Incorrect DNA methylation of the DAZL promoter CpG island associates with defective human sperm†

Navarro‐Costa, Paulo; Nogueira, Paulo; Carvalho, Marta; Leal, Francisco J. Vaz; Cordeiro, Isabel; Calhaz‐Jorge, Carlos; Gonçalves, João; Plancha, Carlos E.

doi:10.1093/humrep/deq200

Cited by 138 publications

(106 citation statements)

References 35 publications

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“…0 Flanking promoter of SPEF2 is hypomethylated in ejaculated semen and its methylation pattern is unrelated to sperm quality DNA methylation defects in genes are reportedly associated with impaired human sperm production and quality (Navarro-Costa et al 2010, Krausz et al 2012. Whether these differences in semen quality between fullsib bulls reflect differences in DNA methylation pattern has not been addressed yet.…”

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confidence: 99%

Alternative splicing, promoter methylation, and functional SNPs of sperm flagella 2 gene in testis and mature spermatozoa of Holstein bulls

Guo¹,

Yang²,

Ju³

et al. 2014

Reproduction

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The sperm flagella 2 (SPEF2) gene is essential for development of normal sperm tail and male fertility. In this study, we characterized first the splice variants, promoter and its methylation, and functional single-nucleotide polymorphisms (SNPs) of the SPEF2 gene in newborn and adult Holstein bulls. Four splice variants were identified in the testes, epididymis, sperm, heart, spleen, lungs, kidneys, and liver tissues through RT-PCR, clone sequencing, and western blot analysis. Immunohistochemistry revealed that the SPEF2 was specifically expressed in the primary spermatocytes, elongated spermatids, and round spermatids in the testes and epididymis. SPEF2-SV1 was differentially expressed in the sperms of high-performance and low-performance adult bulls; SPEF2-SV2 presents the highest expression in testis and epididymis; SPEF2-SV3 was only detected in testis and epididymis. An SNP (c.2851GOT) in exon 20 of SPEF2, located within a putative exonic splice enhancer, potentially produced SPEF2-SV3 and was involved in semen deformity rate and post-thaw cryopreserved sperm motility. The luciferase reporter and bisulfite sequencing analysis suggested that the methylation pattern of the core promoter did not significantly differ between the full-sib bulls that presented hypomethylation in the ejaculated semen and testis. This finding indicates that sperm quality is unrelated to SPEF2 methylation pattern. Our data suggest that alternative splicing, rather than methylation, is involved in the regulation of SPEF2 expression in the testes and sperm and is one of the determinants of sperm motility during bull spermatogenesis. The exonic SNP (c.2851GOT) produces aberrant splice variants, which can be used as a candidate marker for semen traits selection breeding of Holstein bulls.

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confidence: 99%

Alternative splicing, promoter methylation, and functional SNPs of sperm flagella 2 gene in testis and mature spermatozoa of Holstein bulls

Guo¹,

Yang²,

Ju³

et al. 2014

Reproduction

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“…Of the sperm biomarkers, the human sperm membrane protein SP22 was shown to decline after exposure to both epidydimal and testicular toxicants in rat and ram models, changes in human sperm gene expression or mRNA transcript content [24,[42][43][44]. DNA methylation profile during human spermatogenesis were correlated with impair of sperm quality (such as concentration, morphology and motility); and another specific group of sperm mRNA transcripts was shown to predict low level exposures to Sertoli cell toxicants in the rat [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Assessing Male Reproductive Toxicity during Drug Development

Sousa¹,

Ferreira²,

Rabaça³

et al. 2017

Andrology

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Medical drug development is a crucial research field that attends to population healthcare needs, comprising several preclinical and clinical steps before the approval of a new compound. One major cause of pharmaceutical drug development failure is toxicity, especially in respect to kidney and liver. Nonetheless, the male reproductive system may also be a target for drug toxicity. Although the reproductive health is an important component of the person life, reproductive toxicology testing is rarely performed, both in pre-clinical and clinical trial phases. As reproductive and testicular toxicity is found at a low incidence during the early stages of drug development, companies devote the majority of research investments to more frequent areas of toxic occurrence. It is here suggested the inclusion of comprehensive studies and more precise methods to uncover the toxic reproductive effects and causes when developing new pharmacological drugs.

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“…Deleted in Azoospermia-like (DAZL) is a key spermatogenesis gene important for primordial germ cell formation, while it is also expressed in mature sperm [71,72]. Single Nucleotide Polymorphisms (SNPs) as well as aberrant methylation in the promoter of DAZL are associated with abnormal semen parameters [73,74], indicating that this is an important gene for male fertility. DAZL has been found to be abundantly expressed in the pre-implantation embryo from the 2-cell stage, however this is thought to come through maternal genome control, and so the contribution of paternal DAZL methylation is yet to be determined [75].…”

Section: Dna Methylation In Sperm Function and Male Infertilitymentioning

confidence: 99%