Reactive Nitrogen Species and Male Reproduction: Physiological and Pathological Aspects
Abstract
:1. Introduction
2. Mechanism of Formation of RNS
3. Physiological Significance of RNS
3.1. RNS as Cell Signal Transducers
3.2. RNS in the Formation of Blood–Testes Barrier (BTB)
3.3. RNS as Male Reproductive Immune Modulators
3.4. NO and Sperm Parameters
3.5. NO and Sperm Genetics
4. Pathological Effects of RNS
4.1. NO and Induction of Apoptosis in Testicular Cells
4.2. NO and Steroidogenesis
4.3. NO-Mediated Sperm Lipid Peroxidation
4.4. NO and Impaired Sperm Function
4.5. RNS and Leukocytospermia
4.6. Varicocele
4.7. Erectile Dysfunction (ED)
4.8. Diabetes Mellitus (DM)
4.9. Strategies to Measure RNS
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Type(s) of RNS | Concentration | Experimental Model | Physiological and Pathological Effects | Reference(s) |
---|---|---|---|---|
TnNOS | - | Human | Aids in the process of steroidogenesis | [19,20] |
eNOS | 50–100 nM | Human | Aberrant patterns of sperm eNOS expression associated with decreased sperm motility (r = −0.46; p < 0.05) | [21,22] |
iNOS | >1 mM | Human | Structural association with various tight junction-proteins, including actin, occludin, vimentin, and α-tubulin, vital in modulating the Sertoli cells tight junctions maintaining the BTB | [14] |
SNP | (i). 0.25–2.5 mM (ii). 10−6 to 10−4 M | Human | NO induced decreased in sperm motility (p < 0.01) and viability (p < 0.05). Reduction of sperm motility in a dose- and time-dependent manner by SNP. Sperm progressive motility, and concentration of motile cells also reduced by all SNP doses (p < 0.005) | [23,24,25] |
SNAP | 0–1.2 nmol/106 spermatozoa | Human | A positive correlation was seen between the concentrations of NO and the percentage of immotile spermatozoa (p < 0.01). | [25] |
Method(s) | Type | Principle | Advantage(s) | Reference(s) |
---|---|---|---|---|
Cytochrome C reduction test | Direct | Reduction of ferricytochrome C to ferrocytochrome C is used to detect superoxide formation. | Gold standard for measuring extracellular superoxide anions. | [87] |
Electron spin resonance (ESR), electron paramagnetic resonance (EPR) | Direct | (i) Magnetic properties of unpaired electrons in free radicals enable them to absorb electromagnetic radiation on application of external magnetic field; this then generates absorption spectra utilizing the energy of the electron spin state, which is measured using ESR spectrophotometers. (ii) Provide direct detection of the “instantaneous” presence of free radical species in a sample. (iii) Play a major role in the assessment of most of the oxidants characterized by very short half-life (nanoseconds to microseconds) usually by using stabilizing molecules called spin-traps/probes. | (i) Used to measure oxidative stress on proteins and lipids. Simple, and have high sensitivity and specificity. (ii) Detects free radicals and paramagnetic molecules. The magnetic field-based EPR detection enables nondestructive (in vitro) and noninvasive (in vivo) measurements of biological samples. EPR spectroscopy, coupled with the use of paramagnetic probes, is a potential technique for accurate and precise determination of ROS concentrations in a variety of biological samples. | [86,90] |
Xylenol orange-based assay | Direct | (i) Uses automated analyzer. (ii) ROS in semen oxidizes ferrous to ferric ion and this forms a colored complex with xylenol orange in an acidic medium, the color intensity of which can be measured spectrophotometrically. (iii) Results are expressed in μmol H O2 2 equiv./L. | It is rapid, easy, stable, inexpensive, reliable, and sensitive. | [104] |
ROS measurement via chemiluminescence | Direct | (i) Measures real-time production of ROS. (ii) Uses two probes—luminol and lucigenin. (iii) Luminol measures global ROS levels, both extracellular and intracellular (superoxide anion, hydrogen peroxide, and hydroxyl radical). (iv) Lucigenin is specific for superoxide anion and hydroxyl radical. | Chemiluminescence is a robust, sensitive, and specific method. | [105,106,107,108,109,110,111] |
Flow cytometry | Direct | (i) ROS measurement of hydrogen peroxide and superoxide anion via flow cytometry. (ii) Dihydroethidium measures intracellular superoxide anion and dichlorofluoroscein diacetate for intracellular hydrogen peroxide. | Requires very low amounts of spermatozoa, and high-specificity intracellular ROS in spermatozoa. | [102,112,113,114] |
Endtz test | Indirect | (i) ROS is mainly generated by leukocytes. (ii) Myeloperoxidase is used to stain polymorphonuclear granulocytes, but does not provide any information regarding ROS generation by spermatozoa. | Indirect indicator of excessive ROS generation by leukocytes in semen. | [91,102,104] |
Redox potential GSH/GSSG | Indirect | (i) Balance of reduced glutathione and its oxidized form (GSSG) gives an indication of ROS levels in vivo. (ii) GSH/GSSG levels are measured biochemically or using high-performance liquid chromatography. | Can be used to measure oxidative stress in vitro and in vivo. | [92,93] |
Thiobarbituric acid assay (TBARS) | Indirect | (i) Measures lipid peroxidation. (ii) Detects malondialdehyde (MDA-TBA) adduct by colorimetry or fluoroscopy. | Simple but non-specific. | [103,104] |
Oxidation-reduction potential | Indirect | (i) Measures the redox balance in a given biological system. (ii) It measures all known and unknown oxidants and antioxidants in a given sample. | Can be measured both in seminal ejaculates and in seminal plasma (both fresh and frozen). | [98,99,100] |
Technique | Principle | Advantage(s) | Disadvantage(s) | Reference(s) |
---|---|---|---|---|
Thiobarbituric acid assay (TBARS) | MDA-TBA adduct detection using colorimetry or fluoroscopy | Simple but non-specific | Rigorous controls are required | [94,95] |
Isoprostane | EIA/liquid chromatography–tandem mass spectrometry | Specificity, stable compound | Labor-intensive and expensive equipment required | [115] |
HNE-His Adduct ELISA | ELISA | Rapid, helps in quantification | Chances of cross-reactivity | [117,118,119] |
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Dutta, S.; Sengupta, P.; Das, S.; Slama, P.; Roychoudhury, S. Reactive Nitrogen Species and Male Reproduction: Physiological and Pathological Aspects. Int. J. Mol. Sci. 2022, 23, 10574. https://doi.org/10.3390/ijms231810574
Dutta S, Sengupta P, Das S, Slama P, Roychoudhury S. Reactive Nitrogen Species and Male Reproduction: Physiological and Pathological Aspects. International Journal of Molecular Sciences. 2022; 23(18):10574. https://doi.org/10.3390/ijms231810574
Chicago/Turabian StyleDutta, Sulagna, Pallav Sengupta, Sanghamitra Das, Petr Slama, and Shubhadeep Roychoudhury. 2022. "Reactive Nitrogen Species and Male Reproduction: Physiological and Pathological Aspects" International Journal of Molecular Sciences 23, no. 18: 10574. https://doi.org/10.3390/ijms231810574