Neuroinflammation is dependent on sex and ovarian hormone presence following acute woodsmoke exposure.

Woodsmoke (WS) exposure is associated with significant health-related sequelae. Different populations can potentially exhibit varying susceptibility, based on endocrine phenotypes, to WS and investigating neurological impacts following inhaled WS is a growing area of research. In this study, a whole-body inhalation chamber was used to expose both male and female C57BL/6 mice (n = 8 per group) to either control filtered air (FA) or acute WS (0.861 ± 0.210 mg/m3) for 4 h/d for 2 days. Neuroinflammatory and lipid-based biological markers were then assessed. In a second set of studies, female mice were divided into two groups: one group was ovariectomized (OVX) to simulate an ovarian hormone-deficient state (surgical menopause), and the other underwent Sham surgery as controls, to mechanistically assess the impact of ovarian hormone presence on neuroinflammation following FA and acute WS exposure to simulate an acute wildfire episode. There was a statistically significant impact of sex (P ≤ 0.05) and statistically significant interactions between sex and treatment in IL-1ß, CXCL-1, TGF-ß, and IL-6 brain relative gene expression. Hippocampal and cortex genes also exhibited significant changes in acute WS-exposed Sham and OVX mice, particularly in TGF-ß (hippocampus) and CCL-2 and CXCL-1 (cortex). Cortex GFAP optical density (OD) showed a notable elevation in male mice exposed to acute WS, compared to the control FA. Sham and OVX females demonstrated differential GFAP expression, depending on brain region. Overall, targeted lipidomics in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) serum and brain lipids demonstrated more significant changes between control FA and acute WS exposure in female mice, compared to males. In summary, male and female mice show distinct neuroinflammatory markers in response to acute WS exposure. Furthermore, ovarian hormone deficiency may impact the neuroinflammatory response following an acute WS event.

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 63Cu, 182W, 208Pb, and 238U, 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-1ß, TNF-α, CXCL-1, CCL-5, TGF-ß, 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-1ß, and TNF-α. Significant diverse alterations were observed in BAL cytokines, specifically IL-1ß, 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.

VCAM-1 Is Upregulated in Uranium Miners Compared to Other Miners.

The United States has a rich history of mining including uranium (U)-mining, coal mining, and other metal mining. Cardiovascular diseases (CVD) are largely understudied in miners and recent literature suggests that when compared to non-U miners, U-miners are more likely to report CVD. However, the molecular basis for this phenomenon is currently unknown. In this pilot study, a New Mexico (NM)-based occupational cohort of current and former miners (n = 44) were recruited via a mobile screening clinic for miners. Serum- and endothelial-based endpoints were used to assess circulating inflammatory potential relevant to CVD. Non-U miners reported significantly fewer pack years of smoking than U-miners. Circulating biomarkers of interest revealed that U-miners had significantly greater serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (ICAM-1, ng/mL), soluble vascular cell adhesion molecule 1 (VCAM-1, ng/mL), and VCAM-1 mRNA expression, as determined by the serum cumulative inflammatory potential (SCIP) assay, an endothelial-based assay. Even after adjusting for various covariates, including age, multivariable analysis determined that U-miners had significantly upregulated VCAM-1 mRNA. In conclusion, VCAM-1 may be an important biomarker and possible contributor of CVD in U-miners. Further research to explore this mechanism may be warranted.

Inhalation of Tungsten Metal Particulates Alters the Lung and Bone Microenvironments Following Acute Exposure.

Inhalation of tungsten particulates is a relevant route of exposure in occupational and military settings. Exposure to tungsten alloys is associated with increased incidence of lung pathologies, including interstitial lung disease and cancer. We have demonstrated, oral exposure to soluble tungsten enhances breast cancer metastasis to the lungs through changes in the surrounding microenvironment. However, more research is required to investigate if changes in the lung microenvironment, following tungsten particulate exposure, can drive tumorigenesis or metastasis to the lung niche. This study examined if inhalation to environmentally relevant concentrations of tungsten particulates caused acute damage to the microenvironment in the lungs and/or systemically using a whole-body inhalation system. Twenty-four female BALB/c mice were exposed to Filtered Air, 0.60 mg/m3, or 1.7 mg/m3 tungsten particulates (<1 µm) for 4 h. Tissue samples were collected at days 1 and 7 post-exposure. Tungsten accumulation in the lungs persisted up to 7 days post-exposure and produced acute changes to the lung microenvironment including increased macrophage and neutrophil infiltration, increased levels of proinflammatory cytokines interleukin 1 beta and C-X-C motif chemokine ligand 1, and an increased percentage of activated fibroblasts (alpha-smooth muscle actin+). Exposure to tungsten also resulted in systemic effects on the bone, including tungsten deposition and transient increases in gene expression of proinflammatory cytokines. Taken together, acute whole-body inhalation of tungsten particulates, at levels commonly observed in occupational and military settings, resulted in changes to the lung and bone microenvironments that may promote tumorigenesis or metastasis and be important molecular drivers of other tungsten-associated lung pathologies such as interstitial lung disease.