According to the article of Pallav Sengupta & Sulagna Dutta published in The European Journal of Contraception & Reproductive Health Care the 09/ 07 / 2020 and disclosed in #OKILAB

Does SARS-CoV-2 infection cause sperm DNA
fragmentation? Possible link with oxidative stress

Pallav Sengupta & Sulagna Dutta
To cite this article: Pallav Sengupta & Sulagna Dutta (2020) Does SARS-CoV-2 infection cause sperm DNA fragmentation? Possible link with oxidative stress, The European Journal of Contraception & Reproductive Health Care, 25:5, 405-406,
To link to this article: https://doi.org/10.1080/13625187.2020.1787376

Dear Editor,
The severe acute respiratory syndrome (SARS)-coronavirus-2 (SARS-CoV-2) was first identified in December, 2019 in the Wuhan city, China [1] and subsequently declared pan-demic causing coronavirus disease-2019 (COVID-19), by the World Health Organisation (WHO) [1]. The occurrence of COVID-19 shows gender differences with men being more susceptible to SARS-CoV-2 infection and showing higher fatality rate compared to women. Angiotensin converting enzyme-2 (ACE2) receptor plays a key role in the COVID-19 pathogenesis. The SARS-CoV-2 infectivity initiates with the proteases-mediated priming of viral spike proteins with host cell receptors, mainly via the transmembrane protease, serine-2 (TMPRSS2), which cleaves ACE2 receptor, aiding the virus entry into host cell [2]. A breakthrough revelation in male fertility research is that testes show almost the highest ACE2 mRNA and protein expressions among vari-ous body tissues, mainly in seminiferous duct cells, sperma-togonia, Leydig and Sertoli cells [2].
SAR-CoV2 operates though multifaceted mechanisms which may lead to male reproductive disruption [3]. It acti-vates oxidant-sensitive pathways via inflammatory responses, thereby inducing oxidative stress (OS). In SARS-CoV infections, it has been reported that the excessive pro-duction of reactive oxygen species (ROS) may trigger mainly the NF-jB (nuclear factor kappa-light-chain-enhan-cer of activated B-cells)-toll-like receptor (mainly TLR-4) pathways [4]. This further stimulate release of cytokines causing exaggeration of the inflammatory responses [4]. It has also been reported that, this virus can potentially cause orchitis which also can lead to induction of OS, spermato-genic disruptions, germ cell apoptosis, thus, reduced semen quality [5]. Moreover, SARS-CoV-2 infection inflicts psychological stress, a major route to systemic OS [1,4]. Besides the direct relation of SARS-CoV-2 infection and OS, antiviral drugs like ribavirin, used for the management of COVID-19, reportedly induce OS, decrease testosterone level, impair spermatogenesis, reduce sperm count and cause sperm abnormalities. Moreover, ribavirin treatment reportedly is associated with SDF up to eight months fol-lowing cessation of treatment [6].
Impact of OS on testicular functions have been reported both at macro-levels depicted by reduced semen quality and endocrine disruptions, and at micro-levels via lipid per-oxidation of sperm membranes, and intracellular oxidative damage to spermatozoa, prominently sperm DNA fragmen-tation (SDF) [4,7]. These OS-induced damages, specifically SDF may adversely affect reproductive outcomes, as inher-ent integrity of the sperm DNA determines the success rate of fertilisation and subsequent embryo development [8]. OS-induced SDF can also be linked with miscarriage and infertility [8]. ROS disrupts sperm nuclear DNA integrity causing base modification, single or double strand breaks, and chromatin cross-link. Organisation, compaction and integrity of sperm chromatin protect it from ROS-induced damage. Indigent protamination of sperm chromatin and impaired compaction make it prone to OS-induced damage [8]. Oxidative base adducts and compromised spermiogen-esis are intensely associated with SDF. OS disrupts spermio-genesis and generates spermatozoa with poorly remodelled chromatin. Defective spermatozoa possess the tendency to initiate apoptotic pathways by caspase activa-tion, phosphatidylserine exteriorisation and the activation of free radical generation by the mitochondria. Generated radicals cause lipid peroxidation of sperm and SDF [8].
Aetiologies of SARS-CoV-2-mediated sperm DNA dam-age is not yet revealed. As the seminal dynamics of the virus is still not understood, till date there is no positive report of the occurrence of SARS-CoV-2 in human semen [9]. A study with limited cases reported absence of SARS-CoV-2 as observed via semen and testis biopsy and reverse transcription polymerase chain reaction test, while it is devoid of histopathological evidences [10]. However, a study based on SARS-CoV infected patients with orchitis, revealed histopathological evidences of inflammatory infil-trates in the seminiferous tubules [5], most strikingly, IgG deposition was found in seminiferous epithelium, intersti-tium, degenerated germ cells and Sertoli cells [5]. Thus, routes of secondary infection of SARS-CoV-2 stands a warn-ing of inflammatory progression in the testis thereby ren-dering the latter a hotbed for OS. This secondary infection-mediated OS in testis, thereby, may affect semen quality by elevating SDF by above-discussed mechanism.
Moreover, evidences indicate that SARS-CoV-2 infection in male causes acute-stage hypogonadism which has been linked with increased levels of pro-inflammatory cytokines, mainly IL-1b, IL-6, and TNF-a [11], suggesting exaggerated inflammatory progression following SARS-CoV-2 infection. Acute inflammatory conditions and associated OS predom-inantly suppress the HPT axis, resulting in low luteinizing hormone (LH), follicle-stimulating hormone (FSH) and tes-tosterone levels. But in case of COVID-19, a study con-ducted on 81 male patients reported higher LH levels, while lower serum testosterone levels, and lower T:LH ratio in comparison to 100 age-matched healthy men [12]. It has been reported that low testosterone and high levels of LH and FSH are associated with elevated levels of SDF [13]. Thus, following the limited literature correlating SARS-CoV-2 infection and male reproductive disruption, it can be hypothesised that OS is the central player of this infection-induced male reproductive changes, resulting in sperm DNA damage and subsequent infertility. In addition, as dis-cussed above, some anti-SARS-CoV-2 drugs, such as riba-virin treatment can also cause SDF even following cessation of treatment [6](Figure 1).

Thus, it can be concluded that SARS-CoV-2 infection may possibly affect sperm DNA and cause SDF through induction of OS following various direct oxidant-sensitive pathways, altering reproductive endocrinological milieu, or through the course of COVID-19 treatment using certain broad-spectrum anti-viral drugs. These reflections suggest that SARS-CoV-2-mediated SDF is surprisingly an unex-plored area awaiting immediate research attention.

Author contributions
P Sengupta: Conceptualisation, Literature search, Manuscript writing, Manuscript editing and review.
S Dutta: Conceptualisation, Literature search, Manuscript writing.

Disclosure statement
The authors declare that they have no conflict of interest.

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