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Recent insights on the significance of transcriptomic and metabolomic analysis of male factor infertility

Lee LK, Foo KY

Clin Biochem, 2014 Jul;47(10-11):973-82.
PMID: 24875852 DOI: 10.1016/j.clinbiochem.2014.05.053

Infertility is a worldwide reproductive health problem which affects approximately 15% of couples, with male factor infertility dominating nearly 50% of the affected population. The nature of the phenomenon is underscored by a complex array of transcriptomic, proteomic and metabolic differences which interact in unknown ways. Many causes of male factor infertility are still defined as idiopathic, and most diagnosis tends to be more descriptive rather than specific. As such, the emergence of novel transcriptomic and metabolomic studies may hold the key to more accurately diagnose and treat male factor infertility. This paper provides the most recent evidence underlying the role of transcriptomic and metabolomic analysis in the management of male infertility. A summary of the current knowledge and new discovery of noninvasive, highly sensitive and specific biomarkers which allow the expansion of this area is outlined.

Matched MeSH terms: Infertility, Male/metabolism*
Fulltext SARS-CoV-2 and Male Infertility: Possible Multifaceted Pathology

Dutta S, Sengupta P

Reprod Sci, 2021 Jan;28(1):23-26.
PMID: 32651900 DOI: 10.1007/s43032-020-00261-z

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19) has been declared a pandemic by the World Health Organization (WHO) on 11th March 2020. Bulk of research on this virus are carried out to unveil its multivariate pathology. Surprisingly, men are reportedly more vulnerable to COVID-19 even with higher fatality rate compared to women. Thus, it is crucial to determine whether SARS-CoV-2 infection can even affect male fertility as an immediate or long-term consequence of the disease. Among the discrete data available, an important finding is that angiotensin converting enzymes 2 (ACE2) receptor, that aids the SARS-CoV-2 entry into host cells, is profoundly expressed in testicular cells. In addition, the endogenous androgen milieu and its receptors are associated with ACE2 activation reflecting that enhanced testosterone levels may trigger the pathogenesis of COVID-19. In contrary, hypogonadism has also been reported in the acute phase of some COVID-19 cases. Moreover, SARS-CoV-2 infection-induced uncontrolled inflammatory responses may lead to systemic oxidative stress (OS), whose severe disruptive effects on testicular functions are well-documented. This article aims to precisely present the possible impact of COVID-19 on male reproductive functions, and to highlight the speculations that need in-depth research for the exact underlying mechanisms how COVID-19 is associated with men's health and fertility.

Matched MeSH terms: Infertility, Male/metabolism
Differential proteomic profiling of spermatozoal proteins of infertile men with unilateral or bilateral varicocele

Agarwal A, Sharma R, Durairajanayagam D, Cui Z, Ayaz A, Gupta S, et al.

Urology, 2015 Mar;85(3):580-8.
PMID: 25733269 DOI: 10.1016/j.urology.2014.11.030

To compare the sperm protein profile between infertile men with unilateral varicocele and infertile men with bilateral varicocele.

Matched MeSH terms: Infertility, Male/metabolism*
Aberrant Upregulation of Compensatory Redox Molecular Machines May Contribute to Sperm Dysfunction in Infertile Men with Unilateral Varicocele: A Proteomic Insight

Swain N, Samanta L, Agarwal A, Kumar S, Dixit A, Gopalan B, et al.

Antioxid Redox Signal, 2020 03 10;32(8):504-521.
PMID: 31691576 DOI: 10.1089/ars.2019.7828

Aims:
To understand the molecular pathways involved in oxidative stress (OS)-mediated sperm dysfunction against a hypoxic and hyperthermic microenvironment backdrop of varicocele through a proteomic approach.
Results:
Protein selection (261) based on their role in redox homeostasis and/or oxidative/hyperthermic/hypoxic stress response from the sperm proteome data set of unilateral varicocele (UV) in comparison with fertile control displayed 85 to be differentially expressed. Upregulation of cellular oxidant detoxification and glutathione and reduced nicotinamide adenine dinucleotide (NADH) metabolism accompanied with downregulation of protein folding, energy metabolism, and heat stress responses were observed in the UV group. Ingenuity pathway analysis (IPA) predicted suppression of oxidative phosphorylation (OXPHOS) (validated by Western blotting [WB]) along with augmentation in OS and mitochondrial dysfunction in UV. The top affected networks indicated by IPA involved heat shock proteins (HSPs: HSPA2 and HSP90B1). Their expression profile was corroborated by immunocytochemistry and WB. Hypoxia-inducible factor 1A as an upstream regulator of HSPs was predicted by MetaCore. Occurrence of reductive stress in UV spermatozoa was corroborated by thiol redox status.
Innovation:
This is the first evidence of a novel pathway showing aberrant redox homeostasis against chronic hypoxic insult in varicocele leading to sperm dysfunction.
Conclusions:
Upregulation of antioxidant system and dysfunctional OXPHOS would have shifted the redox balance of biological redox couples (GSH/GSSG, NAD+/NADH, and NADP+/NADPH) to a more reducing state leading to reductive stress. Chronic reductive stress-induced OS may be involved in sperm dysfunction in infertile men with UV, where the role of HSPs cannot be ignored. Intervention with antioxidant therapy warrants proper prior investigation.

Matched MeSH terms: Infertility, Male/metabolism*
Leptin and reproductive dysfunction in obese men

Almabhouh FA, Md Mokhtar AH, Malik IA, Aziz NAAA, Durairajanayagam D, Singh HJ

Andrologia, 2020 Feb;52(1):e13433.
PMID: 31773771 DOI: 10.1111/and.13433

Infertility is somewhat more prevalent in men who are obese. They are also reported to have low sperm concentration, higher fraction of spermatozoa that look morphologically abnormal, higher DNA fragmentation index and evidence of oxidative stress. The precise cause for this remains uncertain. Leptin levels in serum and percentage body fat correlate positively, and obese men therefore usually have elevated serum leptin levels. Although leptin is important for normal reproductive function, but when present in excess, leptin could seriously affect reproductive function in men. Reports on the findings of sperm parameters in obese men, particularly those who are subfertile or infertile, seem to be similar to those reported from studies on normal-weight rats treated with leptin. Collectively, the observations reported in human and experimental animal studies point to leptin as a possible link between infertility and obesity. Herein, we review some findings on sperm function in obese subfertile or infertile men and those from animal studies following leptin treatment, and discuss the possible link between leptin and reproductive dysfunction in obese men. The large amounts of leptin secreted by the adipose tissue and its higher circulating levels could indeed be responsible for the higher prevalence of infertility in obese men.

Matched MeSH terms: Infertility, Male/metabolism
Fulltext Mammalian sperm fertility related proteins

Ashrafzadeh A, Karsani SA, Nathan S

Int J Med Sci, 2013;10(12):1649-57.
PMID: 24151436 DOI: 10.7150/ijms.6395

Infertility is an important aspect of human and animal reproduction and still presents with much etiological ambiguity. As fifty percent of infertility is related to the male partner, molecular investigations on sperm and seminal plasma can lead to new knowledge on male infertility. Several comparisons between fertile and infertile human and other species sperm proteome have shown the existence of potential fertility markers. These proteins have been categorized into energy related, structural and other functional proteins which play a major role in sperm motility, capacitation and sperm-oocyte binding. The data from these studies show the impact of sperm proteome studies on identifying different valuable markers for fertility screening. In this article, we review recent development in unraveling sperm fertility related proteins.

Matched MeSH terms: Infertility, Male/metabolism
Orlistat attenuates obesity-induced decline in steroidogenesis and spermatogenesis by up-regulating steroidogenic genes

Suleiman JB, Nna VU, Othman ZA, Zakaria Z, Bakar ABA, Mohamed M

Andrology, 2020 09;8(5):1471-1485.
PMID: 32438512 DOI: 10.1111/andr.12824

BACKGROUND: Steroidogenesis decline is reported to be one of the mechanisms associated with obesity-induced male factor subfertility/infertility.
OBJECTIVES: We explored the possible preventive/therapeutic effects of orlistat (a medication prescribed for weight loss) on obesity-induced steroidogenesis and spermatogenesis decline.
MATERIALS AND METHODS: Twenty-four adult male Sprague Dawley rats weighing 250-300 g were randomized into four groups (n = 6/group), namely; normal control, high-fat diet, high-fat diet plus orlistat preventive group and high-fat diet plus orlistat treatment group. Orlistat (10 mg/kg/b.w./d suspended in distilled water) was either concurrently administered with high-fat diet for 12 weeks (high-fat diet plus orlistat preventive group) or administered from week 7-12 post- high-fat diet feeding (high-fat diet plus orlistat treatment group). Thereafter, serum, testes and epididymis were collected for analyses.
RESULTS: Obesity increased serum leptin and decreased adiponectin levels, decreased serum and intra-testicular levels of follicle stimulating hormone, luteinising hormone and testosterone, sperm count, motility, viability, normal morphology and epididymal antioxidants, but increased epididymal malondialdehyde level and sperm nDNA fragmentation. Testicular mRNA transcript levels of androgen receptor, luteinizing hormone receptor, steroidogenic acute regulatory protein, cytochrome P450 enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase were significantly decreased in the testes of the high-fat diet group. Further, the levels of steroidogenic acute regulatory protein protein and enzymatic activities of CYP11A1, 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase were also significantly decreased in the testes of the high-fat diet group. Treatment with orlistat significantly decreased leptin and increased adiponectin levels, improved sperm parameters, decreased sperm DNA fragmentation, increased the levels of steroidogenic hormones, proteins and associated genes in high-fat diet-induced obese male rats, with the preventive group (high-fat diet plus orlistat preventive group) having better results relative to the treatment group (high-fat diet plus orlistat treatment group).
DISCUSSION AND CONCLUSION: Orlistat attenuated impaired spermatogenesis and steroidogenesis decline by up-regulating steroidogenic genes. This may not be unconnected to its significant effect in lowering serum leptin levels, since the hormone is known to dampen fertility potential. Therefore, orlistat may improve fertility potential in overweight/obese men.

Matched MeSH terms: Infertility, Male/metabolism*
Reactive oxygen species-induced alterations in H19-Igf2 methylation patterns, seminal plasma metabolites, and semen quality

Darbandi M, Darbandi S, Agarwal A, Baskaran S, Dutta S, Sengupta P, et al.

J Assist Reprod Genet, 2019 Feb;36(2):241-253.
PMID: 30382470 DOI: 10.1007/s10815-018-1350-y

PURPOSE: This study was conducted in order to investigate the effects of reactive oxygen species (ROS) levels on the seminal plasma (SP) metabolite milieu and sperm dysfunction.
METHODS: Semen specimens of 151 normozoospermic men were analyzed for ROS by chemiluminescence and classified according to seminal ROS levels [in relative light units (RLU)/s/106 sperm]: group 1 (n = 39): low (ROS male infertility and its management through assisted reproduction technology (ART).

Matched MeSH terms: Infertility, Male/metabolism
Fulltext Chlorophytum borivilianum (Safed Musli) root extract prevents impairment in characteristics and elevation of oxidative stress in sperm of streptozotocin-induced adult male diabetic Wistar rats

Giribabu N, Kumar KE, Rekha SS, Muniandy S, Salleh N

BMC Complement Altern Med, 2014;14:291.
PMID: 25104050 DOI: 10.1186/1472-6882-14-291

We hypothesized that C. borivilianum root, known to improve male reproductive performance, prevents impairment in characteristics, morphology and elevation of oxidative stress in sperm of diabetics. We therefore investigated the effect of aqueous root extract of C. borivilianum on these parameters in diabetic rat model.

Matched MeSH terms: Infertility, Male/metabolism