Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes
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Abstract
The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
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SciScore for 10.1101/2020.04.21.051201: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Study approval: Mouse studies were performed under a protocol approved by the Institutional Animal Care and Use Committee (IACUC) of the Cleveland Clinic Lerner Research Institute. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The male mice were arbitrarily divided between two groups receiving control chow or Enz diet 62.5 mg/kg. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources The lysates were then centrifuged for 15 min at 16,000 x g and the supernatants were collected for immunoblot analysis with antibodies for TMPRSS2 (Abcam: ab92323 and Proteintech: 14437-1-AP), … SciScore for 10.1101/2020.04.21.051201: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Study approval: Mouse studies were performed under a protocol approved by the Institutional Animal Care and Use Committee (IACUC) of the Cleveland Clinic Lerner Research Institute. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The male mice were arbitrarily divided between two groups receiving control chow or Enz diet 62.5 mg/kg. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources The lysates were then centrifuged for 15 min at 16,000 x g and the supernatants were collected for immunoblot analysis with antibodies for TMPRSS2 (Abcam: ab92323 and Proteintech: 14437-1-AP), AR (EMD Millipore: PG-21 and Santa Cruz Biotechnology: N-20), PSA (Cell signaling: D6B1) and GAPDH (D16H11). TMPRSS2suggested: (Abcam Cat# ab56111, RRID:AB_883079)GAPDHsuggested: (Cell Signaling Technology Cat# 5174, RRID:AB_10622025)The antibodies were visualized using the OmniMap anti-Rabbit HRP (05269679001; Roche), and OmniMap anti-Goat HRP (06607233001; Roche) in conjunction with the ChromoMap DAB detection kit (05266645001; Roche). anti-Rabbitsuggested: NoneHRPsuggested: NoneExperimental Models: Cell Lines Sentences Resources ChIP-seq: ChIP-Seq analysis was performed in LNCaP cells treated with vehicle (DMSO) or Enz 10 μM. LNCaPsuggested: NoneExperimental Models: Organisms/Strains Sentences Resources Mice, treatments and lung harvest: A cohort of adult NSG mice (> 6 weeks old) were obtained from Cleveland Clinic Biological Resources Unit. NSGsuggested: NoneSoftware and Algorithms Sentences Resources Gene expression in human lung: The public genomics data repository Gene Expression Omnibus (GEO, ncbi.nlm.nih.gov/geo) was searched for data sets containing expression profiling of samples from non-cancerous human lung and bronchial/airway epithelial cells with samples identified by gender and/or smoking status of subjects. Gene Expression Omnibussuggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)Analyses were performed in R or GraphPad Prism. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04374279 Not yet recruiting Trial to Promote Recovery From COVID-19 With Endocrine Thera… NCT04475601 Recruiting Enzalutamide Treatment in COVID-19 NCT04509999 Recruiting Bicalutamide to Block TMPRSS2 in Males With COVID-19 Infecti… NCT04397718 Recruiting Hormonal Intervention for the Treatment in Veterans With COV… NCT045009999 Trial number did not resolve on clinicaltrials.gov. Is the number correct? NA Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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