Toxicology letters最新文献

Manganese is an essential trace element required for various physiological processes. However, excessive exposure to this metal can lead to health issues. This study aims to evaluate whether adequate zinc intake can influence the relationship between blood manganese levels and markers indicating damage to the liver and other organs in populations using epidemiological data. We conducted a comprehensive analysis utilizing 2013-2016 data from the National Health and Nutrition Examination Survey (NHANES). The findings indicated that blood manganese exhibits a significant positive association with the serum levels of enzymatic markers of liver damage alkaline phosphatase and aspartate aminotransferase. However, when investigating the interaction between blood manganese and zinc intake at the second quartile, a significant negative association was found with alkaline phosphatase in three different linear regression models. A similar association was found between the fourth quartile of zinc intake and lactate dehydrogenase activity in all three models of the study. The findings suggest that unhealthy high levels of manganese in populations may lead to tissue injury and disease. Nevertheless, having an adequate zinc intake could help mitigate manganese toxicity.

Disruption of circadian rhythm caused by night-shift work has been associated with several disorders, including cancer. Health care personnel often works at night to insure the continuity of care. Aim of this study was to evaluate the influence of night-shift work on serum and saliva levels of steroid hormones, vitamin D, and melatonin in hospital female workers. Ninety-seven female hospital workers were recruited: 46 nurses performing clockwise rapid rotating shift schedule on a 5-day cycle, including one night, and 51 day workers. Thirteen steroid hormones and vitamin D were assessed in morning serum samples; cortisol, cortisone and melatonin were assessed in morning and evening saliva samples. We fitted multiple regression models adjusted for age, BMI, sampling month, ovarian cycle phase, and use of oral contraceptives (OC). Rapidly rotating clockwise shift work was associated with increased levels of serum corticosterone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), and androstenedione, and decreased levels of estradiol and vitamin D. OC modulated the association between serum cortisol, corticosterone and 11-deoxycortisol and work shift. The normal circadian phase of salivary melatonin, cortisol and cortisone was not affected by shift work. In female hospital nurses, the clockwise rapid rotating shift schedule increases the level of some hormones, likely associated with stress. No increase of estradiol, nor modification of salivary hormones was observed.

The mechanism of action of propofol, a common intravenous anaesthetic, in early life stages is not well understood with contradictory studies showing neurotoxic and neurogenic effects in the developing brain. Zebrafish early life stages have been established as an alternative model for animal experimentation with propofol toxicological effects reported following chronic exposure. Yet, the acute exposure to other anaesthetics has been shown to induce early life stage-dependent toxicological outcomes. Therefore, the present study aimed to evaluate the teratogenic effects of propofol at the 256-cell, 50 % epiboly and 1-4 somite stages following a 20 min exposure. Embryos were exposed after primarily assessment of propofol acute toxicity (24h-LC₅₀=9.82 μg mL^-1) and absorption at different developmental stages by chromatography. Embryos (2 hours post-fertilization, hpf) were treated with an anaesthetic and toxicological concentration of propofol (2.5 and 10 μg mL^-1, respectively) for 20-min. Mortality and developmental toxicity were then evaluated until 144 hpf, when the behaviour and oxidative-stress-related biomarkers were assessed. Exposure at the 256-cell stage resulted in a concentration-dependent increased number of abnormalities in head, fins and tail and a decreased body length as well as in changes in ATPase activity for the lowest concentration. On the other hand, exposure at later stages resulted in a decreased survival while no significant malformations were detected. Yet, exposure during the 50 % epiboly stage resulted in the increase of ROS levels as well as glutathione (GST and GSSG) levels while exposure at 1-4 somite stage resulted in increased DNA damage and ATPase alterations. The behaviour of zebrafish was similar among treatments. Overall, these findings show highlight the stage-dependent teratogenic potential of short propofol exposures during zebrafish early development. The alterations observed may be linked to the activation of the zygotic transcription in embryos, requiring further studies to delve into the molecular changes underlying the observed effects.

Derivation of occupational biomonitoring levels (OBLs) is needed to effectively utilize biomonitoring for assessing exposures to chemical substances, and consequently, implement risk reduction measures to reduce health risks among workers. OBLs are the appropriate option for chemical substances that can be absorbed through the skin. This methodology for derivation of OBLs has been developed in collaboration with scientific and regulatory experts from more than 40 institutes in 15 countries within the Organization for Economic Cooperation and Development (OECD) framework. This manuscript provides a summary of the guidance on derivation of OBLs destined for scientists, risk assessors, and regulators who are tasked with establishing OBLs for regulatory purposes and implementing occupational biomonitoring programs. The derivation methodology follows a tiered approach based on the strength of evidence and quality of the data that we have labeled level of confidence. The tiered approach serves as a practical framework in occupational health risk assessment and management. We distinguish between four OBL levels depending on the strength of scientific evidence and confidence level: health-based derivation of OBL based on robust epidemiological data showing causal exposure-health effect relationship and Provisional OBL (POBL) based on robust toxicological animal data showing dose-response relationship as well as two assessment values which are not health based: reference levels in the general population (Reference OBL or (ROBL)), and Technical achievable OBL or (TOBL). Four case studies illustrating the derivation methods for OBLs and POBLs are also provided. Using this state-of-the-art approach (OECD guidance document no. 370) will lead to a harmonized derivation of OBLs and subsequently to evidence-based risk management measures.

Although N⁶-methyladenosine (m⁶A) and its regulatory proteins were involved in multiple cellular damage processes, the roles of m⁶A and its regulatory proteins in cadmium-induced pulmonary cell damage remain largely unknown. Our present data indicated that cadmium exposure caused serious damage in bronchial epithelial cells, as evidenced by reduction of cell viability and elevation of oxidative damage and apoptosis. These processes were accompanied by alterations of m⁶A modification and its regulatory proteins (FTO, ALKBH5, YTHDC2). It is noteworthy that pretreatment with the m⁶A agonist entacapone (ENT) markedly attenuated the detrimental effects of cadmium, including cell death, oxidative damage, and the activation of the nuclear factor erythroid 2-related factor 2 (NRF2）signalling pathway. Conversely, the detrimental effects of CdSO₄ were significantly exacerbated when m⁶A levels were inhibited by 3-deazidyladenosine (DAA). Further prediction result revealed that multiple m⁶A-modified sites occur on NRF2 mRNA with high confidence level, implicating that m⁶A modification on NRF2 mRNA may affect the protein expression of NRF2. In conclusion, our data together suggest that m⁶A modification play critical roles in cadmium-induced bronchial epithelial cell damage, during which NRF2 signaling pathway may act as an important bridge for m⁶A modification to regulate cellular damage. This study offer a promising avenue for further investigation into the mechanisms underlying cadmium-induced bronchial epithelial cell damage from the perspective of RNA epigenetics.

Considering the increasingly demand for printing in daily life, more attention should be paid to the health risks of printer emissions to consumers. This study designed a two-stage cross-over study with 20 volunteers to investigate whether the short-term exposure to printing shop particles (PSPs) could cause inflammatory responses and genetic damage in healthy young volunteers. According to the study, short-term exposure to high level of PSPs caused the elevation of eotaxin and TNF-α levels in serum, indicating PSPs exposure led to the inflammation in healthy subjects. However, no significant changes of the urine 8-OH-dG was observed after PSPs exposure and there was no significant difference of micronucleus frequency in peripheral blood lymphocytes of volunteers between the high-exposure-level and low-exposure-level period. Our study suggested that short-term exposure to high level of PSPs could cause mild inflammatory responses but no DNA damage in healthy subjects. More attention should be paid to the health hazards of the regular use of laser printers in daily life.

Antineoplastic drugs are carcinogens, mutagens, or teratogenic substances, which can pose serious risks to professionals. Concerns about chronic exposure to these hazardous medicinal products (HMPs) have led to their prominence in the EU strategic framework on health and safety at work 2021-2027. To estimate and mitigate human exposure to HMPs, regular monitoring programs and, consequently, reliable, sensitive, multicomponent methods are crucial. In this study, an unconventional liquid-liquid extraction coupled with liquid chromatography-tandem mass spectrometry analysis is proposed to simultaneously identify and quantify seven HMPs of high concern in urine: cyclophosphamide, etoposide, ifosfamide, paclitaxel, megestrol, mycophenolate mofetil, and tamoxifen, the last three for the first time. Recoveries of all drugs from urine samples were close to 100 %, and method detection limits (0.6-4.1 ng/L) were noticeably lower than most previously reported. This novel, non-invasive method for biomonitoring is thus suitable to unequivocally identify the target drugs at the expected trace levels in urine and to infer about workers' exposure. The method contributes to the conception of regular monitoring programs for antineoplastic drugs, in line with recommendations under EU Directive 2004/37/EC. This is especially relevant in Portugal, where neither analytical methods nor exposure data exist due to lack of formal surveillance.

Previous investigations have shown that high glucose can promote breast cancer progression. However, the relationship between high glucose microenvironment and triple-negative breast cancer (TNBC) remains to be explored. In this study, we performed RNA-seq to explore the effect of short-term high glucose and long-term high glucose on MDA-MB-231 cell line. A total of 896 highly ranked differentially expressed genes (DEGs) were identified, including 57 DEGs of short-term high glucose group and 839 DEGs of long-term high glucose group. The DEGs of short-term high glucose group were mainly associated with IL-17 signaling pathway. Nonetheless, the DEGs of long-term high glucose group were primarily involved in IL-17 signaling pathway, MAPK signaling pathway, TNF signaling pathway, AGE-RAGE signaling pathway in diabetic complications, Toll-like receptor signaling pathway, and VEGF signaling pathway. Additionally, 8 hub genes of short-term high glucose group were enriched in metabolic pathway. Moreover, 10 hub genes of long-term high glucose group were enriched in ribosome pathway. Subsequently, in vitro experiment results found that high glucose can promote cell proliferation, and has a time accumulation effect. In addition, high glucose can induce the accumulation of inflammatory factors and promote angiogenesis. Collectively, these findings provide novel insights into the effect of diabetes mellitus type 2 (T2DM) on TNBC.

The immune system is one of the common targets of drugs' toxicity (Immunotoxicity) and/or efficacy (Immunotherapy). Immunotoxicity leads to adverse effects on human health, which raises serious concerns for the regulatory agencies. Currently, immunotoxicity assessment is conducted using different in vitro and in vivo assays. In silico and in vitro human cell-based immunotoxicity assays should also be explored for screening purposes as these are time and cost effective as well as for ethical reasons. For in vivo studies, tier 1-3 assessments (Tier 1: hematology, serum globulin levels, lymphoid organ's weight and histopathology; Tier 2: immunophenotyping, TDAR and cell mediated immunity; and Tier 3: host resistance) should be used. These non-clinical in vivo assessments are useful to select immunological endpoints for clinical trials as well as for precautionary labeling. As per regulatory guidelines, adverse immunogenicity information of drug should be included in product's labeling to make health care practitioner aware of safety concerns before prescribing medicines and patient management (USFDA, 2022a, 2022b). This review mainly focuses on the importance of immunotoxicity assessment during drug discovery and development.

Jellyfish stings can trigger abrupt heart failure via toxins, leading acute mortality rise. Proposed mechanisms involve oxidative stress and apoptosis, but evidence for effective treatments is lacking. To explore the concrete molecular mechanisms of jellyfish toxin-induced cardiotoxicity and to explore effective therapeutic approaches, we established tentacle extract (TE) of jellyfish Nemopilema nomurai induced cardiotoxicity models in vivo and in vitro based Intelligent Character Recognition (ICR) mice and H9C2 cells, respectively,.We assessed toxin-induced cardiac injury and screened antagonists from natural compounds to evaluate their antagonistic effects and explore their mechanisms of action. In vitro experiments showed that TE reduced the viability of H9C2 cells and induced a large number of cells apoptotic, accompanied by the elevation of reactive oxygen species (ROS), malondialdehyde (MDA) and the decrease of total superoxide dismutase (T-SOD), activated the phosphorylation level of mitogen-activated protein kinase (MAPK) nuclear transcription factors p38, extracellular regulated protein kinases (ERK) and c-Jun N-terminal kinase (JNK), and increased the transcription level of upstream cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), and OMT can significantly antagonize the above changes caused by TE; in vivo experiments demonstrated that TE could lead to the death of mice, as well as induce cardiac edema and rupture of myocardial fibers. In contrast, Oxymatrine (OMT) effectively counteracts the lethal effects of TE and reduces both cardiac edema and myocardial fiber rupture. In summary, OMT can antagonise TE-induced cardiac injury and lethal effects by inhibiting the activation of the MAPK pathway and reducing oxidative stress and apoptosis. As a natural compound, OMT offers a potential therapeutic strategy for jellyfish stings.