Spermatozoon and male infertility

Goal of spermatozoon (2)

1. To fertilize to oocyte

2. To transfer the paternal genome to make the embryo

Where does sperm production start?

Sertoli cells in seminiferous tubules in the testis

How do the immobile spermatozoa move from the testis to the epididymis?

The seminiferous tubules squeeze them out

Why are Leydig cells in the interstitium essential to spermatozoon development?

Bc they produce testosterone which is an essential steroid hormones for spermatogenesis and for the normal function of the epididymis

Role of the macrophages in the interstitium

Immunological death cells

Epidiymal sperm maturation

Acquisition of motility and fertilizing ability (receptors for recognition of the oocyte)

Why can’t spermatozoon translate proteins?

Bc their nucleus is incredibly compacted

Seminal plasma

Fluid produced by prostate and seminal vesicle = antioxidant protection and nutrition

Important substance in the seminal plasma

Proteins that are de-capacitating factors = incapable to fertilize

Sperm count from vagina to oviduct/Fallopian tubes

40 millions to 1:1 ratio of sperm to oocyte

Capacitation of sperm

• Hyperactivation of sperm

• Increases from isthmus to the ampulla

Zona pellucida

Glycoprotein matrix that can be recognized and will induce the acrosome reaction

Acrosome reaction

Sperm releases hydrolytic enzymes that dissolve the zona pellucida and allow fertilization (zygote)

Changes in plasma membrane

Cholesterol efflux and lipid rearrangement

Changes in ions and ion channels

• Increase in Ca2+/Na+/pH

• Decrease of zinc and K+

• Activation of CatSper2 (Ca2+ channels)

Changes in enzymatic activities

• Kinase activities A and C, PI3K and AKT

• Increased RONS or reactive oxygen and nitrogen species

Infertility and males

1. 17.5% suffer from infertility

2. Comparable in high vs low income but more diagnostics in high-income

3. 50% of infertility is male infertility

Techniques that aide conception

IVF (in vitro) and ICSI (intracytoplasmic sperm injection)

Flaws associated with ICSI (5)

Increased risk of: obesity, type 2 diabetes, cardivascular disease, birth defects and childhood cancer

Main causes of male infertility

Unexplained (34%) and varicocele (17%, blocked veins)

Hypothesis behind the unexplained causes

High ROS + low antioxidant defense

Consequences of high ROS/low antioxydant defense

Oxidative stress causes impairment of motility, capacitation and acrosome reaction

Antioxydant enzymes in spermatozoon

No catalase so requires peroxiredoxins (PRDXs)

Roles of PRDXs (2)

1. Scavenge H2O2 (hydrogen peroxide) and peroxynitrite (NO3-)

2. Repair oxidized lipids

How was PRDX6 identified as the main peroxiredoxine?

90% of Idiopathic (on the rise and unknown causes) infertile men had an inactive PRDX6

Low PRDX6=

HIGH:

1. Lipid peroxidation

2. DNA fragmentation through oxidation

3. Tyrosine nitration

4. Cytoplasmic droplet retention

Specific PRDX6

Ca2+ PLA2 and peroxidase activities

How is PRDX6 provided to patients today vs in the future?

Antioxidant cocktails (Vit. Mixes) vs Personalized treatments