title: Charged iron particles, components of space radiation, destroy ovarian follicles.
abstract: Do charged iron particles, components of space radiation, cause premature ovarian failure?
  
  
  
  Exposure to charged iron particles causes ovarian DNA damage, oxidative damage and apoptosis, resulting in premature ovarian failure.
  
  
  
  The ovary is very sensitive to follicle destruction by low linear energy transfer (LET) radiation, such as X-rays and γ-rays. However, it is completely unknown whether high-LET radiation, such as charged iron particles, also destroys ovarian follicles.
  
  
  
  Twelve week old C57BL/6J female mice were exposed to single doses of 0, 5, 30 or 50 cGy (n = 8/group) charged iron particles (LET = 179 keV/µm) at energy of 600 MeV/u. Two groups were irradiated at the highest dose, one fed AIN-93M chow and the other fed AIN-93M chow supplemented with 150 mg/kg diet alpha lipoic acid (ALA).
  
  
  
  We quantified the numbers of ovarian follicles, measured serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations, and analyzed histone H2AX phosphorylation, oxidative damage and apoptosis markers in the ovarian follicles.
  
  
  
  H2AX phosphorylation, lipid peroxidation, protein nitration and apoptosis were highly induced in ovarian follicles at 6 h and remained increased 1 week after irradiation. As a result, numbers of healthy ovarian follicles were significantly and dose-dependently depleted at 1 and 8 weeks post-irradiation, with 57, 84 and 99% decreases in primordial follicles at 8 weeks at the 5, 30 and 50 cGy doses, respectively (P < 0.05 versus 0 cGy). Consistent with near-total depletion of ovarian follicles in the 50 cGy group, serum concentrations of FSH and LH were significantly elevated at 8 weeks. Dietary supplementation with ALA partially prevented the adverse ovarian effects of 50 cGy iron particles.
  
  
  
  About 21% of the estimated radiation dose from exposure to galactic cosmic rays during a multi-year Mars mission will be due to high-LET particles, of which iron is only one. The effects of galactic cosmic rays, which contain a mixture of multiple charged particles, as well as protons, neutrons, and helium ions, may differ from the effects of iron alone.
  
  
  
  We show for the first time that charged high-LET ions are highly damaging to the ovary even at low doses, causing premature ovarian failure. In addition to raising concerns for female astronauts, these findings raise concerns for ovarian damage due to clinical uses of high-LET particles for cancer treatment. In addition to causing infertility, premature ovarian failure has adverse implications for the functions of heart, brain, bone and muscle later in life.
  
  
  
  This work was supported by a National Aeronautics and Space Administration grant NNX14AC50G to U.L. B.M. was partially supported by a National Space Biomedical Research Institute First Award, PF04302. Additional support was received from the University of California Irvine Center for Occupational and Environmental Health. The authors have no conflicts of interests.
authors.affiliation: Department of Medicine, University of California Irvine, Irvine, CA 92617, USA.
authors.forename: Birendra
authors.initials: B
authors.lastname: Mishra
authors.affiliation: Department of Medicine, University of California Irvine, Irvine, CA 92617, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Ortiz
authors.affiliation: Department of Medicine, University of California Irvine, Irvine, CA 92617, USA Developmental and Cell Biology, University of California Irvine, Irvine, CA 92617, USA Program in Public Health, University of California Irvine, Irvine, CA 92617, USA uluderer@uci.edu.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Luderer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D003359:Cosmic Radiation; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006657:Histones / Q000378:metabolism; D007501:Iron; D015227:Lipid Peroxidation / Q000187:drug effects / Q000528:radiation effects; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011829:Radiation Dosage; D008063:Thioctic Acid / Q000008:administration & dosage*
chemical_list: D005640:Follicle Stimulating Hormone; D006657:Histones; D007501:Iron; D007986:Luteinizing Hormone; D008063:Thioctic Acid; C475961:gamma-H2AX protein, mouse
keywords: apoptosis; charged particles; ionizing radiation; ovarian follicle; oxidative stress; premature ovarian failure