Journal of Toxicology and Environmental Health-Part A-Current Issues最新文献

Workers regularly using vibrating hand tools may develop a disorder referred to as hand-arm vibration syndrome (HAVS). HAVS is characterized by cold-induced vasospasms in the hands and fingers that result in blanching of the skin, loss of sensory function, pain, and reductions in manual dexterity. Exposure to vibration induces some of these symptoms. However, the soft tissues of the hands and fingers of workers are compressed as a result of the force generated when a worker grips a tool. The compression of these soft tissues might also contribute to the development of HAVS. The goal of this study was to use an established rat tail model to determine the mechanisms by which compression of the tail tissues affects (1) the ventral tail artery (VTA) and ventral tail nerves (VTN), (2) nerves and sensory receptors in the skin, (3) dorsal root ganglia (DRG), and (4) spinal cord. Tissue compression resulted in the following changes (1) circulating pituitary and steroid hormone concentrations, (2) expression of factors that modulate vascular function in the skin and tail artery, and (3) factors associated with nerve damage, DRG, and spinal cord. Some of these observed effects differed from those previously noted with vibration exposure. Based upon these findings, the effects of applied force and vibration are different. Studies examining the combination of these factors might provide data that may potentially be used to improve risk assessment and support revision of standards.

During the spring of 2024, 33 members of a group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents were seen at the Baltimore VA Medical Center for surveillance related to their combat exposure. The cohort was assessed with a protocol which includes exposure monitoring for total and isotopic uranium (U) concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism and bone mineral density (BMD). An audiometry examination of the cohort was added to assess for acoustic trauma and toxic metal effects in this surveillance episode marking over 30 years since this exposure event. Elevated urine U concentrations were detected in cohort members with retained DU shrapnel fragments. In addition, a measure of bone resorption, N-telopeptide, determined in urine, exhibited a significant increase in the high DU sub-group. In addition, and similar to our previous surveillance report, a significant decrease was found in bone mass in the high DU sub-group compared to the low DU sub-group. It has been 30 years since the first surveillance visit occurred. An aging cohort of military veterans continues to demonstrate few U-related adverse health effects in known target organs attributed to U toxicity exposure. The new finding of impaired BMD in older cohort members has now been detected in three consecutive surveillance visits. This is a biologically plausible outcome related to the diminished bone mass in those with an elevated DU burden in combination with advancing age. The accumulating U burden derived from fragment absorption over time and the effect of aging on bone mineral loss recommends that our surveillance efforts need to continue. Our findings enable early detection of bone effects and other signs of target organ insult, which may occur when tissue injury thresholds are reached in the future and thus, permitting indicated medical management.

Di-n-butyl phthalate (DBP) is a phthalate-based material used as a plasticizer to soften polyvinyl chloride, and classified as an endocrine disruptor with antiandrogen effects. Exposure to DBP induces oxidative stress in rat testes, resulting in testicular toxicity. Black ginseng (BG) exhibits a higher antioxidant activity than white or red ginseng following repeated heat treatment and processing. This study aimed to investigate whether the antioxidant activity of BG might protect against DBP-induced testicular toxicity in juvenile Sprague-Dawley rats. A significant decrease in testicular weight was observed in most groups treated with DBP alone or in combination with BG. However, a significant testicular weight increase was detected after exposure to BG (10 ml/kg) + DBP (500 mg/kg). The epididymal weight was significantly reduced with associated histological changes including irregular arrangement, atrophy of seminiferous tubules and Sertoli cells, and Leydig cell damage following exposure to DBP alone as well as BG (2.5 ml/kg) + DBP (500 mg/kg). However, no marked changes were observed in the shape of seminiferous tubules in control and BG + DBP groups. A significant decrease in serum testosterone levels was found after exposure to DBP, but no marked alterations in the BG + DBP groups. Protein expression levels of nuclear factor erythroid-derived 2-related factor (Nrf2), NAD(P)H dehydrogenase 1 (NQO1), and, heme oxygenase-1; (HO-1) were significantly higher following DBP treatment, but lowered in the BG + DBP groups. Evidence indicates that BG exerts a protective effect against DBP-induced testicular toxicity in rats.

The mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT) is a biocide widely used as a preservative in various commercial products. This biocide has also been used as an active ingredient in humidifier disinfectants in South Korea, resulting in serious health effects among users. Recent evidence suggests that the underlying mechanism of CMIT/MIT-initiated toxicity might be associated with defects in mitochondrial functions. The aim of this study was to utilize the C2C12 skeletal muscle model to investigate the effects of CMIT/MIT on mitochondrial function and relevant molecular pathways associated with skeletal muscle dysfunction. Data demonstrated that exposure to CMIT/MIT during myogenic differentiation induced significant mitochondrial excess production of reactive oxygen species (ROS) and a decrease in intracellular ATP levels. Notably, CMIT/MIT significantly inhibited mitochondrial oxidative phosphorylation (Oxphos) and reduced mitochondrial mass at a lower concentration than the biocide amount, which diminished the viability of myotubes. CMIT/MIT induced activation of autophagy flux and decreased protein expression levels of myosin heavy chain (MHC). Taken together, CMIT/MIT exposure produced damage in C2C12 myotubes by impairing mitochondrial bioenergetics and activating autophagy. Our findings contribute to an increased understanding of the underlying mechanisms associated with CMIT/MIT-induced adverse skeletal muscle health effects.

Polyhexamethyleneguanidine phosphate (PHMG), a widely used antimicrobial agent, has been implicated in humidifier disinfectant-associated lung injuries (HDLI). PHMG exposure suppressed interferon regulatory factor 3 (IRF3) activation and interferon-β (IFN-β) expression induced by a cGAS agonist or a STING agonist in human monocytic cells (THP-1), which are known to transition to alveolar macrophages during pulmonary fibrosis development. However, the mechanisms underlying PHMG-induced pulmonary toxicity in lung remain unclear. Thus, it was of interest to investigate the effects of PHMG on the innate immune system in male C57BL/6 mouse, focusing on the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and potential role in pulmonary fibrosis. Intratracheal administration of PHMG (1 or 2 mg/kg) in mice resulted in lung fibrosis, as evidenced by H&E staining with Szapiel scoring, Masson's trichrome staining with Ashcroft scoring, and increased mRNA levels of TGF-β and collagen type I. Interestingly, lower dose of PHMG enhanced IFN-β production in the lungs, whereas higher dose decreased IFN-β levels, indicating a biphasic effect that initially promotes inflammation but ultimately impairs host defense mechanisms, leading to pulmonary fibrosis. Our findings demonstrate the critical role of the cGAS/STING pathway in PHMG-induced mouse lung injury and suggest that targeting this pathway might serve as a potential therapeutic strategy for treating pulmonary fibrosis.

The advent of nanotechnology has significantly spurred the utilization of nanoparticles (NPs) across diverse sectors encompassing industry, agriculture, engineering, cosmetics, and medicine. Metallic oxides including zinc oxide (ZnO), copper oxide (CuO), manganese oxide (Mn₂O₃), and aluminum oxide (Al₂O₃), in their NP forms, have become prevalent in cosmetics and various dermal products. Despite the expanding consideration of these compounds for dermal applications, their potential for initiating skin sensitization (SS) has not been comprehensively examined. An in vivo assay, local lymph node assay: 5-bromo-2-deoxyuridine-flow cytometry method (LLNA: BrdU-FCM) recognized as an alternative testing method for screening SS potential was used to address these issues. Following the OECD TG 442B guidelines, NPs suspensions smaller than 50 nm size were prepared for ZnO and Al₂O₃ at concentrations of 10, 25, and 50%, and Mn₂O₃ and CuO at concentrations of 5, 10, and 25%, and applied to the dorsum of each ear of female BALB/c mice on a daily basis for 3 consecutive days. Regarding the prediction of test substance to skin sensitizer if sensitization index (SI)≥2.7, all 4 NPs were classified as non-sensitizing. The SI values were below 2.06, 1.33, 1.42, and 0.99 for ZnO, Al₂O₃, Mn₂O₃, and CuO, respectively, at all test concentrations. Although data presented were negative with respect to adverse SS potential for these 4 NPs, further confirmatory tests addressing other key events associated with SS adverse outcome pathway need to be carried out to arrive at an acceptable conclusion on the skin safety for both cosmetic and dermal applications.

Dry eye disease (DED) is an ophthalmic disease associated with poor quality and quantity of tears, and the number of patients is steadily increasing. The aim of this study was to determine plasma and urine metabolites obtained from DED scopolamine animal model where dry eye conditions (DRY) are induced. It was also of interest to examine whether DED (scopolamine) rat model was exacerbated by treatment with benzalkonium chloride (BAC). Subsequently, plasma and urine metabolites were analyzed using liquid chromatography (LC) and gas chromatography (GC)-mass spectrometry (MS), respectively. Data demonstrated that DED indicators such as tear volume, tear breakup time (TBUT), and corneal damage in the DED groups (DRY and BAC group) differed from those of control (CON). Similar results were noted in inflammatory factors such as interleukin (IL-1β), IL-6, and tumor necrosis factor (TNF)-α. In the partial least squares-discriminant analysis (PLS-DA) score plots, the three groups were distinctly separated from each other. In addition, the related metabolites were also associated with these distinct separations as evidenced by 9 and 14 in plasma and urine, respectively. Almost all of the selected metabolites were decreased in the DRY group compared to CON, and the BAC group was lower than the DRY. In plasma and urine, lysophosphatidylcholine/lysophosphatidylethanolamine, organic acids, amino acids, and sugars varied between three groups, and these metabolites were related to inflammation and oxidative stress. Data suggest that treatment with scopolamine with/without BAC-induced DED and affected the level of systemic metabolites involved in inflammation and oxidative stress.

Inflammatory bowel disease (IBD) is a complex gastrointestinal disorder attributed to genetic and environmental factors. Microcystin-leucine-arginine (MC-LR) is an environmental toxin that accumulates in the gut and produces intestinal damage. The aim of this study was to investigate the effects of exposure to MC-LR on development and progression of IBD as well examine the underlying mechanisms of microcystin-initiated tissue damage. Male C57BL/6 mice were treated with either MC-LR alone or concurrently with dextran-sulfate sodium (DSS). Mice were divided into 4 groups (1): PBS gavage (control, CT) (2); 200 μg/kg MC-LR gavage (MC-LR) (3); 3% DSS Drinking Water (DSS); and (4) 3% DSS Drinking Water + 200 μg/kg MC-LR gavage (DSS + MC-LR). The mice in each experimental group exhibited reduced body weight, shortened colon length, increased disease activity index (DAI) score, a disrupted intestinal barrier, and elevated levels of proinflammatory cytokines compared to control. Compared to the group treated with MC-LR alone, colitis symptoms were exacerbated following combined exposure to both DSS and MC-LR. Subsequent experiments confirmed that MC-LR or DSS increased protein phosphorylation levels of Janus Kinase1 (JAK1) and Signal Transducer and Activator of Transcription3 (STAT3). Compared to group treated with MC-LR alone, the combined treatment of DSS and MC-LR also significantly upregulated the expression of related proteins. In conclusion, our study indicates that MC-LR-induced colitis involves activation of JAK1/STAT3 signaling pathway and that MC-LR exacerbates DSS-induced colitis through the same pathway.

Accidental crude oil spills to the marine environment cause dispersion of oil into the water column through the actions of breaking waves, a process that can be facilitated using chemical dispersants. Oil dispersions contain dispersed micron-sized oil droplets and dissolved oil components, and the toxicity of oil dispersions has been assumed to be associated primarily with the latter. However, most hydrophobic, bioaccumulative and toxic crude oil components are retained within the droplets which may interact with marine filter-feeders. We here summarize the findings of 15 years of research using a unique methodology to generate controlled concentrations and droplet size distributions of dispersed crude oil to study effects on the filter-feeding cold-water copepod Calanus finmarchicus. We focus primarily on the contribution of chemical dispersants and micron-sized oil droplets to uptake and toxicity of oil compounds. Oil dispersion exposures cause PAH uptake and oil droplet accumulation on copepod body surfaces and inside their gastrointestinal tract, and exposures to high exposure (mg/L range) reduce feeding activity, causes reproductive impairments and mortality. These effects were slightly higher in the presence of chemical dispersants, possibly due to higher filtration of chemically dispersed droplets. For C. finmarchicus, dispersions containing oil droplets caused more severe toxic effects than filtered dispersions, thus, oil droplets contribute to the observed toxicity. The methodology for generating crude oil dispersion is a valuable tool to isolate impacts of crude oil microdroplets and can facilitate future research on oil dispersion toxicity and produce data to improve oil spill models.

The demand for mineral resources is increasing mining activities worldwide. In Norway, marine tailing disposal (MTD) is practiced, introducing mineral particles into fjord ecosystems. We investigated the effects of two concentrations (high and low) of fine tailings from a CaCO₃ processing plant on early life stages of the marine copepod Calanus finmarchicus. Results show that the exposure did not significantly impact hatching success or development in non- and early feeding life stages. However, feeding stage nauplii ingested tailings, which caused a significantly slower development in later nauplii stages in high exposure groups, with most individuals being two stages behind the control group. Further, high mortality occurred in late nauplii and early copepodite stages in low exposure groups, which could be caused by insufficient energy accumulation and depleted energy reserves during development. Individuals exposed to high exposure concentrations seemed to survive by arresting development and potentially by reduced activity, thereby conserving energy reserves. In nature, slower development could affect lipid storage buildup and reproduction.