Sperm DNA Methylation Epimutation Biomarkers for Male Infertility and FSH Therapeutic Responsiveness

Marco, S. Luján; Caroppo, Ettore; Niederberger, Craig S.; Arce, Joan‐Carles; Sadler‐Riggleman, Ingrid; Beck, Daniel; Nilsson, Eric; Skinner, Michael K.

doi:10.1038/s41598-019-52903-1

Cited by 56 publications

(39 citation statements)

References 37 publications

(52 reference statements)

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“…A strong association has been reported between aberrant sperm DNA methylation and male infertility (Darbandi et al, 2019). Studies have shown that germ cell-specific DNA methylation aberrations might result in oligozoospermia, abnormal sperm morphology and decreased progressive sperm motility (Gunes, Agarwal, et al, 2018;Lujan et al, 2019). In oligozoospermic men, the maternally imprinted MEST gene DNA methylation was found to be significantly associated with elevated serum FSH levels and decreased testicular volume (Klaver et al, 2013).…”

Section: Methylation Characteristicsmentioning

confidence: 99%

Role of genetics and epigenetics in male infertility

Güneş

Esteves

2020

Andrologia

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Male infertility is a heterogeneous and common condition that might be a result of genetic or epigenetic variations or both. The frequency of genetic aberrations in azoospermic or severely oligozoospermic men is at least 15%, and the major genetic causes are karyotype abnormalities, microdeletions on Y chromosome, and mutations of cystic fibrosis transmembrane conductance regulator (CFTR) (Hamada, Esteves, & Agarwal, 2013; Hotaling & Carrell, 2014). Beyond these widely accepted genetic causes, a number of both autosomal and particularly X-chromosomal genes are associated with male infertility (Ropke & Tuttelmann, 2017). Furthermore, epigenetic control of gene expression plays a crucial role in both sperm function and fertilising ability (Gunes, Arslan, Hekim, & Asci, 2016a). Epigenetic regulation might be changed by external and internal factors or both, including environmental factors, nutrition and stress (Gunes, 2018b). This review summarises the latest evidence concerning the role of genetics and epigenetics on male infertility. 1.1 | Overview of human genome and genetics The haploid human genome consists of about 3 billion letters (3.3 billion nucleotides) distributed in 24 chromosomes. However, only 1.5% of the human genome encodes a protein (Gregory & Gilbert, 2005; Maher, 2012). The human genome project (HGP) has shown that genomes of nonrelated people exhibit a single base variation in every 1,200-1,500 DNA bases. These variations are

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Section: Methylation Characteristicsmentioning

confidence: 99%

Role of genetics and epigenetics in male infertility

Güneş

Esteves

2020

Andrologia

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“…Similarly, DNA methylation-mediated wide genomic imprinting is frequently altered in men with oligoasthenoteratozoospermia and oligozoospermia [ 129 , 130 ]. A molecular analysis of genome wide alterations in sperm DNA methylation has been used to identify male idiopathic infertility, being also responsive to follicle stimulating hormone (FSH) therapeutic approach [ 131 ].…”

Section: Epigenetic Signature Of Male Germlinementioning

confidence: 99%

“…Interestingly, toxicants also change DNA methylation status in sperm [ 210 ], at the level of paternally imprinted genes [ 211 ]. Abnormalities in the sperm’s nucleus due to altered DNA methylation are, indeed, one of the primary sources of environmental exposure-dependent male infertility [ 131 ]. Human genome includes a high percentage of long-interspersed nucleotide elements (LINE-1) which are heavily methylated in normal conditions; BPA exposure specifically influences LINE-1 methylation in SPZ [ 212 ].…”

Section: Epigenetic Mechanisms Are Sensitive To Environment and LImentioning

confidence: 99%

Environmental Impact on Male (In)Fertility via Epigenetic Route

Cescon

Chianese

Tavares

2020

JCM

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In the last 40 years, male reproductive health—which is very sensitive to both environmental exposure and metabolic status—has deteriorated and the poor sperm quality observed has been suggested to affect offspring development and its health in adult life. In this scenario, evidence now suggests that epigenetics shapes endocrine functions, linking genetics and environment. During fertilization, spermatozoa share with the oocyte their epigenome, along with their haploid genome, in order to orchestrate embryo development. The epigenetic signature of spermatozoa is the result of a dynamic modulation of the epigenetic marks occurring, firstly, in the testis—during germ cell progression—then, along the epididymis, where spermatozoa still receive molecules, conveyed by epididymosomes. Paternal lifestyle, including nutrition and exposure to hazardous substances, alters the phenotype of the next generations, through the remodeling of a sperm epigenetic blueprint that dynamically reacts to a wide range of environmental and lifestyle stressors. With that in mind, this review will summarize and discuss insights into germline epigenetic plasticity caused by environmental stimuli and diet and how spermatozoa may be carriers of induced epimutations across generations through a mechanism known as paternal transgenerational epigenetic inheritance.

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“…Another new and interesting line of investigation by Luj an et al (5) has involved the use of sperm DNA methylation patterns to identify potential responsiveness to FSH therapy. These investigators developed a molecular diagnostic study to determine genomewide alterations in sperm DNA methylation patterns that might categorize patients as being either responsive or nonresponsive to FSH therapy.…”

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confidence: 99%

“…Furthermore, they found that DMR results could be used to efficiently separate FSH therapy responders from nonresponders and concluded that their work serves as one of the first proof-of-principle studies that a therapeutic epigenetic biomarker could be developed. The investigators concluded their work by calling for the initiation of further studies, including clinical trials, to both validate and apply this new technology (5).…”

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confidence: 99%