Publications

There are a number of peer-reviewed scientific publications in the areas of epigenetics, computational biology, development, and reproductive medicine that support the development of Episona’s Sperm Test. Please contact us if you would like us to include any additional publications.

Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans


Feb 2016 | Cell Metabolism

Ida Donkin, Soetkin Versteyhe, Lars R. Ingerslev, Kui Qian, Mie Mechta, Loa Nordkap, Brynjulf Mortensen, Emil Vincent R. Appel, Niels Jørgensen, Viggo B. Kristiansen, Torben Hansen, Christopher T. Workman, Juleen R. Zierath, Romain Barrès

Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized that weight loss remodels the epigenetic signature of spermatozoa in human obesity.


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Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring


Feb 2016 | Cell Metabolism

Ling Wu, Yan Lu, Yang Jiao, Bin Liu, Shangang Li, Yao Li, Fengying Xing, Dongbao Chen, Xing Liu, Jiejie Zhao, Xuelian Xiong, Yanyun Gu, Jieli Lu, Xuejin Chen, and Xiaoying Li

Both epidemiologic and experimental animal studies demonstrate that chronic psychological stress exerts adverse effects on the initiation and/or progression of many diseases. However, intergenerational effects of this environmental information remains poorly understood. Here, using a C57BL/6 mouse model of restraint stress, we show that offspring of stressed fathers exhibit hyperglycemia due to enhanced hepatic gluconeogenesis and elevated expression of PEPCK.

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Aberrant sperm DNA methylation predicts male fertility status and embryo quality


Dec 2015 | Fertility Sterility

Kenneth I. Aston, Philip J. Uren, Timothy G. Jenkins, Alan Horsager, Bradley R. Cairns, Andrew D. Smith, Douglas T. Carrell

To evaluate whether male fertility status and/or embryo quality during in vitro fertilization (IVF) therapy can be predicted based on genomewide sperm deoxyribonucleic acid (DNA) methylation patterns. Participants were 127 men undergoing IVF treatment (where any major female factor cause of infertility had been ruled out), and 54 normozoospermic, fertile men. The IVF patients were stratified into 2 groups: patients who had generally good embryogenesis and a positive pregnancy (n = 55), and patients with generally poor embryogenesis (n = 72; 42 positive and 30 negative pregnancies) after IVF.

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Methylation analysis of histone H4K12ac-associated promoters in sperm of healthy donors and subfertile patients


Mar 2015 | Clinical Epigenetics

Markus Vieweg, Katerina Dvorakova-Hortova, Barbora Dudkova, Przemyslaw Waliszewski, Marie Otte, Berthold Oels, Amir Hajimohammad, Heiko Turley, Martin Schorsch, Hans-Christian Schuppe, Wolfgang Weidner, Klaus Steger, Agnieszka Paradowska-Dogan

Histone to protamine exchange and the hyperacetylation of the remaining histones are hallmarks of spermiogenesis. Acetylation of histone H4 at lysine 12 (H4K12ac) was observed prior to full decondensation of sperm chromatin after fertilization suggesting an important role for the regulation of gene expression in early embryogenesis. Similarly, DNA methylation may contribute to gene silencing of several developmentally important genes.

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Decreased fecundity and sperm DNA methylation patterns


Oct 2015 | Fertility Sterility

Timothy G. Jenkins, Kenneth I. Aston, Tyson D. Meyer, James M. Hotaling, Monis B. Shamsi, Erica B. Johnstone, Kyley J. Cox, Joseph B. Stanford, Christina A. Porucznik, Douglas T. Carrell

To evaluate the relationship between epigenetic patterns in sperm and fecundity. Twenty-seven semen samples from couples who conceived within 2 months of attempting a pregnancy and 29 semen samples from couples unable to achieve a pregnancy within 12 months. Genomewide assessment of differential sperm DNA methylation and standard semen analysis.

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X chromosome-linked CNVs in male infertility: discovery of overall duplication load and recurrent, patient-specific gains with potential clinical relevance


Jun 2014 | PLoS One

Chiara Chianese, Adam C. Gunning, Claudia Giachini, Fabrice Daguin, Giancarlo Balercia, Elisabet Ars, Deborah Lo Giacco, Eduard Ruiz-Castañé, Gianni Forti, Csilla Krausz

Spermatogenesis is a highly complex process involving several thousand genes, only a minority of which have been studied in infertile men. In a previous study, we identified a number of Copy Number Variants (CNVs) by high-resolution array-Comparative Genomic Hybridization (a-CGH) analysis of the X chromosome, including 16 patient-specific X chromosome-linked gains. Of these, five gains (DUP1A, DUP5, DUP20, DUP26 and DUP40) were selected for further analysis to evaluate their clinical significance

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Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility


Oct 2010 - Fertil Steril

Saher Sue Hammoud, Jahnvi Purwar, Christian Pflueger, Bradley R. Cairns, Douglas T. Carrell

To evaluate the associations between proper protamine incorporation and DNA methylation at imprinted loci. Three populations were tested-abnormal protamine patients, oligozoospermic patients, and fertile donors. The CpG methylation patterns were examined at seven imprinted loci sequenced: LIT1, MEST, SNRPN, PLAGL1, PEG3, H19, and IGF2.

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Disruption of histone methylation in developing sperm impairs offspring health transgenerationally


Nov 2015 - Science

Keith Siklenka, Serap Erkek, Maren Godmann, Romain Lambrot, Serge McGraw, Christine Lafleur, Tamara Cohen, Jianguo Xia, Matthew Suderman, Michael Hallett, Jacquetta Trasler, Antoine H. F. M. Peters, Sarah Kimmins

A father's lifetime experiences can be transmitted to his offspring to affect health and development. However, the mechanisms underlying paternal epigenetic transmission are unclear. Unlike in somatic cells, there are few nucleosomes in sperm, and their function in epigenetic inheritance is unknown.

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Association of the patterns of global DNA methylation and expression analysis of DNA methyltransferases in impaired spermatogenic patients


Dec 2015 - APJR

Deepika Jaiswal, Sameer Trivedi, Neeraj K. Agrawal, Kiran Singh

To analyze global DNA methylation along with DNA methyltransferases (DNMTs) expression at transcript level in patients with impaired spermatogenesis to dissect its role in pathophysiology of human male infertility. The content of Global methylated cytosine (mC) was determined using ELISA system (Imprint Methylated DNA Quantification Kit, Sigma–Aldrich) in 31 testicular biopsies showing impaired spermatogenesis and 8 with normal spermatogenesis. Real-time reverse transcription-polymerase chain reaction was done to analyze DNMTs (DNMT1, DNMT3A, DNMT3B and DNMT3L) mRNA levels in biopsies with different testicular phenotypes.

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Genome-wide 5-hydroxymethylcytosine modification pattern is a novel epigenetic feature of globozoospermia


Mar 2015 - Oncotarget

Xiu-Xia Wang, Bao-Fa Sun, Jiao Jiao, Ze-Chen Chong, Yu-Shen Chen, Xiao-Li Wang, Yue Zhao, Yi-Ming Zhou, Da Li

Discovery of 5-hydroxymethylcytosine (5hmC) in mammalian genomes has excited the field of epigenetics, but information on the genome-wide distribution of 5hmC is limited. Globozoospermia is a rare but severe cause of male infertility. To date, the epigenetic mechanism, especially 5hmC profiles involved in globozoospermia progression, remains largely unknown.

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Methylation status of imprinted genes and repetitive elements in sperm DNA from infertile males


Mar 2011 - Sex Dev

El Hajj N., Zechner U., Schneider E., Tresch A., Gromoll J., Hahn T., Schorsch M., Haaf T.

Stochastic, environmentally and/or genetically induced disturbances in the genome-wide epigenetic reprogramming processes during male germ-cell development may contribute to male infertility. To test this hypothesis, we have studied the methylation levels of 2 paternally (H19 and GTL2) and 5 maternally methylated (LIT1, MEST, NESPAS, PEG3, and SNRPN) imprinted genes, as well as of ALU and LINE1 repetitive elements in 141 sperm samples, which were used for assisted reproductive technologies (ART), including 106 couples with strictly male-factor or combined male and female infertility and 28 couples with strictly female-factor infertility. Aberrant methylation imprints showed a significant association with abnormal semen parameters, but did not seem to influence ART outcome.

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Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring


Apr 2015 - Reprod Biol Endocrinol

Rakesh Sharma, Ashok Agarwal, Vikram K Rohra, Mourad Assidi, Muhammad Abu-Elmagd, Rola F Turki

Over the last decade, there has been a significant increase in average paternal age when the first child is conceived, either due to increased life expectancy, widespread use of contraception, late marriages and other factors. While the effect of maternal ageing on fertilization and reproduction is well known and several studies have shown that women over 35 years have a higher risk of infertility, pregnancy complications, spontaneous abortion, congenital anomalies, and perinatal complications. The effect of paternal age on semen quality and reproductive function is controversial for several reasons.

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Methylation of the Gpat2 promoter regulates transient expression during mouse spermatogenesis


Oct 2015 - Biochem J

Maria B. Garcia-Fabiani, Mauro A. Montanaro, Ezequiel Lacunza, Elizabeth R. Cattaneo, Rosalind A. Coleman, Magali Pellon-Maison, Maria R. Gonzalez-Baro

Spermatogenesis is a highly regulated process that involves both mitotic and meiotic divisions, as well as cellular differentiation to yield mature spermatozoa from undifferentiated germinal stem cells. Although Gpat2 was originally annotated as encoding a glycerol-3-phosphate acyltransferase by sequence homology to Gpat1, GPAT2 is highly expressed in testis but not in lipogenic tissues and is not up-regulated during adipocyte differentiation. New data show that GPAT2 is required for the synthesis of piRNAs (piwi-interacting RNAs), a group of small RNAs that protect the germ cell genome from retrotransposable elements.

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Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia


Feb 2008 - Mol Hum Reprod

C.J. Marques, P. Costa, B. Vaz, F. Carvalho, S. Fernandes, A. Barros, M. Sousa

Genomic imprinting marks in the male germ line are already established in the adult germinal stem cell population. We studied the methylation patterns of H19 and MEST imprinted genes in sperm of control and oligozoospermic patients, by bisulphite genomic sequencing. We here report that 7 out of 15 (46.7%) patients with a sperm count below 10 x 10(6)/ml display defective methylation of H19 and/or MEST imprinted genes. In these cases, hypomethylation was observed in 5.54% (1.2-8.3%) and complete unmethylation in 2.95% (0-5.9%) of H19 clones.

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Genome-wide study of single-nucleotide polymorphisms associated with azoospermia and severe oligozoospermia


Nov 2009 - J Androl

Kenneth I. Aston, Douglas T. Carrell

Male infertility affects a large proportion of the population. In spite of the magnitude of the problem and the considerable research effort that has been made to understand its causes, a large proportion of male infertility cases remain idiopathic in nature. This pilot genome-wide association study employed genotyping microarray technology to interrogate over 370,000 single-nucleotide polymorphisms (SNPs) in men with azoospermia and severe oligozoospermia, along with normozoospermic controls, in an effort to discover novel genetic variants significantly associated with male infertility.

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Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1


Aug 2010 - Int J Androl

Poplinski A, Tüttelmann F, Kanber D, Horsthemke B, Gromoll J

Aberrant imprinting in spermatozoa in a subset of infertile men has been postulated to be a risk factor for congenital diseases in children conceived via assisted reproduction techniques (ART). Studies in clinically well characterized large cohorts, however, have been missing. Using bisulfite sequencing, we determined the degree of methylation of the IGF2/H19 imprinting control region 1 (ICR1) and MEST differentially methylated regions in swim-up purified spermatozoa from 148 idiopathic infertile men and 33 normozoospermic controls

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Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility


Jul 2013 - PNAS

Bedrich Mosinger, Kevin M. Redding, M. Rockwell Parker, Valeriya Yevshayeva, Karen K. Yee, Katerina Dyomina, Yan Li, Robert F. Margolskee

TAS1R taste receptors and their associated heterotrimeric G protein gustducin are involved in sugar and amino acid sensing in taste cells and in the gastrointestinal tract. They are also strongly expressed in testis and sperm, but their functions in these tissues were previously unknown. Using mouse models, we show that the genetic absence of both TAS1R3, a component of sweet and amino acid taste receptors, and the gustducin α-subunit GNAT3 leads to male-specific sterility.

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Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans


Dec 2015 - Cell Metab

Ida Donkin, Soetkin Versteyhe, Lars R. Ingerslev, Kui Qian, Mie Mechta, Loa Nordkap, Brynjulf Mortensen, Emil Vincent R. Appel, Niels Jørgensen, Viggo B. Kristiansen, Torben Hansen, Christopher T. Workman, Juleen R. Zierath, Romain Barrès

Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized that weight loss remodels the epigenetic signature of spermatozoa in human obesity.

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Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health


Nov 2015 - Clin Epigenetics

Liborio Stuppia, Marica Franzago, Patrizia Ballerini, Valentina Gatta, Ivana Antonucci

The correlation between epigenetics and human reproduction represents a very interesting field of study, mainly due to the possible transgenerational effects related to epigenetic modifications of male and female gametes. In the present review, we focused our attention to the role played by epigenetics on male reproduction, evidencing at least four different levels at which sperm epigenetic modifications could affect reproduction: (1) spermatogenesis failure; (2) embryo development; (3) outcome of assisted reproduction technique (ART) protocols, mainly as concerning genomic imprinting; and (4) long-term effects during the offspring lifetime.

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Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans


Apr 2015 - Epigenomics

Joshua Denham, Brendan J. O’Brien, Jack T. Harvey, Fadi J. Charchar

DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation.

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Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility


May 2015 - Hum Reprod

Rocío G. Urdinguio, Gustavo F. Bayón, Marija Dmitrijeva, Estela G. Toraño, Cristina Bravo, Mario F. Fraga, Lluís Bassas, Sara Larriba, Agustín F. Fernández

Aberrant DNA methylation of sperm has been associated with human male infertility in patients demonstrating either deficiencies in the process of spermatogenesis or low semen quality. This study compares 46 sperm samples obtained from 17 normospermic fertile men and 29 normospermic infertile patients. Illumina Infinium HD Human Methylation 450K arrays were used to identify genomic regions showing differences in sperm DNA methylation patterns between five fertile and seven infertile individuals.

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Paternal long-term exercise programs offspring for low energy expenditure and increased risk for obesity in mice


Oct 2015 - FASEB J

Alexander K. Murashov, Elena S. Pak, Michael Koury, Ajay Ajmera, Maneesh Jeyakumar, Matthew Parker, Oksana Williams, Jian Ding, Dianne Walters, P. Darrell Neufer

Obesity has more than doubled in children and tripled in adolescents in the past 30 yr. The association between metabolic disorders in offspring of obese mothers with diabetes has long been known; however, a growing body of research indicates that fathers play a significant role through presently unknown mechanisms. Recent observations have shown that changes in paternal diet may result in transgenerational inheritance of the insulin-resistant phenotype.

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The epigenetic processes of meiosis in male mice are broadly affected by the widely used herbicide atrazine


Oct 2015 - BMC Genomics

Aurore Gely-Pernot, Chunxiang Hao, Emmanuelle Becker, Igor Stuparevic, Christine Kervarrec, Frédéric Chalmel, Michael Primig, Bernard Jégou, Fatima Smagulova

Environmental factors such as pesticides can cause phenotypic changes in various organisms, including mammals. We studied the effects of the widely used herbicide atrazine (ATZ) on meiosis, a key step of gametogenesis, in male mice. Gene expression pattern was analysed by Gene-Chip array.

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Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress


Nov 2015 - PNAS

Ali B. Rodgers, Christopher P. Morgan, N. Adrian Leu, and Tracy L. Bale

Epigenetic signatures in germ cells, capable of both responding to the parental environment and shaping offspring neurodevelopment, are uniquely positioned to mediate transgenerational outcomes. However, molecular mechanisms by which these marks may communicate experience-dependent information across generations are currently unknown. In our model of chronic paternal stress, we previously identified nine microRNAs (miRs) that were increased in the sperm of stressed sires and associated with reduced hypothalamic-pituitary-adrenal (HPA) stress axis reactivity in offspring.

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Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates


Sept 2011 - Cell

Antoine Molaro, Emily Hodges, Fang Fang, Qiang Song, W. Richard McCombie, Gregory J. Hannon, and Andrew Smith

During germ cell and preimplantation development, mammalian cells undergo nearly complete reprogramming of DNA methylation patterns. We profiled the methylomes of human and chimp sperm as a basis for comparison to methylation patterns of ESCs. Although the majority of promoters escape methylation in both ESCs and sperm, the corresponding hypomethylated regions show substantial structural differences.

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