Cardiopulmonary Inflammatory Response to Meteorite Dust Exposures - Implications for Human Health on Earth and Beyond

This year marks the 50th anniversary of Apollo 11, the first time humans set foot on the Moon. The Apollo missions not only help answer questions related to our solar system, they also highlight many hazards associated with human space travel. One major concern is the effect of extraterrestrial dust on astronaut health. In an effort to expand upon previous work indicating lunar dust is respirable and reactive, the authors initiated an extensive study evaluating the role of a particulates innate geochemical features (e.g., bulk chemistry, internal composition, morphology, size, and reactivity) in generating adverse toxicological responses in vitro and in vivo. To allow for a broader planetary and geochemical assessment, seven samples were evaluated: six meteorites from either the Moon, Mars, or Asteroid 4 Vesta and a terrestrial basalt analogue. Even with the relatively small geochemical differences (all samples basaltic in nature), significant difference in cardiopulmonary inflammatory markers developed in both single exposure and multiple exposure studies. More specifically: 1) the single exposure studies reveal relationships between toxicity and a meteorite samples origin, its pre-ejected state (weathered versus un-weathered), and geochemical features (e.g. bulk iron content) and 2) multiple exposure studies reveal a correlation with particle derived reactive oxygen species (ROS) formation and neutrophil infiltration. Extended human exploration will further increase the probability of inadvertent and repeated exposures to extraterrestrial dusts. This comprehensive dataset allows for not only the toxicological evaluation of extraterrestrial materials but also clarifies important correlations between geochemistry and health. The utilization of an array of extraterrestrial samples from Moon, Mars, and asteroid 4Vesta will enable the development of a geochemical based toxicological hazard model that can be used for: 1) mission planning, 2) rapid risk assessment in cases of unexpected exposures, and 3) evaluation of the efficacy of various in situ techniques in gauging surface dust toxicity. Furthermore, by better understanding the importance of geochemical features on exposure related health outcomes in space, it is possible to better understand of the deleterious nature of dust exposure on Earth

Never tear us a-PARP:Dealing with DNA lesions during mitosis

Tumors defective in homologous recombination (HR) are highly sensitive to poly ADP-ribose polymerase (PARP) inhibition, however the cell biological mechanisms underlying this synthetic lethality remain elusive. We recently identified that PARP inhibitor-induced DNA lesions persist until mitosis, subsequently causing mitotic chromatin bridges, multinucleation and apoptosis. Here, we discuss the implications of these findings

Pulmonary Inflammatory Responses to Acute Meteorite Dust Exposures - to Acute Meteorite Dust Exposures - Exploration

New initiatives to begin lunar and martian colonization within the next few decades are illustrative of the resurgence of interest in space travel. One of NASA's major concerns with extended human space exploration is the inadvertent and repeated exposure to unknown dust. This highly interdisciplinary study evaluates both the geochemical reactivity (e.g. iron solubility and acellular reactive oxygen species (ROS) generation) and the relative toxicity (e.g. in vitro and in vivo pulmonary inflammation) of six meteorite samples representing either basalt or regolith breccia on the surface of the Moon, Mars, and Asteroid 4Vesta. Terrestrial mid-ocean ridge basalt (MORB) is also used for comparison. The MORB demonstrated higher geochemical reactivity than most of the meteorite samples but caused the lowest acute pulmonary inflammation (API). Notably, the two martian meteorites generated some of the highest API but only the basaltic sample is significantly reactive geochemically. Furthermore, while there is a correlation between a meteorite's soluble iron content and its ability to generate acellular ROS, there is no direct correlation between a particle's ability to generate ROS acellularly and its ability to generate API. However, assorted in vivo API markers did demonstrate strong positive correlations with increasing bulk Fenton metal content. In summary, this comprehensive dataset allows for not only the toxicological evaluation of astromaterials but also clarifies important correlations between geochemistry and health

Cardiopulmonary Inflammatory Responses to Subacute Meteorite Dust Exposures Implications for Human Space Exploration

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Pulmonary Inflammatory Responses to Acute Meteorite Dust Exposures - Implications for Human Space Exploration

New initiatives to begin Lunar and Martian human surface operations within the next few decades are illustrative of the resurgence of interest in human space exploration. However, as with all exploration, there are risks. The previous manned missions to the Moon highlight a major hazard for future human exploration of the Moon and beyond: surface dust. Not only did the dust cause mechanical and structural integrity issues with the suits, the dust 'storm' generated upon reentrance into the crew cabin caused "lunar hay fever" and "almost blindness.". It was further reported that the allergic response to the dust worsened with each exposure. Due to the prevalence of these high exposures, the Human Research Roadmap developed by NASA identifies the Risk of Adverse Health and Performance Effects of Celestial Dust Exposure as an area of concern

Pulmonary Inflammatory Responses to Acute Meteorite Dust Exposures - Implications for Human Space Exploration

New initiatives to send humans to Mars within the next few decades are illustrative of the resurgence of interest in space travel. However, as with all exploration, there are risks. The Human Research Roadmap developed by NASA identifies the Risk of Adverse Health and Performance Effects of Celestial Dust Exposure as an area of concern. Extended human exploration will further increase the probability of inadvertent and repeated exposures to celestial dusts

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors