By Paulo Navarro-Costa, University of Lisbon
By the time the average reader finishes reading this article, an estimated 400 babies will have been born around the world. Yet, the latest global figures indicate that 72.4 million people are denied, for clinical reasons, the joys of parenthood. Although advances in healthcare and therapeutic options over the past few decades have dramatically improved the chances of infertile couples to be natural parents, the underlying cause of infertility remains unknown in a significant number of cases. This fact reflects our as yet limited understanding of the intricate biological mechanisms regulating human reproduction. Our research at the Faculty of Medicine of the University of Lisbon aims to clarify some of these mechanisms. By doing so, we have established for the first time a link between male infertility and defects in DNA methylation in genes essential for normal sperm production.
In those couples in which the cause for infertility can be ascertained, available evidence indicates that males and females are equally likely to contribute to the condition. Nonetheless, recent data from the UK suggest that male infertility has been on the rise. Such type of infertility is most frequently the result of defects in the production or functioning of the sperm. The sperm corresponds to the male germ cell, the cell that carries the paternal information required by its female counterpart, the egg, to develop into an embryo. Not surprisingly, a descriptive analysis of observable defects such as the number, shape, and motility of sperm cells is a key test in diagnosing male infertility. However, finding out what causes such defects is an extremely difficult task. Male infertility is a complex, multi-factorial disease caused by a combination of genetic, lifestyle-related, and environmental aspects.
A most perplexing observation is that although male infertility is considered a disease with a significant genetic component, the number of mutations (changes in DNA sequence) effectively known to cause sperm defects in our species is small. Such paucity of known mutations is particularly bewildering given the significant effort directed at identifying new infertility-causing mutations. In an attempt to address this problem from a different angle, our team took an alternative approach: instead of focusing on what is written in the DNA sequences of infertile males, we looked at how such information is written.
For about half a century, scientists have appreciated the importance of genetic information encoded in the form of DNA sequences in separating health and disease. DNA sequences consist of a succession of building blocks, called nucleotides. Each gene, the functional unit of genetic information, is defined by a specific nucleotide sequence. Deviations from this sequence (referred to as mutations) usually result in defective genes that are incapable of carrying out their function.
More recently, it has become evident that heritable factors other than the actual nucleotide sequence play equally decisive roles in regulating biological processes. The term epigenetics was coined to refer to these heritable mechanisms that operate without changing the DNA sequence. Modifying DNA by adding methyl groups at specific regions, a process referred to as DNA methylation, is one of the most common epigenetic mechanisms in our species. DNA methylation serves as a regulator of the expression of genetic information: if a given gene is methylated, the cell will not express the information encoded by that gene.
Our research focused on finding out, for the first time, if DNA methylation of genes required for sperm production was in any way altered in infertile men. For this we selected two genes that were previously shown to be essential for normal sperm production, namely DAZ and DAZL, and compared their methylation between men with normal and abnormal sperm production. We observed that in cases of defective sperm production, the DAZL gene displayed significant methylation defects. This result, by linking defective sperm production to epigenetic disruption, is a first step in unravelling the complex epigenetic processes regulating male fertility.
Our observations may serve as a starting point for future clinically oriented developments in the field. Hopefully, these developments will lead in not-too-distant future, to a more effective treatment of male infertility through correction of methylation defects in the genes required for sperm production. Ultimately, this will benefit a significant number of infertile couples.
Paulo Navarro-Costa
University of Lisbon
www.atomiumculture.eu
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