Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review
Abstract
:1. Introduction
2. Space-Environmental Factors: Microgravity and Space Radiation
2.1. Microgravity
2.2. Space Radiation
3. Effect of Spaceflight on Female Reproduction
3.1. Microgravity
3.2. Hormonal Modalities in Spaceflight
3.3. Space Radiation
4. Effect of Space Travel on Cancer
Cancer Type | Microgravity Model | Model | Effect | Study |
---|---|---|---|---|
Breast cancer | 6 min of r-µg *; PF ** maneuvers | MCF-7 cell line | Rearrangement of F-actin and tubulin, appearance of filopodia- and lamellipodia-like structures; PF-induced differential regulation of KRT8, RDX, TIMP1, CXCL8 (up), VCL, and CDH1 (down) genes | Nassef et al., 2019 [56] |
Breast cancer | Exposure to an RPM ## | MCF-7 cell line | Cells formed multicellular spheroids resembling epithelial ducts; microgravity-induced differential regulation of IL8, VEGFA, FLT1, ESR1 (up), ACTB, TUBB, FN1, CASP9, CASP3, and PGR1 (down) genes | Kopp et al., 2016 [57] |
Breast cancer | PF ** maneuvers; incubator RPM ## | MDA-MB-231 cells | Differential regulation of ICAM1, CD44, ERK1, NFKB1, FAK1 (up), ANXA2, and BAX (down) genes | Nassef et al., 2019 [58] |
Glioma | Exposure to an RPM ## | U251 cells | Induction of apoptosis; reduced FAK/RhoA/Rock and FAK/Nek2 signaling events | Deng et al., 2019 [59] |
Lung cancer (non small cell) | Exposure to an RPM ## | NCI-H1703 (CRL-5889) cells | Formation of multicellular spheroids; spherical rearrangement of actin filaments in the outer region of cytoplasm; increased apoptosis, upregulation of TP53, CDKN2A, RB1, PTEN, and SOX2 in stimulated adherent cells | Dietz et al., 2019 [60] |
Melanoma | Exposure to a 3-D Clinostat # | A375 cells | Decreased cell viability; increase in caspase 3/7 activity; reduced cell proliferation; change in cell morphology (presence of membrane blebbing lamellipodia, and stress fibers, absence of filopodia) | Przystupski et al., 2021 [61] |
Thyroid cancer | Exposure to an RPM ## | FTC-133 cells | Cells formed multicellular spheroids; differential regulation of ERK1, EGF (up), CTGF, and CAV (down) genes in multicellular spheroids | Warnke et al., 2014 [62] |
Thyroid cancer | 10 day of r-µg * | FTC-133 cells | Differential expression of IL6, IL7, IL8, VEGF, TIMP1, MMP3, CCL4, and B2M (up) proteins | Riwaldt et al., 2015 [63] |
Cell Type | Radiation Model | Cell/Animal Model | Effect | Study |
---|---|---|---|---|
Lung cells | Iron ion (Fe) beam (180 MeV/nucleon; LET 300 keV/µm) for 0.1 Gy | SV40-immortalized human bronchial epithelial cells (NL20) | Progeny of Fe-irradiated cells showed elevated micronucleus formation, increased markers for DNA double-strand breaks (γ-H2AX foci), reduced cell proliferation, persistent oxidative stress, and increased colony formation. | Cao et al., 2018 [64] |
Lung cells | 56Fe (600 MeV/u at 0, 0.1, 0.3, 1.0 Gy) and 28Si (300 MeV/u at 0, 0.3, 1.0 Gy) high LET irradiation | Immortalized human bronchial epithelial cell line (HBEC3-KT) | Global differential CpG island methylation in response to 56Fe and 28Si ion exposure suggests a lasting impact on the epigenome relevant to lung cancer | Kennedy et al., 2018 [65] |
Hematopoietic stem cells | 100 cGy of 1000 MeV/n protons (LET 0.23 keV/micron); 28Si 300 MeV/n ions (LET 70 keV/micron) | Mlh1+/− mice (B6.129-Mlh1tm1Rak/NCI) representing loss of MLH1 that occurs in human hematopoietic stem cells with age | High LET 28Si ion irradiation affected hematopoietic stem cell differentiation; high LET irradiation caused early and higher incidence of tumorigenesis in Mlh1 heterozygous mice; frequent occurrence of T-cell rich B-cell (TRB) lymphomas with altered mismatch repair pathway | Patel et al., 2020 [66] |
Spleen cells | 0.5 Gy Proton irradiation (1-GeV; LET 0.24-keV/µm) | Murine Lewis lung carcinoma (LLC) cells-bearing C57BL/6 mice | Upregulation of genes involved in DNA repair and cell cycle, including CDK2, MCM7, CD74, and RUVBL2 | Wage et al., 2015 [67] |
Intestinal cells | 56Fe-irradiation (1.6 Gy; energy-1000 MeV/nucleon; LET-148 keV/µm) | Intestinal tissue from Female C57BL/6J mice | 56Fe-irradiation upregulated metabolites belonging to prostanoid biosynthesis and eicosanoid signaling pathways linked with cellular inflammation, which has been associated with intestinal inflammatory disease and colon cancer | Cheema et al., 2014 [68] |
Liver cells | 56Fe ion irradiation (1 GeV/nucleon) | CBA/CaJ mice | Higher incidence of hepatocellular carcinoma than γ-irradiated mice | Weil et al., 2009 [69] |
Kidney cells | 56Fe ions irradiation (1 GeV/amu, 151 keV/μm) | Aprt heterozygous (Aprt+/−) B6D2F1 mice | Increased mutant frequencies leading to DNA damage | Turker et al., 2017 [70] |
Cervical cancer cells | Kept at the Russian Mir space station (40 days); American space shuttle (10 days) | HeLa cells | DNA damage | Ohnishi et al., 2002 [71] |
Normal human foreskin fibroblast cells | Kept at the International Space Station (14 days) | AG1522 cells | Larger size γ-H2AX foci suggest DNA damage | Lu et al., 2017 [72] |
Normal human foreskin fibroblast cells | Kept at the International Space Station (14 days) | AG1522 cells | Downregulation of miRNA Let-7a, which was found to be downregulated to γ ray and UV ray radiation in another study | Zhang et al., 2016 [73] |
5. Gynecological Cancers and Space
5.1. Brief Overview on Gynecological Cancers
5.2. Effects of Microgravity and Radiation on Gynecological Cancers: In Vitro and In Vivo Studies
5.2.1. Ovarian Normal and Cancer Cells Exposed to Microgravity and/or Radiation
Altered Gravity and Microgravity
Radiation
5.2.2. Cervical Normal and Cancer Cells Exposed to Microgravity and/or Radiation
Microgravity
Spaceflight Studies
Radiation
Viral Reactivation
5.2.3. Endometrial Normal and Cancer Cells Exposed to Microgravity and/or Radiation
Microgravity
Radiation
Tissue Type | Microgravity/Space Flight | Cell/Animal Models | Effect | Study |
---|---|---|---|---|
Ovarian | simulated microgravity RWV | LN1 human ovarian tumor cells | LN1 cells grew as spheroids free in suspension | Becker et al., 1993; Goodwin et al., 1997 [134,135] |
spaceflight (cells were cultured on the ISS) | LN1 human ovarian tumor cells | Cells showed reduced expression of VIM and EMA | Hammond et al., 2005 [136] | |
simulated microgravity 3D-C | SKOV-3 human ovarian cancer cells | Cells showed reduced proliferation, migration, and higher sensitivity of cancer cells to the cisplatin | Przystupski et al., 2021 [137] | |
microgravity | set of systems-biology tools and databases | identified several cancer related signatures induced by microgravity | Mukhopadhyay et al., 2016 [138] | |
Cervical | simulated microgravity RWV | Co-culture of HUVEC and tumor primary cells | Co-culture presented tubular structures penetrating the tumor cell masses, | Chopra et al., 1997 [143] |
simulated microgravity HFB and RCCS | HeLa human cervical cancer cells | HFB exposure increased CD133-positive cell growth | Kelly et al., 2010 [144] | |
spaceflight (cells were flown on “Shen Zhou IV” space shuttle mission) | Human cervical carcinoma CaSki cells | Cells exhibited morphologic differences, characterized by rounder, smoother, decreased, smaller, and low adhesion cells. Furthermore, space-grown cells showed altered gene expression that generally corresponded to changes in genes regulating the cell cycle, cell morphology, apoptosis, and signal transduction | Zhang et al., 2011; Guo et al., 2012 [145,146] | |
Endometrial | simulated microgravity 3D-C | human endometrial stromal cells (eSCs) | Cells showed reduced proliferation and migration. This was accompanied by a simultaneous decrease in the phosphorylation of Akt and the level of matrix metalloproteinase (MMP)-2 and FOXO3a. | Cho et al., 2019 [156] |
simulated microgravity RCCS | Human tumor primary cells | 3D model endometrial cancer cell culture was established | Grun et al., 2009 [157] |
Tissue Type | Radiation Type | Cell/Animal Models | Effect | Study |
---|---|---|---|---|
Ovarian | 0.439 Gy as a 290 MeV/u carbon-ion beam (LET 10 keV/micron) | B6C3F1 mice | Induction of ovarian tumors | Watanabe et al., 1998 [139] |
0.426 Gy heavy ion irradiation of 290 MeV/u carbon-ion beam (LET 60–210 KeV/micron) at the dose rate of 0.4 +/− 0.2 Gy/min; 0.5 Gy of X-ray irradiation at 0.1 Gy/min or 5 Gy of X-ray irradiation at 1 Gy/min. | B6C3F1 mice | Tumorigenicity was lower for heavy ion than for 0.5 Gy and 5 Gy X-ray irradiation | Watanabe et al., 1998 [140] | |
high and low LET radiations. 1.0 Gy monoenergetic neutrons (0.317, 0.525 and 1.026 MeV), 252Cf fission neutron (2.13 MeV) or 137Cs γ-rays | C57BL/6N mice | Higher effectiveness of neutrons than γ-rays to induce oocyte and pregranulosa cell apoptosis correlates with the inhibition of granulosa cell tumor development | Nitta & Hoshi, 2003 [141] | |
HZE particles. 50 cGy iron ions | C57BL/6J | Induction of ovarian tumors | Mishra et al., 2018 [142] | |
Cervical | spaceflight (cells were flown on “Russian MIR” space station or on the Space Shuttle) | HeLa human cervical cancer cells | Increased DNA damage | Ohnishi, et al., 2002 [71] |
Endometrial | Monoenergetic protons (1–10 Gy; LET 8.35 keV/μm and 4.86 MeV) and γ-rays (0.2–1.6 Gy) | Human endometrial carcinoma cell lines (HEC1B and AN3CA cells) | Decreased cell survival | Palumbo et al., 2001 [158] |
6. Current Challenges in Gynecological Cancer Risk Prediction for Spaceflight
6.1. Gynecologic Medical Standards for Career and Private Astronauts
6.2. Countermeasures
7. Future Perspectives
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ACMG | American College of Medical Genetics and Genomics |
ACOG | American College of Obstetricians and Gynecologists |
ASCCP | American Society for Colposcopy and Cervical Pathology |
CC | cervical cancer |
CSA | Canadian Space Agency |
3D-C | 3D-clinostat |
EC | endometrial cancer |
ESA | European Space Agency |
GCR | galactic cosmic radiation |
HFB | hydrofocusing bioreactor |
HPV | human papillomavirus |
HZE | high Z and energy |
ISS | International Space Station |
JAXA | Japan Aerospace Exploration Agency |
LEO | low Earth orbit |
LET | Linear Energy Transfer |
MSMBIP | Multilateral Space Medicine Board of the ISS International Partners |
NAC | N-Acetyl-L-Cysteine |
NASA | National Aeronautics and Space Administration |
NSGC | National Society of Genetic Counselors |
OC | ovarian cancer |
RBE | relative biological effectiveness |
RCCS | rotary cell culture system |
RER | radiation effects ratio |
RWV | rotating-wall vessel |
SGO | Society of Gynecologic Oncology |
SPE | solar particle events |
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Type of Radiation | Radiation Weighting Factor (WR) |
---|---|
X-rays/Gamma rays | 1 |
Electrons | 1 |
Protons | 2–5 |
Neutrons | 5–20 |
Heavy ions | 20 |
Age | Dose, mGy | Effect |
---|---|---|
All ages | 1700 | Temporary sterility lasting 1–3 years |
1250–1500 | Amenorrhea in 50% | |
3200–6250 | Permanent sterility | |
Ages 15–40 | 1250–2500 | Temporary amenorrhea |
2500–5000 | Ovulary suppression in 40–100% | |
5000–8000 | Permanent ovulary suppression in 40–100% | |
8000–20,000 | Permanent ovulary suppression in 100% |
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Drago-Ferrante, R.; Di Fiore, R.; Karouia, F.; Subbannayya, Y.; Das, S.; Aydogan Mathyk, B.; Arif, S.; Guevara-Cerdán, A.P.; Seylani, A.; Galsinh, A.S.; et al. Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review. Int. J. Mol. Sci. 2022, 23, 7465. https://doi.org/10.3390/ijms23137465
Drago-Ferrante R, Di Fiore R, Karouia F, Subbannayya Y, Das S, Aydogan Mathyk B, Arif S, Guevara-Cerdán AP, Seylani A, Galsinh AS, et al. Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review. International Journal of Molecular Sciences. 2022; 23(13):7465. https://doi.org/10.3390/ijms23137465
Chicago/Turabian StyleDrago-Ferrante, Rosa, Riccardo Di Fiore, Fathi Karouia, Yashwanth Subbannayya, Saswati Das, Begum Aydogan Mathyk, Shehbeel Arif, Ana Paula Guevara-Cerdán, Allen Seylani, Aman Singh Galsinh, and et al. 2022. "Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review" International Journal of Molecular Sciences 23, no. 13: 7465. https://doi.org/10.3390/ijms23137465
APA StyleDrago-Ferrante, R., Di Fiore, R., Karouia, F., Subbannayya, Y., Das, S., Aydogan Mathyk, B., Arif, S., Guevara-Cerdán, A. P., Seylani, A., Galsinh, A. S., Kukulska, W., Borg, J., Suleiman, S., Porterfield, D. M., Camera, A., Christenson, L. K., Ronca, A. E., Steller, J. G., Beheshti, A., & Calleja-Agius, J. (2022). Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review. International Journal of Molecular Sciences, 23(13), 7465. https://doi.org/10.3390/ijms23137465