Spaceflight Disrupts Gene Expression of Estrogen Signaling in Rodent Mammary Tissue
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Sep 11, 2024
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Abstract
Life aboard spacecraft poses various dangers to astronaut health, with hazards including microgravity, radiation, and enclosed spaces. Research into mitigating these health issues includes analysis of the transcriptome of rodents sent to the International Space Station. This project investigates the effects of spaceflight on the gene expression of mammary tissue of female mice of two age groups, 10-12 and 32 weeks, in order to assess the impact of age and spaceflight on gene expression. Spaceflight-induced changes to gene expression in rodent mammary tissue could contribute to the characterization of the impact of spaceflight on female astronaut health, which has been historically underserved. Analysis of the OSD-511 dataset from NASA’s Open Science Data Repository utilized a containerized implementation of their RNA-Seq pipeline on the San José State University High Performance Computing Cluster. Seven genes were found to be differentially expressed across all comparison groups; one gene, Greb1, is implicated in hormone mediated disease. Age appears to influence biological pathways affected by spaceflight in mammary tissue, with young mice experiencing metabolic changes while older mice undergo changes to inflammatory pathways. Further research is needed to determine the mechanism of spaceflight-induced gene expression changes.
Keywords:
Spaceflight, Differential Gene Expression, RNA-Seq, Mouse, Mammary, Greb1
Article Details
How to Cite
ARNOLD, Cleoma; CASALETTO, James; HELLER, Philip.
Spaceflight Disrupts Gene Expression of Estrogen Signaling in Rodent Mammary Tissue.
Medical Research Archives, [S.l.], v. 12, n. 3, sep. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5220>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i3.5220.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Cucinotta FA, Durante M. Risk of radiation car-cinogenesis. Human health and performance risks of space exploration missions. NASA SP-2009-3405. Houston: National Aeronautics and Space Administration. 2009:119-70.
2. Goel N, Bale TL, Epperson CN et al. Effects of sex and gender on adaptation to space: be-havioral health. J of Women's Health. 2014;23(11):975-86. Doi:10.1089/jwh.2014.4911
3. National Aeronautics and Space Administra-tion. Artemis - nasa. Accessed October 20, 2023. https://www.nasa.gov/humans-in-space/artemis/
4. Reynolds R, Little MP, Day S et al. Cancer inci-dence and mortality in the USA Astronaut Corps, 1959–2017. Occ and env Med. 2021;78(12):869-75. Doi:10.1136/oemed-2020-107143
5. Barr YR, Bacal K, Jones JA, Hamilton DR. Breast cancer and spaceflight: risk and management. Aviation, space, and env med. 2007;78(4):A26-37.
6. National Aeronautics and Space Administra-tion. Rodent research-8 (rr-8). Accessed Novem¬ber 16, 2023. https://www.nasa.gov/mis-sion/station/research-explorer/ investiga-tion/?#id=7713
7. Berrios DC, Galazka J, Grigorev K, Gebre S, Costes SV. NASA GeneLab: interfaces for the exploration of space omics data. Nucleic acids research. 2021;49(D1):D1515-22.
8. da Silveira WA, Fazelinia H, Rosenthal SB et al. Comprehensive multi-omics analysis reveals mi¬tochondrial stress as a central biological hub for spaceflight impact. Cell. 2020;183(5):1185-201. Doi:10.1016/j.cell.2020.11.002
9. Nassef MZ, Melnik D, Kopp S et al. Breast can¬cer cells in microgravity: new aspects for cancer research. Internat J of Mol Sci. 2020;21(19):7345.
Doi: 10.3390/ijms21197345
10. Afshinnekoo E, Scott RT, MacKay MJ et al.. Fun¬damental biological features of spaceflight: advancing the field to enable deep-space ex¬ploration. Cell. 2020;183(5):1162-84. Doi: 10.1016/j.cell.2020.10.050
11. Brenner DJ, Doll R, Goodhead DT et al. Cancer risks attributable to low doses of ionizing radi¬ation: assessing what we really know. Proceed of Nat Acad of Sci. 2003;100(24):13761-6. Doi: 10.1073/pnas.2235592100
12. Beheshti A, Cekanaviciute E, Smith DJ, Costes SV. Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: A systems biology GeneLab case study. Scientific reports. 2018;8(1):4191. Doi: 10.1073/pnas.2235592100
13. Garrett-Bakelman FE, Darshi M, Green SJ et al. The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Sci¬ence. 2019;364(6436):eaau8650.
14. Galazka JM, Roberts M, Stodieck L et al. Tran¬scriptional profiling of mammary glands from mice flown on the RRRM-1 mission. NASA Open Sci Data Repository, Version 2. Updated August 3, 2022. Accessed September 12, 2023. Doi:10.26030/wdpr-va45 https://osdr.nasa.gov/bio/repo/data/stud-ies/OSD-511
15. Oribello J, Saravia-Butler A, Costes S, Gebre S, Galazka, J. GeneLab bioinformatics pro-cessing pipeline for Illumina RNA-seqencing data. Github. Updated August 18, 2022. Ac-cessed September 12, 2023. https://github.com/J-81/Gen-eLab_Data_Processing/blob/DEV_NF_RCP-F/RNAseq/Pipeline_GL-DPPD-7101_Ver-sions/GL-DPPD-7101-F.md
16. Di Tommaso P, Chatzou M, Floden EW, Barja PP, Palumbo E, Notredame C. Nextflow ena-bles reproducible computational workflows. Nature biotechnology. 2017;35(4):316-9.
Doi: 10.1038/nbt.3820
17. Cunningham F, Allen JE, Allen J et al. Ensembl 2022. Nucleic acids research. 2022;50(D1):D988-95.
Doi: 10.1093/nar/gkab1049
18. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful ap-proach to multiple testing. J of Royal statistical society: series B (Methodological). 1995;57(1):289-300. Doi: 10.1016/s0166-4328(01)00297-2
19. Love MI, Huber W, Anders S. Moderated esti-mation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology. 2014;15(12):1-21. Doi: 10.1186/s13059-014-0550-8
20. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signa¬tures database hallmark gene set collection. Cell sys. 2015;1(6):417-25. Doi:10.1016/j.cels.2015.12.004
21. Subramanian A, Tamayo P, Mootha VK et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceed of Nat Acad of Sci. 2005;102(43):15545-50. Doi:10.1073/pnas.0506580102
22. Huang DW, Sherman BT, Lempicki RA. System-atic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature protocols. 2009;4(1):44-57.
Doi: 10.1038/nprot.2008.211
23. Shahi PK, Srinivasan A, Pattnaik BR. A novel Kcnv2 nonsense mutation mouse model of Cone Dystrophy with Supernormal Rod Response. In¬vestigative Ophthalmology & Visual Sci. 2022;63(7):1784-F0333.
24. Jorge BS, Campbell CM, Miller AR et al. Volt-age-gated potassium channel KCNV2 (Kv8. 2) contributes to epilepsy susceptibility. Proceed of Nat Acad of Sci. 2011;108(13):5443-8. Doi:10.1073/pnas.1017539108
25. Swanton C. My Cancer Genome: a unified ge-nomics and clinical trial portal. The Lancet On-cology. 2012;13(7):668-9.
26. Kanehisa M, Goto S. KEGG: kyoto encyclope-dia of genes and genomes. Nucleic acids re-search. 2000;28(1):27-30.
27. Chonat S, Risinger M, Sakthivel H et al. The spectrum of SPTA1-associated hereditary sphe¬rocytosis. Front in physiology. 2019;10:815. Doi: 10.3389/fphys.2019.00815
28. Trudel G, Shahin N, Ramsay T, Laneuville O, Louati H. Hemolysis contributes to anemia dur-ing long-duration space flight. Nature Med. 2022;28(1):59-62. Doi:10.1038/s41591-021-01637-7
29. Korhonen L, Hansson I, Kukkonen JP et al. Hip-pocalcin protects against caspase-12-induced and age-dependent neuronal degeneration. Mol and Cellular Neurosci. 2005;28(1):85-95. Doi:10.1016/j.mcn.2004.08.015
30. Strollo F, Riondino G, Harris B et al. The effect of microgravity on testicular androgen secre-tion. Aviation, space, and env med. 1998;69(2):133-6.
31. Greve S, Kuhn GA, Saenz-de-Juano MD, Ghosh A, von Meyenn F, Giller K. The major urinary protein gene cluster knockout mouse as a novel model for translational metabolism research. Scientific Reports. 2022;12(1):13161. Doi:10.1038/s41598-022-17195-y
32. Wheeler DL, Barrett T, Benson DA et al. Data-base resources of the national center for bio-technology information. Nucleic acids research. 2007;36(suppl_1):D13-21.
Doi: 10.1093/nar/gkm1000
33. Hodgkinson K, Forrest LA, Vuong N, Garson K, Djordjevic B, Vanderhyden BC. GREB1 is an es¬trogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer. Oncogene. 2018;37(44):5873-86. Doi:10.1038/s41388-018-0377-y
34. Shin EM, Huynh VT, Neja SA et al. GREB1: An evolutionarily conserved protein with a glyco-syltransferase domain links ERα glycosylation and stability to cancer. Sci Advances. 2021;7(12):eabe2470. Doi:10.1126/sci-adv.abe2470
35. Wu Y, Zhang Z, Cenciarini ME et al. Tamoxifen resistance in breast cancer is regulated by the EZH2–ERα–GREB1 transcriptional axis. Cancer research. 2018;78(3):671-84.
Doi: 10.1158/0008-5472.CAN-17-1327
36. Hegarty KG, Drummond FJ, Daly M, Shanahan F, Molloy MG. GREB1 genetic variants are as-sociated with bone mineral density in Cauca-sians. J of bone and mineral metabolism. 2018;36:189-99. Doi:10.1007/s00774-017-0823-x
37. Fitts RH, Trappe SW, Costill DL et al. Prolonged space flight‐induced alterations in the structure and function of human skeletal muscle fibres. J of physiology. 2010;588(18):3567-92. Doi: 10.1113/jphysiol.2010.188508
38. Smith SM, Heer M, Wang Z, Huntoon CL, Zwart SR. Long-duration space flight and bed rest ef¬fects on testosterone and other steroids. J of Clin Endocrinology & Metabolism. 2012;97(1):270-8. Doi:10.1210/jc.2011-2233
39. Koebele SV, Bimonte-Nelson HA. Modeling menopause: The utility of rodents in transla-tional behavioral endocrinology research. Ma-turitas. 2016;87:5-17. Doi:10.1016/j.maturi-tas.2016.01.015
40. Rose BI. Female astronauts: Impact of space ra¬diation on menopause. Euro J of Obstetrics & Gynecology and Reprod Bio. 2022;271:210-3. Doi:10.1016/j.ejogrb.2022.02.022
41. Strollo F, Gentile S, Strollo G, Mambro A, Ver-nikos J. Recent progress in space physiology and aging. Frontiers in physiology. 2018;9:1551. Doi:10.3389/fphys.2018.01551
42. Hagan C. When are mice considered old? JAX Blog. November 7, 2017. Accessed October 14, 2023. https://www.jax.org/news-and-in-sights/jax-blog/2017/November/when-are-mice-considered-old
43. Shuryak I, Sachs RK, Brenner DJ. Cancer risks after radiation exposure in middle age. J of Nat Cancer Instit. 2010;102(21):1628-36. Doi:10.1093/jnci/djq346
2. Goel N, Bale TL, Epperson CN et al. Effects of sex and gender on adaptation to space: be-havioral health. J of Women's Health. 2014;23(11):975-86. Doi:10.1089/jwh.2014.4911
3. National Aeronautics and Space Administra-tion. Artemis - nasa. Accessed October 20, 2023. https://www.nasa.gov/humans-in-space/artemis/
4. Reynolds R, Little MP, Day S et al. Cancer inci-dence and mortality in the USA Astronaut Corps, 1959–2017. Occ and env Med. 2021;78(12):869-75. Doi:10.1136/oemed-2020-107143
5. Barr YR, Bacal K, Jones JA, Hamilton DR. Breast cancer and spaceflight: risk and management. Aviation, space, and env med. 2007;78(4):A26-37.
6. National Aeronautics and Space Administra-tion. Rodent research-8 (rr-8). Accessed Novem¬ber 16, 2023. https://www.nasa.gov/mis-sion/station/research-explorer/ investiga-tion/?#id=7713
7. Berrios DC, Galazka J, Grigorev K, Gebre S, Costes SV. NASA GeneLab: interfaces for the exploration of space omics data. Nucleic acids research. 2021;49(D1):D1515-22.
8. da Silveira WA, Fazelinia H, Rosenthal SB et al. Comprehensive multi-omics analysis reveals mi¬tochondrial stress as a central biological hub for spaceflight impact. Cell. 2020;183(5):1185-201. Doi:10.1016/j.cell.2020.11.002
9. Nassef MZ, Melnik D, Kopp S et al. Breast can¬cer cells in microgravity: new aspects for cancer research. Internat J of Mol Sci. 2020;21(19):7345.
Doi: 10.3390/ijms21197345
10. Afshinnekoo E, Scott RT, MacKay MJ et al.. Fun¬damental biological features of spaceflight: advancing the field to enable deep-space ex¬ploration. Cell. 2020;183(5):1162-84. Doi: 10.1016/j.cell.2020.10.050
11. Brenner DJ, Doll R, Goodhead DT et al. Cancer risks attributable to low doses of ionizing radi¬ation: assessing what we really know. Proceed of Nat Acad of Sci. 2003;100(24):13761-6. Doi: 10.1073/pnas.2235592100
12. Beheshti A, Cekanaviciute E, Smith DJ, Costes SV. Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: A systems biology GeneLab case study. Scientific reports. 2018;8(1):4191. Doi: 10.1073/pnas.2235592100
13. Garrett-Bakelman FE, Darshi M, Green SJ et al. The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Sci¬ence. 2019;364(6436):eaau8650.
14. Galazka JM, Roberts M, Stodieck L et al. Tran¬scriptional profiling of mammary glands from mice flown on the RRRM-1 mission. NASA Open Sci Data Repository, Version 2. Updated August 3, 2022. Accessed September 12, 2023. Doi:10.26030/wdpr-va45 https://osdr.nasa.gov/bio/repo/data/stud-ies/OSD-511
15. Oribello J, Saravia-Butler A, Costes S, Gebre S, Galazka, J. GeneLab bioinformatics pro-cessing pipeline for Illumina RNA-seqencing data. Github. Updated August 18, 2022. Ac-cessed September 12, 2023. https://github.com/J-81/Gen-eLab_Data_Processing/blob/DEV_NF_RCP-F/RNAseq/Pipeline_GL-DPPD-7101_Ver-sions/GL-DPPD-7101-F.md
16. Di Tommaso P, Chatzou M, Floden EW, Barja PP, Palumbo E, Notredame C. Nextflow ena-bles reproducible computational workflows. Nature biotechnology. 2017;35(4):316-9.
Doi: 10.1038/nbt.3820
17. Cunningham F, Allen JE, Allen J et al. Ensembl 2022. Nucleic acids research. 2022;50(D1):D988-95.
Doi: 10.1093/nar/gkab1049
18. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful ap-proach to multiple testing. J of Royal statistical society: series B (Methodological). 1995;57(1):289-300. Doi: 10.1016/s0166-4328(01)00297-2
19. Love MI, Huber W, Anders S. Moderated esti-mation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology. 2014;15(12):1-21. Doi: 10.1186/s13059-014-0550-8
20. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signa¬tures database hallmark gene set collection. Cell sys. 2015;1(6):417-25. Doi:10.1016/j.cels.2015.12.004
21. Subramanian A, Tamayo P, Mootha VK et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceed of Nat Acad of Sci. 2005;102(43):15545-50. Doi:10.1073/pnas.0506580102
22. Huang DW, Sherman BT, Lempicki RA. System-atic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature protocols. 2009;4(1):44-57.
Doi: 10.1038/nprot.2008.211
23. Shahi PK, Srinivasan A, Pattnaik BR. A novel Kcnv2 nonsense mutation mouse model of Cone Dystrophy with Supernormal Rod Response. In¬vestigative Ophthalmology & Visual Sci. 2022;63(7):1784-F0333.
24. Jorge BS, Campbell CM, Miller AR et al. Volt-age-gated potassium channel KCNV2 (Kv8. 2) contributes to epilepsy susceptibility. Proceed of Nat Acad of Sci. 2011;108(13):5443-8. Doi:10.1073/pnas.1017539108
25. Swanton C. My Cancer Genome: a unified ge-nomics and clinical trial portal. The Lancet On-cology. 2012;13(7):668-9.
26. Kanehisa M, Goto S. KEGG: kyoto encyclope-dia of genes and genomes. Nucleic acids re-search. 2000;28(1):27-30.
27. Chonat S, Risinger M, Sakthivel H et al. The spectrum of SPTA1-associated hereditary sphe¬rocytosis. Front in physiology. 2019;10:815. Doi: 10.3389/fphys.2019.00815
28. Trudel G, Shahin N, Ramsay T, Laneuville O, Louati H. Hemolysis contributes to anemia dur-ing long-duration space flight. Nature Med. 2022;28(1):59-62. Doi:10.1038/s41591-021-01637-7
29. Korhonen L, Hansson I, Kukkonen JP et al. Hip-pocalcin protects against caspase-12-induced and age-dependent neuronal degeneration. Mol and Cellular Neurosci. 2005;28(1):85-95. Doi:10.1016/j.mcn.2004.08.015
30. Strollo F, Riondino G, Harris B et al. The effect of microgravity on testicular androgen secre-tion. Aviation, space, and env med. 1998;69(2):133-6.
31. Greve S, Kuhn GA, Saenz-de-Juano MD, Ghosh A, von Meyenn F, Giller K. The major urinary protein gene cluster knockout mouse as a novel model for translational metabolism research. Scientific Reports. 2022;12(1):13161. Doi:10.1038/s41598-022-17195-y
32. Wheeler DL, Barrett T, Benson DA et al. Data-base resources of the national center for bio-technology information. Nucleic acids research. 2007;36(suppl_1):D13-21.
Doi: 10.1093/nar/gkm1000
33. Hodgkinson K, Forrest LA, Vuong N, Garson K, Djordjevic B, Vanderhyden BC. GREB1 is an es¬trogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer. Oncogene. 2018;37(44):5873-86. Doi:10.1038/s41388-018-0377-y
34. Shin EM, Huynh VT, Neja SA et al. GREB1: An evolutionarily conserved protein with a glyco-syltransferase domain links ERα glycosylation and stability to cancer. Sci Advances. 2021;7(12):eabe2470. Doi:10.1126/sci-adv.abe2470
35. Wu Y, Zhang Z, Cenciarini ME et al. Tamoxifen resistance in breast cancer is regulated by the EZH2–ERα–GREB1 transcriptional axis. Cancer research. 2018;78(3):671-84.
Doi: 10.1158/0008-5472.CAN-17-1327
36. Hegarty KG, Drummond FJ, Daly M, Shanahan F, Molloy MG. GREB1 genetic variants are as-sociated with bone mineral density in Cauca-sians. J of bone and mineral metabolism. 2018;36:189-99. Doi:10.1007/s00774-017-0823-x
37. Fitts RH, Trappe SW, Costill DL et al. Prolonged space flight‐induced alterations in the structure and function of human skeletal muscle fibres. J of physiology. 2010;588(18):3567-92. Doi: 10.1113/jphysiol.2010.188508
38. Smith SM, Heer M, Wang Z, Huntoon CL, Zwart SR. Long-duration space flight and bed rest ef¬fects on testosterone and other steroids. J of Clin Endocrinology & Metabolism. 2012;97(1):270-8. Doi:10.1210/jc.2011-2233
39. Koebele SV, Bimonte-Nelson HA. Modeling menopause: The utility of rodents in transla-tional behavioral endocrinology research. Ma-turitas. 2016;87:5-17. Doi:10.1016/j.maturi-tas.2016.01.015
40. Rose BI. Female astronauts: Impact of space ra¬diation on menopause. Euro J of Obstetrics & Gynecology and Reprod Bio. 2022;271:210-3. Doi:10.1016/j.ejogrb.2022.02.022
41. Strollo F, Gentile S, Strollo G, Mambro A, Ver-nikos J. Recent progress in space physiology and aging. Frontiers in physiology. 2018;9:1551. Doi:10.3389/fphys.2018.01551
42. Hagan C. When are mice considered old? JAX Blog. November 7, 2017. Accessed October 14, 2023. https://www.jax.org/news-and-in-sights/jax-blog/2017/November/when-are-mice-considered-old
43. Shuryak I, Sachs RK, Brenner DJ. Cancer risks after radiation exposure in middle age. J of Nat Cancer Instit. 2010;102(21):1628-36. Doi:10.1093/jnci/djq346