Role of sperm chromatin abnormalities and DNA damage in male infertility.

Abstract

Sperm DNA integrity is essential for the accurate transmission of genetic information. It has a highly compact and complex structure and is capable of decondensation-features that must be present in order for a spermatozoon to be considered fertile. Any form of sperm chromatin abnormalities or DNA damage may result in male infertility. In support of this conclusion, it was reported that in-vivo fecundity decreases progressively when > 30% of the spermatozoa are identified as having DNA damage. Several methods are used to assess sperm chromatin/DNA, which is considered an independent measure of sperm quality that may yield better diagnostic and prognostic approaches than standard sperm parameters (concentration, motility and morphology). The clinical significance of this assessment lies in its association not only with natural conception rates, but also with assisted reproduction success rates. Also, it has a serious impact on the offspring and is highly prognostic in the assessment of fertility in cancer patients. Therefore, screening for sperm DNA damage may provide useful information in cases of male idiopathic infertility and in those men pursuing assisted reproduction. Treatment should include methods for prevention of sperm DNA damage.

What is the Y Chromosome?

Functions of the Y chromosome

In mammals, the Y chromosome contains the SRY gene which is key to the development of the testes in males. Without this gene, the testes would not develop and the fetus would become a female.

The Y chromosome spans approximately 58 million base pairs, contains 86 genes, and represents around 2% of the total DNA in a human male. Traits that are passed from father to son on the Y chromosome are referred to as holandric traits, meaning they only occur in males. Aside from very small regions present at the telomeres, the Ychromosome is unable to recombine with an X chromosome. This majority portion of the Y chromosome is referred to as the non-combining region of the Y chromosome and the single nucleotide polymorphisms in this region are used to determine paternal ancestry.

Genes on the Y chromosome

Genes present on the Y chromosome that correspond to a similar gene on the Xchromosome include:

• AMELY/AMELX (amelogenin)
• RPS4Y1/RPS4Y2/RPS4X (ribosomal protein S4)

Genes that are exclusive to the Y chromosome include:

• AZF1 (azoospermia factor 1)
• BPY2 (basic protein on the Y chromosome)
• DAZ1 (deleted in azoospermia 1)
• DAZ2 (deleted in azoospermia 2)
• PRKY (Y-linked protein kinase)
• RBMY1A1 (RNA Binding Motif Protein, Y-linked, family 1, member A1) 
• SRY (sex-determining region Y)
• TSPY (testis-specific protein, Y-linked)
• USP9Y (ubiquitin specific peptidase 9, Y-linked)
• UTY (ubiquitously transcribed tetratricopeptide repeat containing, TPR gene on Y-linked)
• ZFY (zinc finger protein, Y-linked)

Y-linked disease or disorders

Severalc onditions that are specifically linked to the Y chromosome and only transmitted from father to son include:

• Defective or deformed Y chromosome that leads to features of feminization andinfertility
• Numerical disorders – These are conditions that arise due to the presence of an abnormal number of chromosomes. In Klinefelter’s syndrome, for example, an additional X chromosome is present, giving an XXY configuration. This condition is characterized by hypogonadism which usually manifests after puberty and refers to incompetence of the gonads in producing androgen, sperm, or both, which can render the male sterile.

What is the X Chromosome?

There are 23 pairs of chromosomes in the human body. This includes 22 pairs of autosomal or somatic chromosomes that are common to both men and women and onechromosome that differs according to what gender a person is (sex chromosomes).

The sex chromosomes are the X chromosome and the Y chromosome. In a man, both an X and a Y chromosome are present, giving an XY configuration. In a woman, there are two X chromosomes, giving an XX configuration. The X chromosome is therefore one of the two sex chromosomes that determines an individual’s gender.

Functions of the X chromosome

The X chromosome contains over 153 million base pairs, the building blocks of DNA. In women, the X chromosome represents almost 5% of the total DNA and in men, who have only one X chromosome, it represents about 2.5% of the total DNA.

Men inherit the X chromosome they have from their mother and the Y chromosome from their father, while women inherit one X chromosome from the mother and the other from the father.

There are around 2000 genes located on the X chromosome and genetic research is focused on identifying these genes. This compares with 78 genes on the Y chromosome out of approximately 20,000 to 25,000 present in the human genome.

When X chromosomal genes are mutated, they may give rise to genetic conditions and these are termed X-linked disorders.

Genetic disorders that arise from missing, additional or malformed copies of the X chromosome are termed numerical disorders. Examples include Klinefelter’s syndrome where a male has one or more extra copies; Triple X syndrome, where a female has one extra copy and Turner syndrome where a female has one normal X chromosome and one missing or abnormal one.

sperm

The cellular biology of a sperm

Each human cell contains 23 pairs of chromosomes. These undergo division in a process called mitosis. Mitosis produces daughter cells that contain 23 pairs of chromosomes, one one half of which is inherited from the mother and the other from the father.

For this purpose, the male and female reproductive cells or gametes need to undergo another form of cell division called meiosis where the cell is divided into cell generated contains only 23 or half of the 46 chromosomes. The gamete cells are the eggs or ova found in females and the sperm found in males. The termed used to describe these cells containing only half the total chromosme number is "haploid".

Structure of the sperm

When the sperm has the usual single flagellum (or "tail"), it is called a spermatozoon and may be described as uniflagellate. The flagellum moves in a whip-like manner, propelling the the sperm towards the egg and uniflagellated sperm are also termed motile sperm.

A non-motile sperm that lacks a flagellum is called a spermatium. A sperm may contain an X chromosome and produce female off spring after fertilizing the ovum or it may have a Y chromosome, in which case fertilization will lead to the development of male offspring.

The sperm consists of a head that is about 5 µm by 3 µm in size and a flagellum of around 50 μm in length. There is little cytoplasm in sperm and the "head" is densely packed with DNA. Sperm is released from the male in a fluid called semen. Semen is alkaline and does not allow the sperm to be completely motile until they reach the female reproductive tract or the vagina which is acidic in pH.