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Reprod Biomed Online ; 33(6): 709-719, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27692602


The influence of aberrant sperm DNA methylation on the reproductive capacity of couples has been postulated as a cause of infertility. This study compared the DNA methylation of spermatozoa of 19 fertile donors and 42 infertile patients using the Illumina 450K array. Clustering analysis of methylation data arranged fertile and infertile patients into two groups. Bivariate clustering analysis identified a differential distribution of samples according to the characteristics of seminogram and age, suggesting a possible link between these parameters and specific methylation profiles. The study identified 696 differentially methylated cytosine-guanine dinucleotides (CpG) associated with 501 genes between fertile donors and infertile patients. Ontological enrichment analysis revealed 13 processes related to spermatogenesis. Data filtering identified a set of 17 differentially methylated genes, some of which had functions relating to spermatogenesis. A significant association was identified between RPS6KA2 hypermethylation and advanced age (P = 0.016); APCS hypermethylation and oligozoospermia (P = 0.041); JAM3/NCAPD3 hypermethylation and numerical chromosome sperm anomalies (P = 0.048); and ANK2 hypermethylation and lower pregnancy rate (P = 0.040). This description of a set of differentially methylated genes provides a framework for further investigation into the influence of such variation in male fertility in larger patient cohorts.

Metilação de DNA , Infertilidade Masculina/genética , Espermatogênese/genética , Espermatozoides/metabolismo , Adulto , Análise por Conglomerados , Ilhas de CpG , Feminino , Fertilidade/genética , Humanos , Masculino , Oligospermia/genética , Gravidez , Taxa de Gravidez , Regiões Promotoras Genéticas , Reprodução , Adulto Jovem
Fertil Steril ; 104(3): 591-601, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26143365


OBJECTIVE: To compare the microRNA (miRNA) expression profile in spermatozoa from three infertile populations vs. a group of fertile men. DESIGN: Evaluation of the expression level of 736 miRNAs in human spermatozoa using TaqMan quantitative reverse transcription-polymerase chain reaction. SETTING: University research facility. PATIENT(S): Semen samples with a single seminal alteration were collected from infertile individuals: asthenozoospermic (n = 10), teratozoospermic (n = 10), and oligozoospermic (n = 10). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Correlation of the expression level of each miRNA with seminal parameters, age, and chromosome instability; clustering of the individuals according to their miRNA expression profiles and influence of the seminogram, age, chromosome instability, and assisted reproductive technology outcome in the clustering; analysis of the differentially expressed miRNAs (DE-miRNAs) in each infertile population; genome annotation of these DE-miRNAs; and ontological analysis of their predicted targets. RESULT(S): The hsa-miR-34b-3p correlated with age, the hsa-miR-629-3p with sperm motility, and the hsa-miR-335-5p, hsa-miR-885-5p, and hsa-miR-152-3p with sperm concentration. The individuals clustered into two groups, and only the seminogram was differentially distributed. We identified 32 DE-miRNAs in the asthenozoospermic group, 19 in the teratozoospermic group, and 18 in the oligozoospermic group. The up-regulated miRNAs presented an enriched localization in introns, affecting relevant genes for spermatogenesis. The predicted targets of the DE-miRNAs contained critical genes associated to infertility, and their ontological analysis revealed significantly associated functions related to the seminal alterations of each group. CONCLUSION(S): Spermatozoa from patients with seminal alterations exhibit a differential miRNA profile. This provides new evidence that miRNAs have an essential role in spermatogenesis, contributing to the mechanisms involved in human fertility.

Fertilidade/genética , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/genética , MicroRNAs/genética , Espermatozoides/química , Astenozoospermia/diagnóstico , Astenozoospermia/genética , Astenozoospermia/fisiopatologia , Azoospermia/diagnóstico , Azoospermia/genética , Azoospermia/fisiopatologia , Estudos de Casos e Controles , Instabilidade Cromossômica , Análise por Conglomerados , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Humanos , Infertilidade Masculina/fisiopatologia , Masculino , Oligospermia/diagnóstico , Oligospermia/genética , Oligospermia/fisiopatologia , Idade Paterna , Fatores de Risco , Contagem de Espermatozoides , Motilidade Espermática , Espermatozoides/patologia
Reprod Biomed Online ; 31(1): 79-88, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25985997


The aim of this study was to assess whether there is a relationship between numerical chromosome abnormalities and certain segregation modes in spermatozoa from Robertsonian translocation carriers. A sequential fluorescence in-situ hybridization protocol based on two successive hybridization rounds was performed on sperm samples from one t(13;22) and ten t(13;14) carriers. Patient inclusion criteria included the presence of a positive interchromosomal effect (ICE). In the first round, numerical abnormalities for chromosomes 15/22, 18, 21, X and Y were analysed. In the second round, the segregation outcome of the rearranged chromosomes was evaluated in the numerically abnormal spermatozoa detected in the first round, as well as in randomly assessed spermatozoa. Aneuploid spermatozoa showed statistical differences in all segregation modes when compared with randomly assessed spermatozoa: alternate (50.7% versus 84.3%), adjacent (36.6% versus 14.6%) and 3:0 (10.2% versus 1%). Diploid/multiple disomic spermatozoa showed differences in alternate (3.7% versus 84.3%) and 3:0 (67.6% versus 1%). We concluded that in Robertsonian translocation carriers that exhibit ICE, numerically abnormal spermatozoa preferentially contain unbalanced segregation products. This might be explained by heterosynapsis acting as a rescue mechanism that would lead to aberrant recombination, which is a predisposing factor for non-disjunction events.

Aberrações Cromossômicas , Segregação de Cromossomos , Heterozigoto , Espermatozoides/ultraestrutura , Translocação Genética , Aneuploidia , Cromossomos Humanos/metabolismo , Humanos , Infertilidade Masculina/genética , Masculino
J Assist Reprod Genet ; 30(9): 1115-23, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23975190


PURPOSE: To find out the meiotic segregation behaviour of the t(1;8;2)(q42;p21;p15), to evaluate the occurrence of interchromosomal effects, and to determine whether there is an accumulation of unbalanced products in aneuploid/diploid gametes. METHODS: A sequential FISH protocol based on two successive hybridization rounds over the same spermatozoa was performed to determine the segregation outcome of the rearranged chromosomes. The presence of numerical abnormalities for 13, 18, 21, X and Y was also evaluated by sperm FISH. Those aneuploid/diploid gametes were subsequently relocalized and analyzed for their segregation content through additional hybridization rounds. RESULTS: The segregation pattern observed reported a very low production of normal/balanced gametes (11.7 %). Significant increased frequencies of diploidies and disomies for chromosomes X/Y and 18 were detected (p < 0.001). Aneuploid and diploid spermatozoa displayed significant increases of 5:1, 6:0 and other unexpected disjunction modes (p < 0.001). CONCLUSIONS: The strategy developed in this study is a reliable new approach to establish the full segregation pattern of complex chromosome rearrangements (CCR). Results corroborate the low number of normal/balanced spermatozoa produced by CCR carriers and support previous findings regarding an altered segregation pattern in gametes with numerical abnormalities. Altogether this confirms the importance of PGD as a tool to prevent the transmission of chromosomal abnormalities to the offspring in CCR patients.

Segregação de Cromossomos/genética , Hibridização in Situ Fluorescente/métodos , Espermatozoides/citologia , Translocação Genética , Adulto , Aneuploidia , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Células Germinativas , Heterozigoto , Humanos , Masculino , Meiose/genética