Archives of Toxicology最新文献

Given the ubiquitous presence of plastic products in daily life, human exposure to nanoplastics (NPs) is inevitable. Previous studies have suggested that exposure to polystyrene nanoplastics (PSNPs) may contribute to reproductive disorders; however, the underlying mechanism remains elusive. The goal of this study was to investigate the impact of PSNPs on KGN human ovarian granulosa cells. KGN cells were exposed to varying concentrations of PSNPs (0-400 μg/mL) for 48 h; alterations in cell survival and morphology were assessed to elucidate potential toxic effects. PSNPs were shown to enter KGN cells. Exposure to PSNPs did not induce significant changes in cytotoxicity, Calcein intensity, or active mitochondria levels in KGN cells. However, PSNP exposure did induce a dose-dependent increase in cytoplasmic vacuoles and an increase in total lysosome area and in the numbers of lipid droplets in KGN cells. Our findings provide compelling evidence that PSNPs can penetrate cell cytoplasm and induce toxicity, resulting in an elevation in the numbers of lysosomes and lipid droplets. This may represent one mechanism by which PSNPs exert damage on the reproductive system.

Aflatoxin B1 (AFB₁) taints feeds stuffs, endangering livestock's health and resulting in the liver and breast damage. At the same time, while breastfeeding, AFB₁ crosses the mammary glands and enters the milk, harming the offspring. This study investigated the liver damaging effects of maternal AFB₁ exposure during pregnancy and lactation in offspring mice. The livers of 8-day-old offspring mice were obtained from female mice who were administered AFB₁ (2 mg/kg) 1 week prior to and 1 week following birth. The results showed that AFB₁ increased the levels of malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), pro-inflammatory-related proteins (iNOS, COX-2, IL-6), and apoptosis-related proteins (Caspase-3, Caspase-9, Bax) by AFB₁-induced in liver of offspring mice. Furthermore, the use of F40/80, HE, and TUNEL staining further demonstrated the existence of inflammation and apoptosis in the liver. Intriguingly, in the liver of offspring mice, AFB₁ increased antioxidant protein and inhibit ferroptosis-related protein activity (FTH, GPX4), mitochondrial function-associated proteins (UQCRC2, COX IV, Cyt C), lipid metabolism-associated proteins (HMGCR, SPEBE1, FAS), and autophagy-related proteins (Atg7, Beclin-1, LC3I/II) in the liver of mice. In conclusion, AFB₁ enters the liver of offspring mice through milk, which in turn causes liver injury. This outcome explains how AFB₁ exposure affects female animals and their progeny and lays the strategy for livestock prevention.

About one-fifth of people in industrialised countries are tattooed, potentially putting them at risk of exposure to possible carcinogenic or otherwise harmful substances. This study aims to determine the exposure to soluble tattoo ink ingredients and their excretion within 24 h after tattooing. In this clinical study, 24 subjects were tattooed with black or red tattoo ink to which the 3 tracer substances, potassium iodide, 4-aminobenzoic acid (PABA) and 2-phenoxyethanol (PEtOH), had been added to mimic known substances found in tattoo inks. Tracers and their metabolites were quantified in blood, urine, ink and consumables pre- and post-tattooing. Tattooed skin area was determined using picture analysis. PABA metabolism upon tattooing was compared to peroral administration. Skin fibroblasts and macrophages were tested in vitro for their ability to metabolise PABA. All tracers or their metabolites were identified in urine; iodide and the PABA metabolite 4-acetamidobenzoic acid (ACD) were identified in plasma. The worst-case scenario for systemic ink exposure was estimated to be 0.31 g ink per tattoo session (75th percentile). Peroral administration resulted in lower levels of ACD than tattooing. Fibroblasts and macrophages were capable of converting PABA into ACD. Our results are the first human in vivo data on soluble tattoo ink ingredients and suggest that the overall exposure might be lower than the estimates previously used for regulatory purposes. In addition, the first-pass effect by skin metabolism leads to an altered metabolite profile compared to oral exposure. Skin metabolism might also contribute to detoxification of certain carcinogenic substances through N-acetylation.

Chlorpyrifos (CPF) is an organophosphorus pesticide of concern because many in vivo animal studies have demonstrated developmental toxicity exerted by this substance; however, despite its widespread use, evidence from epidemiological studies is still limited. In this study, we have collected all the information generated in the twenty-first century on the developmental toxicity of CPF using new approach methodologies. We have critically evaluated and integrated information coming from 70 papers considering human, rodent, avian and fish models. The comparison of the collected evidence with available adverse outcome pathways allows us to conclude that adverse outcomes observed in animals, such as memory and learning impairments as well as reduction in cognitive function, could involve several mechanisms of action including inhibition of acetylcholinesterase, overactivation of glutamate receptors and activation of mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, followed by both disruption of neurotransmitter release and increase in oxidative stress and apoptosis.

Hexabromocyclododecane (HBCD) is a brominated flame retardant, that is added, but not chemically bonded, to consumer products. HBCD is sold as a commercial-grade HBCD mixture containing three major stereoisomers: alpha (α), beta (β), and gamma (γ), with relative amounts of 12% for α-HBCD, 6% for β-HBCD, and 82% for γ-HBCD. HBCDs are widely measured in the environment and in biological matrices. The toxicological effects of its exposure in humans are not clearly understood. A recent reassessment pointed out potential thyroid disruption as a primary effect. This current work aims to update a physiologically based pharmacokinetic (PBPK) model for γ-HBCD in C57BL/6 mice and incorporate equations and codes for α-HBCD and β-HBCD isomers and simulate them as a mixture. Physiological parameters were taken from the literature, calculated based on the log K_ow or optimized with the dataset. The elimination of HBCDs in urine and feces was optimized to reflect the percent dose excreted, as published in the literature. Compared with data from the literature for α-HBCD, β-HBCD, and γ-HBCD in multiple tissues, the model simulations accurately described the pharmacokinetics of HBCDs in the mouse. The utility of the model was demonstrated by predicting blood concentrations from three studies in adult mice evaluating dopaminergic changes in the brain. Although this PBPK model for the mixture explicitly describes α-HBCD, β-HBCD, and γ-HBCD as individual exposures, but also as a mixture, more experimental data with commercial HBCD mixtures is still needed to improve the model.

Given the lack of accurate diagnostic methods of acetaminophen (APAP)-induced acute liver failure (ALF), the search for new biomarkers for its diagnosis is an urgent need. The aim of this study was to evaluate the role of bone morphogenetic protein 6 (BMP6) in APAP-induced ALF progression and its potential value as a biomarker of ALF. Hepatic and circulating BMP6 expression was assessed in APAP-treated mice and in serum samples from patients with APAP overdose. In addition, BMP6 expression and release was evaluated in hepatocytes after APAP exposure. BMP6 gene was silenced in Huh7 cells prior to APAP treatment and the culture medium (CM) was added to THP1 cells to evaluate the paracrine effects of hepatocyte BMP6 on APAP toxicity. Hepatic and serum BMP6 levels were increased in mice after APAP-induced ALF. In addition, a positive correlation was observed between circulating BMP6 and ALT activity in patients exposed to APAP overdose. Moreover, hepatocytes expressed and released BMP6 to the CM after APAP treatment. Indeed, the CM from APAP-treated Huh7 cells upregulated M1 and M2 markers in THP1 monocytes. The CM from BMP6-silenced Huh7, which was depleted of BMP6, reduced the expression of M2 markers in THP1 cells. In fact, expression of M2 markers was increased in THP1 cells exposed to BMP6. This study reveals that hepatic BMP6 expression is increased in APAP-induced acute liver injury, positioning it as a potential new biomarker of liver damage severity. Moreover, our data indicate that BMP6 might play a role in the hepatocyte-macrophage crosstalk during APAP-induced hepatotoxicity.

Formaldehyde (FA) is a ubiquitous indoor air pollutant emitted from construction, consumer, and combustion-related products, and ozone-initiated reactions with reactive organic volatiles. The derivation of an indoor air quality guideline for FA by World Health Organization in 2010 did not find convincing evidence for bronchoconstriction-related reactions as detrimental lung function. Causal relationship between FA and asthma has since been advocated in meta-analyses of selected observational studies. In this review, findings from controlled human and animal exposure studies of the airways, data of FA retention in the respiratory tract, and observational studies of reported asthma applied in meta-analyses are analyzed together for coherence of direct association between FA and asthma. New information from both human and animal exposure studies are evaluated together with existing literature and assessed across findings from observational studies and associated meta-analyses thereof. Retention of FA in the upper airways is > 90% in agreement with mice exposure studies that only extreme FA concentrations can surpass trachea, travel to the lower airways, and cause mild bronchoconstriction. However, taken together, detrimental lung function effects in controlled human exposure studies have not been observed, even at FA concentrations up 4 ppm (5 mg/m³), and in agreement with controlled mice exposure studies. Typical indoor FA concentrations in public buildings and homes are far below a threshold for sensory irritation in the upper airways, based on controlled human exposure studies, to induce sensory-irritative sensitization nor inflammatory epithelial damage in the airways. Analysis of the observational heterogeneous studies applied in the meta-analyses suffers from several concomitant multifactorial co-exposures, which invalidates a direct association with asthma, thus the outcome of meta-analyses. The evidence of a direct causal relationship between FA and asthma is insufficient from an experimental viewpoint that includes retention data in the upper airways and controlled animal and human exposure studies. Taken together, a coherence of controlled experimental findings with individual observational studies and associated meta-analyses, which suffer from caveats, is absent. Further, lack of identified evidence of FA-IgE sensitization in both experimental studies and observational studies agrees with indoor FA concentrations far below threshold for sensory irritation. The assessment of experimental data with uncontrolled observational studies in meta-analyses is incompatible with a direct causal relationship between FA and asthma or exacerbation thereof due to lack of coherence and plausibility.

Exposomics is a field that studies environmental exposures and their impact on human health. The MRM-IDA-EPI method, which combines targeted and untargeted mass spectrometry methods, is useful for identifying and quantifying biomarkers in various biological matrices. The method's accuracy and precision in forensic toxicological screening suggest potential applications for detecting low-level environmental exposures. It can help detect and understand environmental exposures, explain their metabolic processes, and assess their impact on human health more effectively.

Femtosecond lasers represent a novel tool for tattoo removal as sources that can be operated at high power, potentially leading to different removal pathways and products. Consequently, the potential toxicity of its application also needs to be evaluated. In this framework, we present a comparative study of Ti:Sapphire femtosecond laser irradiation, as a function of laser power and exposure time, on water dispersions of Pigment Green 7 (PG7) and the green tattoo ink Green Concentrate (GC), which contains PG7 as its coloring agent. The treated samples were subsequently analyzed via UV‒Vis spectroscopy, gas chromatography‒mass spectrometry (GC‒MS), SEM imaging and associated statistical analysis. We found that, on average, the discoloration efficacy of femtosecond laser treatment was comparable to that of nanosecond lasers as were the decomposition products. In fact, two primary types of fragments are produced, both of which are potentially harmful, resulting either from the decomposition of chlorinated phthalocyanine (i.e., PG7) or from the active chlorination of naphthalene impurities. However, the outcomes for the PG7 and GC treatments differed significantly from each other from several points of view. The spectral intensity patterns of GC and PG7 were distinct, depending on the treatment conditions, and showed linearity with power only in the case of GC. Additionally, the relative ratios of the fragment products differed significantly, with the production rate showing a linear dependence on power only in the case of GC and no discernible trend for PG7. Shape and size distribution of the generated particles were highly dependent on the type of sample. Femtosecond laser irradiation of GCs primarily produces nanoparticles with a homogeneous size distribution, which are typically considered nontoxic. Large aggregates also formed, exhibiting a regular shape. In contrast, PG7 yielded rods and needles with aspect ratios similar to those of toxic fibers.

Human UDP-glucuronosyltransferases (UGTs) are pivotal phase II metabolic enzymes facilitating the transfer of glucuronic acid from UDP-glucuronic acid (UDPGA) to various substrates. UGTs are classic type I transmembrane glycoproteins, mainly localized in the endoplasmic reticulum (ER) membrane. This review comprehensively explores UGTs, encompassing gene expression, functional characteristics, substrate specificity, and metabolic mechanisms. A recent analysis of C-terminal structures, compared with original data, underscores the pivotal role of α3, α4, and β4 functional domains in selectively recognizing diverse glycosyl donors. Accumulating evidence suggests that UGTs function as homo- and heterodimers, with oligomers likely stabilizing UGTs and modulating their activity. The review sheds light on the implications of UGT oligomerization on substrate glucuronidation and the interplay between protein-protein interaction and glucuronidation activity. UGT-mediated drug resistance, often underestimated, emerges as a clinically relevant form of chemical resistance, with delineated outcomes in tumors and other diseases. This review provides a multifaceted exploration of the physiological significance of UGTs, spanning genetics, proteins, oligomerization, drug resistance, and more, offering insights into their metabolic mechanisms. Understanding interactions between UGT isoforms is crucial for predicting drug-drug interactions, preventing drug toxicity, and enabling precision treatment.