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At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
NASA NTRS2010

The Biotoxicity of Mars Soils

Recent evidence from the Opportunity and Spirit rovers suggests that the soils on Mars might be very high in biotoxic materials induding sulfate salts, chlorides, and acidifying agents. Yet, very little is known about how the chemistries of Mars soils might affect the survival and growth of terrestrial microorganisms. The primary objectives of the proposed research will be to: (1) prepare and characterize Mars analog soils amended with potential biotoxic levels of sulfates, chlorides, and acidifying minerals; (2) use the stimulants to conduct a series of toxicology assays to determine if terrestrial microorganisms from spacecraft or extreme environments can survive direct exposure to the biotoxic soils, and (3) mix soils from extreme environments on Earth into Mars analog soils to determine if terrestrial microorganisms can grow and replicate under Martian conditions. The Mars analog soils will be thoroughly characterized by a wide diversity of soil chemistry assays to determine the exact nature of the soluble biotoxic components following hydration. The microbial experiments will be designed to test the effects of Mars stimulants on microbial survival, growth and replication during direct challenge experiments. Toxicology experiments will be designed to mimic terrestrial microbes coming into contact with biotoxic soils with and without liquid water. Results are expected to help" ... characterize the limits of life in ... planetary environments ... " and may help constrain the search for life on Mars.

Kerney, Krystal↗
NASA NTRS2011

Legacy of Environmental Research During the Space Shuttle Program

The Space Shuttle Program provided many opportunities to study the role of spaceflight on human life for over the last 30 years and represents the longest and largest U.S. human spaceflight program. Risks to crewmembers were included in the research areas of nutrition, microbiology, toxicology, radiation, and sleep quality. To better understand the Shuttle environment, Crew Health Care System was developed. As part of this system, the Environmental Health Subsystem was developed to monitor the atmosphere for gaseous contaminants and microbial contamination levels and to monitor water quality and radiation. This program expended a great deal of effort in studying and mitigating risks related to contaminations due to food, water, air, surfaces, crewmembers, and payloads including those with animals. As the Shuttle had limited stowage space and food selection, the development of nutritional requirements for crewmembers was imperative. As the Shuttle was a reusable vehicle, microbial contamination was of great concern. The development of monitoring instruments that could withstand the space environment took several years and many variations to come up with a suitable instrument. Research with space radiation provided an improved understanding of the various sources of ionizing radiation and the development of monitoring instrumentation for space weather and the human exposure within the orbiter's cabin. Space toxicology matured to include the management of offgassing products that could pollute the crewmembers air quality. The Shuttle Program implemented a 5-level toxicity rating system and developed new monitoring instrumentation to detect toxic compounds. The environment of space caused circadian desynchrony, sleep deficiency, and fatigue leading to much research and major emphasis on countermeasures. Outcomes of the research in these areas were countermeasures, operational protocols, and hardware. Learning Objectives: This symposium will provide an overview of the major environmental lessons learned and the development of countermeasures, monitoring hardware, and procedures.

Lane, Helen W.↗
NASA NTRS2012

Whole Module Offgas Test Report: Space-X Dragon Module

Between 7 April and 11 April 2012 a chemist from the JSC Toxicology Group acquired samples of air in 500 ml evacuated canisters from the sealed Dragon Module at the Space-X facility at KSC. Three samples were taken of facility air (two before the test and one after the test), and a total of 9 samples were taken from the sealed module in triplicate at the following times: 0 hours, 48 hours, and 96 hours. The module contained 470 kg, which was 100% of the mass to be launched. Analytical data contained in the Toxicology Group Report (attached) show that the ambient facility air was clean except for almost 9 milligrams per cubic meter of isopropanol (IPA) in the sample taken at the end of the test. Space-X must ensure that IPA is not introduced into the module before it is sealed for launch. Other minor contaminants in the ambient air included the following: perfluoro(2-methyl)pentane and hexamethylcyclotrisiloxane. The first-acquired samples of each triplicate from the module were not analyzed. Analyses of pairs of samples that were taken during the test show excellent agreement between the pairs and a linear increase in the T-values during the 4 days of the test (figure below). The rate of increase averaged 0.124 T units per day. If the time from last purge of the module on the ground to crew first entry on orbit is 10 days, then the T value at first entry should be less than 1.2 units, which is well below the criterion of 3.0 for consideration of additional protection of the crew from offgas products. The primary contributors were as follows: trimethylsilanol (0.057), fluorotrimethylsilane (0.047), acetaldehyde (0.004), hexamethylcyclopentasiloxane (0.003), and toluene (0.002).

James, John T.↗
NASA NTRS2014

Protecting Astronaut Health at First Entry into Vehicles Visiting the international Space Station: Insights from Whole-Module Offgas Testing

NASA has accumulated considerable experience in offgas testing of whole modules prior to their docking with the International Space Station (ISS). Since 1998, the Space Toxicology Office has performed offgas testing of the Lab module, both MPLM modules, US Airlock, Node 1, Node 2, Node 3, ATV1, HTV1, and three commercial vehicles. The goal of these tests is twofold: first, to protect the crew from adverse health effects of accumulated volatile pollutants when they first enter the module on orbit, and secondly, to determine the additional pollutant load that the ISS air revitalization systems must handle. In order to predict the amount of accumulated pollutants, the module is sealed for at least 1/5th the worst‐case time interval that could occur between the last clean air purge and final hatch closure on the ground and the crew's first entry on orbit. This time can range from a few days to a few months. Typically, triplicate samples are taken at pre‐planned times throughout the test. Samples are then analyzed by gas chromatography and mass spectrometry, and the rate of accumulation of pollutants is then extrapolated over time. The analytical values are indexed against 7‐day spacecraft maximum allowable concentrations (SMACs) to provide a prediction of the total toxicity value (T‐value) at the time of first entry. This T‐value and the toxicological effects of specific pollutants that contribute most to the overall toxicity are then used to guide first entry operations. Finally, results are compared to first entry samples collected on orbit to determine the predictive ability of the ground‐based offgas test.

Meyers, Valerie↗
NASA NTRS2016

Effects of Acute Exposures to Carbon Dioxide Upon Cognitive Functions

Large quantities of carbon dioxide (CO2) originate from human metabolism and typically, within spacecraft, remain about 10-fold higher in concentration than at the earth's surface. There have been recurring complaints by crew members of episodes of "mental viscosity" adversely affecting their performance, and there is evidence from the International Space Station (ISS) that associates CO2 levels with reports of headaches by crewmembers. Additionally, there is concern that CO2 may contribute to vision impairment and intracranial pressure that has been observed in some crewmembers. Consequently, flight rules have been employed to control the level of CO2 below 4 mm Hg, which is well below the existing Spacecraft Maximum Allowable Concentration (SMAC) of 10 mm Hg for 24-hour exposures, and 5.3 mm Hg for exposures of 7 to 180 days. However, the flight rule imposed limit, which places additional demands upon resources and current technology, still exceeds the lower bound of the threshold range for reportable headaches (2 - 5 mm Hg). Headaches, while sometime debilitating themselves, are also symptoms that can provide evidence that physiological defense mechanisms have been breached. The causes of the headaches may elicit other subtle adverse effects that occur at CO2 levels well below that for headaches. The concern that CO2 may have effects at levels below the threshold for headaches appears to be substantiated in unexpected findings that CO2 at concentrations below 2 mm Hg substantially reduced some cognitive functions that are associated with the ability to make complex decisions in conditions that are characterized by volatility, uncertainty, complexity, ambiguity, and delayed feedback. These are conditions that could be encountered by crews in off-nominal situations or during the first missions beyond low earth orbit. If findings of the earlier study are confirmed in crew-like subjects, our findings would provide additional evidence that CO2 may need to be controlled at levels that are well below current spacecraft limits. Our study will extend the earlier study to determine if crew-like subjects are similarly effected by CO2. In addition to employing the Strategic Management Simulation tool, we will use the Cognition battery of psychometric measures that are being utilized aboard the ISS. It will be important to learn, by using Cognition, if additional cognitive domains are sensitive to concentrations of CO2 at or below limits currently controlled by flight rules. While spaceflight Cognition data will greatly enhance the knowledge base related to inflight behavioral health and performance, some of the measures may be influenced by fatigue (related to sleep deprivation and or workload) and changes in circadian rhythms. Therefore our use of this battery of tests in a well-controlled, ground-based study that is free of these potential confounding influences will establish a baseline terrestrial data set against which Cognition data collected in flight may be assessed. The findings from this study will be useful to the NASA Toxicology Office and the National Research Council Committee on Toxicology, which assists NASA in setting environmental standards, for revision of the SMAC for CO2, and for designing further studies on effects of CO2 upon cognitive functions.

Scully, R. R.↗
NASA NTRS2022

Spacecraft Maximum Allowable Concentrations for Airborne Contaminants: Revision B

The enclosed table lists official Spacecraft Maximum Allowable Concentrations (SMACs) for selected airborne contaminants. They are based upon experiments conducted at standard pressure and oxygen environments and may or may not be applicable to altered atmospheres. These are guideline values set by the National Aeronautics and Space Administration (NASA)/Johnson Space Center (JSC) Toxicology Group in cooperation with the National Research Council Committee on Toxicology (NRCCOT) or through publication in the peer-reviewed scientific literature. Based on documented guidance (NRC, 1992; NRC, 2016), NASA has established SMACs for 60 chemical compounds that are particularly relevant to atmospheric contamination of the International Space Station (ISS) and targets of Exploration. Some long‐term limits (1000‐days) have also been established to support manned deep‐space exploration. Summaries of these SMACs are presented in tabular form as part of this publication. Short-term (1- and 24-hour) SMACs apply to off nominal situations, such as accidental releases aboard a spacecraft. These limits permit risk of minor, reversible effects, such as mild mucosal irritation. In contrast, the long term SMACs are set to fully protect healthy crewmembers from adverse effects resulting from continuous exposure to specific air pollutants for up to 1000 days. Because allergic reactions or chemical idiosyncrasy to certain airborne pollutants are very difficult to predict, crewmembers with allergies or unusual sensitivity to trace pollutants may not be afforded complete protection, even when long-term SMACs are not exceeded. Conversely, exceedance of a SMAC does not mean that health impairment is certain (there are many other factors that influence ultimate health outcomes), although it does indicate that the crew may be subject to increased risks that must be closely evaluated. Environmental pollutant control to mitigate exposure will likely be triggered.

SMACs↗
NASA NTRS2023

Spacecraft Water Exposure Guidelines: Revision A

The enclosed table lists official Spacecraft Water Exposure Guidelines (SWEGs), which are guideline values set by the NASA/JSC Toxicology Group in cooperation with the National Research Council Committee on Toxicology (NRCCOT) or through publication in the peer‐reviewed scientific literature. Based on documented guidance (NRC, 2000), NASA has established SWEGs for 30 chemical compounds that are particularly relevant to water systems on the International Space Station (ISS) as well as on spacecraft for deep‐space exploration. Summaries of these SWEGs are presented in tabular form as part of this publication.

SWEGs↗
NASA NTRSDate not supplied

High Risk Spacecraft Materials Offgassing

NASA-STD-6001B, Determination of Offgassed Products (Test 7), provides the offgassing characteristics under standardized conditions for materials and assembled articles to be located within habitable spacecraft environments. Experience with Test 7 has found certain material types to be of higher risk for offgassing undesirable compounds aboard spacecraft than others. Formaldehyde and acrolein are historically high T value offgassed components of the offgassed compound target list because they have low spacecraft maximum allowable concentration (SMAC) values assigned by the JSC Toxicology Group. Carbon disulfide, benzene, acrylonitrile, and furan are additional target compounds of concern due to their lower thresholds of toxicity as determined by the JSC Toxicology Group. Materials offgassing siloxanes are also of concern due to their degradation effects on environmental control and life support system (ECLSS) components and performance. Spacecraft materials and articles defined in this manuscript as high risk were identified after examining and condensing data for these compounds of concern from approximately 3000 tests performed over 30 years. Summaries of high risk material and article types based on highest Multi-Purpose Crew Vehicle (MPCV) T values are also presented. Historical analysis shows high risk components are produced largely from test materials and articles in the general categories of electronic/powered components, foams, paints/coatings/films, adhesives/tapes, epoxy/resins, liquids/gels, Nomex® with surface treatments, markers/pens/inks, dry film lubricants, thermoplastics, hygiene items (deodorants, lip balms), and silicone rubber. These data are intended to be a resource for spacecraft materials and processes managers, designers, and toxicologists. High risk materials and articles intended for use aboard spacecraft should be tested in accordance with NASA-STD-6001B Test 7.

Vanessa D Buchanan↗
DOE OSTI2022

Effects of Lead and Arsenic in Soils from Former Orchards on Growth of Three Plant Species

Abstract Historical use of lead arsenate as a pesticide in former orchards of eastern Washington State (USA) has resulted in legacy lead (Pb) and arsenic (As) soil contamination. However, the impacts on plant growth in soils with residual Pb and As contamination have not yet been quantified. To this end, a comparative study of plant growth impacts was performed for native bluegrass ( Poa secunda ), invasive cheatgrass ( Bromus tectorum ), and buttercrunch lettuce ( Lactuca sativa ). Using standard plant growth protocols, germination frequency and biomass growth were measured over a wide range of Pb and arsenate concentrations, with maximum concentrations of 3400 and 790 mg kg −1 for Pb and As, respectively. Results indicated that only the biomass growth for all species decreased in soils with the highest concentrations of Pb and As in the soil, with no impacts on soils with lower residual Pb and arsenate concentrations. No impact on percentage of germination was observed at any soil concentration. These results can be used to determine site‐specific soil screening levels for use in ecological risk assessments for Pb and arsenate in soils. Environ Toxicol Chem 2022;41:1459–1465. © 2022 Battelle Memorial Institute. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Bioaccumulation of Mercury and Radiocesium in Waterfowl Introduced to a Site with Legacy Contamination

Despite the propensity of waterfowl species to readily accumulate anthropogenic contaminants within polluted environments, few studies have examined bioaccumulation rates over time when entering such a contaminated site. We examined mercury (Hg) and radiocesium ( 137 Cs) bioaccumulation over time in two waterfowl species released into a wetland system containing legacy contamination on the US Department of Energy's Savannah River Site in South Carolina. Released birds were collected at select time intervals over an exposure period of 94 days. We quantified total Hg concentrations in blood, muscle, and liver tissues, and 137 Cs activity in whole-body and muscle tissues. The relationship between the contaminant burdens of different body tissue types was examined over time. Likely a result of microhabitat selection, mallards in our study readily accumulated both Hg and 137 Cs at consistent rates over time within our study system, while ring-neck ducks did not. The findings demonstrated that whole blood can be used as a robust, nondestructive sampling alternative to estimate Hg burdens within muscle and liver, and whole-body 137 Cs activity is a good predictor of muscle burdens. Understanding such bioaccumulation information in waterfowl is useful for the assessment of the potential health risk in wildlife, as well as being important for human risk assessment toward the consumption of popular game species. Environ Toxicol Chem 2022;41:2479–2487. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Acute Copper Toxicity Displays a Nonmonotonic Relationship with Age Across the Medaka ( Oryzias latipes ) Life Span

The ability of an organism to cope with environmental stressors varies across the life span because of developmental stage–specific responses and age-related functional declines. In the present study, we examined the effect of age on acute copper toxicity in Japanese medaka (Oryzias latipes). We first determined the median lethal concentration (LC50) at 96 h for embryos, 7-day-old fry, and 6-month-old medaka. Embryos were exposed to 0, 15, 30, 60, 125, 250, and 500 ppb CuSO 4 through hatching. Fry were exposed to 0, 20, 50, 75, 100, 150, 250, and 500 ppb CuSO 4 for 96 h. Adult fish were exposed to 0, 100, 150, 200, 250, and 300 ppb CuSO 4 for 96 h. The 96-h LC50 was 804 ppb for embryos, 262 ppb for embryonically exposed larvae, 60.3 ppb for 7-day-old fry, and 226 ppb for adults. We then challenged cohorts of fish aged 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, and 16 months with a 225-ppb CuSO 4 exposure to determine the acute toxicity across the life span. The fish exhibited a bimodal tolerance to copper, with tolerance peaking in 2- and 3-month-old fish and again at 10 and 11 months of age. Our data demonstrate that copper sensitivity is dynamic throughout the medaka life span and may be influenced by trade-offs with reproduction. Environ Toxicol Chem 2022;41:2999–3006. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Transcriptomics-Based Points of Departure for Daphnia magna Exposed to 18 Per- and Polyfluoroalkyl Substances

Here, per- and polyfluoroalkyl substances (PFAS) represent a large group of contaminants of concern based on their widespread use, environmental persistence, and potential toxicity. Many traditional models for estimating toxicity, bioaccumulation, and other toxicological properties are not well suited for PFAS. Consequently, there is a need to generate hazard information for PFAS in an efficient and cost-effective manner. In the present study, Daphnia magna were exposed to multiple concentrations of 22 different PFAS for 24 h, in 96-well plate format. Following exposure, whole body RNA was extracted and extracts, each representing five exposed individuals, were subjected to RNA sequencing. Following analytical measurements to verify PFAS exposure concentrations, and quality control on processed cDNA libraries for sequencing, concentration-response modeling was applied to the data sets for 18 of the tested compounds, and the concentration at which a concerted molecular response occurred (transcriptomic point of departure; tPOD) was calculated. The tPODs, based on measured concentrations of PFAS, generally ranged from 0.03-0.58 µM (9.9-350 µg/L; interquartile range). In most cases, these concentrations were two orders of magnitude lower than similarly calculated tPODs for human cell lines exposed to PFAS. They were also lower than apical effect concentrations reported for seven PFAS for which some crustacean or invertebrate toxicity data were available, although there were a few exceptions. Despite being lower than most other available hazard benchmarks, Daphnia magna tPODs were, on average, four orders of magnitude greater than the maximum aqueous concentrations of PFAS measured in Great Lakes tributaries. Overall, this high throughput transcriptomics assay with Daphnia magna holds promise as a component of a tiered hazard evaluation strategy employing new approach methodologies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Spatiotemporal Changes in Trace Metal Bioavailability in the Sediment Pore water of a Constructed Wetland Using Passive Pore water Samplers

Sediments in aquatic systems often act as a major sink for contaminants. Diffusive gradient in thin films (DGTs) and in situ equilibrium dialysis samplers (peepers) are two major in situ pore water sampling devices that overcome the problems associated with conventional pore water sampling methods. In the present study, DGTs and peepers were used to study the spatial and seasonal effects (cool months, October–February; warm months, May–September) on metal bioavailability in the H‐02 constructed wetland and the sink versus source role of the sediments by calculating the metal resupply capacity. Data showed similar seasonal trends in metal concentrations using passive samplers, peepers, and DGTs. Pooled Cu and Zn concentrations measured using DGTs were lower in warm months (1.67 ± 1.50 and 2.62 ± 0.68 μg L –1 , respectively, p < 0.001) versus in cool months (2.12 ± 0.65 and 5.58 ± 1.33 μg L –1 , respectively, p < 0.001; mean ± 95% confidence interval). Sulfate (SO 4 2− ) concentrations were significantly (p = 0.0139) lower in warm months (averaged at 0.22 ± 0.05 mg L –1 ) compared to in cool months (0.16 ± 0.05 mg L –1 ). The increase in SO 4 2− concentration is an indicator of the lower activity of sulfate‐reducing bacteria, which need SO 4 2− during anaerobic respiration, in which SO 4 2− is reduced to sulfide (S 2– ) that forms insoluble salts with Cu and Zn, which could partially explain the higher bioavailability of these metals in the cool season. Metal resupply capacity of the sediments was mostly <0.2 for Cu and Zn. Taken together, the H0‐2 wetland sediments mostly acted as a sink to both Cu and Zn over the course of the present study. Environ Toxicol Chem 2023;42:2726–2736. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Differential DNA methylation and metabolite profiling of Atlantic killifish (Fundulus heteroclitus) from the New Bedford Harbor Superfund site

Atlantic killifish (Fundulus heteroclitus) is a valuable model in evolutionary toxicology to study how the interactions between genetic and environmental factors serve the adaptive ability of organisms to resist chemical pollution. Killifish populations inhabiting environmental toxicant-contaminated New Bedford Harbor (NBH) show phenotypes tolerant to polychlorinated biphenyls (PCBs) and differences at the transcriptional and genomic levels. However, limited research has explored epigenetic alterations and metabolic effects in NBH killifish. To identify the involvement of epigenetic and metabolic regulation in the adaptive response of killifish, we investigated tissue- and sex-specific differences in global DNA methylation and metabolomic profiles of NBH killifish populations, compared to sensitive populations from a non-polluted site, Scorton Creek (SC). The results revealed that liver-specific global DNA hypomethylation and differential metabolites were evident in fish from NBH compared with those from SC. The sex-specific differences were not greater than the tissue-specific differences. We demonstrated liver-specific enriched metabolic pathways (e.g., amino acid metabolic pathways converged into the urea cycle and glutathione metabolism), suggesting possible crosstalk between differential metabolites and DNA hypomethylation in the livers of NBH killifish. Additional investigation of methylated gene regions is necessary to understand the functional role of DNA hypomethylation in the regulation of enzyme-encoding genes associated with metabolic processes and physiological changes in NBH populations.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Transcriptional pathways linked to fetal and maternal hepatic dysfunction caused by gestational exposure to perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) in CD-1 mice

Per- and polyfluoroalkyl substances (PFAS) comprise a diverse class of chemicals used in industrial processes, consumer products, and fire-fighting foams which have become environmental pollutants of concern due to their persistence, ubiquity, and associations with adverse human health outcomes, including in pregnant persons and their offspring. Multiple PFAS are associated with adverse liver outcomes in adult humans and toxicological models, but effects on the developing liver are not fully described. Here we performed transcriptomic analyses in the mouse to investigate the molecular mechanisms of hepatic toxicity in the dam and its fetus after exposure to two different PFAS, perfluorooctanoic acid (PFOA) and its replacement, hexafluoropropylene oxide-dimer acid (HFPO-DA, known as GenX). Pregnant CD-1 mice were exposed via oral gavage from embryonic day (E) 1.5-17.5 to PFOA (0, 1, or 5 mg/kg-d) or GenX (0, 2, or 10 mg/kg-d). Maternal and fetal liver RNA was isolated (N = 5 per dose/group) and the transcriptome analyzed by Affymetrix Array. Differentially expressed genes (DEG) and differentially enriched pathways (DEP) were obtained. DEG patterns were similar in maternal liver for 5 mg/kg PFOA, 2 mg/kg GenX, and 10 mg/kg GenX (R2: 0.46-0.66). DEG patterns were similar across all 4 dose groups in fetal liver (R2: 0.59-0.81). There were more DEGs in fetal liver compared to maternal liver at the low doses for both PFOA (fetal = 69, maternal = 8) and GenX (fetal = 154, maternal = 93). Upregulated DEPs identified across all groups included Fatty Acid Metabolism, Peroxisome, Oxidative Phosphorylation, Adipogenesis, and Bile Acid Metabolism. Transcriptome-phenotype correlation analyses demonstrated > 1000 maternal liver DEGs were significantly correlated with maternal relative liver weight (R 2 >0.92). These findings show shared biological pathways of liver toxicity for PFOA and GenX in maternal and fetal livers in CD-1 mice. The limited overlap in specific DEGs between the dam and fetus suggests the developing liver responds differently than the adult liver to these chemical stressors. This work helps define mechanisms of hepatic toxicity of two structurally unique PFAS and may help predict latent consequences of developmental exposure.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Impact of Surface Chemistry of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles on Protein Corona Formation and Endothelial Cell Uptake, Toxicity, and Barrier Function

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have been investigated for biomedical applications, including novel contrast agents, magnetic tracers for tumor imaging, targeted drug delivery vehicles, and magneto-mechanical actuators for hyperthermia and thrombolysis. Despite significant progress, recent clinical reports have raised concerns regarding USPION safety related to endothelial cell dysfunction; however, there is limited information on factors contributing to these clinical responses. The influence of USPION surface chemistry on nanoparticle interactions with proteins may impact endothelial cell function leading to adverse responses. Therefore, the goal of this study was to assess the effects of carboxyl-functionalized USPION (CU) or amine-functionalized USPION (AU) (approximately 30 nm diameter) on biological responses in human coronary artery endothelial cells. Increased protein adsorption was observed for AU compared with CU after exposure to serum proteins. Exposure to CU, but not AU, resulted in a concentration-dependent decrease in cell viability and perinuclear accumulation inside cytoplasmic vesicles. Internalization of CU was correlated with endothelial cell functional changes under non-cytotoxic conditions, as evidenced by a marked decreased expression of endothelial-specific adhesion proteins (eg, vascular endothelial-cadherin and platelet endothelial cell adhesion molecule-1) and increased endothelial permeability. Evaluation of downstream signaling indicated endothelial permeability is associated with actin cytoskeleton remodeling, possibly elicited by intracellular events involving reactive oxygen species, calcium ions, and the nanoparticle cellular uptake pathway. This study demonstrated that USPION surface chemistry significantly impacts protein adsorption and endothelial cell uptake, viability, and barrier function. This information will advance the current toxicological profile of USPION and improve development, safety assessment, and clinical outcomes of USPION-enabled medical products.

Toxicology↗
DOE OSTI2024

Systemic immunological responses are dependent on sex and ovarian hormone presence following acute inhaled woodsmoke exposure

Background: Rural regions of the western United States have experienced a noticeable surge in both the frequency and severity of acute wildfire events, which brings significant challenges to both public safety and environmental conservation efforts, with impacts felt globally. Identifying factors contributing to immune dysfunction, including endocrinological phenotypes, is essential to understanding how hormones may influence toxicological susceptibility. Methods: This exploratory study utilized male and female C57BL/6 mice as in vivo models to investigate distinct responses to acute woodsmoke (WS) exposure with a focus on sex-based differences. In a second set of investigations, two groups were established within the female mouse cohort. In one group, mice experienced ovariectomy (OVX) to simulate an ovarian hormone-deficient state similar to surgical menopause, while the other group received Sham surgery as controls, to investigate the mechanistic role of ovarian hormone presence in driving immune dysregulation following acute WS exposure. Each experimental cohort followed a consecutive 2-day protocol with daily 4-h exposure intervals under two conditions: control HEPA-filtered air (FA) and acute WS to simulate an acute wildfire episode. Results: Metals analysis of WS particulate matter (PM) revealed significantly increased levels of 63 Cu, 182 W, 208 Pb, and 238 U, compared to filtered air (FA) controls, providing insights into the specific metal components most impacted by the changing dynamics of wildfire occurrences in the region. Male and female mice exhibited diverse patterns in lung mRNA cytokine expression following WS exposure, with males showing downregulation and females displaying upregulation, notably for IL-1β, TNF-α, CXCL-1, CCL-5, TGF-β, and IL-6. After acute WS exposure, there were notable differences in the responses of macrophages, neutrophils, and bronchoalveolar lavage (BAL) cytokines IL-10, IL-6, IL-1β, and TNF-α. Significant diverse alterations were observed in BAL cytokines, specifically IL-1β, IL-10, IL-6, and TNF-α, as well as in the populations of immune cells, such as macrophages and polymorphonuclear leukocytes, in both Sham and OVX mice, following acute WS exposure. These findings elucidated the profound influence of hormonal changes on inflammatory outcomes, delineating substantial sex-related differences in immune activation and revealing altered immune responses in OVX mice due to ovarian hormone deficiency. In addition, the flow cytometry analysis highlighted the complex interaction between OVX surgery, acute WS exposure, and their collective impact on immune cell populations within the hematopoietic bone marrow niche. Conclusions: In summary, both male and female mice, alongside females subjected to OVX and those who had sham surgery, exhibit significant variations in the expression of proinflammatory cytokines, chemokines, lung mRNA gene expression, and related functional networks linked to signaling pathways. These differences potentially act as mediators of sex-specific and hormonal influences in the systemic inflammatory response to acute WS exposure during a wildfire event. Understanding the regulatory roles of genes expressed differentially under environmental stressors holds considerable implications, aiding in identifying sex-specific therapeutic targets for addressing acute lung inflammation and injury.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA)

Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female Sprague Dawley rats were exposed to perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) acid (HFPO-TeA) by oral gavage for five days over multiple dose levels (0.3–335.2 mg/kg/day). Clinically, we observed mortality at doses >17 mg/kg/day and body weight changes at doses ≤ 17 mg/kg/day. For the 17 mg/kg/day dose level, T3 and T4 thyroid hormone concentrations were significantly decreased (p < 0.05) from controls and HFPO-TeA plasma concentrations were significantly different between sexes. Non-targeted analysis of plasma and in vitro hepatocyte assay extractions revealed the presence of another GenX oligomer, perfluoro-(2,5-dimethyl-3,6-dioxanonanoic) acid (HFPO-TA). In vitro to in vivo extrapolation (IVIVE) parameterized with in vitro toxicokinetic data predicted steady-state blood concentrations that were within seven-fold of those observed in the in vivo study, demonstrating reasonable predictivity. The evidence of thyroid hormone dysregulation, sex-based differences in clinical results and dosimetry, and IVIVE predictions presented here suggest that the replacement PFECA HFPO-TeA induces a complex and toxic exposure response in rodents.

54 ENVIRONMENTAL SCIENCES↗