MICROGRAVITY NEGATIVELY AFFECTS DNA DAMAGE REPAIR AND THE ANTI-LEUKEMIC FUNCTION OF HUMAN NATURAL KILLER CELLS

Future manned deep space missions will expose astronauts to galactic cosmic ray (GCR) radiation and solar energetic particles (SEPs) not present on Earth. The hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. Therefore, leukemias may pose a distinct threat to astronauts during these prolonged space missions. We have previously shown that exposure of human hematopoietic stem cells (HSC) to mission-relevant doses of accelerated high-energy protons (the primary component of SEPs) and high atomic number and energy (HZE) ions (the high-energy nuclei component of GCR) induces DNA damage, alters HSC function/differentiative capacity, and triggers leukemogenesis when these cells repopulate murine hosts. Importantly, astronaut on missions beyond low-Earth orbit are exposed to these unique high-energy species of radiation while in conditions of microgravity (G), which can alter radiation response and immunity. We therefore examined the impact exposing human HSC to μG had upon their capacity to repair DNA damage and on the functionality of Natural Killer (NK) cells, cytotoxic lymphocytes within the innate immune system, that play a key role in the recognition and elimination of tumor cells. μG dramatically reduced human HSC-like KG1a cells’ ability to repair DNA lesions induced with the radiomimetic drug bleomycin, as assessed by γH2AX foci. Furthermore, brief exposure of human NK cells to conditions of μG dramatically reduced the cytotoxicity of NK-92MI cells against two different human leukemic cell lines. Studies utilizing activated primary NK cells and ionizing radiation to determine the mechanism of μG-altered DNA damage repair and are currently ongoing. Together, these data suggest conditions of μG may increase the risk of carcinogenesis, and highlight the need for further study to better define the relationship between μG and cancer risk in astronauts on prolonged missions in deep space.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2019

Author dc:creator

• Kuhlman, Bradford M

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/93908

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/93908