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1.
Nat Rev Urol ; 19(2): 116-127, 2022 02.
Article in English | MEDLINE | ID: covidwho-1541219

ABSTRACT

Although many studies have focused on SARS-CoV-2 infection in the lungs, comparatively little is known about the potential effects of the virus on male fertility. SARS-CoV-2 infection of target cells requires the presence of furin, angiotensin-converting enzyme 2 (ACE2) receptors, and transmembrane protease serine 2 (TMPRSS2). Thus, cells in the body that express these proteins might be highly susceptible to viral entry and downstream effects. Currently, reports regarding the expression of the viral entry proteins in the testes are conflicting; however, other members of the SARS-CoV family of viruses - such as SARS-CoV - have been suspected to cause testicular dysfunction and/or orchitis. SARS-CoV-2, which displays many similarities to SARS-CoV, could potentially cause similar adverse effects. Commonalities between SARS family members, taken in combination with sparse reports of testicular discomfort and altered hormone levels in patients with SARS-CoV-2, might indicate possible testicular dysfunction. Thus, SARS-CoV-2 infection has the potential for effects on testis somatic and germline cells and experimental approaches might be required to help identify potential short-term and long-term effects of SARS-CoV-2 on male fertility.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , Renin-Angiotensin System/physiology , SARS-CoV-2/physiology , Testis/metabolism , Testis/physiopathology , Humans , Male , Serine Endopeptidases/metabolism , Virus Internalization
2.
Andrology ; 9(1): 39-41, 2021 01.
Article in English | MEDLINE | ID: covidwho-1388168

ABSTRACT

BACKGROUND: The recent report of SARS-CoV-2 presence in semen samples of six patients, including two subjects who were recovering from the clinical disease, re-opened the discussion on possible male genital tract infection, virus shedding in semen, sexual transmission and safety of fertility treatments during the pandemic period. OBJECTIVES: To explore current data and hypothesis on the possible sites of SARS-CoV-2 infection in the male reproduction system. MATERIALS AND METHODS: We reviewed the current literature to describe: a) the evidences on angiotensin-converting enzyme 2 (AC2E) and transmembrane serine protease 2 (TMPRSS2) expression in the testes, accessory glands (including prostate) and the urinary tract; b) other coronaviruses' (SARS and MERS) ability to infect these sites. RESULTS: The co-expression of both ACE2 and TMPRSS2 genes was reported in spermatogonial stem cells, elongated spermatids, in at least a small percentage of prostate hillock cells and in renal tubular cells. Testicular damage was described in autopsies of SARS patients, without evidence of the virus in the specimens. Prostate is a known infection site for MERS-CoV. SARS-CoV-2 was detected in urines. DISCUSSION: There are still al lot of open questions on the effects of SARS-CoV-2 infection on the male reproductive tract. The presence of receptors is not a proof that the testis provides a site for viral infection and it is still unknown if SARS-CoV-2 is capable to pass the blood-testis barrier. The possibility of a prostate involvement has not been investigated yet: we have no data, but theoretically it cannot be excluded. Moreover, the RNA detected in semen could have been just a residual of urinary shedding. CONCLUSION: Opening our prospective beyond the testis could be the key to better understand the possibility of a semen-related viral transmission as well as COVID19 short and long-term effects on male reproductive function.


Subject(s)
COVID-19/virology , SARS-CoV-2/isolation & purification , Semen/virology , Testis/virology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/transmission , Humans , Male , Receptors, Virus/metabolism , Serine Endopeptidases/metabolism , Testis/metabolism , Testis/pathology , Virus Internalization , Virus Shedding
3.
Cells ; 10(6)2021 06 12.
Article in English | MEDLINE | ID: covidwho-1270010

ABSTRACT

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA-lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA-lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.


Subject(s)
COVID-19/complications , Gene Regulatory Networks , Infertility, Male/virology , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Adult , Angiotensin-Converting Enzyme 2/physiology , COVID-19/genetics , Computational Biology/methods , Computer Simulation , Gene-Environment Interaction , Humans , Infertility, Male/genetics , Male , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/physiology , Testis/metabolism , Testis/pathology , Testis/virology , Virus Internalization
4.
Apoptosis ; 26(7-8): 415-430, 2021 08.
Article in English | MEDLINE | ID: covidwho-1252148

ABSTRACT

To evaluate the incidence of apoptosis within the testes of patients who died from severe acute respiratory syndrome coronavirus 2 (COVID-19) complications, testis tissue was collected from autopsies of COVID-19 positive (n = 6) and negative men (n = 6). They were then taken for histopathological experiments, and RNA extraction, to examine the expression of angiotensin-converting enzyme 2 (ACE2), transmembrane protease, serine 2 (TMPRSS2), BAX, BCL2 and Caspase3 genes. Reactive oxygen species (ROS) production and glutathione disulfide (GSH) activity were also thoroughly examined. Autopsied testicular specimens of COVID-19 showed that COVID-19 infection significantly decreased the seminiferous tubule length, interstitial tissue and seminiferous tubule volume, as well as the number of testicular cells. An analysis of the results showed that the Johnsen expressed a reduction in the COVID-19 group when compared to the control group. Our data showed that the expression of ACE2, BAX and Caspase3 were remarkably increased as well as a decrease in the expression of BCL2 in COVID-19 cases. Although, no significant difference was found for TMPRSS2. Furthermore, the results signified an increase in the formation of ROS and suppression of the GSH activity as oxidative stress biomarkers. The results of immunohistochemistry and TUNEL assay showed that the expression of ACE2 and the number of apoptotic cells significantly increased in the COVID-19 group. Overall, this study suggests that COVID-19 infection causes spermatogenesis disruption, probably through the oxidative stress pathway and subsequently induces apoptosis.


Subject(s)
COVID-19/complications , Oxidative Stress/physiology , SARS-CoV-2/pathogenicity , Spermatogenesis/physiology , Testis/virology , Apoptosis , Humans , Male , Middle Aged , Reactive Oxygen Species/metabolism , Serine Endopeptidases/metabolism , Testis/metabolism
5.
Biochemistry (Mosc) ; 86(4): 389-396, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1150206

ABSTRACT

The novel coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health emergency worldwide with over 118.27-million confirmed COVID-19 cases and 2.62-million deaths recorded, as of March 12, 2021. Although this disease primarily targets lungs, damages in other organs, such as heart, kidney, liver, and testis, may occur. Testis is the cornerstone of male reproduction, while reproductive health is the most valuable resource for continuity of the human race. Given the unique nature of SARS-CoV-2, the mechanisms of its impact on the testes have yet to be fully explored. Notably, coronaviruses have been found to invade target cells through the angiotensin-converting enzyme 2 receptor, which can be found in the respiratory, gastrointestinal, cardiovascular, urinary tract, and reproductive organs, such as testes. Coronavirus studies have suggested that testes might be a potential target for SARS-CoV-2 infection. The first etiopathogenic concept proposed by current hypotheses indicates that the virus can invade testes through the angiotensin-converting enzyme 2 receptor. Next, the activated inflammatory response in the testes, disease-associated fever, and COVID-19 medications might be implicated in testicular alterations. Although evidence regarding the presence of SARS-CoV-2 mRNA in semen remains controversial, this emphasizes the need for researchers to pay closer attention to sexually transmitted diseases and male fertility after recovering from COVID-19. In this review the latest updates regarding COVID-19-associated testicular dysfunction are summarized and possible pathogenic mechanisms are discussed.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Fertility , Pandemics , SARS-CoV-2/metabolism , Testis/metabolism , COVID-19/mortality , COVID-19/pathology , Humans , Male , Testis/pathology , Testis/virology
6.
Reprod Sci ; 28(10): 2735-2742, 2021 10.
Article in English | MEDLINE | ID: covidwho-1014275

ABSTRACT

Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients are highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has incresingly been evident. The reduced level of testosterone production in COVID-19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.


Subject(s)
COVID-19/epidemiology , Fertility , Hypothalamus/pathology , Infertility, Male/epidemiology , SARS-CoV-2/pathogenicity , Testis/pathology , Animals , Atrophy , COVID-19/diagnosis , COVID-19/virology , Gonadotropins/metabolism , Host-Pathogen Interactions , Humans , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/pathology , Hypothalamo-Hypophyseal System/physiopathology , Hypothalamo-Hypophyseal System/virology , Hypothalamus/metabolism , Hypothalamus/physiopathology , Hypothalamus/virology , Incidence , Infertility, Male/pathology , Infertility, Male/physiopathology , Infertility, Male/virology , Male , Testis/metabolism , Testis/physiopathology , Testis/virology , Testosterone/metabolism
7.
Andrology ; 9(1): 107-114, 2021 01.
Article in English | MEDLINE | ID: covidwho-908746

ABSTRACT

BACKGROUND: A novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causing the pandemic of coronavirus disease 2019 (COVID-19), may attack testes by angiotensin-converting enzyme 2. OBJECTIVE: To assess whether SARS-CoV-2 infection can affect sex-related hormones and testicular function in recovering patients. MATERIALS AND METHODS: The patients were separately classified according to the duration of viral shedding (long-term positive vs normal-term group, with the former cases having a duration > 50 days) and disease severity (moderate vs severe group). Differences in sex-related hormone levels were compared between groups and linear regression analysis was used to compare the associations of testosterone (T) and estradiol with various clinical and laboratory factors. RESULTS: A total of 39 COVID-19-infected patients were included in this study. The mean T level was in the normal reference range while the mean estradiol level was above the normal limit. There were no significant differences between the long-term positive and normal-term groups in T (P = .964), follicle-stimulating hormone (FSH; P = .694), luteinizing hormone (LH; P = .171), prolactin (PRL; P = .836), or T/LH (P = .512). However, estradiol was higher in the normal-term group than the long-term positive group (P < .001). Moreover, there were also no significant differences between the moderate and severe groups in sex-related hormones, duration of viral shedding, or serum biochemical or inflammation indicators. Additionally, regression analyses showed that there were no associations between the T level and the clinical and laboratory factors, while estradiol was negatively associated with the duration of viral shedding. CONCLUSION: In males infected with SARS-CoV-2, most sex-related hormones (T, FSH and LH levels) remain within the normal reference ranges after recovery from COVID-19, and no significant associations were observed between T level and disease duration or severity. At present, there is insufficient evidence to show that SARS-CoV-2 causes hypogonadism and sterility, but the potential risk should not be ignored.


Subject(s)
COVID-19/blood , Estradiol/blood , SARS-CoV-2/pathogenicity , Testis/metabolism , Testosterone/blood , Aged , Biomarkers/blood , COVID-19/diagnosis , COVID-19/therapy , COVID-19/virology , Case-Control Studies , Follicle Stimulating Hormone, Human/blood , Host-Pathogen Interactions , Humans , Luteinizing Hormone/blood , Male , Middle Aged , Prolactin/blood , Remission Induction , Severity of Illness Index , Time Factors , Virus Shedding
8.
J Basic Clin Physiol Pharmacol ; 31(6)2020 Oct 05.
Article in English | MEDLINE | ID: covidwho-810191

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) that causes COVID-19 infections penetrates body cells by binding to angiotensin-converting enzyme-2 (ACE2) receptors. Evidence shows that SARS-CoV-2 can also affect the urogenital tract. Hence, it should be given serious attention when treating COVID-19-infected male patients of reproductive age group. Other viruses like HIV, mumps, papilloma and Epstein-Barr can induce viral orchitis, germ cell apoptosis, inflammation and germ cell destruction with attending infertility and tumors. The blood-testis barrier (BTB) and blood-epididymis barrier (BEB) are essential physical barricades in the male reproductive tract located between the blood vessel and seminiferous tubules in the testes. Despite the significant role of these barriers in male reproductive function, studies have shown that a wide range of viruses can still penetrate the barriers and induce testicular dysfunctions. Therefore, this mini-review highlights the role of ACE2 receptors in promoting SARS-CoV-2-induced blood-testis/epididymal barrier infiltration and testicular dysfunction.


Subject(s)
Blood-Testis Barrier/enzymology , Blood-Testis Barrier/pathology , Coronavirus Infections/enzymology , Coronavirus Infections/pathology , Infertility, Male/etiology , Infertility, Male/pathology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Pneumonia, Viral/pathology , Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , Infertility, Male/enzymology , Male , Pandemics , Testis/metabolism
11.
Andrologia ; 52(9): e13791, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-712969

ABSTRACT

Male infertility is linked to some viral infections including human papillomavirus (HPV), herpes simplex viruses (HSV) and human immunodeficiency viruses (HIVs). Almost nothing is known about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) effect on fertility. The possible risk factors of coronavirus disease 2019 (COVID-19) infection on fertility comes from the abundance of angiotensin-Converting Enzyme-2 (ACE2), receptor entry of the virus, on testes, a reduction in important sex hormone ratios and COVID-19-associated fever. Recent studies have shown a gender difference for COVID-19 rates and comorbidity. In this review, we will discuss the potential effect of COVID-19 on male fertility and talk about what needs to be done by the scientific community to tackle our limited understanding of the disease. On the other side, we will focus on what is known so far about the risk of COVID-19 on pregnancy, neonatal health and the vertical transfer of the virus between mothers and their neonates. Finally, because reproduction is a human right and infertility is considered a health disease, we will discuss how assisted reproductive clinics can cope with the pandemic and what guidelines they should follow to minimise the risk of viral transmission.


Subject(s)
Coronavirus Infections/complications , Infectious Disease Transmission, Vertical , Infertility, Male/virology , Pneumonia, Viral/complications , Pregnancy Complications, Infectious/virology , Reproductive Health , Angiotensin-Converting Enzyme 2 , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Female , HIV Infections/complications , HIV Infections/transmission , HIV Infections/virology , Herpes Simplex/complications , Herpes Simplex/transmission , Herpes Simplex/virology , Humans , Infertility, Male/pathology , Male , Pandemics , Papillomavirus Infections/complications , Papillomavirus Infections/transmission , Papillomavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Pregnancy , Risk Factors , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Testis/metabolism , Testis/pathology
12.
J Cell Mol Med ; 24(16): 9472-9477, 2020 08.
Article in English | MEDLINE | ID: covidwho-692648

ABSTRACT

The serious coronavirus disease-2019 (COVID-19) was first reported in December 2019 in Wuhan, China. COVID-19 is an infectious disease caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Angiotensin converting enzyme 2(ACE2) is the cellular receptor for SARS-CoV-2. Considering the critical roles of testicular cells for the transmission of genetic information between generations, we analyzed single-cell RNA-sequencing (scRNA-seq) data of adult human testis. The mRNA expression of ACE2 was expressed in both germ cells and somatic cells. Moreover, the positive rate of ACE2 in testes of infertile men was higher than normal, which indicates that SARS-CoV-2 may cause reproductive disorders through pathway activated by ACE2 and the men with reproductive disorder may easily to be infected by SARS-CoV-2. The expression level of ACE2 was related to the age, and the mid-aged with higher positive rate than young men testicular cells. Taken together, this research provides a biological background of the potential route for infection of SARS-CoV-2 and may enable rapid deciphering male-related reproductive disorders induced by COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Infertility, Male/metabolism , Receptors, Virus/metabolism , Sertoli Cells/metabolism , Spermatozoa/metabolism , Testis/metabolism , Adult , Angiotensin-Converting Enzyme 2/genetics , COVID-19/complications , Humans , Infertility, Male/genetics , Infertility, Male/virology , Male , Middle Aged , RNA-Seq , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Receptors, Serotonin, 5-HT3/genetics , Receptors, Serotonin, 5-HT3/metabolism , Single-Cell Analysis
13.
Mol Syst Biol ; 16(7): e9610, 2020 07.
Article in English | MEDLINE | ID: covidwho-680519

ABSTRACT

The novel SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150 different cell types corresponding to all major human tissues and organs based on stringent immunohistochemical analysis. The results were compared with several datasets both on the mRNA and protein level. ACE2 expression was mainly observed in enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature. In the respiratory system, the expression was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only. Our data constitute an important resource for further studies on SARS-CoV-2 host cell entry, in order to understand the biology of the disease and to aid in the development of effective treatments to the viral infection.


Subject(s)
Peptidyl-Dipeptidase A/metabolism , Respiratory System/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus , Blood Vessels/metabolism , Conjunctiva/metabolism , Enterocytes/metabolism , Female , Gallbladder/metabolism , Host Microbial Interactions , Humans , Immunohistochemistry , Kidney Tubules, Proximal/metabolism , Male , Mass Spectrometry , Myocytes, Cardiac/metabolism , Organ Specificity , Peptidyl-Dipeptidase A/genetics , Placenta/metabolism , Pregnancy , RNA-Seq , SARS-CoV-2 , Single-Cell Analysis , Testis/metabolism
14.
Reprod Sci ; 28(1): 23-26, 2021 01.
Article in English | MEDLINE | ID: covidwho-640228

ABSTRACT

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.


Subject(s)
COVID-19/epidemiology , COVID-19/pathology , Infertility, Male/epidemiology , Infertility, Male/pathology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Humans , Infertility, Male/metabolism , Male , SARS-CoV-2/metabolism , Testis/metabolism , Testis/pathology
15.
Fertil Steril ; 114(1): 33-43, 2020 07.
Article in English | MEDLINE | ID: covidwho-634346

ABSTRACT

OBJECTIVE: To identify cell types in the male and female reproductive systems at risk for SARS-CoV-2 infection because of the expression of host genes and proteins used by the virus for cell entry. DESIGN: Descriptive analysis of transcriptomic and proteomic data. SETTING: Academic research department and clinical diagnostic laboratory. PATIENT(S): Not applicable (focus was on previously generated gene and protein expression data). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Identification of cell types coexpressing the key angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) genes and proteins as well as other candidates potentially involved in SARS-CoV-2 cell entry. RESULT(S): On the basis of single-cell RNA sequencing data, coexpression of ACE2 and TMPRSS2 was not detected in testicular cells, including sperm. A subpopulation of oocytes in nonhuman primate ovarian tissue was found to express ACE2 and TMPRSS2, but coexpression was not observed in ovarian somatic cells. RNA expression of TMPRSS2 in 18 samples of human cumulus cells was shown to be low or absent. There was general agreement between publicly available bulk RNA and protein datasets in terms of ACE2 and TMPRSS2 expression patterns in testis, ovary, endometrial, and placental cells. CONCLUSION(S): These analyses suggest that SARS-CoV-2 infection is unlikely to have long-term effects on male and female reproductive function. Although the results cannot be considered definitive, they imply that procedures in which oocytes are collected and fertilized in vitro are associated with very little risk of viral transmission from gametes to embryos and may indeed have the potential to minimize exposure of susceptible reproductive cell types to infection in comparison with natural conception.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Fertility/physiology , Gene Expression Regulation, Viral/physiology , Pneumonia, Viral/metabolism , Reproduction/physiology , Virus Internalization , Adolescent , Adult , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/genetics , COVID-19 , Cell Line , Coronavirus Infections/genetics , Female , Humans , Macaca fascicularis , Male , Ovary/cytology , Ovary/metabolism , Ovary/virology , Pandemics , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pregnancy , Proteomics/methods , SARS-CoV-2 , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Testis/cytology , Testis/metabolism , Testis/virology , Transcriptome/physiology , Young Adult
16.
Eur J Clin Microbiol Infect Dis ; 39(12): 2447-2455, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-622381

ABSTRACT

This study compared the laboratory indexes in 40 non-severe COVID-19 patients with those in 57 healthy controls. In the peripheral blood system of non-severe symptom COVID-19 patients, lymphocytes, eosinophils, basophils, total procollagen type 1 amino-terminal propeptide, osteocalcin N-terminal, thyroid-stimulating hormone, growth hormone, and insulin-like growth factor-binding protein 3 significantly decreased, and total protein, albumin, alanine transaminase, alkaline phosphatase, γ-glutamyl transferase, activated partial thromboplastin time, prothrombin time, fibrinogen, D-dimer, fibrinogen degradation products, human epididymal protein 4, serum ferritin, and C-reactive protein were elevated. SARS-CoV-2 infection can affect hematopoiesis, hemostasis, coagulation, fibrinolysis, bone metabolism, thyroid, parathyroid glands, the liver, and the reproductive system.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Adult , Biomarkers/blood , Bone and Bones/metabolism , Bone and Bones/pathology , Bone and Bones/virology , C-Reactive Protein/metabolism , COVID-19 , Case-Control Studies , China/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Cross-Sectional Studies , Female , Ferritins/blood , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinolysis , Hematopoiesis , Hemostasis , Humans , Liver/metabolism , Liver/pathology , Liver/virology , Male , Middle Aged , Ovary/metabolism , Ovary/pathology , Ovary/virology , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Glands/virology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , SARS-CoV-2 , Serum Albumin/metabolism , Severity of Illness Index , Testis/metabolism , Testis/pathology , Testis/virology , Thyroid Gland/metabolism , Thyroid Gland/pathology , Thyroid Gland/virology
17.
Andrologia ; 52(9): e13712, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-613270

ABSTRACT

We performed this systematic review to evaluate the possibility of an impact of SARS-CoV-2 infection on male fertility. SARS-CoV-2 enters the cells with the help of ACE2; therefore, testicular expression of ACE2 was analysed from transcriptome sequencing studies and our unpublished data. Literature suggested that SARS-CoV-1 (2002-2004 SARS) had a significant adverse impact on testicular architecture, suggesting a high possibility of the impact of SARS-CoV-2 as well. Out of two studies on semen samples from COVID-19 affected patients, one reported the presence of SARS-CoV-2 in the semen samples while the other denied it, raising conflict about its presence in the semen samples and the possibility of sexual transmission. Our transcriptome sequencing studies on rat testicular germ cells showed ACE expression in rat testicular germ cells. We also found ACE2 expression in transcriptome sequencing data for human spermatozoa, corroborating its presence in the testicular germ cells. Transcriptome sequencing data from literature search revealed ACE2 expression in the germ, Sertoli and Leydig cells. The presence of ACE2 on almost all testicular cells and the report of a significant impact of previous SARS coronavirus on testes suggest that SARS-CoV-2 is highly likely to affect testicular tissue, semen parameters and male fertility.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/complications , Infertility, Male/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Testis/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/metabolism , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Gene Expression Profiling , Humans , Infertility, Male/pathology , Male , Models, Animal , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Rats , SARS-CoV-2 , Semen/virology , Spermatozoa/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Testis/pathology
18.
Aging Cell ; 19(7)2020 07.
Article in English | MEDLINE | ID: covidwho-608386

ABSTRACT

The COVID-19 coronavirus is now spreading worldwide. Its pathogen, SARS-CoV-2, has been shown to use angiotensin-converting enzyme 2 (ACE2) as its host cell receptor, same as the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. Epidemiology studies found males although only slightly more likely to be infected than females account for the majority of the severely ill and fatality, which also bias for people older than 60 years or with metabolic and cardiovascular diseases. Here by analyzing GTEx and other public data in 30 tissues across thousands of individuals, we found a significantly higher level in Asian females, an age-dependent decrease in all ethnic groups, and a highly significant decrease in type II diabetic patients of ACE2 expression. Consistently, the most significant expression quantitative loci (eQTLs) contributing to high ACE2 expression are close to 100% in East Asians, >30% higher than other ethnic groups. A shockingly common enrichment of viral infection pathways was found among ACE2 anti-expressed genes, and multiple binding sites of virus infection related transcription factors and sex hormone receptors locate at ACE2 regulatory regions. Human and mice data analysis further revealed ACE2 expression is reduced in T2D patients and with inflammatory cytokine treatment and upregulated by estrogen and androgen (both decrease with age). Our findings revealed a negative correlation between ACE2 expression and COVID-19 fatality at both population and molecular levels. These results will be instrumental when designing potential prevention and treatment strategies for ACE2 binding coronaviruses in general.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/genetics , Coronavirus Infections/virology , Gene Expression Regulation , Genetic Variation/genetics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Angiotensin-Converting Enzyme 2 , Betacoronavirus/pathogenicity , COVID-19 , Computational Biology , Female , Humans , Male , Pandemics , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2 , Testis/metabolism , Testis/virology
19.
Eur Urol Focus ; 6(5): 1124-1129, 2020 Sep 15.
Article in English | MEDLINE | ID: covidwho-437089

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), involves multiple organs. Testicular involvement is largely unknown. OBJECTIVE: To determine the pathological changes and whether SARS-CoV-2 can be detected in the testes of deceased COVID-19 patients. DESIGN, SETTING, AND PARTICIPANTS: Postmortem examination of the testes from 12 COVID-19 patients was performed using light and electron microscopy, and immunohistochemistry for lymphocytic and histiocytic markers. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the virus in testicular tissue. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Seminiferous tubular injury was assessed as none, mild, moderate, or severe according to the extent of tubular damage. Leydig cells in the interstitium were counted in ten 400× microscopy fields. RESULTS AND LIMITATIONS: Microscopically, Sertoli cells showed swelling, vacuolation and cytoplasmic rarefaction, detachment from tubular basement membranes, and loss and sloughing into lumens of the intratubular cell mass. Two, five, and four of 11 cases showed mild, moderate, and severe injury, respectively. The mean number of Leydig cells in COVID-19 testes was significantly lower than in the control group (2.2 vs 7.8, p < 0.001). In the interstitium there was edema and mild inflammatory infiltrates composed of T lymphocytes and histiocytes. Transmission EM did not identify viral particles in three cases. RT-PCR detected the virus in one of 12 cases. CONCLUSIONS: Testes from COVID-19 patients exhibited significant seminiferous tubular injury, reduced Leydig cells, and mild lymphocytic inflammation. We found no evidence of SARS-CoV-2 virus in the testes in the majority (90%) of the cases by RT-PCR, and in none by electron microscopy. These findings can provide evidence-based guidance for sperm donation and inform management strategies to mitigate the risk of testicular injury during the COVID-19 disease course. PATIENT SUMMARY: We examined the testes of deceased COVID-19 patients. We found significant damage to the testicular parenchyma. However, virus was not detected in testes in the majority of cases.


Subject(s)
Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Seminiferous Tubules/pathology , Testis/pathology , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2 , Betacoronavirus , COVID-19 , Cell Count , Coronavirus Infections/metabolism , Coronavirus Infections/physiopathology , Humans , Inflammation , Leydig Cells/pathology , Leydig Cells/ultrastructure , Male , Microscopy, Electron , Middle Aged , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/physiopathology , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Seminiferous Tubules/ultrastructure , Sertoli Cells/pathology , Sertoli Cells/ultrastructure , Spermatogenesis/physiology , Testis/metabolism , Testis/ultrastructure , Testis/virology
20.
Mol Biol Rep ; 47(6): 4383-4392, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-260333

ABSTRACT

The ACE2 gene is a receptor of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) for COVID-19 (coronavirus disease 2019). To analyze the expression profiles and clinical significances for this gene in humans, RNA-seq data representing 27 different tissues were analyzed using NCBI; total RNA was extracted from different tissues of mouse and semi-quantitative reverse transcriptional-polymerase chain reaction (Q-RT-PCR) was carried out. Immunohistochemistry expression profiles in normal tissues and cancer tissues and TCGA survival analysis in renal and liver cancer were conducted. ACE2 was highly conserved in different species. In normal tissues, ACE2 expression distributions were organ-specific, mainly in the kidney, male testis and female breast, and cardiovascular and gastrointestinal systems. High level of expression in testis, cardiovascular and gastrointestinal system indicated that SARS-CoV-2 might not only attack the lungs, but also affect other organs, particularly the testes, thus it may severely damage male sexual development for younger male and lead to infertility in an adult male, if he contracted COVID-19. On the other side, high expression of ACE2 was correlated with increased survival rate in renal and liver cancer, indicating that ACE2 is a prognostic marker in both renal cancer and liver cancers. Thus, the ACE2 is a functional receptor for SARS-CoV-2 and has a potential anti-tumor role in cancer. Taken together, this study may not only provide potential clues for further medical pathogenesis of COVID-19 and male fertility, but also indicate the clinical significance of the role of the ACE2 gene in cancer.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Kidney Neoplasms/genetics , Liver Neoplasms/genetics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Receptors, Virus/genetics , Spike Glycoprotein, Coronavirus/genetics , Adult , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/drug effects , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Databases, Genetic , Female , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Kidney/metabolism , Kidney/pathology , Kidney/virology , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Kidney Neoplasms/virology , Liver/metabolism , Liver/pathology , Liver/virology , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Liver Neoplasms/virology , Lung/metabolism , Lung/pathology , Lung/virology , Male , Mammary Glands, Human/metabolism , Mammary Glands, Human/pathology , Mammary Glands, Human/virology , Mice , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Protein Binding , Receptors, Virus/metabolism , SARS-CoV-2 , Sequence Analysis, RNA , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism , Survival Analysis , Testis/metabolism , Testis/pathology , Testis/virology
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