The occupation of firefighting is classified as a Group 1 carcinogen. Increased cancer risk among firefighters may be partly attributable to increased occupational exposure to a range of chemicals, including per- and polyfluoroalkyl substances (PFAS). Some PFAS are known and suspect human carcinogens. Investigating epigenetic response to these PFAS exposures in firefighters may help to identify biological pathways of specific cancers, and previously unidentified health outcomes that are associated with PFAS. We therefore investigated the associations of serum PFAS concentrations with miRNA expression in firefighters. Serum samples collected from 303 firefighters from 6 sites across the USA were analyzed for 9 PFAS along with miRNA expression. Covariate-adjusted linear regression was used to estimate associations between log PFAS and miRNA expression, with false discovery rate (FDR) set to 0.05 for significance, and an exploratory cutoff of FDR q < 0.20. Gene set enrichment analysis (GSEA) was performed using miRTarBase's miRWalk pathways. Age, race-ethnicity, BMI, fire department, and sex were controlled for in all models. At FDR<0.05, the linear isomer of perfluorooctane sulfonic acid (PFOS) was inversely associated with miR-128-1-5p expression (Beta = -0.146, 95 % CI -0.216, -0.076). At a relaxed FDR of 0.20, we observed inverse associations for the sum of branched isomers of PFOS (Sm-PFOS) with 5 miRNAs (let-7d-5p, let-7a-5p, miR-423-5p, let-7b-5p, miR-629-5p). Several pathways were enriched for multiple PFAS, including those correlated with certain cancers, blood diseases, thyroid disorders, autoimmune disorders, and neurological outcomes. Some PFAS in firefighters were found to be associated with alteration of miRNA consistent with increased risk for a range of chronic diseases.

Firefighters have elevated rates of urinary tract cancers and other adverse health outcomes, which may be attributable to environmental occupational exposures. Untargeted metabolomics was applied to characterize this suite of environmental exposures and biological changes in response to occupational firefighting. 200 urine samples from 100 firefighters collected at baseline and two to four hours post-fire were analyzed using untargeted liquid-chromatography and high-resolution mass spectrometry. Changes in metabolite abundance after a fire were estimated with fixed effects linear regression, with false discovery rate (FDR) adjustment. Partial least squares discriminant analysis (PLS-DA) was also used, and variable important projection (VIP) scores were extracted. Systemic changes were evaluated using pathway enrichment for highly discriminating metabolites. Metabolome-wide-association-study (MWAS) identified 268 metabolites associated with firefighting activity at FDR q < 0.05. Of these, 20 were annotated with high confidence, including the amino acids taurine, proline, and betaine; the indoles kynurenic acid and indole-3-acetic acid; the known uremic toxins trimethylamine n-oxide and hippuric acid; and the hormone 7a-hydroxytestosterone. Partial least squares discriminant analysis (PLS-DA) additionally implicated choline, cortisol, and other hormones. Significant pathways included metabolism of urea cycle/amino group, alanine and aspartate, aspartate and asparagine, vitamin b3 (nicotinate and nicotinamide), and arginine and proline. Firefighters show a broad metabolic response to fires, including altered excretion of indole compounds and uremic toxins. Implicated pathways and features, particularly uremic toxins, may be important regulators of firefighter’s increased risk for urinary tract cancers.

Introduction Firefighters face regular exposure to known and probable human carcinogens, such as polycyclic aromatic hydrocarbons (PAHs), benzene, and formaldehyde, leading to an increased risk of various cancers compared to the general population. Hispanic and black firefighters are at increased risk of additional cancers not elevated in non-Hispanic white firefighters, yet biological pathways underlying these differences are unknown. Objectives The study objectives were to evaluate differences in the urinary metabolome between Hispanic and non-Hispanic firefighters, pre-and post-fireground exposure. Methods To investigate the metabolic patterns, we employed a comprehensive metabolomics pipeline that leveraged liquid chromatography coupled with high-resolution mass spectrometry. We applied linear mixed effects regression to identify the differential metabolites at an FDR < 0.05 among 19 Hispanic and 81 non-Hispanic firefighters. We also performed overrepresentation analysis using Mummichog to identify enriched pathways at FDR < 0.05. Results Out of 175 features in HILIC(−) mode and 1847 features in RP(+) mode, we found 26 and 276 differential urinary features, respectively, when comparing Hispanic and non-Hispanic firefighters. We noted pathway enrichment in tryptophan and galactose metabolism. However, post-exposure, we did not observe differences in the metabolomic response by ethnicity despite differing fireground exposures. Conclusion Dysregulation in the tryptophan and galactose pathway is an important contributor to cancer risks and may explain the increased cancer risk among Hispanic firefighters.

Background: Currently there are no clinically validated biomarkers recommended for prostate cancer (PCa) risk stratification other than prostate-specific antigen (PSA). Objective: This study aimed to identify urine metabolites that are associated with the presence of high-grade PCa at the time of radical prostatectomy. Methods: Urine samples were collected from patients who underwent radical prostatectomy. High-resolution metabolomics were implemented using liquid chromatography mass spectrometry (LC-MS). To enhance metabolic feature identification, sample extracts were analyzed in two modes, C18 chromatography [reverse-phase (RP)] and hydrophilic interaction chromatography (HILIC). Results: This analysis included a total of 22 patients with PCa (10 high-grade and 12 low-grade) and identified 52 differential metabolites, 40 in RP and 12 in HILIC, at the p-value 0.05 level. Among these, methyl alpha-aspartyl phenylalaninate was most significantly differentiated, while 3-methylbutanoicacid had the largest difference (slope −3.488). In the pathway analysis, the histidine metabolism pathway was significantly enriched (p < 0.05) with an enrichment factor of 3.5. Although not statistically significant, alterations were also observed in the vitamin B12, B7 (biotin), B6, and B3 (niacin) pathways. Conclusions: These findings suggest that urinary metabolites may have the potential to differentiate high-grade from low-grade PCa. Our study also highlights the metabolic reprogramming that occurs as PCa becomes more aggressive and potential differences in dietary patterns.

Background: Firefighters have frequent exposure to carcinogens and an increased risk of cancer. Wildland-urban interface (WUI) fires, which involve both structures and undeveloped wildland fuels, pose unique challenges to the health of firefighters. However, the extent of health risks associated with these fires remains underexplored. Objectives: This study aims to identify altered urine metabolites and metabolic processes among male firefighters that were associated with WUI fires as compared with municipal structure fires (MSF). Methods: Untargeted metabolomic profiling was applied to pre-exposure (baseline) and postfire urine samples collected from firefighters responding to WUI and MSF fires. Differential analysis was conducted by fitting linear mixed effects regression models on preprocessed ion intensity and exposure status while adjusting for demographic covariates. Differential metabolites by post-exposure status were identified using a false discovery rate (FDR) threshold of < 0.05. Pathway analysis was performed to identify pathways that were significantly perturbed at a Bonferroni adjusted p-value < 0.05 level. We conducted differential and pathway analyses in both the WUI and MSF cohorts and compared the two fire types in terms of the number of differentially expressed metabolites and patterns of metabolic pathway enrichment. Results: Eighty-five firefighters contributed paired baseline and post-fire samples from WUI events, and 98 firefighters contributed paired baseline and post-fire samples from MSF events. We performed metabolic profiling on baseline and postfire urine samples from WUI and MSF using four modes: HILIC(-), HILIC(+), C18(-), and C18(+) and identified metabolites against an in-house library. We identified 244, 297, 320, and 266 level-1 metabolites from the four respective modes. In the statistical analysis, the main model identified a total of 176 differential metabolites from WUI fires. For MSF, the model identified a total of 652 differential metabolites from the four respective modes. Most metabolites with significant changes after a WUI fire also changed significantly after an MSF event. Two metabolic pathways were significantly enriched after WUI fires, while 7 pathways were significantly enriched after MSF exposure and 2 pathways overlapped between the two types of fires. Conclusion: Fire exposure induces numerous metabolic perturbations in firefighters responding to WUI fires, potentially contributing to their elevated cancer risk. Although individual metabolites changed in a similar fashion across both WUI and MSF, MSF were associated with an increased number of metabolite changes and some of the enriched pathways differed between exposures to WUI fires vs. MSF. These findings suggest that WUI and MSF exposures may share common biological responses while also posing unique health risks to firefighters.

Female firefighters face elevated risks for cancer and reproductive disorders, but the underlying metabolic mechanisms remain unclear. This study aimed to identify urinary metabolites and metabolic processes associated with training fire exposure among female municipal firefighters. High-resolution metabolomics (HRM) was conducted on urine samples collected before and after live-fire training from female firefighters enrolled in the Fire Fighter Cancer Cohort Study. Linear mixed-effects models, adjusting for age, education, and Hispanic ethnicity, were used to identify differentially expressed metabolites (DEMs) with false discovery rate correction. Functional enrichment analysis (FEA) via metabolite-set enrichment analysis (MSEA) from MetaboAnalyst was performed to identify enriched metabolic processes. A stratified analysis examined the influence of fire types on post-fire metabolic profiles. One hundred female firefighters donated a total of 200 urine samples (100 pre-, 100 post-fire). HRM was performed in four modes including HILIC(+), HILIC(-), C18(+), and C18(-). We identified 200, 300, 280, and 306 metabolites and 10, 9, 23, and 19 post-training fire DEMs from the four modes, respectively. FEA highlighted enrichment of glycerophospholipid metabolism (p < 0.05). Stratified analysis identified 11 DEMs by fire type with greater changes observed following burn room/tower exposures compared to flashover fires. Training fire exposure induced widespread metabolic alterations in female firefighters, particularly in pathways related to oxidative stress and cell damage. These findings suggest potential biological pathways linking repeated fire exposure to chronic inflammation and disease risk. Burn room/tower burn exercises elicited more pronounced metabolic shifts than flashover fires.