Chem. Res. Toxicol. [JOURNAL]
Sun
200 papers
Unraveling the Toxicological Effects of Hydroxyacetone─A Reaction Product in Electronic Cigarette Aerosols.
Wong M, Martinez T, Hua M … +2 more , Hendricks NG, Talbot P
Chem Res Toxicol · 2026 Mar · PMID 41650339 · Publisher ↗
Hydroxyacetone was previously detected at high concentrations (up to ∼12 mg/mL) in electronic cigarette (EC) aerosols, including those derived from products associated with adverse health effects. Given the limited under...
Hydroxyacetone was previously detected at high concentrations (up to ∼12 mg/mL) in electronic cigarette (EC) aerosols, including those derived from products associated with adverse health effects. Given the limited understanding of its inhalation toxicology, we investigated hydroxyacetone's impact on human airway epithelial cells. Acute exposures at the air-liquid interface (ALI) using 3D EpiAirway tissues─a surrogate for human tracheobronchial epithelium─were analyzed via proteomics. Differential expression analysis identified numerous affected proteins, with enrichment pointing to alterations in mitochondrial function and actin cytoskeletal disruption as major targets. Ingenuity Pathway Analysis (IPA) highlighted "Mitochondrial Dysfunction" and "NRF2-Mediated Oxidative Stress" among top toxicological categories, and "Nuclear Cytoskeletal Signaling" as a key canonical pathway. To validate and extend these findings, submerged cultures of BEAS-2B cells were exposed to hydroxyacetone (0.01-10 mg/mL) and assessed for mitochondrial activity, oxidative stress, and F-actin integrity. At 1 mg/mL, mitochondrial membrane potential and reactive oxygen species (ROS) increased, with elevated hydrogen peroxide detected in the culture medium. At 10 mg/mL, mitochondrial activity declined significantly, accompanied by cell rounding and apoptotic blebbing within 2 h. F-actin destabilization occurred at 1, 3.33, and 10 mg/mL, with cytoplasmic and perinuclear filaments more affected than cortical actin. Findings from ALI and submerged models were concordant, supporting hydroxyacetone-induced mitochondrial stress, oxidative damage, and cytoskeletal disruption. These results suggest that hydroxyacetone concentrations found in EC aerosols may contribute to respiratory toxicity and warrant further investigation.
Flavoring Compound Chemical Class and Vaping Conditions Determine Toxic Carbonyl Emissions from E-Cigarettes.
Fazeli E, Martinez B, Son Y … +1 more , Khlystov A
Chem Res Toxicol · 2026 Mar · PMID 41649144 · Full text
The increasing use of flavored electronic cigarettes (e-cigarettes) raises concerns about their potential impact on the emission of harmful chemicals, particularly carbonyl compounds. This study systematically examines t...
The increasing use of flavored electronic cigarettes (e-cigarettes) raises concerns about their potential impact on the emission of harmful chemicals, particularly carbonyl compounds. This study systematically examines the effects of eight representative flavoring chemicals from four major classes including esters (ethyl acetate, ethyl butyrate), alcohols (menthol, ethyl maltol), aromatic aldehydes (benzaldehyde, vanillin), and terpenes (limonene, linalool) under varying power outputs (50 and 90 W), base liquid composition [propylene glycol (PG)/vegetable glycerin (VG) ratios (80:20, 50:50, and 20:80)], and flavor concentrations (1 and 5 mg/mL). Across all conditions, flavored e-liquids tend to produce carbonyl emissions that are higher than those of unflavored controls. Terpene-based flavors showed the strongest effects, with formaldehyde emissions being up to 2-fold higher and acrolein emissions up to 8-fold higher, frequently exceeding short-term exposure limits. Aromatic aldehydes and alcohols also increased emissions, though to a lesser extent, while esters showed smaller or inconsistent effects. The influence of flavors was further modulated by their concentration, PG/VG ratio, and device power, with higher concentration, VG content, and power amplifying emissions. These results highlight the complex interactions among e-liquid composition, flavor class, and vaping conditions, demonstrating that certain flavorings substantially elevate toxicant emissions. These findings underscore the importance of considering flavor composition, device power, and base material in evaluating the potential health risks associated with e-cigarette use.
Chemical Clustering Analysis of Ambient and Emission Source Particulate Matter Reveals Compositional Determinants of Pulmonary Toxicity Responses.
Klein LM, Gavett SH, Pancras JP … +4 more , Williams WC, Nored A, Gilmour MI, Kim YH
Chem Res Toxicol · 2026 Mar · PMID 41643067 · Full text
Comparative toxicological studies of heterogeneous particulate matter (PM) samples are needed to evaluate the influence of particle chemistry on pulmonary toxicity outcomes. Here, groups of mice were exposed by oropharyn...
Comparative toxicological studies of heterogeneous particulate matter (PM) samples are needed to evaluate the influence of particle chemistry on pulmonary toxicity outcomes. Here, groups of mice were exposed by oropharyngeal aspiration of a 100 μg dose of one of seven PM samples, including three coarse and two fine ambient air PM, and 2 fine emission source PM. Acute inflammatory and lung injury markers in the bronchoalveolar lavage fluid (BALF) were assessed. A weighted chemical correlation network analysis (WCCNA) clustered PM chemical constituents into four modules based on comodulation within samples. These modules and their components were then correlated with lung toxicity end points. One module represented the highest levels of zinc, lead, copper, and tin, and was strongly correlated with BALF neutrophils, macrophage inflammatory protein-2, and several markers of lung injury. A second module represented the highest levels of several toxic transition metals including magnesium, nickel, vanadium, and cobalt, and was strongly correlated with pro-inflammatory interleukin-6, in addition to neutrophils, albumin, and lactate dehydrogenase. A third module, represented by high levels of elemental carbon, nitrate, sulfate, and phosphate, was correlated with pro-inflammatory tumor necrosis factor-α (TNF-α), in addition to BALF protein and other lung injury markers. The final module consisted of 7 elements associated with the 3 coarse crustal PM samples, and these individual elements exhibited moderate correlations with BALF neutrophils and TNF-α. Toxic transition metals produced the greatest effects on lung toxicity, followed by anions and carbon species. These studies demonstrated that chemical and toxicological assessments of heterogeneous samples of PM produce clusters of chemical constituents that can be correlated with separate toxicological outcomes.
PM Is a Toxic Mixture: Not Just a Matter of Concentration.
Sangkham S
Chem Res Toxicol · 2026 Mar · PMID 41642031 · Full text
Fine particulate matter (PM) is a complex mixture of air pollutants that may contain hazardous substances and emerging contaminants. It penetrates deep into the lungs, inducing oxidative stress, inflammation, and systemi...
Fine particulate matter (PM) is a complex mixture of air pollutants that may contain hazardous substances and emerging contaminants. It penetrates deep into the lungs, inducing oxidative stress, inflammation, and systemic toxicity, and interacts with O, NO, SO, and organic and inorganic constituents, thereby increasing health risks.
From Barriers to Bridges: Application of Tools in Regulatory (Eco)toxicology─An Industry Perspective.
Weyrich A, Preibisch A, Przybylak KR … +1 more , Lo Piparo E
Chem Res Toxicol · 2026 May · PMID 41627131 · Publisher ↗
tools offer rapid, cost-efficient alternatives to animal testing in (eco)toxicology. The following ToxWatch highlights the limitations that slow down regulatory application and discusses opportunities that could turn bar...
tools offer rapid, cost-efficient alternatives to animal testing in (eco)toxicology. The following ToxWatch highlights the limitations that slow down regulatory application and discusses opportunities that could turn barriers into bridges.
Perfluorohexyloctane: More than Meets the Eye?
Alijagic A, Orešič M, Hyötyläinen T
Chem Res Toxicol · 2026 Feb · PMID 41628141 · Full text
Perfluorohexyloctane (F6H8) is a semifluorinated alkane increasingly used in medical applications. Emerging evidence, however, indicates that this compound can persist in biological systems and influence cellular process...
Perfluorohexyloctane (F6H8) is a semifluorinated alkane increasingly used in medical applications. Emerging evidence, however, indicates that this compound can persist in biological systems and influence cellular processes. These observations suggest that the exceptional stability of F6H8, while beneficial for medical performance, may also have implications for long-term biological and health outcomes.
Outpacing Emerging Drug Threats: Validation of ToxBox Kits That Automate LC-MS/MS Analyses.
Avram M, Ritter IL, Muslin O … +8 more , Parikh S, Ahmed YM, Gosselin MI, Fantegrossi WE, James LP, Endres GW, Reed JM, Moran JH
Chem Res Toxicol · 2026 Feb · PMID 41612865 · Publisher ↗
The Centers for Disease Control and Prevention (CDC) recently began addressing critical informational gaps associated with the emergence of novel psychoactive substances (NPSs) through the formation of the Overdose Data...
The Centers for Disease Control and Prevention (CDC) recently began addressing critical informational gaps associated with the emergence of novel psychoactive substances (NPSs) through the formation of the Overdose Data to Action (OD2A) biosurveillance program. This program uses public health laboratories (PHLs) to report drug trends in nonfatal and fatal overdose cases, but meeting the OD2A program's goal of reporting use trends in near real-time is a challenge for resource-limited PHLs. New technology that automates NPS testing will help PHLs meet this goal and sustain OD2A testing. This study uses commercially available test kits capable of automating clinical and forensic testing platforms to validate a single liquid chromatography tandem mass spectrometry (LC-MS/MS) analytical procedure for opioids, barbiturates, benzodiazepines, cannabinoids, stimulants, and several other drug classes. Kits incorporated Suspended-State and Just-Go technologies to stabilize NIST-traceable standards and enzymatic buffers at precise concentrations in a format that does not require sample cleanup or dilution prior to LC-MS/MS analysis. OD2A test kits were activated at 37 °C prior to the addition of 10 μL sample aliquots, and hydrolysis of conjugated urinary metabolites was complete after a 90 min incubation inside the autosampler held at 37 °C. Samples were injected directly on the column for LC-MS/MS analysis and method validation. Accuracy, precision, measurement uncertainty, calibration models, reportable range, sensitivity, specificity, carryover, interference, ion suppression/enhancement, and analyte stability met the testing requirements established for toxicology laboratories. Suitability studies using fortified human urine demonstrated that the automated LC-MS/MS method validated for OD2A biosurveillance produces highly accurate and precise results. The LC-MS/MS method was also successfully transferred and validated in an independent state public health laboratory to demonstrate how this new technology can be used to support a national biosurveillance program. This new approach will enable PHLs to provide actionable data in a timely manner.
High Risk of Drug-Drug Interactions Caused by Pexidartinib UDP-Glucuronosyltransferases Inhibition.
Wang Z, Lv X, Yin H … +3 more , Jiang L, Li W, Liu Y
Chem Res Toxicol · 2026 Feb · PMID 41575265 · Publisher ↗
Since pexidartinib was approved by the FDA for adult patients with tenosynovial giant cell tumor, increasing attention has been paid to its high frequency of adverse reactions. This study purposes to investigate the risk...
Since pexidartinib was approved by the FDA for adult patients with tenosynovial giant cell tumor, increasing attention has been paid to its high frequency of adverse reactions. This study purposes to investigate the risk potential of pexidartinib-associated drug-drug interactions (DDIs) from the perspective of UDP-glucuronosyltransferases (UGTs) inhibition. Our results demonstrated that pexidartinib was a pan-inhibitor of UGTs, and it exhibited broad inhibition against 11 human recombinant UGT isoforms at clinically achievable concentrations, with IC values ranging from 0.97 to 20.02 μM. Further inhibition kinetic analysis showed that pexidartinib competitively inhibited UGT1A1, UGT1A6, UGT1A7, and UGT1A9, while exhibiting mixed inhibition toward UGT2B15. The values for them were calculated to be 4.27 ± 0.28, 1.72 ± 0.12, 1.67 ± 0.11, 0.65 ± 0.13, and 2.37 ± 0.45 μM, respectively. The results of - extrapolation (IVIVE) indicated that coadministration of pexidartinib at a clinically approved dose (400 mg twice daily) with the drugs primarily cleared by UGT1A1, UGT1A6, UGT1A7, UGT1A9, and UGT2B15 would result in a higher risk of DDI. In summary, our results provide useful information for the mechanism underlying pexidartinib-induced hepatotoxicity and clinical safe medication of pexidartinib.
The Bladder as a Target for PCB Toxicity: Evidence from PCB Levels, Phase I Metabolite Levels, and Cytochrome P450 Expression Following Developmental Exposure to a Human-Relevant PCB Mixture in Mice.
Wang H, Schumacher EA, Spiegelhoff A … +5 more , Kennedy CL, Ridlon MM, Marek RF, Keil Stietz KP, Lehmler HJ
Chem Res Toxicol · 2026 Feb · PMID 41568709 · Full text
Lower urinary tract dysfunction is multifactorial, yet the role of environmental exposure remains poorly investigated. Developmental exposure to polychlorinated biphenyls (PCBs) has been linked to altered voiding in mice...
Lower urinary tract dysfunction is multifactorial, yet the role of environmental exposure remains poorly investigated. Developmental exposure to polychlorinated biphenyls (PCBs) has been linked to altered voiding in mice; however, the disposition of PCBs in the bladder, their bioactivation, and their effects on cytochrome P450 (CYP) expression remain unclear. We exposed mice to an environmentally relevant PCB mixture via maternal diet during gestation and lactation (vehicle, 0.1, 1, or 6 mg/kg/day). Offspring were euthanized at 6 to 7 weeks of age. PCB and hydroxylated PCB (OH-PCB) levels were quantified in the bladder, liver, blood, and urine. CYP expression was measured in the bladder and liver. PCBs and OH-PCBs accumulated in all tissues in dose- and sex-dependent manners, with higher-chlorinated congeners (e.g., PCB118, PCB138, PCB153, and PCB180) preferentially retained. Females exhibited greater hepatic accumulation, reduced urinary elimination, and distinct CYP regulation characterized by increased hepatic and decreased bladder expression. These findings, for the first time, define the signature of PCBs and OH-PCBs in the bladder and reveal a sex-specific PCB disposition and CYP responses. Our results provide new mechanistic insights into developmental PCB exposure and its potential contribution to voiding dysfunction in wildlife, domestic animals, and humans.
Hemolytik 2: An Updated Database of Hemolytic Peptides and Proteins.
Singh A, Sa KR, Rathore AS … +1 more , Raghava GPS
Chem Res Toxicol · 2026 Feb · PMID 41525503 · Publisher ↗
Hemolytik 2.0 (http://webs.iiitd.edu.in/raghava/hemolytik2/) is a comprehensive, manually curated database that provides experimentally validated information on both hemolytic and nonhemolytic peptides. Data were meticul...
Hemolytik 2.0 (http://webs.iiitd.edu.in/raghava/hemolytik2/) is a comprehensive, manually curated database that provides experimentally validated information on both hemolytic and nonhemolytic peptides. Data were meticulously extracted from peer-reviewed publications and established peptide repositories, including the Antimicrobial Peptide Database, UniProt, the Collection of Antimicrobial Peptides (CAMP-R4), and the data repository of antimicrobial peptides (DRAMP 4.0). This updated version of the original Hemolytik resource comprises 13,215 unique entries from 1645 research articles, representing approximately 7534 unique peptides. Each entry in Hemolytik 2.0 offers detailed annotations, including peptide name, amino acid sequence, biological source and origin, functional characterization, terminal modifications, stereochemistry, structural classification (linear or cyclic), and experimentally determined hemolytic activity. In addition, the database provides molecular representations of peptides in SMILES (Simplified Molecular Input Line Entry System) format, alongside predicted tertiary structures and annotated secondary structural states. Additionally, a RESTful API has been integrated into the Hemolytik 2.0 repository to enable programmatic access and automated retrieval of peptide data. Hemolytik 2.0 serves as a valuable resource for the scientific community, particularly for researchers involved in the design and development of therapeutic peptides, by facilitating the identification and optimization of peptide candidates with minimal hemolytic potential and enhanced safety profiles. In addition, Hemolytik 2.0 is also available on GitHub (https://github.com/raghavagps/Hemolytik2), where users can download the complete systematic data in different formats.
Bioaccumulation of PFOS Isomers in Transporter Proteins.
James D, Paddayuman JZ, Cristobal JR … +4 more , Loganathan N, Atilla-Gokcumen GE, Aga DS, Wilson AK
Chem Res Toxicol · 2026 Jan · PMID 41503917 · Full text
The many-decade use of perfluorooctanesulfonic acid (PFOS) in firefighting foams and other products has resulted in their accumulation in water sources and terrestrial environments. Long-term exposure of PFOS has been li...
The many-decade use of perfluorooctanesulfonic acid (PFOS) in firefighting foams and other products has resulted in their accumulation in water sources and terrestrial environments. Long-term exposure of PFOS has been linked to detrimental effects on human health. PFOS, primarily manufactured through electrochemical fluorination (ECF), yielded both linear and branched isomers. While progress has been made in understanding the health impacts of linear PFOS exposure on human health, there is far less understanding about the toxicological effects and bioaccumulative potential of their branched isomers. In this study, the bioaccumulation potential of linear PFOS and five different branched isomers in the long-chain fatty acid (LCFA) transport protein from () is investigated using molecular dynamics simulations. The bioaccumulative potential of the PFOS isomers was assessed by computing their binding strength at both the low-affinity site and the high-affinity site in comparison with natural ligands. The binding characteristics of PFOS isomers from examinations are in good agreement with cellular studies. Our study demonstrates a preferential bioaccumulation potential for certain branched isomers rather than linear PFOS. The low hydrogen bonding network of disubstituted isomers compared to monosubstituted isomers at the low-affinity site corroborates with their minimal abundance in the studies. The interactions between the PFOS isomers with residues ARG_157 and GLU_319 determine their binding potential. Additionally, the location of -CF substitutions in branched PFOS isomers plays a crucial role in governing their overall bioaccumulation potential, providing insight about the bioaccumulation potential in living organisms.
Covalently Active Metabolites of Bisphenol A Analogs by Mass Spectrometry Diagnostic Ions: Possible Mechanisms of Their Toxicity.
He Q, Hu X, Li X … +2 more , Li N, Wu JL
Chem Res Toxicol · 2026 Jan · PMID 41493763 · Full text
Bisphenol A analogs (BPs), used as BPA alternatives, have drawn great concerns due to their potential adverse effects. Studies have shown that reactive metabolites (RMs) formed in vitro and in vivo could covalently bind...
Bisphenol A analogs (BPs), used as BPA alternatives, have drawn great concerns due to their potential adverse effects. Studies have shown that reactive metabolites (RMs) formed in vitro and in vivo could covalently bind to nucleophilic macromolecules to elicit toxicity. However, the bioactivation potential of BPs and their capacity to covalently modify amino acid residues within proteins have been poorly characterized. Thus, this study systematically characterized the metabolic activation of eight BPs and their reactivity toward cysteine. Using -acetylcysteine (NAC) as a trapping agent to capture RMs, we developed a novel nontargeted fragment screening strategy for cysteine adduct identification and mechanistic exploration. Integrating calculated electron affinity results, mechanistic analyses revealed a common activation pathway across multiple BPs involving oxidation, ipso-addition, and ipso-substitution. Also, the abundances of cysteine adducts correlated with metabolic rates of individual BPs, underscoring structure-reactivity relationships. These results provided critical mechanistic insight into BPs bioactivation, implicating their potential toxicity risk and supporting environmental risk evaluation.
Differential Organ Distribution of 7-(Deoxyadenosin--yl)-aristolactam I in Mice Exposed to Aristolochic Acid I: Insights from Acute and Chronic Exposure Studies.
Kwok HC, Wang S, Ham YH … +1 more , Chan W
Chem Res Toxicol · 2026 Jan · PMID 41486970 · Publisher ↗
The distribution of 7-(deoxyadenosin--yl)-aristolactam I (ALI-dA) in mice treated with the same amount of aristolochic acid I (AA-I) at different dosage rates was investigated. The results showed a distinct organ distrib...
The distribution of 7-(deoxyadenosin--yl)-aristolactam I (ALI-dA) in mice treated with the same amount of aristolochic acid I (AA-I) at different dosage rates was investigated. The results showed a distinct organ distribution pattern of ALI-dA, with the highest adduct levels observed in the bladders of mice that received chronic doses of AA-I. In contrast, in mice that received AA-I acutely, the highest levels were found in the kidneys and were over ten times higher than those observed with chronic exposure. These results indicate that, in addition to the cumulative dose, the rate at which humans are exposed to AA-I is an under-recognized risk factor in the development of aristolochic acid nephropathy.
Impact of Arsenite on Transient and Persistent Histone H3 Modifications and Transcriptional Response.
Lumpp T, Hijazi H, Stößer S … +6 more , Tekin E, Brunner L, Fischer F, Brugière S, Pflieger D, Hartwig A
Chem Res Toxicol · 2026 Jan · PMID 41481778 · Full text
Arsenite-contaminated groundwater poses a major health concern affecting millions of people. Chronic exposure to elevated levels of inorganic arsenic is implicated in carcinogenesis, with impaired DNA repair and dysregul...
Arsenite-contaminated groundwater poses a major health concern affecting millions of people. Chronic exposure to elevated levels of inorganic arsenic is implicated in carcinogenesis, with impaired DNA repair and dysregulated DNA and histone modifications as key factors. Using human A549 lung carcinoma cells, we investigated the persistence of acute arsenite-induced cellular stress at the epigenetic and transcriptional levels after 24 h of exposure to 1-25 μM NaAsO, reflecting low to high acute exposure scenarios, followed by a 48 h arsenite-free postincubation period. The primary objective was to analyze alterations in acetylation and methylation marks on both bulk histone H3 and specific DNA repair gene loci. We conducted immunochemical and proteomic analyses to assess alterations in histone modification patterns. Transient effects were observed at both methylated and acetylated residues, with hypoacetylation specifically detected at promoters of certain DNA repair genes, including , , , and . Among all modifications analyzed, H3K18ac exhibited the most pronounced decline, suggesting its preferential sensitivity toward arsenite. H3 hypoacetylation was further observed in noncancerous human BEAS-2B lung cells, indicating that this effect is not cancer cell-specific. Mechanistically, in A549 cells, increased total HDAC or decreased HAT activity could be excluded. Instead, a persistent moderate decline in HDAC activity and a delayed, pronounced induction of HAT activity suggest targeted arsenite interactions with specific enzymes of the histone acetylation regulatory network.
Toward Specific Detection of Peroxynitrite─Intramolecular Cyclization of Boronobenzylated Pyridinium Probe in Chemical and Cellular Systems.
Grzelakowska A, Zielonka J
Chem Res Toxicol · 2026 Jan · PMID 41481264 · Full text
Detecting and quantifying peroxynitrite (ONOO) under physiological conditions is challenging due to its low steady-state levels, resulting from typically low fluxes of nitric oxide (NO) and superoxide (O), as well as its...
Detecting and quantifying peroxynitrite (ONOO) under physiological conditions is challenging due to its low steady-state levels, resulting from typically low fluxes of nitric oxide (NO) and superoxide (O), as well as its short half-life caused by rapid reactions with cellular and extracellular targets. Low-molecular-weight boronate probes that react rapidly with ONOO to form stable and characteristic products represent the most promising class of redox probes for ONOO detection and quantitative analyses in chemical and biological systems. Because boronates also respond to other nucleophilic oxidants, including hydrogen peroxide (HO), novel approaches to selectively detect ONOO are needed. Here, we report our studies on the application of boronobenzyl (Bz-BA) derivatives of the fluorescent coumarin-pyridine (CP) construct for specific detection of ONOO. We demonstrate that the probe containing a boronate moiety in the position to the fluorophore (CP-Bz--BA) reacts rapidly with ONOO and forms the corresponding cyclization product on the minor, ONOO-specific pathway. We characterized the reaction kinetics and stoichiometry of CP-Bz--BA with ONOO and identified the hydroxybenzyl derivative as the major and stable product, with cyclic and nitrated derivatives as the minor, but ONOO-specific products. Liquid chromatography-mass spectrometry analyses of cell extracts confirmed the formation of the same products in RAW 264.7 macrophages activated to produce ONOO, demonstrating the occurrence of the same chemistry and its applicability for specific detection of ONOO in biological settings. Interestingly, the CP-Bz--BA probe reacts with HO significantly faster (∼5-fold) than the previously reported aromatic boronates (e.g., coumarin-7-boronic acid, CBA), which we attribute to the presence of the positive charge of the pyridinium cation in proximity to the boronic acid moiety.
Ultrasonic Extraction-Based Analysis of Persistent Organic Pollutants in Blubber from False Killer Whales.
Eze MO, Borras E, McCartney MM … +4 more , Bergfelt DR, West KL, Hooper SE, Davis CE
Chem Res Toxicol · 2026 Jan · PMID 41474951 · Publisher ↗
In view of the toxic effects of persistent organic pollutants (POPs), fast and effective assessment of their concentrations in marine mammals is important for understanding individual and population-level health impacts....
In view of the toxic effects of persistent organic pollutants (POPs), fast and effective assessment of their concentrations in marine mammals is important for understanding individual and population-level health impacts. This study developed an ultrasonic-based method that is less time-consuming, uses minimal solvent, and thus is more sustainable than the gold standard Soxhlet method for accurate analysis of organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs), and benzene hexachlorides (BHC) in false killer whale blubber. This method was developed by comparing concentrations of POPs obtained using the traditional Soxhlet and novel ultrasonic extraction methods using blubber from false killer whales ( = 4) that were stranded in the Hawaiian Islands. The average total POPs extracted from the four killer whales and adjusted for lipid weight (lw) were 11,379.57 ± 3,303.03 ng/g lw for Soxhlet extraction and 14,310.39 ± 4,469.00 ng/g lw for the ultrasonic method, indicating a greater extraction efficiency of the ultrasonic method. The results further revealed that false killer whale FKW2013018 (∑OCs 15,447.38 ± 812.17 ng/g lw and ∑PCBs 5,205.32 ± 253.46 ng/g lw) and false killer whale FKW2016016 (∑OCs 18,164.90 ± 1,433.15 ng/g lw and ∑PCBs 4,913.32 ± 447.29 ng/g lw) accumulated organochlorines and PCBs at very high and potentially toxic levels. The low ratio of 4,4'-DDT/4,4'-DDE (0.026 ± 0.004) using both extraction methods indicated that the stranded false killer whales experienced long-term exposure to 4,4'-DDT, leading to bioaccumulation of the stable 4,4'-DDE metabolite. The levels of OCs, PCBs, and BHCs in this study were below toxic threshold levels. However, in view of the susceptibility of cetaceans with reduced lipid content to the toxic effects of POPs, cetaceans with low lipid content (as a result of starvation, fasting, or extended migration events) may be at higher risk of the negative health impacts of organic pollutants.
Chlorotyrosine and Dichlorotyrosine in Hemoglobin of Breast Cancer Patients Analyzed by Liquid Chromatography Tandem Mass Spectrometry.
Pan WR, Lee RJ, Tu CW … +1 more , Chen HC
Chem Res Toxicol · 2026 Jan · PMID 41468570 · Publisher ↗
3-Chlorotyrosine, a product of hypochlorous-acid-induced protein tyrosine chlorination in inflamed tissues, has been considered a marker of oxidative inflammation in vivo. However, it has been proposed that the dichlorin...
3-Chlorotyrosine, a product of hypochlorous-acid-induced protein tyrosine chlorination in inflamed tissues, has been considered a marker of oxidative inflammation in vivo. However, it has been proposed that the dichlorination of tyrosine might serve as a more reliable biomarker for inflammation than tyrosine monochlorination. Hemoglobin adduction plays an important role in the biomonitoring of chemical exposures in humans. An increased level of 3-chlorotyrosine in the hemoglobin of breast cancer patients has been reported as breast cancer is associated with high levels of oxidative stress. In this study, we discovered the presence of 3,5-dichlorotyrosine in tryptic peptides of human hemoglobin by high-resolution tandem mass spectrometry. The peptides containing 3,5-dichlorotyrosine, 3-chlorotyrosine, and methionine sulfoxide were quantified using nanoflow liquid chromatography tandem mass spectrometry. The results show that the extents of chlorination at α-Tyr-42 and β-Tyr-130, dichlorination at α-Tyr-24, and oxidation at α-Met-32 are significantly higher in the globin of breast cancer patients compared with those in healthy subjects. Moreover, the extents of dichlorination at α-Tyr-24 and chlorination at β-Tyr-130 are significantly higher in patients with stage III breast cancer than in healthy subjects. To our knowledge, this is the first report on the identification and quantification of 3,5-dichlorotyrosine in human hemoglobin. Our results suggest that chlorination and dichlorination of tyrosine in human hemoglobin are vital inflammatory biomarkers of breast cancer.
Leveraging Consensus Docking Approaches for Human Mitochondrial Complexes I and III.
Grillberger K, Magel V, Leist M … +1 more , Ecker GF
Chem Res Toxicol · 2026 Jan · PMID 41468401 · Full text
Although recent progress has been made, structure-based methods such as molecular docking are still underexplored in the context of toxicity prediction. These approaches offer added value, particularly in addressing chal...
Although recent progress has been made, structure-based methods such as molecular docking are still underexplored in the context of toxicity prediction. These approaches offer added value, particularly in addressing challenges such as activity cliffs─i.e., caused by stereoisomerism─that are difficult to capture by conventional Quantitative Structure-Activity Relationship (QSAR) methods. In this study, we investigated the ability of docking scoring functions and protein-ligand interaction fingerprints to rank the potential hazard of compounds targeting the human mitochondrial complexes I and III (CI, NADH:ubiquinone oxidoreductase and CIII, cytochrome bc complex). We applied an induced fit docking protocol to account for binding site flexibility and performed a set of binding energy minimizations for rescoring of representative binding modes. Both individual scoring functions and consensus scoring approaches achieved acceptable rank correlation to experimentally derived data from CIII (Spearman : 0.89 and 0.86). Moreover, consensus interaction fingerprints that combine molecular interactions from both docking outputs captured differences of inhibitor subtypes at CIII. Follow-up in vitro testing confirmed an isomerism-dependent activity cliff of E-/Z-Fenpyroximate at CI. These findings support the utility of using consensus docking and scoring as a screening-level tool for prioritizing compounds based on interpretable predicted relative binding affinities at CI and CIII.
Agricultural Copper Pesticide Exposure and Metabolic Profiles among Parkinson's Disease Cases and Community Controls in California.
Gong Y, Paul KC, Lin Y … +11 more , Jones DP, Walker DI, Del Rosario IPC, Folle AD, Yu Y, Zhang K, Cockburn M, Thompson LK, Keener AM, Bronstein J, Ritz BR
Chem Res Toxicol · 2026 Jan · PMID 41460852 · Publisher ↗
Copper-based pesticide exposures have been linked to increased Parkinson's disease (PD) risk through oxidative stress, mitochondrial dysfunction, and neuroinflammation, yet their metabolic effects in PD remain poorly und...
Copper-based pesticide exposures have been linked to increased Parkinson's disease (PD) risk through oxidative stress, mitochondrial dysfunction, and neuroinflammation, yet their metabolic effects in PD remain poorly understood. Using high-resolution metabolomics (HRM) data from 642 PD patients and 277 controls from the Parkinson's Environment and Gene (PEG) study, we evaluated alterations associated with chronic copper pesticide exposure. Composite and individual copper pesticide estimates were derived within a 500-m buffer around residential and workplace addresses over 5 years prior to the blood draw. Metabolome-wide association studies (MWAS) using partial least-squares (PLS) and empirical Bayes linear models were conducted to identify copper-associated metabolites, and pathway enrichment was performed using the Mummichog algorithm with 100 permutations to identify enriched metabolic pathways. In the primary analysis of the composite copper metric, we detected 215 copper-associated metabolite features, 88 of which were annotated, while none of them survived the FDR < 0.05 threshold. In individual-pesticide analyses, only copper sulfate (pentahydrate) yielded significant results: 57 metabolite features passed the FDR < 0.05 threshold (51 in PD patients, 4 in controls, and 2 in the full sample). The strongest metabolite association was with a phosphatidylcholine, PC(22:2(13Z,16Z)/16:1(9Z)) (β = 0.07, = 1.51 × 10). Pathway enrichment supported involvement of inflammation metabolism, lipid metabolism, amino acid metabolism, etc. These findings suggest that chronic copper pesticide exposure is linked to serum metabolic changes, particularly in inflammation-related metabolism pathways. Given the cross-sectional study design, these associations should be interpreted cautiously, as they do not establish causality.
Polystyrene Microplastics and Bisphenol A Exposure Worsen Intestinal Injury in Diabetic Mice by Disrupting Gut Microbiota and Metabolites.
Zhang Y, Nong Q, Zhang Y … +6 more , Meng F, Hao X, Tian Y, Zhang Z, Xu F, Zhang P
Chem Res Toxicol · 2026 Jan · PMID 41456157 · Publisher ↗
Environmental pollutants can induce multiorgan damage, with the digestive tract particularly susceptible. Diabetic enteropathy is a significant complication of type 2 diabetes mellitus (T2D). However, the relationship be...
Environmental pollutants can induce multiorgan damage, with the digestive tract particularly susceptible. Diabetic enteropathy is a significant complication of type 2 diabetes mellitus (T2D). However, the relationship between environmental pollutant exposure and T2D-associated intestinal injury has not been previously explored. In this study, T2D mice were subjected to polystyrene microplastics (, 100 μg/day, 3 weeks) and bisphenol A (BPA, 100 μg/kg/day, 2 weeks). Metabolomics and 16S rRNA sequencing were used to detect changes in colonic metabolites and gut microbial composition. Caco-2 cells were utilized to investigate the functions of the altered metabolites. Compared to the T2D group, mice exposed to and BPA exhibited shorter colon length and reduced levels of gut barrier proteins ZO-1 and Occludin. Metabolomics analysis revealed that primarily affected colonic long-chain fatty acids (LCFAs) and adenosine metabolism, while BPA disrupted α-ketoisovaleric acid (KIVA) and pyruvic acid (PyrA) homeostasis. Moreover, exposure altered the abundance of and , while BPA primarily affected and . In vitro experiments showed that palmitoleic acid (C16:1), γ-linolenic acid (C18:3), adenosine (Ado), and KIVA promoted the expression of ZO-1 in Caco-2 cells. Our findings provide valuable insights into the impact of environmental pollutants on intestinal injury in T2D, underscoring the importance of environmental contaminant management, particularly in susceptible populations.
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