Skip to main content
Download PDF
Download ePub

Pro-inflammatory effects of inhaled Great Salt Lake dust particles

Particle and Fibre Toxicology volume 22, Article number: 2 (2025) Cite this article

Abstract

Background

Climate change and human activities have caused the drying of marine environments around the world. An example is the Great Salt Lake in Utah, USA which is at a near record low water level. Adverse health effects have been associated with exposure to windblown dust originating from dried lakebed sediments, but mechanistic studies evaluating the health effects of these dusts are limited.

Results

Monitoring data and images highlight the impact of local crustal and Great Salt Lake sediment dusts on the Salt Lake Valley/Wasatch front airshed. Great Salt Lake sediment and derived PM< 3.1 (quasi-PM2.5 or qPM2.5) contained metals/salts, natural and anthropogenic chemicals, and bacteria. Exposure of mice via inhalation and oropharyngeal aspiration caused neutrophilia, increased expression of mRNA for Il6, Cxcl1, Cxcl2, and Muc5ac in the lungs, and increased IL6 and CXCL1 in bronchoalveolar lavage. Inhaled GSLD qPM2.5 caused a greater neutrophilic response than coal fly ash qPM2.5 and was more cytotoxic to human airway epithelial cells (HBEC3-KT) in vitro. Pro-inflammatory biomarker mRNA induction was replicated in vitro using HBEC3-KT and differentiated monocyte-derived (macrophage-like) THP-1 cells. In HBEC3-KT cells, IL6 and IL8 (the human analogue of Cxcl1 and Cxcl2) mRNA induction was attenuated by ethylene glycol-bis(β-aminoethyl ether)-N, N,N′,N’-tetraacetic acid (EGTA) and ruthenium red (RR) co-treatment, and by TRPV1 and TRPV3 antagonists, but less by the Toll-like Receptor-4 (TLR4) inhibitor TAK-242 and deferoxamine. Accordingly, GSLD qPM2.5 activated human TRPV1 as well as other human TRP channels. Dust from the Salton Sea playa (SSD qPM2.5) also stimulated IL6 and IL8 mRNA expression and activated TRPV1 in vitro, but inhibition by TRPV1 and V3 antagonists was dose dependent. Alternatively, responses of THP-1 cells to the Great Salt Lake and Salton Sea dusts were partially mediated by TLR4 as opposed to TRPV1. Finally, “humanized” Trpv1N606D mice exhibited greater neutrophilia than C57Bl/6 mice following GSLD qPM2.5 inhalation.

Conclusions

Dust from the GSL playa and similar dried lakebeds may affect human respiratory health via activation of TRPV1, TRPV3, TLR4, and oxidative stress.

Background

The Great Salt Lake (GSL) in Utah, USA is a terminal lake formed from glacial melt and subsequent desiccation of remnants of Lake Bonneville starting 10–20,000 years ago [1, 2]. The GSL is primarily fed by rivers originating in local mountains that now run through densely populated and industrialized areas. The GSL has no outlet al.lowing for the accumulation and concentration of minerals over time, giving the lake its trademark salinity [3]. While the extraction of minerals such as lithium, magnesium, and potassium sulfate from the GSL are of major economic importance, GSL sediments also contain toxic metals such as iron, aluminum, copper, lead, arsenic, and mercury which is attributable to upstream natural sources and possibly being juxtaposed to one of the world’s largest copper mines [4, 5]. As shown later, GSL sediments also harbor natural and anthropogenic chemicals.

Preservation of the GSL is of paramount importance for both environmental and economic reasons, however, it is in jeopardy due to climate change and water diversion/use by Utah’s residents, ultimately reducing water input and volume [6,7,8,9]. Exposed GSL lakebed sediment is a major source of windblown dust (particulate matter; PM2.5 and PM10) and in 2020, was estimated to contribute ~ 23–34% of dust flux along the Wasatch front [10, 11]. In the summer of 2022, the GSL reached historic lows, exposing new areas of lakebed that further contribute to dust in the local airshed, particularly during high wind events. In a vicious cycle, the GSL dust (GSLD) also impacts snowpack, further exacerbating water loss [10,11,12]. News stories repeatedly highlight the potential dangers of being exposed to “toxic” GSLD, but no studies have formally evaluated the effects of inhalation or other routes of exposure to GSLD [13, 14].

Exposure to PM in general, whether from mining [15,16,17,18,19,20,21], coal burning [21,22,23,24,25,26], wood/biomass [27,28,29,30,31,32,33] and fossil/biofuel [34,35,36,37,38] combustion contributes to adverse effects in the lungs and impacts human health in general. These effects are generally accepted to be dependent upon specific interactions between the PM, lung cells (e.g., epithelial, macrophages, neurons) that sense the presence of a foreign substance and respond by triggering inflammation and the transfer of materials into systemic circulation. Crucial factors include the dose and duration of exposure and the presence/absence of specific chemicals (e.g., metals, PAHs, etc.), pathogens, and physical characteristics. While the adverse effects and mechanisms associated with GSLD inhalation are unknown, studies of similar lakebed dusts (e.g., dust from the Salton Sea and Owens Lake in California, Lake Urmia, the Aral Sea and others) imply the potential for both acute and long-term adverse health effects including respiratory effects such as asthma-like hypersensitivity, increased rates of infections and other malaise [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53].

The goals of this study were to illustrate the effects of windblown dust on local air quality, assess the impact of GSLD in the lungs of mice, and to identify potential mechanisms underlying the pro-inflammatory effects of GSLD and a related lakebed dust (i.e., Salton Sea dust; SSD) in the lungs. The hypothesis was that GSLD would be acutely pro-inflammatory at inhaled doses achievable in humans during local dust events via interactions between specific components of GSLD and biological sensors such as TRP ion channels [21, 25, 26, 30, 32, 33, 37, 38, 54] and TLR4, as shown for other types of PM and SSD extract [39, 50, 55].

Methods and materials

Reagents and chemicals

Allyl-isothiocyanate (AITC), menthol, carvacrol, HC-067047, icilin, AMTB, EGTA, ruthenium red (RR), deferoxamine (DFO), and LPS (E.coli O111:B4) were purchased from Sigma-Aldrich (St. Louis, MO). A967079, nonivamide, TAK-242 (Resatorvid), AMG-9810, and GSK1016790A were purchased from Cayman Chemical (Ann Arbor, MI). LJO-328 was provided by Dr. Jeewoo Lee, Seoul National University, and 2-(5-trifluoromethyl-pyridine-2ylsulfanyl)-1-(8-methyl-3,4-dihydro-2 H-quinolin-1-yl)-ethanone (abbreviated as 007) was synthesized as previously described [56].

GSLD, coal fly ash (CFA), and Salton Sea dust (SSD)

GSL sediment was collected in July 2022 from the following locations near the Great Saltair, Great Salt Lake State Park, and Kennecott Copper mine/refinery and tailings pond on the southeast shore of the GSL: 40.74741717055637, -112.19173244734307; 40.7510 2960965917, -112.19785977880764; 40.7600657 0075401, -112.1951335289701; 40.761191 14860347, -112.19305240202357; 40.7584999 10,134,354, -112.18936958930033; and 40.7531012387659504, -112.18056548236991 (Additional File 1). Material was collected from the top ~ 2.54 cm of sediment and ranged in consistency and moisture content. Some samples were a mix of grey, brown, and black sand while others were black and tar-like or spongy and brown. The samples were dried for 10 days at 40oC in the laboratory and 100 g of each was combined and subjected to resuspension using compressed filtered air in a 4 L Erlenmeyer flask from which suspended PM was pulled through a 10-stage Andersen cascade impactor (1 L/min; Thermo Andersen Inc., Smyrna GA). The stainless-steel impactor stages were weighed before and after to obtain the mass of each particle size fraction and the PM collected by brushing into glass storage vials. PM < 3.1 μm from multiple collections was pooled to generate quasi-PM2.5 (qPM2.5). A similar PM, CFA, used for comparison, was collected from the Hunter power plant in Castledale, UT. CFA composition and its effects on TRP channels and lungs of mice have been previously described [21, 57, 58]. For inhalation studies CFA qPM2.5 was prepared as above. Salton Sea playa and sediments adjacent to the lake were collected in March 2024 from the following locations: 33.28616, -115.53463; 33.28608, -115.53497; 33.28584, -115.53506; 33.47647, -115.89211; 33.34564, -115.73151; and 33.34535, -115.73265. The materials varied from muddy/sandy material to grey/black beach sand. SSD qPM2.5 was also prepared from a pool of these samples as above. Annotated maps from Google and Bing show the collection site locations of the various samples (Additional File 1).

Dust event modeling and characterization

PM data were collected from a network of low-cost sensors deployed across the Salt Lake valley/Wasatch front. Readings from April 18, 2022-April 24, 2022, were used to construct an animation depicting real-time PM10 (an accepted marker of dust as opposed to typical anthropogenic PM) in the Salt Lake Valley/Wasatch front airshed using scaled PM2.5 data (Additional File 2). This analysis used measurements from 438 low-cost particulate matter sensors from the University of Utah (AirU; www.aqandu.org) and PurpleAir (www.map.purpleair.com) and Federal Reference/Equivalence Measurements (FRMs/FEMs) from the Utah Division of Air Quality (UDAQ). The low-cost sensor measurements were adjusted using correction factors (CFs) developed by co-locating the AirU and PurpleAir sensors at UDAQ’s Hawthorne and Utah Technical Institute monitoring stations. These measurements were screened for outliers, adjusted using the co-located correction factors, and incorporated into a Gaussian Process (GP) regression model which included customized kernel functions that incorporate distance, time, and elevation to obtain continuous-valued spatial-temporal estimates of PM concentration throughout study region, complete with a confidence value describing the accuracy of the measurement. This model allowed the construction of dense colormaps representing PM10, as shown in the animation in Fig. 1 and Additional File 2. The performance of the PM sensors, the infrastructure, and the accuracy of the PM2.5 estimates have been previously demonstrated [59,60,61,62,63]. PM10 concentrations were estimated using the ratio of PM2.5 to PM10 concentration from the UDAQ’s Hawthorne monitoring station using the method described in Kaur and Kelly [64]. The locations of these monitoring stations are also shown in Additional File 1.

Fig. 1
figure 1

Time coded images of a dust event on April 21, 2022. (a-f) Snapshots were taken from Additional File 2 (movie). Purple represents PM10 concentrations 0–10 µg/m3 and red represents ≥ 100 µg/m3 based on PM2.5 measurements

Full size image

PM2.5 and PM10 data, as well as accompanying meteorological data were also obtained from local air quality monitoring stations operated by the UDAQ (https://air.utah.gov/dataarchive/index.htm). A second date range (April 16–19, 2023) surrounded a separate dust event on April 18, 2023, triggered by an approaching storm. Data for this event are from the following monitoring stations: Harrisville (41.3028593, -111.9874424), Herriman (40.4950126, -112.0347781), Lindon (40.3387775, -111.7152311), the Utah Technical Center (40.7746306, -111.9471611), and Hawthorne Elementary School (40.7544692, -111.8734927) in Salt Lake City, UT. The locations of these monitoring stations, as well as the prevailing wind directions associated with the April 18, 2023, event are also shown in Additional File 1. Finally, photographs illustrating an event on March 2–3, 2024, were taken from the corresponding author’s office window at the University of Utah on March 1 and 2, 2024 using an iPhone SE.

GSLD characterization

The percentage of extractable material was determined by weighing materials before and after serial extraction of the PM and the recovered dried extracts: (1) 2 × 2 mL water and (2) a pool of 2 × 2 mL ethanol, 1 × 1 mL n-butyl chloride, and 1 × 1 mL methyl tert-butyl ether. The Organic/elemental carbon ratio of GSLD qPM2.5 was determined by Sunset Laboratories (Cary, NC). Briefly, ~ 10 mg of qPM2.5 was deposited on quartz filters mounted in a conical filter/concentrator under constant flow (~ 1 L/min) and sent to Sunset Laboratories for analysis for analysis. Lipopolysaccharides/endotoxin (LPS) associated with GSLD qPM2.5 was quantified using the Pierce™ Chromogenic Endotoxin Quant Kit from Thermo Fisher Scientific. Bacterial growth from GSLD qPM2.5 was evaluated by dispersing PM onto salt-fortified (0, 5% and 12%) yeast peptone agar plates and incubating for 1 week at 37oC. Colonies were picked, numbered based on order, and subjected to colony PCR and sequencing of the 16 S RNA amplicons obtained using the 27 F and 1492R primers to identify bacteria. Results are provided in Additional File 3.

Inductively coupled plasma mass spectrometry (ICP-MS) analysis was performed at the University of Utah Iron and Heme Core using an Agilent 7900 operated in He collision mode. GSLD qPM2.5 (5 mg) was placed in 500 µL HNO3 + 100 µL H2O2, incubated overnight, and 300 µL heated to dryness at 98oC. The solution was then incubated overnight in 2 mL 2% HNO3 containing 100 ppb Ge internal standard. The supernatant was diluted 10x and 100x with 1x Ge solution to a final volume of 2 mL. Samples were run in triplicate and results from the 10x and 100x dilutions were averaged.

The physical and elemental characteristics of GSLD were also evaluated using scanning electron microscopy energy-dispersive spectroscopy (SEM-EDS) using an FEI Quanta 600 FEG scanning electron microscope with energy dispersive X-ray spectroscopy. Electron microscopy was performed at the University of Utah Electron Microscopy Core Laboratory.

Finally, plastics were evaluated by pyrolysis gas chromatography/MS by Dr. Matthew Campen’s group at the University of New Mexico, as described [65,66,67].

Discovery level liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis of GSLD sediment and qPM2.5

GSLD associated chemicals were also evaluated using water/ethanol extracts from 100 mg GSLD sediment and qPM2.5. The extracts were dried under air and assayed using electrospray LC/MS/MS on a Thermo Vanquish Flex UPLC system interfaced with an LTQ Velos Pro linear ion trap mass spectrometer. Data interrogation/spectral matching was performed using the Global Natural Products Social (GNPS) Molecular Networking Knowledge Base [68], as previously described [31]. Chromatographic fractionation was achieved using a BEH C18 column (150 × 3 mm i.d., 1.7 μm particle size; Waters, Milford, MA) at 50 °C with gradient elution. The mobile phases were (A) 0.1% formic acid in H2O and (B) methanol and a flow rate of 100 µL/min was used. The percentage of B varied as follows: 2% B at 0 min, 2%→100% (0 to 50 min), hold at 100% (50 to 55 min), 100%→2% (55.0 to 55.1 min), and hold at 2% (55.1 to 60 min). The mass spectrometer was programmed to either positive or negative ions m/z 100–750 (in separate acquisitions) using the “double play” data-dependent MS/MS mode. MS/MS scans were triggered by analytes having a signal intensity set at ~ 5x baseline using a collision energy of 35%. The top 3 peaks of each scan were analyzed, and dynamic exclusion was active: The parameters were repeat count = 3; repeat duration = 5 s; exclusion list size = 25; and exclusion duration = 5 s. Data were analyzed using GNPS. The raw files were converted to mzML files using MS Convert, uploaded into GNPS and processed using the Library Search feature. Default criteria were used with the exception that the minimum matched peaks = 4 and top hits per spectrum = 5. A cosine score of 0.85 was used as a cut-off criterion for including chemicals in Additional File 4.

Mice and PM exposures

Studies were approved by the University of Utah IACUC committee. Male and female C57Bl/6 mice (8–10 weeks of age) were used. The mice were housed (~ 5/cage) in an AALAC accredited vivarium and fed and watered ad libitum with standard chow. Mice were either exposed to GSLD qPM2.5 by oropharyngeal (OPA) aspiration using a total volume of 25 µL or inhalation (whole body) using an inExpose system (Scireq, Quebec Canada). OPA was used to establish a dose-response and to compare the effects of GSLD to the effects of other forms of PM we have studied [30, 33, 37, 69]. Doses of 2.5, 12.5, 62.5, and 250 µg qPM2.5 were used to model potential inhalable doses of ~ 86.4–375 µg PM2.5 for humans, estimated using the following criteria: PM2.5=50 µg/m3, at rest tidal volume (Vt) = 450 mL, breathing frequency (f) = 12 breaths/min, and exposure time = 240 min or exercising Vt = 2500 mL, f = 50 breaths/min, and 60 min exposure time, and Eqs. 1 and 3 from Borghi et al. [70]. Using the same criteria and a PM10 value of 800 µg/m3, the inhalable dose ranges for humans were 1,500 and 6,000 µg. The qPM2.5 OPA doses were also based on prior OPA studies [20, 25, 33, 71,72,73].

For inhalation, mice were exposed to GSLD qPM2.5 for ~ 12 min intervals (1x, 2x, 3x in 1 day, or 6x over 2 days) as follows. GSLD qPM2.5 (1.25 g) was resuspended at a rate of ~ 100 mg/min using a PALAS RBG 1000ID operated at 1,200 RPM with a 7 mm diameter piston feed rate of 200 mm/h. The bias airflow was 2 L/min. The PM concentration was monitored in real time using a Casella CEL-712 Microdust Pro (1/chamber) immediately prior to the exposure chambers and by gravimetric analysis post-chamber using an impactor and a DustTrack II system with a PM2.5 inlet filter (TSI, Shoreview, MN). PM concentrations averaged ~ 1,800 mg/m3 pre-chamber and ~ 200 mg/m3 post-chamber, with ~ 75% being ≤ 2.5 μm. Inhalable doses of 76–86, 150–170, 23–26, and 460–520 µg were estimated for the 1x, 2x, 3x, and 6x exposures using a mouse tidal volume of 0.18 mL, a breathing frequency of 243 breaths/min from Schwarte et al. [74], a 12 min exposure time, and a PM2.5 value of 195-220.8 mg/m3 to encompass the range of concentrations measured over multiple experiments. A representation of the relationship between these doses and those for humans is shown in Supplemental Fig. 1. Applying deposition estimates of ~ 4%, ~ 12.5% and ~ 50% for the deep lung/alveolar, tracheobronchial, and nasal/oropharyngeal regions [75], deposited doses of ~ 3.2, ~ 10.1, and ~ 40.5 µg of PM were estimated for a 1x exposure. Inhalation exposure to CFA qPM2.5 was also performed using the 3x exposure paradigm and in all cases, 24 h after exposure, mice were sacrificed by Euthasol injection.

Generation of the Trpv1 N606D “humanized” mice

CRISPR Cas9 reagents were designed by the University of Utah Mutation Generation and Detection Core. The sgRNA N20 sequence used was 5’-GTAGTGACACTGATCGAGGA-3’ and the single-stranded oligo deoxyribonucleic acid (DNA) nucleotide (ssODN) HDR donor sequence was 5’-cacccacacctctttctcttgcgacctgtagCCGTAGTGACcCTGATtGAGGATGGGAAGA ATgACTCACTGCCTGTGGAGTCCCCACCACACAAGTGTC-3’. Nucleotide changes are in lower case. The ssODN contained stabilizing 5’ and 3’ phosphorothioate modifications, a single base change to introduce the N606D mutation and two silent changes to block CRISPR cutting after HDR and to introduce a unique restriction enzyme site for genotyping (EcoN1) (see Additional File 5). The University of Utah Transgenic & Gene Targeting Mouse Core Facility co-electroporated a ribonucleoprotein complex and the ssODN donor molecule into single cell embryos harvested at day 0.5. Electroporated embryos were rinsed and surgically implanted into oviducts of 0.5-day pseudopregnant females. Founders were genotyped with simple PCR (F primer: 5’-AGTGGCTTTCCTGCTGAGGG-3’; R primer: 5’-AACTCCAGGTCACCCATGCC-3’) and EcoN1 restriction enzyme digestion. Founders with insertion were bred and the resulting N1 mice were sequenced to confirm correctness. All protocols followed AALAC procedures and were approved by the University of Utah IACUC committee.

Bronchoalveolar lavage (BAL) and differential cell counting and cytokine ELISAs

BAL was collected from mice by inserting a cannula through a small incision in the trachea. Cold saline (1 mL) was slowly infused into the lungs, first adding 0.5 mL, retracting, then adding the entire 1 mL. This first 1 mL of BAL fluid was immediately placed on ice, clarified by centrifugation, and the supernatant frozen at -80 °C for protein analysis by ELISA; mouse CXCL1 (KC) and IL6 kits were purchased from Invitrogen, and performed as specified by the supplier. An additional 4 mL of BAL fluid was collected 1 mL at a time and immediately placed on ice. The cells from the initial 1 mL and 4 mL sample were then pooled, concentrated by centrifugation, resuspended in 1 mL cold saline, counted, and 5,000 cells fixed to slides using a cytospin. Cells were stained with Giemsa for manual differential cell counts.

Differential cell counting was also evaluated by tissue flow cytometry, using the antibody staining protocol and gating described by Nguyen et al. [76] Briefly, following lavage, lungs were cleared of blood by cardiac perfusion with saline, removed from the chest cavity, minced, transferred into a 50 mL conical tube, and incubated (37 °C, 30 min) in DMEM + 5% FBS + 2 mg/ml Collagenase D (Roche, Indianapolis, Indiana). Digested lungs were then passed through 70-µm nylon mesh to obtain a single-cell suspension, counted, and mixed with ACK Lysis Buffer (Thermo Fisher Scientific) to remove remaining red blood cells. The BAL and tissue cell pellets (1 M cells) were resuspended in 100 µl staining buffer (PBS + 0.1% sodium azide) and incubated with anti-mouse CD16/32 antibody for 10 min at 4 °C to block nonspecific binding. This was followed by 30 min incubation with fluorescently tagged antibodies or appropriate isotype controls (0.25–1.5 µg/106 cells) for 30 min (4 °C). Cells were then spun and resuspended in staining buffer for viability staining (30 min at 4 °C) followed by fixation in 2% paraformaldehyde. Analysis was performed on a Cytek Aurora flow cytometer (Cytek Biosciences, Fremont, California) using a gating strategy of singlet, viable, CD45 + cells as described by Nguyen et al. [76] Data analysis was performed using FlowJo software (FlowJo, LLC, Ashland, Oregon).

Histological analysis

Following BAL collection and perfusion, the lungs were inflated with 10% neutral buffered formalin at 20 cm H2O fixed pressure for 5 min. The cannula was then removed, and the trachea tied closed while maintaining inflation. The lungs and trachea were then removed and placed in 10% neutral buffered formalin for 48 h, dissected to obtain tissue from the hilum to the lower portion of the left lobe, rinsed with (2%) sucrose and dehydrated in 70% ethanol. Lungs were embedded in paraffin, and serially sectioned (5 μm) followed by staining with Eosin and Hematoxylin by ARUP Laboratories (Salt Lake City, UT).

RNA purification and mouse cytokine mRNA expression

Before fixation, the left bronchus was tied closed and the left lobe of the lung removed and placed in RNALater solution at 4oC. Within 1 week, the lungs were homogenized in Trizol Reagent (1 mL/50–100 mg of tissue) and phase separated with chloroform. The RNA was then precipitated with ethanol followed by RNA purification using the PureLink RNA Mini Kit (Invitrogen; Carlsbad, CA). RNA was stored at -80oC until used. RNA (2 µg) was reverse transcribed using the ABI High-Capacity cDNA Kit + RNase Inhibitor (Applied Biosystems, Foster City, CA). Cytokine gene expression was analyzed by quantitative real-time polymerase reaction using a Life Technologies QuantStudio 6 Flex instrument and TaqMan probes (Applied Biosystems) for mouse Il6 (Mm00446190_m1), Cxcl1 (Mm04207460_m1), Cxcl2 (Mm00436450_m1), and Muc5ac (Mm01276718_m1). Values for relative gene expression were normalized to the housekeeping gene mouse glyceraldehyde-3-phosphate dehydrogenase (Gapdh; Mm99999915_g1), which exhibited stability across treatments utilizing the comparative cycle threshold (ΔΔCT) method.

Cell culture

Cells were maintained in a humidified cell culture incubator at 37 °C with 95% air: 5% CO2. Immortalized human bronchial epithelial (HBEC3-KT) cells (ATCC; Rockville, MD) were grown in Airway Epithelial Basal Medium supplemented with Bronchial Epithelial Cell Growth Kit (ATCC; Rockville, MD). HEK-293 cells (ATCC; Rockville, MD) stably overexpressing the ultrasensitive fluorescent calcium sensor protein GCaMP6s [21, 77] were cultured in DMEM: F12 media containing 5% fetal bovine serum and 1x penicillin/streptomycin. THP-1 cells (ATCC; Rockville, MD) were maintained in RPMI 1640 media supplemented with 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol at 0.3-1 M cells/mL.

In vitro cytotoxicity

HBEC3-KT cells were plated at ~ 10k/well in a 96 well plate in Airway Epithelial Cell Basal Medium. After 24 h at 80–90% confluence, the media was removed and replaced with 200 µL of media containing PM. Cells were treated with GSLD and an elementally similar PM, CFA at concentrations ranging from 0 to 10 mg/mL (i.e., 0-6.25 mg/cm2). After 24 h, cell viability was determined using the Dojindo CCK8 Reagent (8% v/v) by incubating cells for 2 h at 37oC. To avoid particle interference, the plate was briefly centrifuged and the clarified supernatant transferred to a new plate for measuring the absorbance at 490 nm. Results were normalized to cells treated with media only. THP-1 cells were plated and differentiated at 120k/well in a 96 well growth media supplemented with 25 µM PMA and 1x penicillin/streptomycin. Cells were treated with GSLD ranging from 0 to 1.125 mg/mL (i.e., 0-0.53 mg/cm2). In all cases, treatment solutions were prepared in media at the highest concentration, sonicated for 30 min, and vortex mixed for 1 min followed by serial dilution in Eppendorf tubes with 1 min of vortex mixing between each dilution step.

Human TRP channel activation assays

Calcium flux assays were conducted using HEK-293 GCaMP6s over-expressing cells transiently transfected with the TRPA1, TRPM8, truncated ΔM801 TRPM8, TRPV1, TRPV3, and TRPV4 expression plasmids in 96-well plates (coated with 1% gelatin) 48 h prior to assay, as previously described [21, 25, 33, 54, 76]. Thirty minutes prior to analysis, the media was replaced with LHC-9 containing 1 mM probenecid and 0.75 mM trypan red (ATT Bioquest). Changes in fluorescence were captured on an EVOS FL Auto Imaging System (Life Technologies) and treatment-induced changes in cellular fluorescence were quantified from fluorescence micrographs. Agonist/particle treatment solutions were prepared in LHC-9 at 3x concentration and added to cells at room temperature. Activation studies used a final PM concentration of 2.3 mg/mL (180 µg/cm2). Data were normalized to the maximum attainable change in fluorescence elicited by ionomycin (10 µM).

IL6/8 mRNA expression studies in human cells

HBEC3-KT and THP-1 cells were plated in 12-well plates essentially as above. HBEC3-KT cells were plated at a density of 25k/cm2 and after 72 h, the media was aspirated and replaced with 1 mL of media containing the desired treatments. THP-1 cells were differentiated for 72 h using phorbol 12-myristate acetate (25 nM) prior to experiments. GSLD PM2.5 treatments were prepared by suspending in media, sonicating for 20 min, vortex mixing for 1 min, and briefly vortex mixing immediately prior to applying to cells to ensure a homogenous suspension. For these studies, a concentration of 0.25 mg/mL or 66 µg/cm2 was used for HBEC3-KT cells and 0.045 mg/mL or 12 µg/cm2 for THP-1 cells. For pathway inhibitor studies, cells were pre-treated for 30 min followed by co-treatment. At the desired time-point, the media was aspirated and stored. Cells were then washed with PBS and stored frozen at -80 °C. RNA was isolated using the PureLink RNA Mini Kit. Cytokine mRNA quantification was achieved as above using TaqMan probes for human IL6 (Hs00174131_m1) and IL8 (Hs00174103_m1). Values for relative gene expression were normalized to the housekeeping gene human beta-2-microglobulin (b2M; Hs00187842_m1), which exhibited stability across treatments utilizing the comparative cycle threshold (ΔΔCT) method.

Statistics

Results were analyzed using a combination of t-tests (two-tailed), 1- and 2-way ANOVA with post-testing using either a Dunnett, Tukey, or Bonferroni test, as specified in the figure legends. Graphing and statistical analyses were carried out using GraphPad Prism (10.3.1; GraphPad Software, Boston, MA) using a p-value of 0.05 for significance. In general studies were designed to have > 80% power using conservative estimates of a ≥ 2-fold difference in means with 40% standard deviation. Post-hoc analysis revealed this to be the case for all reported differences.

Results

Wind events increase dust (PM2.5/10) along the Wasatch front

Figure 1a-g show screenshots from an animation (Additional File 2) illustrating the distribution of PM10 in the Salt Lake Valley/Wasatch front airshed surrounding a dust event on April 21, 2022. Hourly PM2.5 data from state-run air quality monitoring stations are shown for 2022 (a), April 2022 (b), and April 19–23, 2022 (c), in Supplemental Fig. 2 (Additional File 6).

Similarly, on April 18, 2023, winds shifted from the east (~ 100o; ~5 mph) to west-northwest (200-300o; 10–15 mph) at ~ 10:00 am through 7 pm MDT (Fig. 2a), which corresponded to an increase in PM2.5 and PM10 in the air of Salt Lake Valley/the Wasatch front (Fig. 2b-d). As in the 2022 event, hourly PM2.5 and PM10 concentrations were low (< 10–20 µg/m3) on April 16, 17, and 19, 2023 but spiked to ~ 35 ± 7 and ~ 400 ± 40 µg/m3. A local news story describing this event was titled: “Blowing dust causes dirty rain to fall across northern Utah.” [78] Of significance, the PM2.5 and PM10 concentrations measured at the Harrisville monitoring station, which is north of Salt Lake City, and partially sheltered from west-northwest winds by Promontory Point, exhibited smaller increases in PM (PM10 ~ 108 µg/m3; Fig. 2b, and Additional File 1).

Fig. 2
figure 2

Meteorological conditions and PM2.5/10 measurements from a dust event on April 18, 2023. (a) Wind speed (left y-axis, black line) and direction (right y-axis, red line). (b-d) Hourly PM10 and PM2.5 readings from state monitoring stations from distinct locations in the Salt Lake Valley/along the Wasatch front. The red line is the Hawthorne monitoring station in downtown Salt Lake City and the green line for Harrisville, north of Salt Lake City. Additional information and monitoring site locations is presented in Additional File 1

Full size image

Finally, images of a similar dust event occurring on March 2–3, 2024, are shown in Fig. 3. While the precise contribution of GSLD was not determined for any of these events, prior studies indicate that GSLD would be a substantial contributor to the overall dust burden [10,11,12, 14].

Fig. 3
figure 3

Images of (a) isolated and (b) widespread dust events on March 2 and 3, 2024. Images were taken from the corresponding author’s office window on the University of Utah campus, looking west towards Salt Lake City and the south end of the Great Salt Lake

Full size image

GSLD contained metals, organic materials/chemicals including LPS, and was non-sterile

Electron micrographs of unfractionated GSLD showed sheet-like materials varying in size (Fig. 4a), while qPM2.5 was similar irregularly shaped particles (Fig. 4b). qPM2.5 represented ~ 5% of total mass recovered during resuspension of the GSL sediment in the laboratory, whereas PM3.1−10 was ~ 37%, consistent with the relative ratios of PM2.5 and PM10 during dust events.

Fig. 4
figure 4

Characteristics of GSL sediment and qPM2.5. Electron micrographs (5,000x) of (a) unfractionated GSL sediment and (b) GSLD qPM2.5. (c) Percentage of particle size fractions of GSLD by mass from resuspension of GSL sediments in the laboratory. Data points represent the stages of the Andersen cascade impactor, where the x-value of 15 represents the fraction present in the pre-separation stage. (d) Elemental composition of GSLD qPM2.5 using ICP-MS. Major constituents (> 1%) are represented as a pie chart with those < 1% and 0.1% listed in rank order below the pie chart

Full size image

ICP-MS analysis of GSLD sediment and GSLD qPM2.5 revealed an abundance of sodium, magnesium, aluminum, iron, potassium, calcium, and copper (Fig. 4d and Supplemental Fig. 3). GSLD sediment and qPM2.5 also contained metals known to be toxic including manganese, lead, arsenic, cadmium, uranium, etc., albeit at concentrations < 1%. Enrichment (> 2-fold) in the qPM2.5 sample was observed for silver, copper, strontium, uranium, beryllium, selenium, cadmium, and calcium, whereas lead was ~ 2-fold lower. Of note, the ICP-MS analysis was limited in that only the elements sufficiently leached from the PM using HNO3 + H2O2 treatment were analyzed. However, a similar, albeit less detailed elemental composition was found using SEM-EDS (Supplemental Figs. 4 and 5).

GSLD sediment and qPM2.5 was largely insoluble. The average aqueous soluble mass was 11 ± 5% (n = 5 sites; range 5–16%) and 27 ± 3% for the qPM2.5. The average organic soluble mass was 0.5 ± 0.1% (n = 5 sites; range 0.38-59%) and 0.48 ± 0.02% for the qPM2.5. The total carbon content of GSLD qPM2.5 was low and consisted of 97.9 ± 0.6% organic vs. 2.1% elemental carbon (i.e., organic carbon). Specific organic species included LPS (90 ± 2 EU/mg) and numerous chemicals preliminarily identified in pooled aqueous and ethanol extracts using LC/MS/MS analysis and GNPS database searching (Additional File 4). Traces of polyethylene, polyethylene terephthalate, and polypropylene, among other plastics, were also detected. Finally, GSLD qPM2.5 was not sterile and harbored multiple bacteria that were cultured and preliminarily identified by 16s sequencing including Rossellomorea vietnamensis, Virgibacillus dokdenensis, Bacillus pakistanensis, bacillus haikouensis, Thalassobacillus cyri, Thalassobacillus devorans, Crenalkalicoccus roseus, Methyloglobulus morosus, Bacillus zhangzhouensis, Bacillus safensis, Streptococcus pyogenes, Mesobacillus subterraneus, Mesobacillus boroniphilus (Additional File 3). A more comprehensive metagenomics study of GSL sediments has identified hundreds of novel taxa [79].

GSLD qPM2.5 inhalation and OPA caused acute lung inflammation in mice

Mice exposed to/treated with GSLD qPM2.5 by inhalation (Fig. 5a and b and Supplemental Fig. 6) and OPA (Supplemental Fig. 7a-f) exhibited dose-dependent increases in total cells and neutrophils in BAL fluid collected 24 h after treatment. Histological analysis of post-lavage tissue from both exposure paradigms confirmed pulmonary inflammation, increased neutrophils, and alveolar edema (Fig. 5c-f). Neutrophilia (Ly6G+), changes in eosinophils, alveolar, interstitial, and monocyte-derived macrophages, CD3+ T cells, CD8+ T cells, and B cells were also shown using tissue flow cytometry (Supplemental Fig. 8).

Fig. 5
figure 5

Effect of GSLD qPM2.5 inhaled dose on BAL cell counts. (a) Total cell counts and (b) percentage of neutrophils in BAL following inhalation exposure of mice to GSLD qPM2.5 for 12 min (1x), 24 min (2x), or 36 min (3x) over the course of one day or 72 min over 2 days (6x). (c-d) Photomicrographs (40x) and (e-f) expanded areas of interest of hematoxylin and eosin-stained lung tissue from mice exposed 2x or 6x to GSLD qPM2.5. Data are the mean and standard deviation. **p < 0.01 and ****p < 0.0001 using 1-way ANOVA and a Dunnett post-test

Full size image

At the molecular level, both inhaled (Fig. 6a-d) and OPA-delivered GSLD qPM2.5 (Supplemental Fig. 9a-d) induced the expression of mRNA for Cxcl1, Cxcl2, Il6 and Muc5ac in mouse lungs. IL6 and CXCL1 protein in BAL was also elevated 2-3-fold in BAL following inhalation (Fig. 6e and f). The effects of GSLD were dose dependent and no differences were observed between male and female mice. Note: In all cases, there was no evidence of lung infection. Additionally, ICP-MS analysis of lung tissue revealed > 2-fold changes in sodium, aluminum, strontium, lead, lithium, and barium following 6x exposure to GSLD qPM2.5.

Fig. 6
figure 6

Effect of GSLD qPM2.5 inhalation dose and duration on the expression of mRNA for pro-inflammatory gene mRNA: (a) Il6, (b) Cxcl1, (c) Cxcl2, and (d) Muc5ac mRNA abundance as a function of GSLD PM2.5 exposure. (e) CXCL1 and (f) IL6 protein concentrations in BAL of 3x exposed mice determined by ELISA. Data are the mean and standard deviation. *p < 0.05, **p < 0.01, p < 0.001 using 1-way ANOVA and a Dunnett post-test

Full size image

GSLD qPM2.5 inhalation produced greater neutrophilia in mice than CFA qPM2.5

Using the 3x exposure paradigm, GSLD qPM2.5 elicited greater neutrophilia as well as Cxcl2 and Muc5ac mRNA expression than an equivalent dose of CFA qPM2.5 (Supplemental Fig. 10).

GSLD was acutely cytotoxic to HBEC3-KT and THP-1 cells

The acute cytotoxic effects of unfractionated GSLD and GSLD qPM2.5 were compared to CFA (< 10 μm) in HBEC3-KT cells (Fig. 7a). GSLD qPM2.5 was more cytotoxic than unfractionated GSLD and CFA; the LC50 for unfractionated GSLD and GSLD qPM2.5 were 1.13 mg/mL (710 µg/cm2) and 0.73 mg/mL (459 µg/cm2), respectively. The LC50 for CFA was 4.36 mg/mL (2,740 µg/cm2). Finally, the LC50 for GSLD qPM2.5 in differentiated THP-1 cells was ~ 0.024 mg/mL (15 µg/cm2; Fig. 7b).

Fig. 7
figure 7

In vitro cytotoxicity of GSLD. (a) Dose response cytotoxicity curves comparing CFA, unfractionated GSL sediment, and GSLD qPM2.5 in HBEC3-KT cells. Residual viability after 24 h treatment is on the y-axis. (b) Cytotoxicity of GSLD qPM2.5 in THP-1 cells. Data are the mean and standard deviation. A four-parameter non-linear fit was used to estimate the LC50 values

Full size image

Mechanisms of IL6 and IL8 mRNA induction in HBEC3-KT cells

Treatment of HBEC3-KT cells for 24 h with GSLD qPM2.5 (0.25 mg/mL; 66 µg/cm2) replicated the induction of Il6, Cxcl1, and Cxcl2 mRNA observed in mice. IL8 is the human analogue of mouse Cxcl1 and Cxcl2. MUC5AC induction was negligible and variable (not shown). Induction of IL6 and IL8 mRNA was significantly reduced by co-treating cells with a combination of the metal/calcium chelator EGTA and the non-selective calcium channel blocker ruthenium red (RR; Fig. 8a and b). The TLR4 inhibitor TAK-242 and the iron chelator deferoxamine also reduced IL6, but not IL8 induction (Fig. 8a and b). Finally, IL6 induction was enhanced by pre-extracting GSLD qPM2.5 with water and ethanol to sterilize the PM and remove soluble (and seemingly inhibitory) components (chemicals and/or salts) from the residual PM (Fig. 8c). Alternatively, heating the GSLD qPM2.5 to 500oC for 4 h, which sterilized the PM, removed/degraded semi-volatile and other organic compounds, and oxidized metals, reduced IL6 induction. However, IL8 induction was not affected by either treatment, although there was a trend for enhanced IL8 induction following heating (Fig. 8d).

Fig. 8
figure 8

Effects of metal chelators (EGTA and DFO), a non-specific calcium channel blocker (RR), and TLR4 inhibition (TAK-242) on (a) IL6 and (b) IL8 mRNA induction in HBEC3-KT cells treated for 24 h with GSLD qPM2.5 (66 µg/cm2). The concentrations of inhibitors were: EGTA + RR (10 + 50 µM; green), TAK-242 (1 µM; blue), and DFO (50µM; grey). Effects of GSLD qPM2.5 on (c) IL6 and (d) IL8 mRNA induction in HBEC3-KT cells following extraction with water and ethanol (yellow) and heating for 4 h at 500oC (brown). All treatment groups were corrected for the respective controls and normalized to GSLD qPM2.5 treated cells. Data are the mean and standard deviation and were analyzed using 1-way ANOVA and Dunnett post-test. **p < 0.01 and ****p < 0.0001

Full size image

GSLD qPM2.5 activated human and mouse TRP channels in HBEC3-KT cells

Activation of TRP family calcium channels has previously been demonstrated for CFA and other PM, and associated with cytokine gene induction and cytotoxicity in lung cells/lungs [21, 25, 54]. Activation of TRP channels by GSLD qPM10 and qPM2.5 was quantified using calcium flux assays. Activation of mouse (m) and human (h) TRPA1, TRPM8, the truncated TRPM8 ΔM801 variant expressed by human lung airway epithelial cells [21, 80], and TRPV1 was observed (Fig. 9a-f). TRPV3 and TRPV4 activation was not observed. Similarly, activation of mTRPA1, m/hTRPM8, and m/h TRPV1 was observed using SSD qPM2.5 (Supplemental Fig. 11a-c).

Fig. 9
figure 9

Activation of TRP ion channels by GSLD qPM2.5 and PM3.1−10. (a-f) Normalized (to ionomycin, 10 µM) calcium flux from HEK-293 cells transiently transfected with a control (empty) or human and mouse TRP expression plasmids following treatment with GSLD. Agonists of each channel are shown on the left side of each panel and include TRPA1 (AITC; 150µM), TRPM8 and ΔM801 (menthol; 500µM), TRPV1 (nonivamide; 20µM), and TRPV4 (GSK1016790A; 35nM). Effects of LHC9 (negative control) are on the right side of each panel. Data are the mean and standard deviation. Results were compared to the control vector for each treatment using 2-way ANOVA and a Dunnett post-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

Full size image

TRPV1 and V3 regulated IL6/8 mRNA induction in HBEC3-KT but not THP-1 cells

The effects of pre- and co-treatment of HBEC3-KT cells with GSLD qPM2.5 and TRP channel antagonists was screened using IL6 and IL8 mRNA induction as an endpoint (Supplemental Fig. 12a and b). Inhibitors of TRPA1 (A967079), TRPM8/TRPM8 ΔM801 (AMTB), and TRPV4 (HC-067047) did not affect mRNA induction, while inhibition of TRPV1 (LJO-328) and TRPV3 (007) showed different effects, as a function of the mRNA target. IL6 induction was attenuated by both LJO-328 and 007, while IL8 was increased by 007. Subsequent experiments confirmed the inhibition of IL6 induction by LJO-328, AMG-9810 (another TRPV1 antagonist), and a combination of LJO-328 and 007 (Fig. 10a). As above, different effects were observed for IL8 induction, where either TRPV1 or TRPV3 inhibition alone appeared to increase IL8 induction (Fig. 10b), while the combination of LJO-328 and 007 was inhibitory. Similar inhibition of IL6 and IL8 was observed using SSD qPM2.5 (Supplemental Fig. 12c-e), also implicating a role for TRPV1 and V3 in the inflammatory response triggered by SSD qPM2.5.

Fig. 10
figure 10

Effect of TRP channel inhibitors on IL6 and IL8 mRNA induction in HBEC3-KT cells. Expression of (a) IL6 and (b) IL8 mRNA by HBEC3-KT cells treated for 24 h with GSLD PM2.5 (66 µg/cm2) with and without co-treatment with the TRPV1 inhibitors LJO-328 (20 µM; red) and AMG-9810 (1 µM; red), the TRPV3 inhibitor 007 (50 µM; orange), and a combination of LJO-328 and 007 (20 + 50µM; red/orange checkered). All treatment groups were corrected for the respective controls and normalized to GSLD qPM2.5 treated cells. Data are the mean and standard deviation and were analyzed using 1-way ANOVA and a Dunnett post-test. *p < 0.05, ***p < 0.001, and ****p < 0.0001

Full size image

Induction of mRNA for IL6, IL8 and TNFa was also evaluated in THP-1 cells. TNFa induction was < 2-fold vehicle control in all cases and was not affected by any co-treatment (not shown). Induction of IL6, but not IL8 mRNA by LPS was reduced > 95% by TAK-242 (p = 0.000002), ~ 22% (p = 0.076) for GSLD qPM2.5, and ~ 51% (p = 0.044) for SSD qPM2.5, respectively (Supplemental Fig. 13a and c) suggesting a role for LPS in driving inflammation in THP-1 cells. Alternatively, TRPV1 inhibition had no effect on the responses of THP-1 cells to GSLD qPM2.5 while DFO enhanced responses (Supplemental Fig. 13b and d). TRPV3 and TRPV1 + V3 inhibition was not tested.

Humanized Trpv1 N606D mice exhibited greater inflammation than wild-type mice

Trpv1N606D mice were created based on in vitro calcium assay results showing that mouse TRPV1 was intrinsically less sensitive to CFA (but not nonivamide) than human TRPV1. Further, mouse TRPV1 was sensitized to CFA, and GSLD qPM2.5 by mutation of N606 to the corresponding human residue (D), while mutating human TRPV1 D605 to the mouse residue (N), decreased activation by CFA but not GSLD (Fig. 11a and b). Using the 3x GSLD qPM2.5 inhalation exposure paradigm, Trpv1N606D mice exhibited increased (76 ± 6 vs. 58 ± 9%) neutrophilia compared to wild-type controls (Fig. 11c), further supporting a role for TRPV1 in initiating lung inflammation in the respiratory tract with GSLD qPM2.5 inhalation. However, while comparable increases in mRNA and cytokine protein in BAL were observed for the TRPV1N606D mice, there were no significant differences from wild-type mice.

Fig. 11
figure 11

“Humanization” of mouse TRPV1 increased BAL neutrophils following GSLD PM2.5 inhalation. (a) Comparison of the amino acid sequence of the pore-loop region (residues 600/601–645) of human (h) and mouse (m) TRPV1. (b) Calcium flux data using HEK-293 cells transiently transfected with expression plasmids harboring human and mouse TRPV1, with and without mutations of residues 605/606 to the corresponding human and mouse residues. Nonivamide (20 mM; positive control, white bars), CFA (180 µg/cm2; light grey bars), and GSLD qPM2.5 (180 µg/cm2; dark grey bars) were used as agonists. Data are the mean and standard deviation. **p < 0.01, ***p < 0.001, and ****p < 0.0001 using two-way ANOVA and a Dunnett post-test. (c) comparison of BAL neutrophils in wild-type C57Bl/6 and Trpv1N606D “humanized” mice (3x exposure paradigm). Data are the mean and standard deviation. p < 0.05, **p < 0.01, and ***p < 0.001 using one-way ANOVA with Bonferroni post-test

Full size image

Discussion

This study confirms that GSLD contributes to PM2.5 and PM10 pollution in the Salt Lake Valley and Wasatch front during high wind events. There are ~ 2.5 M people residing in the Salt Lake valley and along the Wasatch front, and PM concentrations during dust events can temporarily exceed levels defined by the US-EPA and Utah Department of Air Quality as unhealthy for sensitive individuals (PM2.5 35.5–55.4 µg/m3); in some locations during some events, PM2.5 concentrations that are unhealthy for all individuals (> 55.4 µg/m3) occur. As the GSL continues to lose water, additional sediments are being exposed, increasing the diversity of dust and overall dust burden in the local airshed [81]. It is therefore critical to understand the potential health risks posed by inhalation (and other) exposure to GSLD. This study is the first to evaluate the acute effects of inhaled GSLD, and while cursory, provides the first evidence that respirable GSLD could adversely impact pulmonary and presumably other aspects of human health among people living along the Wasatch front in Utah, including Salt Lake City and other major cities (e.g., Ogden and Provo).

In mice, neutrophilia and edema were the principal effects elicited by GSLD qPM2.5, indicating an acute inflammatory response. Consistent with this effect and known biological activities [82, 83], increased expression of mRNA for Il6, Cxcl1, and Cxcl2 occurred. Additionally, Muc5ac RNA was induced, which has been shown to contribute to airway obstruction and hypersensitivity in asthma [84,85,86,87]. These responses are considered normal responses to a variety of pathogens and other foreign materials entering the respiratory tract, including other forms of PM. In the average healthy person, these effects may go unnoticed and resolve quickly when pollution levels return to baseline levels. However, in some individuals, such as those with asthma and other pre-existing conditions including COPD, heart disease, and obesity/metabolic syndrome, the effects could be amplified, slower to resolve, and exacerbate the underlying conditions leading to more serious adverse sequelae including increased risks for hospitalization and even death. Children and the elderly are also at greater risk, and the consequences of lung inflammation and injury early in life are recognized as a risk factor for poor respiratory health later in life [88, 89]. The fact that GSLD is able to elicit inflammation at relevant concentrations and doses, and that the effects were substantially greater than those of a known pneumotoxic PM, CFA, supports the notion that GSLD could be a threat to the well-being of local residents.

Because the health effects and impact of PM can vary as a function of dose and composition, among other human factors (e.g., genetics), the composition of GSLD qPM2.5 was partially elucidated and key facets systematically tested for pro-inflammatory potential in vitro. Of concern, GSL sediments and GSLD qPM2.5 contained multiple known human toxins including LPS, organic pollutants of natural and anthropogenic origin, redox active transition metals (iron, copper) and other toxic metals (arsenic, lead, etc.), as well as (potentially) pathogenic bacteria (Streptococcus pyogenes). LPS/endotoxin is a potent pneumotoxin that triggers neutrophilia and edema [90], and intranasal and systemically administered LPS are used as models for septic lung injury [91]. Indeed, TLR4 inhibition using TAK-242 slightly reduced IL6 induction by HBEC3-KT cells, and IL6 and IL8 induction by THP-1 cells, consistent with reported effects of SSD in mice [50, 55]. This is noteworthy because IL6 (and IL8) is a crucial acute phase response protein that regulates inflammation and impacts health/diseases, including asthma [92,93,94]. While we did not observe lung infection, and sterilization of GSLD qPM2.5 did not appear to affect responses of the lung cells in vitro, the potential of acquired infections, or increased risks to infectious agents, exist and should not be overlooked as a potential risk.

Redox active transition metals such as iron and copper are biologically essential, but are also acutely and chronically toxic in the lungs by virtue of their ability to form insoluble aggregates (e.g. ferruginous bodies) and to catalyze free radical reactions that cause oxidative stress and permanent indiscriminate cell/tissue injury [95]. Additionally, it has been shown that PM containing metals and organic chemicals can form environmentally persistent free radicals which contribute to adverse respiratory and cardiovascular effects [96]. Results using EGTA and deferoxamine support a role for metals, presumably iron, as suggested by Attah et al. [13], and other divalent metals associated with GSLD in mediating inflammatory responses in HBEC3-KT cells; albeit the relative importance appeared to be limited. Regardless, the presence of both redox-active and known toxic metals in GSLD is significant with respect to both the acute and potential long-term risks of exposure to GSLD.

Organic chemicals arising from natural and anthropogenic sources were also preliminarily identified in GSLD. Results indicated the presence of numerous chemicals in extracts of GSLD including human metabolites of common therapeutics and hormones, and industrial and agricultural chemicals. While the presence and concentrations of these various compounds were not validated or quantified, it is possible that one or more of these agents could pose a risk to human health and contribute to the overall effects of GSLD. An example is the identification of the neurotoxin β-methylamino-L-alanine in GSLD samples by Piotrowicz et al. (unpublished). Interestingly, the effects of GSLD were modified by extraction and heating of the PM using IL6 as a biomarker of inflammation, while little to no effect was observed for IL8. These results suggest a multifaceted mechanism of inflammation, and a role for both co-pollutants and insoluble components of the PM as drivers of the composite biological effects.

Overall, there is a relative paucity of information regarding the effects of PM originating from geological and other “natural sources” such as the GSL playa, versus PM derived from burning biomass, fossil fuels, etc., which are widely recognized as unhealthy. Previous work by our group demonstrated that soil dusts are pro-inflammatory and cytotoxic to lung cells, but in general, less than commonly studied emission particles [16, 97, 98]. Here, we compared the effects of inhaled GSLD qPM2.5 to those of CFA qPM2.5. CFA is a combustion by-product from coal burning power plants that is similar in elemental composition to GSLD in that it is a calcium/magnesium/aluminum-rich particle that promotes inflammatory cytokine production in human lung epithelial cells and in mice, in part via activation of TRPV1 [25], TRPM8 [21], and TRPA1 [26]. Interestingly, but perhaps not surprisingly, GSLD was substantially more cytotoxic to human lung cells in vitro, and more pro-inflammatory in mice. Meanwhile, another lakebed dust, SSD, for which adverse human health effects have been described [39,40,41, 50, 52, 53], exhibited overlapping activities with, and seemingly greater potency than GSLD on a per mass basis. Remarkably, both GSLD and SSD appeared to engage TRPV1 and TRPV3 as a basis for stimulating IL6 and IL8 expression by HBEC3-KT cells, as well as TLR4 in THP-1 cells, intimating the potential of perhaps modulating these receptors to mitigate the acute and possibly longer-term effects of GSLD and related lakebed sediment dusts. While highly speculative, the idea of targeting at least TRPV1 is supported by results using humanized TRPV1 mice, which imply that TRPV1 activation is at least in part responsible for lung inflammation elicited by GSLD.

However, this study has several important limitations to consider. First, GSL sediments were sampled from a small area of the playa, which is accessible and frequently visited by people. It is also adjacent to a mine processing/smelter site with open tailing ponds which could introduce metals and contaminants that may not be as abundant in other areas, including human-derived substances and pathogens. Recent comprehensive studies of GSL sediment metal content [13] and microorganism populations [79] from more dispersed locations generally agree with the results presented here, but differences, which may reduce the generalizability and translation of our findings to real-world exposures, exist. Second, only the acute effects of inhaled GSLD qPM2.5 were tested, and the study evaluated only a small subset of potential mechanisms by which GSLD affected lung cells, lungs, and potentially human health. GSLD is likely to have multiple acute and long-term effects that may manifest outside the lungs and involve mechanisms other than TRP channel activation. Further, these are likely to be dose related. Third, actual human exposure and source apportionment data are lacking. Accordingly, the doses used in the inhalation study may not truly model human exposures and the concentration of dust in the inhalation studies may be higher than that experienced by people during dust events due to location and the contribution of regional desert/soil dusts to the local PM measurements used to design this study. Regardless, we opine the exposure used here is relevant because even if the true contribution of GSLD was 20–30% of respirable dust during dust events, mice were only exposed for brief periods of time as opposed to much longer periods for many people. An extended duration of exposure to a lower concentration of dust would yield equivalent intrapulmonary doses and presumably similar effects. Also, prior studies of GSLD dust events support the concept that the GSL playa contributes substantially to PM in the airshed during dust events, particularly in lower elevation locations near the lakes’ eastern perimeter [10,11,12, 14]. Indeed, future research comparing GSLD with regional geological dusts, akin to the comparison to CFA, would be informative. Finally, epidemiological studies evaluating responses to dust events coupled with careful analysis of dust concentrations and composition are warranted.

Conclusions

This study highlights potential risks associated with GSLD inhalation and suggests that the effects of GSLD may be modeled by, and a model for, related lakebed dusts for which health effects have been described. Examples include the Salton Sea [39, 41, 42, 50, 52, 53, 55], Owens Lake [43], the Aral Sea [44,45,46], Lake Urmia [44, 49], and more [47]. Thus, the potential of GSLD and related lakebed dusts to cause adverse health outcomes should be explored in greater depth in order to understand the breadth of effects and risks that these materials have on people living in areas prone to dust events, and to further develop the mechanistic knowledge needed to design effective interventional strategies to protect people at risk for developing acute and potentially long-term adverse effects. Finally, this work supports current efforts to develop aggressive conservation measures to protect the GSL to prevent further loss of water.

Data availability

No datasets were generated or analysed during the current study.

References

  1. Benson LV, Lund SP, Smoot JP, Rhode DE, Spencer RJ, Verosub KL et al. The rise and fall of Lake Bonneville between 45 and 10.5 ka. 2011;235:57–69.

  2. Spencer RJ, Baedecker MJ, Eugster HP, Forester RM, Goldhaber MB, Jones BF et al. Great Salt Lake, and precursors, Utah: The last 30,000 years. 1984;86:321 – 34.

  3. Eardley AJ. Sediments of Great Salt Lake, Utah. Bull Am Association Petroleum Geol. 1938;22(10):1305–411.

    CAS  Google Scholar 

  4. Naftz D, Angeroth C, Kenney T, Waddell B, Darnall N, Silva S et al. Anthropogenic influences on the input and biogeochemical cycling of nutrients and mercury in Great Salt Lake, Utah, USA. 2008;23:1731-44.

  5. Wurtsbaugh WA, Leavitt PR, Moser KA. Effects of a century of mining and industrial production on metal contamination of a model saline ecosystem. Great Salt Lake Utah. 2020;266:115072.

    CAS  Google Scholar 

  6. Baxter BK. Great Salt Lake microbiology: a historical perspective. 2018;21:79–95.

  7. Davis J, Gwynn JW, Rupke A. Commonly Asked Questions About Utah’s Great Salt Lake and Ancient Lake Bonneville. 2022.

  8. Isaacson AE, Hachman F, Robson R. The economics of Great Salt Lake. Great Salt Lake: an overview of change. 2002:187–200.

  9. Bioeconomics I. Economic Significance of the Great Salt Lake to the State of Utah. 2012.

  10. Carling GT, Fernandez DP, Rey KA, Hale CA, Goodman MM, Nelson ST. Using strontium isotopes to trace dust from a drying Great Salt Lake to adjacent urban areas and mountain snowpack. 2020;15:114035.

  11. Lang OI, Mallia D, Skiles SM. The shrinking Great Salt Lake contributes to record high dust-on-snow deposition in the Wasatch Mountains during the 2022 snowmelt season. Environ Res Lett. 2023;18(6).

  12. Carling GT, Fernandez DP, Johnson WP. Dust-mediated loading of trace and major elements to Wasatch Mountain snowpack. Sci Total Environ. 2012;432:65–77.

    Article  CAS  PubMed  Google Scholar 

  13. Attah R, Kaur K, Perry KD, Fernandez DP, Kelly KE. Assessing the oxidative potential of dust from great salt Lake. Atmospheric Environment. 2024;336(1 November 2024):120728.

  14. Grineski SE, Mallia D, Collins TW, Araos M, Lin JC, Anderegg WRL et al. Harmful dust from drying lakes: Preserving Great Salt Lake (USA) water levels decreases ambient dust and racial disparities in population exposure. One Earth. 2024;7(6).

  15. Veranth JM, Kaser EG, Veranth MM, Koch M, Yost GS. Cytokine responses of human lung cells (BEAS-2B) treated with micron-sized and nanoparticles of metal oxides compared to soil dusts. Part Fibre Toxicol. 2007;4:2.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Veranth JM, Reilly CA, Veranth MM, Moss TA, Langelier CR, Lanza DL, et al. Inflammatory cytokines and cell death in BEAS-2B lung cells treated with soil dust, lipopolysaccharide, and surface-modified particles. Toxicol Sci. 2004;82(1):88–96.

    Article  CAS  PubMed  Google Scholar 

  17. He A, Li X, Ai Y, Li X, Li X, Zhang Y, et al. Potentially toxic metals and the risk to children’s health in a coal mining city: an investigation of soil and dust levels, bioaccessibility and blood lead levels. Environ Int. 2020;141:105788.

    Article  CAS  PubMed  Google Scholar 

  18. Tian S, Li K, Moller P, Ying SC, Wang L, Li Z, et al. Assessment of reactive oxygen species production and genotoxicity of rare earth mining dust: implications for public health and mining management. Sci Total Environ. 2020;740:139759.

    Article  CAS  PubMed  Google Scholar 

  19. Wilson A, Velasco CA, Herbert GW, Lucas SN, Sanchez BN, Cerrato JM, et al. Mine-site derived particulate matter exposure exacerbates neurological and pulmonary inflammatory outcomes in an autoimmune mouse model. J Toxicol Environ Health A. 2021;84(12):503–17.

    Article  CAS  PubMed  Google Scholar 

  20. Zychowski KE, Kodali V, Harmon M, Tyler CR, Sanchez B, Ordonez Suarez Y, et al. Respirable uranyl-vanadate-containing particulate matter derived from a legacy Uranium Mine Site exhibits Potentiated Cardiopulmonary Toxicity. Toxicol Sci. 2018;164(1):101–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lamb JG, Romero EG, Lu ZY, Marcus SK, Peterson HC, Veranth JM, et al. Activation of human transient receptor potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate materials and effects on Human Lung cells. Mol Pharmacol. 2017;92(6):653–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Borm PJ. Toxicity and occupational health hazards of coal fly ash (CFA). A review of data and comparison to coal mine dust. Ann Occup Hyg. 1997;41(6):659–76.

    Article  CAS  PubMed  Google Scholar 

  23. Buchanan S, Burt E, Orris P. Beyond black lung: scientific evidence of health effects from coal use in electricity generation. J Public Health Policy. 2014;35(3):266–77.

    Article  PubMed  Google Scholar 

  24. Holme JA, Vondracek J, Machala M, Lagadic-Gossmann D, Vogel CFA, Le Ferrec E, et al. Lung cancer associated with combustion particles and fine particulate matter (PM(2.5)) - the roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR). Biochem Pharmacol. 2023;216:115801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Deering-Rice CE, Johansen ME, Roberts JK, Thomas KC, Romero EG, Lee J et al. Transient receptor potential Vanilloid-1 (TRPV1) is a mediator of lung toxicity for coal fly Ash Particulate Material. 2012;81:411–9.

  26. Deering-Rice CE, Stockmann C, Romero EG, Lu Z, Shapiro D, Stone BL, et al. Characterization of transient receptor potential Vanilloid-1 (TRPV1) variant activation by coal fly Ash particles and associations with altered transient receptor potential Ankyrin-1 (TRPA1) expression and asthma. J Biol Chem. 2016;291(48):24866–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Leiphrakpam PD, Weber HR, McCain A, Matas RR, Duarte EM, Buesing KL. A novel large animal model of smoke inhalation-induced acute respiratory distress syndrome. Respir Res. 2021;22(1):198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schwartz C, Bolling AK, Carlsten C. Controlled human exposures to wood smoke: a synthesis of the evidence. Part Fibre Toxicol. 2020;17(1):49.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Scott AF, Reilly CA. Wood and Biomass smoke: addressing Human Health risks and exposures. Chem Res Toxicol. 2019;32(2):219–21.

    Article  CAS  PubMed  Google Scholar 

  30. Memon TA, Nguyen ND, Burrell KL, Scott AF, Almestica-Roberts M, Rapp E, et al. Wood smoke particles stimulate MUC5AC overproduction by human bronchial epithelial cells through TRPA1 and EGFR Signaling. Toxicol Sci. 2020;174(2):278–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Memon TA, Sun L, Almestica-Roberts M, Deering-Rice CE, Moos PJ, Reilly CA. Inhibition of TRPA1, endoplasmic reticulum stress, human airway epithelial cell damage, and ectopic MUC5AC expression by Vasaka (Adhatoda vasica; Malabar nut) tea. Pharmaceuticals (Basel). 2023;16(6).

  32. Nguyen ND, Memon TA, Burrell KL, Almestica-Roberts M, Rapp E, Sun L, et al. Transient receptor potential Ankyrin-1 and Vanilloid-3 differentially regulate endoplasmic reticulum stress and cytotoxicity in human lung epithelial cells after pneumotoxic Wood smoke particle exposure. Mol Pharmacol. 2020;98(5):586–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Deering-Rice CE, Nguyen N, Lu Z, Cox JE, Shapiro D, Romero EG, et al. Activation of TRPV3 by Wood Smoke Particles and roles in Pneumotoxicity. Chem Res Toxicol. 2018;31(5):291–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Park E, Kim BY, Lee S, Son KH, Bang J, Hong SH, et al. Diesel exhaust particle exposure exacerbates ciliary and epithelial barrier dysfunction in the multiciliated bronchial epithelium models. Ecotoxicol Environ Saf. 2024;273:116090.

    Article  CAS  PubMed  Google Scholar 

  35. Chen R, Hu B, Liu Y, Xu J, Yang G, Xu D, et al. Beyond PM2.5: the role of ultrafine particles on adverse health effects of air pollution. Biochim Biophys Acta. 2016;1860(12):2844–55.

    Article  CAS  PubMed  Google Scholar 

  36. Kwon HS, Ryu MH, Carlsten C. Ultrafine particles: unique physicochemical properties relevant to health and disease. Exp Mol Med. 2020;52(3):318–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Deering-Rice CE, Memon T, Lu Z, Romero EG, Cox J, Taylor-Clark T, et al. Differential activation of TRPA1 by Diesel Exhaust particles: relationships between Chemical Composition, Potency, and lung toxicity. Chem Res Toxicol. 2019;32(6):1040–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jaramillo IC, Sturrock A, Ghiassi H, Woller DJ, Deering-Rice CE, Lighty JS, et al. Effects of fuel components and combustion particle physicochemical properties on toxicological responses of lung cells. J Environ Sci Health Tox Hazard Subst Environ Eng. 2018;53(4):295–309.

    Article  CAS  Google Scholar 

  39. Biddle TA, Li Q, Maltz MR, Tandel PN, Chakraborty R, Yisrael K, et al. Salton Sea aerosol exposure in mice induces a pulmonary response distinct from allergic inflammation. Sci Total Environ. 2021;792:148450.

    Article  CAS  PubMed  Google Scholar 

  40. Frie AL, Dingle JH, Ying SC, Bahreini R. The Effect of a receding saline Lake (the Salton Sea) on Airborne Particulate Matter Composition. Environ Sci Technol. 2017;51(15):8283–92.

    Article  CAS  PubMed  Google Scholar 

  41. Johnston JE, Razafy M, Lugo H, Olmedo L, Farzan SF. The disappearing Salton Sea: a critical reflection on the emerging environmental threat of disappearing saline lakes and potential impacts on children’s health. Sci Total Environ. 2019;663:804–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jones BA, Fleck J. Shrinking lakes, air pollution, and human health: evidence from California’s Salton Sea. Sci Total Environ. 2020;712:136490.

    Article  CAS  PubMed  Google Scholar 

  43. Kittle S. Survey of Reported Health Effects of Owens Lake Particulate Matter 2000.

  44. AghaKouchak A, Norouzi H, Madani K, Mirchi A, Azarderakhsh M, Nazemi A et al. Aral Sea syndrome desiccates Lake Urmia: Call for action. 2015;41:307 – 11.

  45. Crighton EJ, Barwin L, Small I, Upshur R. What have we learned? A review of the literature on children’s health and the environment in the Aral Sea area. Int J Public Health. 2011;56(2):125–38.

    Article  PubMed  Google Scholar 

  46. Micklin P. Aral Sea Disaster. 2007;35:47–72.

    CAS  Google Scholar 

  47. Gill TE. Eolian sediments generated by anthropogenic disturbance of playas: human impacts on the geomorphic system and geomorphic impacts on the human system. Geomorphology. 1996;17(1–3):207–28.

    Article  Google Scholar 

  48. Wurtsbaugh WA, Miller C, Null SE, DeRose RJ, Wilcock P, Hahnenberger M, et al. Decline World’s Saline Lakes. 2017;10:816–21.

    CAS  Google Scholar 

  49. Feizizadeh B, Lakes T, Omarzadeh D, Pourmoradian S. Health effects of shrinking hyper-saline lakes: spatiotemporal modeling of the Lake Urmia drought on the local population, case study of the Shabestar County. 2023;13:1622.

  50. Burr AC, Velazquez JV, Ulu A, Kamath R, Kim SY, Bilg AK, et al. Lung inflammatory response to environmental dust exposure in mice suggests a link to Regional Respiratory Disease Risk. J Inflamm Res. 2021;14:4035–52.

    Article  PubMed  PubMed Central  Google Scholar 

  51. D’Evelyn SM, Vogel C, Bein KJ, Lara B, Laing EA, Abarca RA et al. Differential inflammatory potential of particulate matter (PM) size fractions from Imperial Valley, CA. Atmos Environ (1994). 2021;244.

  52. Marshall JR. Why Emergency Physicians should care about the Salton Sea. West J Emerg Med. 2017;18(6):1008–9.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Miao Y, Porter WC, Schwabe K, LeComte-Hinely J. Evaluating health outcome metrics and their connections to air pollution and vulnerability in Southern California’s Coachella Valley. Sci Total Environ. 2022;821:153255.

    Article  CAS  PubMed  Google Scholar 

  54. Deering-Rice CE, Romero EG, Shapiro D, Hughen RW, Light AR, Yost GS, et al. Electrophilic Components of Diesel Exhaust Particles (DEP) activate transient receptor potential Ankyrin-1 (TRPA1): a probable mechanism of Acute Pulmonary toxicity for DEP. Chem Res Toxicol. 2011;24(6):950–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Biddle TA, Yisrael K, Drover R, Li Q, Maltz MR, Topacio TM, et al. Aerosolized aqueous dust extracts collected near a drying lake trigger acute neutrophilic pulmonary inflammation reminiscent of microbial innate immune ligands. Sci Total Environ. 2023;858(Pt 3):159882.

    Article  CAS  PubMed  Google Scholar 

  56. Deering-Rice CE, Mitchell VK, Romero EG, Abdel Aziz MH, Ryskamp DA, Krizaj D, et al. Drofenine: a 2-APB analogue with Greater selectivity for human TRPV3. Pharmacol Res Perspect. 2014;2(5):e00062.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Smith KR, Veranth JM, Kodavanti UP, Aust AE, Pinkerton KE. Acute pulmonary and systemic effects of inhaled coal fly ash in rats: comparison to ambient environmental particles. Toxicol Sci. 2006;93(2):390–9.

    Article  CAS  PubMed  Google Scholar 

  58. Veranth JM, Smith KR, Huggins F, Hu AA, Lighty JS, Aust AE. Mossbauer spectroscopy indicates that iron in an aluminosilicate glass phase is the source of the bioavailable iron from coal fly ash. Chem Res Toxicol. 2000;13(3):161–4.

    Article  CAS  PubMed  Google Scholar 

  59. Becnel T, Tingey K, Whitaker J, Sayahi T, Le K, Goffin P, et al. A distributed low-cost Pollution Monitoring platform. Ieee Internet Things. 2019;6(6):10738–48.

    Article  Google Scholar 

  60. Kelly KE, Whitaker J, Petty A, Widmer C, Dybwad A, Sleeth D, et al. Ambient and laboratory evaluation of a low-cost particulate matter sensor. Environ Pollut. 2017;221:491–500.

    Article  CAS  PubMed  Google Scholar 

  61. Mallia DV, Kochanski AK, Kelly KE, Whitaker R, Xing W, Mitchell LE, et al. Evaluating Wildfire Smoke Transport within a coupled fire-atmosphere Model using a high-density Observation Network for an episodic smoke event along Utah’s Wasatch Front. J Geophys Research: Atmos. 2020;125(20):e2020JD032712.

    Article  CAS  Google Scholar 

  62. Sayahi T, Butterfield A, Kelly KE. Long-term field evaluation of the Plantower PMS low-cost particulate matter sensors. Environ Pollut. 2019;245:932–40.

    Article  CAS  PubMed  Google Scholar 

  63. Sayahi T, Kaufman D, Becnel T, Kaur K, Butterfield AE, Collingwood S, et al. Development of a calibration chamber to evaluate the performance of low-cost particulate matter sensors. Environ Pollut. 2019;255(Pt 1):113131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kaur KaK KE. Performance evaluation of the Alphasense OPC-N3 and plantower PMS5003 sensor in measuring dust events in the Salt Lake Valley, Utah. Atmos Meas Tech. 2023;16(10):2455–70.

    Article  Google Scholar 

  65. Campen M, Nihart A, Garcia M, Liu R, Olewine M, Castillo E et al. Bioaccumulation of Microplastics in Decedent Human brains assessed by Pyrolysis Gas Chromatography-Mass Spectrometry. Res Sq. 2024.

  66. Forsythe K, Egermeier M, Garcia M, Liu R, Campen M, Minghetti M, et al. Viability of elutriation for the extraction of microplastics from environmental soil samples. Env Sci Adv. 2024;3(7):1039–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Garcia MA, Liu R, Nihart A, El Hayek E, Castillo E, Barrozo ER, et al. Quantitation and identification of microplastics accumulation in human placental specimens using pyrolysis gas chromatography mass spectrometry. Toxicol Sci. 2024;199(1):81–8.

    Article  CAS  PubMed  Google Scholar 

  68. Wang M, Carver JJ, Phelan VV, Sanchez LM, Garg N, Peng Y, et al. Sharing and community curation of mass spectrometry data with Global Natural products Social Molecular networking. Nat Biotechnol. 2016;34(8):828–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Deering-Rice CE, Johansen ME, Roberts JK, Thomas KC, Romero EG, Lee J, et al. Transient receptor potential vanilloid-1 (TRPV1) is a mediator of lung toxicity for coal fly ash particulate material. Mol Pharmacol. 2012;81(3):411–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Borghi F, Spinazze A, Mandaglio S, Fanti G, Campagnolo D, Rovelli S et al. Estimation of the inhaled dose of pollutants in different micro-environments: a systematic review of the literature. Toxics. 2021;9(6).

  71. Kim YH, Warren SH, Kooter I, Williams WC, George IJ, Vance SA, et al. Chemistry, lung toxicity and mutagenicity of burn pit smoke-related particulate matter. Part Fibre Toxicol. 2021;18(1):45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bonner JC, Silva RM, Taylor AJ, Brown JM, Hilderbrand SC, Castranova V, et al. Interlaboratory evaluation of rodent pulmonary responses to engineered nanomaterials: the NIEHS Nano GO Consortium. Environ Health Perspect. 2013;121(6):676–82.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Kim YH, Vance SA, Aurell J, Holder AL, Pancras JP, Gullett B, et al. Chemistry and lung toxicity of particulate matter emitted from firearms. Sci Rep. 2022;12(1):20722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schwarte LA, Zuurbier CJ, Ince C. Mechanical ventilation of mice. Basic Res Cardiol. 2000;95(6):510–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kolanjiyil AV, Kleinstreuer C, Kleinstreuer NC, Pham W, Sadikot RT. Mice-to-men comparison of inhaled drug-aerosol deposition and clearance. Respir Physiol Neurobiol. 2019;260:82–94.

    Article  CAS  PubMed  Google Scholar 

  76. Nguyen J, Deering-Rice CE, Armstrong BS, Massa C, Reilly CA, Venosa A. Parenchymal and inflammatory cell responses to single and repeated ozone exposure in healthy and surfactant Protein-C mutant lung. Toxicol Sci. 2022;189(1):107–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature. 2013;499(7458):295–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. FOX 13 News. Blowing dust causes dirty rain to fall across northern Utah 2023 [Available from: https://www.fox13now.com/weather/blowing-dust-causes-dirty-rain-to-fall-across-northern-utah#:~:text=%22Muddy%20rain%22%20has%20been%20falling,else%20exposed%20to%20the%20weather

  79. Bring Horvath ER, Brazelton WJ, Kim MC, Cullum R, Mulvey MA, Fenical W, et al. Bacterial diversity and chemical ecology of natural product-producing bacteria from Great Salt Lake sediment. ISME Commun. 2024;4(1):ycae029.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Sabnis AS, Reilly CA, Veranth JM, Yost GS. Increased transcription of cytokine genes in human lung epithelial cells through activation of a TRPM8 variant by cold temperatures. Am J Physiol Lung Cell Mol Physiol. 2008;295(1):L194–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hahnenberger M, Nicoll K. Meteorological characteristics of dust storm events in the eastern Great Basin of Utah, USA. Atmos Environ. 2012;60:601–12.

    Article  CAS  Google Scholar 

  82. Sawant KV, Sepuru KM, Lowry E, Penaranda B, Frevert CW, Garofalo RP, et al. Neutrophil recruitment by chemokines Cxcl1/KC and Cxcl2/MIP2: role of Cxcr2 activation and glycosaminoglycan interactions. J Leukoc Biol. 2021;109(4):777–91.

    Article  CAS  PubMed  Google Scholar 

  83. Yang J, Chen Y, Yu Z, Ding H, Ma ZF. The influence of PM2.5 on lung injury and cytokines in mice. Exp Ther Med. 2019;18(4):2503–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Caramori G, Casolari P, Di Gregorio C, Saetta M, Baraldo S, Boschetto P, et al. MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology. 2009;55(3):321–31.

    Article  PubMed  Google Scholar 

  85. Conti C, Montero-Fernandez A, Borg E, Osadolor T, Viola P, De Lauretis A, et al. Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb spaces: comparison among idiopathic pulmonary Fibrosis/Usual interstitial pneumonia, Fibrotic nonspecific interstitial pneumonitis, and control lungs. Am J Respir Crit Care Med. 2016;193(4):462–4.

    Article  CAS  PubMed  Google Scholar 

  86. Evans CM, Raclawska DS, Ttofali F, Liptzin DR, Fletcher AA, Harper DN, et al. The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun. 2015;6:6281.

    Article  CAS  PubMed  Google Scholar 

  87. Livraghi-Butrico A, Grubb BR, Wilkinson KJ, Volmer AS, Burns KA, Evans CM, et al. Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunol. 2017;10(3):829.

    Article  CAS  PubMed  Google Scholar 

  88. Bobolea I, Arismendi E, Valero A, Agusti A. Early Life origins of Asthma: a review of potential effectors. J Investig Allergol Clin Immunol. 2019;29(3):168–79.

    Article  CAS  PubMed  Google Scholar 

  89. Grant T, Brigham EP, McCormack MC. Childhood origins of Adult Lung Disease as opportunities for Prevention. J Allergy Clin Immunol Pract. 2020;8(3):849–58.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Horgan MJ, Palace GP, Everitt JE, Malik AB. Tnf-alpha release in Endotoxemia contributes to Neutrophil-Dependent Pulmonary-Edema. Am J Physiol. 1993;264(4):H1161–5.

    CAS  PubMed  Google Scholar 

  91. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295(3):L379–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Peters MC, Mauger D, Ross KR, Phillips B, Gaston B, Cardet JC, et al. Evidence for exacerbation-prone asthma and predictive biomarkers of exacerbation frequency. Am J Respir Crit Care Med. 2020;202(7):973–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rose-John S. Interleukin-6 signalling in health and disease. F1000Res. 2020;9.

  95. Fariss MW, Gilmour MI, Reilly CA, Liedtke W, Ghio AJ. Emerging mechanistic targets in lung injury induced by combustion-generated particles. Toxicol Sci. 2013;132(2):253–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Aryal A, Noel A, Khachatryan L, Cormier SA, Chowdhury PH, Penn A, et al. Environmentally persistent free radicals: methods for combustion generation, whole-body inhalation and assessing cardiopulmonary consequences. Environ Pollut. 2023;334:122183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Veranth JM, Cutler NS, Kaser EG, Reilly CA, Yost GS. Effects of cell type and culture media on Interleukin-6 secretion in response to environmental particles. Toxicol Vitro. 2008;22(2):498–509.

    Article  CAS  Google Scholar 

  98. Veranth JM, Moss TA, Chow JC, Labban R, Nichols WK, Walton JC, et al. Correlation of in vitro cytokine responses with the chemical composition of soil-derived particulate matter. Environ Health Perspect. 2006;114(3):341–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the University of Utah Mutation Generation Detection Core and the Transgenic & Gene Targeting Mouse Core Facility for generating the Trpv1 N606D mouse line that was used in this research.

Funding

This work was supported in part by development funds and funding from the National Institutes of Health (NIH) Environmental Health Sciences grants R01 ES017431 (C.A.R), R01 ES027015 (C.A.R.), R01 ES032553 (A.V.), and a Margolis Foundation Collaborative Catalyst Award (C.A.R.)

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, 30 S. 2000 E., Room 201 Skaggs Hall, Salt Lake City, UT, 84112, USA

    Jacob M. Cowley, Cassandra E. Deering-Rice, John G. Lamb, Erin G. Romero, Marysol Almestica-Roberts, Samantha N. Serna, Lili Sun, Jenna Cheminant, Alessandro Venosa & Christopher A. Reilly

  2. Department of Chemical Engineering, University of Utah, Salt Lake City, UT, 84112, USA

    Kerry E. Kelly

  3. Department of Computer Science, University of Utah, Salt Lake City, UT, 84112, USA

    Ross T. Whitaker

Authors
  1. Jacob M. Cowley
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Cassandra E. Deering-Rice
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. John G. Lamb
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Erin G. Romero
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Marysol Almestica-Roberts
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Samantha N. Serna
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Lili Sun
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Kerry E. Kelly
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Ross T. Whitaker
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Jenna Cheminant
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Alessandro Venosa
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Christopher A. Reilly
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Conceptualization: CAR; Experimental Design Data Analysis and Visualization: CAR, JMC, CED-R, JGL, EGR, MA-R, SNS, LS, KEK, RTW, JC, AV; Resources: CAR, KEK, RTW, AV; Writing-Original Draft Preparation: CAR, JMC, CED-R, JGL, KEK, RTW, JC, AV; Writing-Review and Editing: CAR, JMC, CED-R, JGL, EGR, MA-R, SNS, LS, KEK, RTW, JC, AV; Supervision: CAR, CED-R, KEK, RTW, AV; Funding Acquisition: CAR, CED-R, KEK, RTW. All authors have read and agreed to the content of the manuscript.

Corresponding author

Correspondence to Christopher A. Reilly.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the University of Utah Institutional Animal Care and Use Committee (IACUC).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12989_2025_618_MOESM1_ESM.pptx

Supplementary Material 1: Additional File 1 shows maps indicating the locations of sediment collections sites and monitoring locations (Utah only) specified in this study.

12989_2025_618_MOESM2_ESM.pptx

Supplementary Material 2: Additional File 2 is a movie illustrating a dust event (changes in PM10 based on PM2.5 monitors) on April 21, 2022.

12989_2025_618_MOESM3_ESM.xlsx

Supplementary Material 3: Additional File 3 contains results from the analysis of bacterial colonies grown from GSLD qPM2.5 and sequenced to reveal potential identities.

12989_2025_618_MOESM4_ESM.xlsx

Supplementary Material 4: Additional File 4 contains results from untargeted LC/MS/MS analysis of GSLD sediments and qPM2.5, and spectral matching using GNPS.

12989_2025_618_MOESM5_ESM.tif

Supplementary Material 5: Additional File 5 shows a map illustrating the genetic changes used to create the Trpv1N606D mouse line.

12989_2025_618_MOESM6_ESM.docx

Supplementary Material 6: Additional File 6 contains all other supplemental figures and data described in the manuscript.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cowley, J.M., Deering-Rice, C.E., Lamb, J.G. et al. Pro-inflammatory effects of inhaled Great Salt Lake dust particles. Part Fibre Toxicol 22, 2 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12989-025-00618-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12989-025-00618-9

Keywords

Particle and Fibre Toxicology

ISSN: 1743-8977

Contact us