Archives of Toxicology最新文献

Ocular exposure to sulfur mustard (SM), infamously called “King of Battle Gases”, may occur during warfare, terrorist activities, or accidentally from improperly discarded munitions/stockpiles. Eyes, particularly corneas, are exceptionally vulnerable to SM toxicity. Notably, SM is a potent genotoxicant that causes damage to proteins, lipids, and nucleic acids. Currently, no approved therapeutics are available for ocular SM injuries. We developed a dexamethasone (DEX; 0.1%) treatment plan (application initiation 2 h post-exposure and every 8 h thereafter for 28 days) that effectively countered mustard vesicant-induced corneal injuries. However, the mechanistic aspects of SM toxicity and DEX efficacy remain elusive. Thus, rRNA-depletion RNA sequencing was performed on day 14 and day 28 post-SM exposure (neat) to assess the progression of SM toxicity and DEX efficacy at the transcriptome level in corneas (in vivo rabbit studies) from control, SM-exposed, and DEX-treated tissues. Transcripts significantly differentially expressed between all three groups (omnibus FDR < 0.01) were further analyzed based on pairwise differences between treatment groups. Further, network analyses and functional enrichment studies were performed to decipher SM toxicity and DEX efficacy-associated effects as a function of time. Twenty-day treatment was found to be more effective than 4-day DEX treatment. Main mechanisms associated with DEX efficacy included NFκB and TGFβ signaling. The most prominent functional aspects associated with SM toxicity and DEX efficacy were preservation of the corneal structural integrity via regulating collagen networks and angiogenesis. These novel outcomes provide in-depth mechanistic insights into DEX efficacy for treating SM-induced corneal injuries.

4-Hydroxyphenylpyruvate dioxygenase inhibitors (HPPDi) are mainly used as herbicides and for therapeutic use in genetic diseases of tyrosine catabolism. Their primary mechanism of action is the inhibition of the second enzyme of tyrosine catabolism, leading to an accumulation of this amino acid in blood and tissues. In this work, rats were administered diets with 1 ppm, 2 ppm, and 10 ppm of HPPD-inhibitor BCS-CR75391 for up to 28 days, and tyrosine levels were measured in blood and in selected organs using mass spectrometry combined with gas or liquid chromatography and analyzed spatially using mass spectrometry imaging (MSI). The highest tyrosine accumulation was recorded in the pancreas, followed by the eyes and the thyroid gland. Metabolomic profiling showed that other amino acids and metabolites of the citric acid cycle were influenced by the treatment. A metabolic adaptation was observed in the liver and kidney 28 days after the treatment, but not in other tissues analyzed. MSI of the thyroid gland seems to reveal an uneven accumulation of tyrosine in the tissue of rats following treatment with BCS-CR75391. Most interestingly, a significant accumulation of iodide was detected in the thyroid gland of all rats treated with the 4-hydroxyphenylpyruvate dioxygenase inhibitor. In addition, induced high tyrosine levels by a tyrosine-rich diet also provoke the accumulation of iodide in the thyroid gland. While the toxicological impact of these results needs to be further investigated, these results support the use of MSI as an innovative and powerful tool to support toxicological assessment.

Cytotoxin (CTX) is one of the major cobra venom components that contributes to dermonecrosis due to its cytotoxicity. However, current antibody-based antivenoms exert limited neutralisation effects against CTX-induced dermonecrosis. This study focused on discovering aptamer-based antivenom that specifically targets CTX, using repetitive centrifugation-based Systematic Evolution of Ligands by EXponential enrichment (SELEX) selection approach and Illumina amplicon next-generation sequencing. A total of 12 repetitive centrifugation-based selection rounds including a negative selection between rounds 7 and 8 were performed. This was followed by amplicon next-generation sequencing and sequencing bioinformatics workflow to analyse the abundance and persistence of the CTX-binding candidates. Sequences with log₁₀ read counts of 2–3 with a round representation of 3–4 were selected as the final candidates. A linear and single-stranded DNA, 40T, was discovered and it exhibited high binding affinity and specificity to CTX with dissociation constant (K_D) of 0.33–0.41 µM, as demonstrated by direct and competitive enzyme-linked aptamer assay (ELAA). 40T acquired a ‘sandwich’ configuration binding to CTX at the functional epitopes. It exhibited neutralisation potency against the CTX-induced cytotoxicity with EC₅₀ of 0.47 µM. To mimic the real envenomation situation, venoms from Naja sputatrix, Naja siamensis, and Naja sumatrana were used to induce experimentally envenomed model for treatment with 40T. 40T demonstrated notable cell viability-restoring effects against these venoms at low micromolar ratios. These findings suggested a modified selection and sequencing workflow to discover the potential of 40T as aptamer-based antivenom to mitigate venom-induced dermonecrosis.

Ring-substituted synthetic cathinones represent a major subgroup within new psychoactive substances. This study investigated the in vitro toxicokinetics of the three 4-methoxy-substituted representatives 4MeO-NE-BP (4’-methoxy-N-ethylbutyrophenone), 4MeO-αP-BP (4’-methoxy-α-pyrrolidinobutyrophenone), and 4MeO-αP-VP (4’-methoxy-α-pyrrolidinovalerophenone) and the three related novel 4-methylthio analogs 4MeS-NE-BP (4’-methylthio-N-ethylbutyrophenone), 4MeS-αP-BP (4’-methylthio-α-pyrrolidinobutyrophenone), and 4MeS-αMor-PrP (4’-methylthio-2-morpholinopropiophenone). This included plasma protein binding (PPB), phase I and phase II metabolism in pooled human liver S9 fraction (pHLS9) and HepaRG cells, and monooxygenases activity. Methoxycathinones exhibited lower PPB (~ 40–60%) compared to methylthiocathinones (~ 85%). Predominant phase I metabolic reactions included O-/S-demethylation and hydroxylation, with additional transformations such as N-dealkylation, N-oxidation, and oxo reduction. Phase II conjugation reactions, such as glucuronidation and sulfation, were observed post-demethylation. Overall, 42 and 45 metabolites were identified in pHLS9 and HepaRG systems, respectively, with metabolite number increasing alongside alkyl chain length and heterocyclic substitution. All compounds were substrates for multiple monooxygenases, suggesting a low risk for drug–drug interactions. Based on metabolic stability and abundance, parent compounds and O-/S-desmethyl and hydroxylated metabolites might be proposed as urinary screening targets in clinical and forensic toxicology, as well as doping control settings.

Recent investigations into the lipid constituents of snake venoms have yielded intriguing findings. Bothrops atrox and Crotalus durissus ruruima are the primary species responsible for snakebite envenomation in the Brazilian Amazon. However, the lipid compounds present in their venoms remain unknown. To address this gap, a lipidomic approach based on LC–HRMS (Liquid Chromatography–High-Resolution Mass Spectrometry) was employed to profile the lipid classes, subclasses, and species in the venoms of B. atrox and C. d. ruruima (yellow and white variations). The venom of B. atrox and the yellow variant of C. d. ruruima showed comparable profiles, with higher proportions of glycerolipids (55% and 46%, respectively) and glycerophospholipids (31% and 37%, respectively). In contrast, the white venom of C. d. ruruima showed a higher sphingolipid content (51%). Lipidomic analysis revealed multi-lipid species, with a high abundance of lipids from the subclasses sphingomyelin, phosphatidylcholine, monoalkylglycerol, and triacylglycerol, as well as monoacylglycerol, cardiolipins, glycerophosphoinositol, N-acylphosphatidylethanolamine, and cholesteryl esters. The lipids annotated are known to play diverse biological roles, particularly in cellular structure and signaling. This study is the first to characterize the lipid components in the venom of these snake species, contributing to a deeper understanding of their chemical composition and opening new avenues for investigating the roles of these compounds in snake venom.

Halogenated organic contaminants (HOCs) pose significant ecological risks to mangrove spiders through bioaccumulation via food webs and maternal transfer to spiderlings. However, it remains unclear which specific HOCs pose the most critical intergenerational threats to spider populations. A study of 107 HOCs in spiders (Nephila pilipes) and their prey within South China mangroves revealed that accumulation varied by habitat (Shenzhen > Zhuhai) and life stage (reduced levels in gravid cephalothoraxes). Bio-magnification factors (BMF) exceeded unity for several HOCs, particularly short- and medium-chain chlorinated paraffins (SCCPs/MCCPs; ~ 2.7). Maternal transfer ratios (MTR) ranged from 0.43 to 0.94, peaked for dichlorodiphenyltrichloroethanes (DDTs, 0.74) and exhibited parabolic trends with carbon chain length (peak at C14) and chlorination degree (peak at Cl8). Although alternative halogenated flame retardants (AHFRs) constituted only 0.72% of total HOCs, they displayed the highest hazard quotients (HQ = 7.53) and the maternal transfer toxicity indices (MTTI = 5.35; MTTI/HQ ratio = 0.70), indicating substantial intergenerational risks. The increasing prevalence of AHFRs among regional fauna, combined with their metabolic persistence, highlights an urgent need to incorporate these compounds into environmental monitoring and regulatory frameworks. The newly proposed MTTI framework provides a quantitative basis for prioritizing both legacy and emerging HOCs, thereby guiding congener-specific eco-toxicological research and targeted management strategies aimed at preserving coastal predator–prey dynamics under escalating chemical stress.

The venom of Bothrops bilineatus, an Amazonian arboreal viper, induces neurotoxicity in mammalian nerve-muscle preparations that is characterized by initial neuromuscular facilitation followed by irreversible blockade. Up until now, the toxins responsible for the neuromuscular excitatory action of this venom have remained unidentified. In this study, we characterized two presynaptically active peptides from B. bilineatus venom using mass spectrometry and electrophysiological analysis at the neuromuscular junction. Fractionation by size-exclusion chromatography yielded eight fractions, with fraction P8 (15 μg/ml) inducing an increase in the twitch amplitude recorded in the mouse phrenic nerve-diaphragm (PND) preparations. Mass spectrometry identified two tripeptides, P8-1 (pEKW) and P8-2 (pENW), in this fraction. Peptide P8-1 was prominently involved in the neuromuscular facilitation and increased the frequency of miniature end-plate potentials (MEPPs) in a manner comparable to the whole fraction (P8). This study provides the first identification of bioactive tripeptides with presynaptic neuromodulatory effects in a Viperidae venom. These findings enhance our understanding of snake venom neurotoxicity and support the potential use of venom-derived peptides as tools for studying synaptic physiology and as templates for novel neuroactive therapeutics.

The cytosolic DNA-sensing cGAS-STING pathway and autophagy represent two evolutionarily conserved systems critical for innate immunity and cellular homeostasis. The cGAS-STING pathway detects mislocalized DNA, triggering inflammation via interferon and cytokine production. Conversely, autophagy maintains equilibrium by degrading damaged organelles and pathogens. Crucially, these systems engage in reciprocal regulation: autophagy constrains cGAS-STING hyperactivity through lysosomal degradation of immunostimulatory DNA and STING itself, while cGAS-STING signaling induces autophagy via TBK1-mediated phosphorylation of autophagy adaptors to mitigate self-damage. Dysregulation of this interplay drives pathology. For instance, defective autophagy in systemic lupus erythematosus permits mitochondrial DNA accumulation and cGAS-driven interferonopathy, whereas persistent STING activation in cancers suppresses autophagic tumor surveillance. This review aims to dissect the molecular mechanisms underpinning their crosstalk, delineate its disruption in autoimmune, neurodegenerative, and oncological diseases, and critically evaluate emerging therapies designed to pharmacologically rebalance this axis. These include combining cGAS-STING inhibitors with autophagy enhancers to suppress inflammation in interferonopathies, and pairing STING agonists with autophagy inducers to potentiate antitumor immunity.By synthesizing preclinical and clinical advances, we establish a framework for developing context-specific therapeutics that exploit the cGAS-STING-autophagy circuit—translating mechanistic insights into precision treatments for immune dysregulation disorders.

The lungs are the primary site of exposure to environmental stressors, making them particularly vulnerable to the effects of inhaled nanoplastic particles. Owing to their nanoscale size, nanoplastics penetrate deeper into the respiratory tract than microplastics do and are capable of interacting directly with alveolar cells. This review focuses on the impact of inhaling nanoplastic particles on mitochondrial function in lung tissue, particularly the activation of mitochondrial stress response pathways. Mitochondria, as central regulators of cellular energy and stress responses, exhibit heightened sensitivity to environmental stress. Many studies have shown that nanoplastic exposure disrupts mitochondrial functions, reduces the membrane potential, and induces oxidative stress, possibly causing inflammation and apoptosis. This review underscores the need for advanced research to understand the systemic effects of nanoplastics and their compounded toxicity when combined with other environmental pollutants. Studying the adaptive processes of mitochondria exposed to the stress of inhaled nanoplastics is particularly important because mitochondria are essential for life-supporting functions and cell fate decisions. Given that mitochondria are key cellular targets, studying their behavior may prove useful in finding strategies to reduce the health risks posed by nanoplastic inhalation.