）, as the most challenging procedure in microsurgeries, is often carried out with a double-armed two-suture technique. In this study, we evaluated the efficacy and safety of the single-armed two-suture VEs on humans and studied the factors that could possibly affect the patency rates. From July 2012 to July 2013, we reviewed 81 patients with consecutive primary epididymal obstruction who underwent single-armed two-suture longitudinal intussusception microsurgical VEs by a single surgeon, Kai Hong （KH）. At the same time, we analyzed seven factors that possibly related to the patency rates. With the single-armed technique, a total of 81 men underwent the microsurgical VEs. Data on 62 patients were completely recorded. 19 patients were lost to follow-up. Mean age was 31 years old. Mean follow-up time was 8.8 （2-17） months. The patency rate was 66.1% （41/62）. Natural pregnancy rate was 34.1% （14/41）. Overall pregnancy rate was 22.6% （14/62）. No severe surgical complications were noted. With logistic regression test analysis, there were two factors related to a higher patency rate： anastomosis sites （P = 0.035） and motile sperm found in the epididymal fluid （P = 0.006）. Motile sperm found in the epididymal fluid were associated with a higher patency rate （OR = 11.80, 95% CI = 1.79, 77.65）. The single-armed two-suture longitudinal VE technique is feasible for microsurgical practice. The patency and pregnancy rates are comparable to the doubled-armed technique. Anastomosis sites and motile sperm found in the epididymal fluid were the most two important factors related to higher patency.
基金supported by the National Key R&D Program of China (2018YFC1002302, 2016YFC0900103)National Natural Science Foundation of China (81671458)+1 种基金Beijing Lab for Cardiovascular Precision Medicine (PXM2018_014226_000013)supported by the Reproduction Center Biobank at Peking University Third Hospital
文摘Marfan syndrome (MFS)(OMIM 154700) is a relatively common autosomal dominant genetic disease that causes skeletal, ocular, and cardiovascular defects and was first described by a French pediatrician in 1896 (Bitterman and Sponseller, 2017). Its prevalence rate is 1/3000—1/5000, and more than 25% of cases are sporadic (Chiu et al., 2014). Studies have shown that about 90% of MFS is caused by variants in the fibrillin-1 gene (FBN1, OMIM 134797). FBN1, located on chromosome 15q21.1, encodes a macromolecular glycoprotein-fibrin 1, which aggregates to form microfibers in the extracellular matrix and distributes in various human connective tissues, such as periosteum, vessel wall, and crystal suspensor ligament. Variants in FNB1 have been reported in 65 exons, but the relationship between genotype and phenotype remains rather unclear (Sakai et al., 2016). Studies have also shown that patients with MFS and similar diseases may have variants in other related genes such as members of the transforming growth factor beta receptor (TGFBR) family (Mizuguchi et al., 2004;Sakai et al., 2006;Bolar et al., 2012;De Cario et al., 2018). For better prevention and treatment of MFS as well as for suspected MFS patients, there is a strong need for efficient genetic testing for early diagnosis and differential diagnoses of patients with related phenotypes (Aubart et al., 2018).
基金supported by the National Natural Science Foundation of China (Nos. 31522034 and 81730038)the National High Technology Research and Development Program Grant (2015AA020407)
文摘The causes of recurrent spontaneous abortion (RSA) and fetal malformations are multifactorial and unclear in most cases. Environmental, maternal, and genetic factors have been shown to contribute to these defects. Whole-exome sequencing (WES) is widely used to detect genetic variations associated with human diseases and has recently been successfully applied to unveil genetic causes of unexplained recurrent spontaneous abortion (URSA) and fetal malformations. Here, we review the current discovery and diagnosis strategies to identify the underlying pathogenic mutations of URSA and fetal malformations using WES technology and propose to further develop WES, both to advance our understanding of these diseases and to eventually lead to targeted therapies for reproductive disorders.
基金Project supported by the Special Research Fund for the Public Welfare Industry of Health of China(No.201302013)
文摘Abstract： With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture （EA） and transcutaneous electrical acupoint stimulation （TEAS）, become more popular world-wide. Increasing evidence has demonstrated that EA and TEAS are effective in treating gynecological disorders, especially infertility. This present paper describes how to select acupoints for the treatment of infertility from the view of theories of traditional Chinese medicine and how to determine critical parameters of electric pulses of ENTEAS based on results from animal and clinical studies. It summarizes the principles of clinical application of EA/rEAS in treating various kinds of reproductive disorders, such as polycystic ovary syndrome （PCOS）, pain induced by oocyte retrieval, diminished ovarian reserve, embryo transfer, and oligosperrnia/ asthenospermia. The possible underlying mechanisms mediating the therapeutic effects of EA/TEAS in reproductive medicine are also examined.
文摘Objective The study is to identify the carrier rate of common deafness mutation in Chinese pregnant women via detecting deafness gene mutations with gene chip. Methods The pregnant women in obstetric clinic without hearing impairment and hearing disorders family history were selected. The informed consent was signed. Peripheral blood was taken to extract genom- ic DNA. Application of genetic deafness gene chip for detecting 9 mutational hot spot of the most common 4 Chinese deafness genes, namely GJB2 （35delG, 176del16bp, 235delC, 299delAT）, GJB3 （C538T） ,SLC26A4 （ IVS72A〉G, A2168G） and mito- chondrial DNA 12S rRNA （A1555G, C1494T） . Further genetic testing were provided to the spouses and newborns of the screened carriers. Results Peripheral blood of 430 pregnant women were detected, detection of deafness gene mutation carri- ers in 24 cases（4.2%）, including 13 cases of the GJB2 heterozygous mutation, 3 cases of SLC26A4 heterozygous mutation, 1 cases of GJB3 heterozygous mutation, and 1 case of mitochondrial 12S rRNA mutation. 18 spouses and 17 newborns took further genetic tests, and 6 newborns inherited the mutation from their mother. Conclusion The common deafness genes muta- tion has a high carrier rate in pregnant women group, 235delC and IVS7-2A〉G heterozygous mutations are common.
基金supported by grants from the National Natural Science Foundation of China (No.81971440)the Beijing Natural Science Foundation (No.7212129).
文摘Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presence of NOA in some patients,a proportion of NOA patients remain to be addressed.This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing.Whole-exome sequencing was performed in 46 male patients diagnosed with NOA.First,screening was performed for 119 genes known to be related to male infertility.Next,further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls.Finally,risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed.The frequency of cystic fibrosis transmembrane conductance regulator(CFTR)gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls.Potential risk genes that may be causes of NOA were identified,including seven genes that were highly/specifically expressed in the testes.Four risk genes previously reported to be involved in spermatogenesis(MutS homolog 5[MSH5],cilia-and flagella-associated protein 54[CFAP54],MAP7 domain containing 3[MAP7D3],and coiled-coil domain containing 33[CCDC33])and three novel risk genes(coiled-coil domain containing 168[CCDC168],chromosome 16 open reading frame 96[C16orf96],and serine protease 48[PRSS48])were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls.This study on clinical NOA patients provides further evidence for the four previously reported risk genes.The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.
文摘Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into spermatids in mammalian testis. SSCs are previously regarded as the unipotent stem cells since they can only give rise to sperm within the seminiferous tubules. However, this concept has recently been challenged because numerous studies have demonstrated that SSCs cultured with growth factors can acquire pluripotency to become embryonic stem-like cells. The in vivo and in vitro studies from peers and us have clearly revealed that SSCs can directly transdifferentiate into morphologic, phenotypic, and functional cells of other lineages. Direct conversion to the cells of other tissues has important significance for regenerative medicine. SSCs from azoospermia patients could be induced to differentiate into spermatids with fertilization and developmental potentials. As such, SSCs could have significant applications in both reproductive and regenerative medicine due to their unique and great potentials. In this review, we address the important plasticity of SSCs, with focuses on their self-renewal, differentiation, dedifferentiation, transdifferentiation, and translational medicine studies.
文摘Objective To compare the roles of fluorescence in situ hybridization （FISH） and karyotype analysis on chorionic villus in spontaneous abortion. Methods A total of 201 cases were included in this study and were randomly divided into 2 groups by the same gestational age. The villi from 100 cases （group A） were cultured and used for karyotype analysis, while the uncultured villi from 101 women （group B） were used for FISH. A case was randomly selected from pregnant patients of 6-11 weeks at each gestational week in each group, 6 cases from each group and a total of 12 cases were analyzed by FISH and karyotype at the same time. Results The successful karyotype analysis rate was 66. 0%, and the abnormality karyotype rate was 30.3%; FISH success analysis rate was 100%, and the abnormality rate was 46. 5%; there were significant differences between FISH and karyotype analysis （P=0.036）. Conclusion There were obvious differences between the two techniques. FISH was more successfully analyzed, and was used to more precisely determine fetal chromo- some number. It is an effective way to determine abnormal chromosome by integrating FISH and karyotype analysis in spontaneous abortion.
基金supported by the National Key Research and Development Program of China(2022YFC2702900 and 2021YFC2701103)National Natural Science Foundation of China(82171654)。
文摘Objective The study aimed to investigate the impact of rare earth elements(REEs)exposure on pregnancy outcomes of in vitro fertilization-embryo transfer(IVF-ET)by analyzing samples from spouses.Methods A total of 141 couples were included.Blood and follicular fluid from the wives and semen plasma from the husbands,were analyzed for REEs using inductively coupled plasma mass spectrometry(ICP-MS).Spearman's correlation coefficients and the Mann–Whitney U test were used to assess correlations and compare REE concentrations among three types of samples,respectively.Logistic models were utilized to estimate the individual REE effect on IVF-ET outcomes,while BKMR and WQS models explored the mixture of REE interaction effects on IVF-ET outcomes.Results Higher La concentration in semen(median 0.089 ng/mL,P=0.03)was associated with a lower fertilization rate.However,this effect was not observed after artificial selection intervention through intracytoplasmic sperm injection(ICSI)(P=0.27).In semen,the REEs mixture did not exhibit any significant association with clinical pregnancy.Conclusion Our study revealed a potential association between high La exposure in semen and a decline in fertilization rate,but not clinical pregnancy rate.This is the first to report REEs concentrations in follicular fluid with La,Ce,Pr,and Nd found at significantly lower concentrations than in serum,suggesting that these four REEs may not accumulate in the female reproductive system.However,at the current exposure levels,mixed REEs exposure did not exhibit reproductive toxicity.
基金supported by the National Natural Science Foundation of China[NSFCno.81741021]the National Key Research and Development Program of China[no.2016YFC1000501,2016YFC1000500]。
文摘Objective To determine if ARHGEF10 has a haploinsufficient effect and provide evidence to evaluate the severity,if any,during prenatal consultation.Methods Zebrafish was used as a model for generating mutant.The pattern of arhgef10 expression in the early stages of zebrafish development was observed using whole-mount in situ hybridization(WISH).CRISPR/Cas9 was applied to generate a zebrafish model with a single-copy or homozygous arhgef10 deletion.Activity and light/dark tests were performed in arhgef10^(−/−),arhgef10^(+/−),and wild-type zebrafish larvae.ARHGEF10 was knocked down using small interferon RNA(siRNA)in the SH-SY5Y cell line,and cell proliferation and apoptosis were determined using the CCK-8 assay and Annexin V/PI staining,respectively.Results WISH showed that during zebrafish embryonic development arhgef10 was expressed in the midbrain and hindbrain at 36-72 h post-fertilization(hpf)and in the hemopoietic system at 36-48 hpf.The zebrafish larvae with single-copy and homozygous arhgef10 deletions had lower exercise capacity and poorer responses to environmental changes compared to wild-type zebrafish larvae.Moreover,arhgef10^(−/−) zebrafish had more severe symptoms than arhgef10^(+/-) zebrafish.Knockdown of ARHGEF10 in human neuroblastoma cells led to decreased cell proliferation and increased cell apoptosis.Conclusion Based on our findings,ARHGEF10 appeared to have a haploinsufficiency effect.
基金supported by National Key Research and Development Program(2022YFC2705305)clinical key project of Peking University Third Hospital(BYSYZD2023007)National Science Fund for Distinguished Young Scholars(81925013).
文摘This study aimed to investigate the associations between the post-wash total progressively motile sperm count(TPMSC)in the first intrauterine insemination(IUI)cycle and pregnancy outcomes of the second IUI cycle.Data were retrieved from the clinical database at the Reproductive Center of Peking University Third Hospital(Beijing,China)between January 2011 and December 2022.Couples were included in this retrospective cohort study if they had unexplained or mild male factor infertility and were treated with IUI for two consecutive cycles using the same protocol.A total of 8290 couples were included in the analysis.The mean±standard deviation(s.d.)age of women was 32.0±3.5 years.We categorized groups based on the post-wash TPMSC(×10^(6))levels in the first IUI cycle:group 1(0<TPMSC<1,n=1290),group 2(1≤TPMSC<2,n=863),group 3(2≤TPMSC<3,n=800),group 4(3≤TPMSC<4,n=783),group 5(4≤TPMSC<5,n=1541),group 6(5≤TPMSC<6,n=522),group 7(6≤TPMSC<7,n=547),group 8(7≤TPMSC<8,n=175),group 9(8≤TPMSC<9,n=556),group 10(9≤TPMSC<10,n=192),and group 11(TPMSC≥10,n=1021).The primary outcome was live birth rate of the second IUI cycle.Live birth rates were 7.9%,5.8%,7.6%,7.4%,7.3%,8.4%,7.5%,7.4%,8.8%,8.9%,and 7.6%in each group,respectively.There were no statistically significant differences in clinical pregnancy rates or live birth rates between any groups and those with the post-wash TPMSC<1×10^(6).In an IUI program for unexplained and mild male factor infertility,the post-wash TPMSC in the first IUI cycle was not significantly associated with the live birth rate in the second IUI cycle.
基金supported by the National Natural Science Foundation of China (No. 31522034)Ministry of Science and Technology of China (2016YFC0900103)the National High Technology Research and Development Program Grant (2015AA020407)
文摘Reciprocal translocation is a chromosomal structural abnormal- ity that arises when two non-homologous chromosomes rearrange and attach with each other, an incidence that occurs in about 1/500 to 1/625 newborns （Mackie and Scriven, 2002）. This event typically does not lead to any significant loss of genetic material, thus recip- rocal translocation carriers do not exhibit any severe abnormal phenotypes （Scriven et al., 1998; Zhang et al., 2016）.
文摘In the present study, we evaluated the impact of sperm origins and concentration on the clinical outcomes of intracytoplasmic sperm injection （ICSI） cycles. A total of 1201 IC51 cycles were retrospectively analyzed for male azoospermia or oligozoospermia between January 2015 and December 2015 in the Peking University Third Hospital. Patients were divided into three groups （Group 1 vs Group 2/3; surgically extracted sperm vs ejaculated sperms）： Group 1 included 343 ICSI cycles and Group 2 analyzed 388 cycles on semen with sperm concentration 〈5 × 10^6 m1-1 （severe oligozoospermia group）. Group 3 included 470 cycles with sperm concentration between 5×10^6 m1-1 and 15 × 10^6 m1-1 （mild oligozoospermia group）. Fertilization rates, clinical pregnancy rates, and live birth rates were analyzed and compared among groups of different semen origins and concentrations on the oocyte retrieval day. Group 2 showed a lower fertilization rate than Group 3 （62.9%± 21.6% vs 66.8% ± 22.1%, P 〈 0.05）. There were no statistically significant differences in clinical pregnancy rate per transfer （51.3%, 46.7%, and 50.0%, respectively）, live birth rate per transfer （44.4%, 40.9%, and 41.4%, respectively）, accumulative live birth rate （58.3%, 51.0%, and 52.1%, respectively）, twin birth rate （18.4%, 10.6%, and 12.6%, respectively）, and birth defects rate （0, 0.3%, and 0.2%, respectively） among three groups. The results of this study indicated that sperm origins and concentration do not imDact the clinical outcomes in ICSI cycles.
基金supported by the National High Technology Research and Development Program(Nos.2018YFC1002904,2018YFC1004000 and 2017YFA0103801)。
文摘Congenital contractural arachnodactyly(CCA,OMIM:121050),also known as Beals syndrome,belongs to a group of rare autosomal dominant(AD)diseases of connective tissue(Maslen et al.,1997).People with CCA share many distinguishing features,such as arachnodactyly,camp tod actyly,multiple joint contractures(especially finger,elbow,and knee joints),crumpled ears,scoliosis,pectus deformities,and muscular hypoplasia(Jurko et al.,2013).It exhibits no specific geographic or ethnic predilection(Frederic et al.,2009).
基金the National Key Research and Development Program(2019YFA0801400)the National Natural Science Foundation of China(81730038).
文摘The worldwide infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)impacts human health and life on multiple levels.People infected with SARS-CoV-2 suffer from physical disorders and psychological distress.At present,no direct evidence indicates that SARS-CoV-2 negatively influences human reproduction,and the possibility that gametes and embryos are affected requires further investigation.To evaluate the potential effects of SARS-CoV-2 infection on human reproduction and fetal health,this review summarizes the basic and clinical research of SARS-CoV-2 on reproduction up to date,hoping to offer guidance and advice to people at reproductive age and provide dues for the prevention and treatment of associated diseases.
