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Iron oxide nanoparticles (IONPs)-based contrast agents are widely used for T -weighted magnetic resonance imaging (MRI) in clinical diagnosis, highlighting the necessity and importance to evaluate their potential systematic toxicities. Although a few previous studies have documented the toxicity concerns of IONPs to major organs, limited data are available on the potential reproductive toxicity caused by IONPs, especially when administrated via intravenous injection to mimic clinical use of MRI contrast agents. Our study aimed to determine whether exposure to IONPs would affect male reproductive system and cause other related health concerns in ICR mice. The mice were intravenously injected with different concentrations IONPs once followed by routine toxicity tests of major organs and a series of reproductive function-related analyses at different timepoints. As a result, most of the contrast agents were captured by reticuloendothelial system (RES) organs such as liver and spleen, while IONPs have not presented adverse effects on the normal function of these major organs. In contrast, although IONPs were not able to enter testis through the blood testicular barrier (BTB), and they have not obviously impaired the overall testicular function or altered the serum sex hormones levels, IONPs exposure could damage Sertoli cells in BTB especially at a relative high concentration. Moreover, IONPs administration led to a short-term reduction in the quantity and quality of sperms in a dose-dependent manner, which might be attributed to the increase of oxidative stress and apoptotic activity in epididymis. However, the semen parameters have gradually returned to the normal range within 14 days after the initial injection of IONPs. Collectively, these results demonstrated that IONPs could cause reversible damage to the reproductive system of male mice without affecting the main organs, providing new guidance for the clinical application of IONPs as T -MRI contrast agents.

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent whose incorporation into nucleic acid plays an essential role in its therapeutic efficacy. 5-FU induces severe reproductive toxicity, which has been shown to be reversible. However, the underlying mechanisms have not been fully elucidated. Since single-strand-selective monofunctional uracil-DNA glycosylase 1 (Smug1) is a key enzyme in the excision of 5-FU, we investigated its potential role in the reversible reproductive toxicity of 5-FU by integrating knockdown, overexpression and LC‒MS/MS approaches. 5-FU treatment increased Smug1 and Dkc1 expression but blocked rRNA maturation in preimplantation embryos. Smug1 knockdown inhibited Dkc1 expression and impaired rRNA maturation, leading to reduced preimplantation embryo development. In contrast, Smug1 overexpression alleviated the inhibitory effects of 5-FU on rRNA and oocyte maturation and partially rescued 5-FU-induced developmental defects in preimplantation embryos. LC‒MS/MS analysis further revealed that overexpression of Smug1 reduced the levels of RNA incorporated 5-FUrd, the metabolite of 5-FU, indicating that Smug1 potentially alleviates reproductive toxicity by excising 5-FU from RNA. Our findings revealed the active involvement of Smug1 in counteracting 5-FU-induced reproductive toxicity and provide valuable references for the development of new strategies to reduce the adverse effects of 5-FU.

Purpose Minnelide is an experimental antineoplastic agent that is currently the subject of a phase 1 clinical trial for the treatment of pancreatic and gastrointestinal malignancies. In this study, we documented two cases of reversible acute cerebellar toxicity (REACT) associated with Minnelide and compared its radiological manifestations with other cerebellotoxic agents. Methods Both patients had histories of progressive metastatic cancer and participated in a phase 1 clinical trial with Minnelide. They had an MRI examination including T2WI, FLAIR and SWI, axial and coronal DWI, and ADC map on admission and follow up. Results In each patient, the initial MRI demonstrated increased signal on FLAIR and restricted diffusion in the cerebellar cortex without involvement of deep cerebellar nuclei or supratentorial areas. The presenting symptoms and the majority of imaging findings resolved on follow up MRI. Conclusion To our knowledge, Minnelide has shown an uncommon radiologic pattern of isolated cerebellar cortical involvement compared to other causes of cerebellar toxicity. Since this is a new medication, physicians’ familiarity with the presenting symptoms and its temporal association with the imaging findings is important.

This chapter contains sections titled: Introduction History and Scope of Toxicology Principles of Toxicology Disposition of Toxicants in Organisms Non‐Organ System Toxicity Mechanistic Toxicology Quantitative Structure–Activity Relationships Environmental Toxicology Risk Assessment Conclusions References

A rapid, sensitive, and selective fluorometric assay is described for the determination of chromium(VI) in real waters and living cells. The method is making use of nitrogen, phosphorus, and sulfur tri-doped carbon dots (NPS-CDs) which have absorption/emission maxima at 360/505 nm/nm. Cr(VI) has an absorption maximum at 350 nm and causes an inner filter effect (IFE) on the blue fluorescence of the NPS-CDs. The NPS-CDs were hydrothermally synthesized using p -aminobenzenesulfonic acid and tetrakis(hydroxymethyl)phosphonium chloride as precursors. The NPS-CDs were characterized by transmission electron microscopy, X-ray diffraction, and several spectroscopic methods. They are biocompatible and negligibly cytotoxic when tested with HeLa cells and MCF-7 cells even after 48 h of incubation. The NPS-CDs were used as fluorescent probes for Cr(VI). The detection limit is 0.23 μM (three times standard deviation versus slope), and the linear response covers the 1 to 500 μM chromate concentration range. The NPS-CDs were applied to the determination of Cr(VI) in real waters and living cells (HeLa and MCF-7) and gave satisfying results. Graphical abstract Schematic representation of hydrothermal synthesis of nitrogen, phosphorus, and sulfur tri-doped carbon dots (NPS-CDs) for Cr(VI) detection via inner filter effect (IFE). NPS-CDs were applied to the determination of Cr(VI) in living cells (HeLa and MCF-7) with satisfying results.

Purpose Immune checkpoint inhibitors (ICIs) are related to various immune-related adverse events (irAEs). However, the knowledge is limited with rare irAEs like hearing loss. Therefore, we evaluated the characteristics, presentation, and treatment of ICI-related hearing loss by reviewing the individual patient data from the previous studies. Methods We conducted a systematic search of the Web of Science, PubMed, and Embase databases for studies published until 17 November 2022. The selected MeSH search terms were “hearing loss” OR “hearing impairment” OR “ototoxicity” OR “vestibular toxicity” OR “audiovestibular toxicity” AND “immune checkpoint inhibitor” OR “immunotherapy.” Results A total of 38 patients were included. Melanoma was the most frequent diagnosis (73.7%). The median time from ICI initiation to hearing loss development was 3 months. The hearing impairment was secondary to bilateral sensorineural hearing loss (SNHL) in 24 (68.6%) patients, and at least one other irAE accompanied the hearing loss in 24 patients. Hearing loss significantly improved in 45.7% of the patients. The overall response rate and disease control rate were 67.6% and 85.3%, respectively. Conclusion We observed that most cases of ICI-related hearing loss were reversible, observed in patients with melanoma, accompanied by other irAEs, and associated with a high response rate to ICIs. With the expanded use of ICIs in the earlier treatment lines and adjuvant settings, the number of survivors with ICI-related hearing loss is expected to increase. Further research is needed to define the true prevalence of ICI-related hearing loss, optimal diagnosis, and management.

Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing the risk of idiosyncratic toxicities caused by the permanent modification of proteins, which leads to higher levels of potential haptens. Herein, we systematically review electrophilic warheads employed during the development of reversible covalent drugs. We hope the structural insights of electrophilic warheads would provide helpful information to medicinal chemists and aid in designing covalent drugs with better on-target selectivity and improved safety. Graphical Abstract

Background Cardiovascular disease is the leading cause of mortality in the advanced world, and age is an important determinant of cardiac function. The purpose of the study is to determine whether the PM 2.5 -induced cardiac dysfunction is age-dependent and whether the adverse effects can be restored after PM 2.5 exposure withdrawal. Methods Female C57BL/6 mice at different ages (4-week-old, 4-month-old, and 10-month-old) received oropharyngeal aspiration of 3 mg/kg b.w. PM 2.5 every other day for 4 weeks. Then, 10-month-old and 4-week-old mice were exposed to PM 2.5 for 4 weeks and withdrawal PM 2.5 1 or 2 weeks. Heart rate and systolic blood pressure were measured using a tail-cuff system. Cardiac function was assessed by echocardiography. Left ventricles were processed for histology to assess myocardial fibrosis. ROS generation was detected by photocatalysis using 2′,7′-dichlorodihydrofluorescein diacetate (DCFHDA). The expression of cardiac fibrosis markers (Col1a1, Col3a1) and possible signaling molecules, including NADPH oxidase 4 (NOX-4), transforming growth factor β1 (TGFβ1), and Smad3, were detected by qPCR and/ or Western blot. Results PM 2.5 exposure induced cardiac diastolic dysfunction of mice, elevated the heart rate and blood pressure, developed cardiac systolic dysfunction of 10-month-old mice, and caused fibrosis in both 4-week-old and 10-month-old mice. PM 2.5 exposure increased the expression of Col1a1, Col3a1, NOX-4, and TGFβ1, activated Smad3, and generated more reactive oxygen species in the myocardium of 4-week-old and 10-month-old mice. The withdrawal from PM 2.5 exposure restored blood pressure, heart rate, cardiac function, expression of collagens, and malonaldehyde (MDA) levels in hearts of both 10-month-old and 4-week-old mice. Conclusion Juvenile and older mice are more sensitive to PM 2.5 than adults and suffer from cardiac dysfunction. PM 2.5 exposure reversibly elevated heart rate and blood pressure, induced cardiac systolic dysfunction of older mice, and reversibly induced fibrosis in juvenile and older mice. The mechanism by which PM 2.5 exposure resulted in cardiac lesions might involve oxidative stress, NADPH oxidase, TGFβ1, and Smad-dependent pathways.

Background With the advent of drugs designed to selectively target the KRAS-G12C mutant protein, sotorasib and adagrasib have exhibited remarkable efficacy in patients with KRAS G12C mutant lung cancers. Nevertheless, the safety profiles of these agents in a real-world context remain undisclosed. Methods Data was systematically extracted from the FDA Adverse Event Reporting System (FAERS) website from January 2021 to December 2023, focusing on adverse events associated with KRAS G12C inhibitors, sotorasib and adagrasib. Results The predominant adverse events attributed to KRAS G12C inhibitors predominantly encompassed general disorders and administration site conditions, investigations, and gastrointestinal disorders. Among these, the significant adagrasib-related adverse events comprised nausea, diarrhea, vomiting, asthenia, dizziness, and weight loss. Notably, incidences of renal failure were also documented in patients receiving adagrasib. Conversely, the primary adverse events associated with sotorasib included diarrhea, nausea, abnormal hepatic function, elevated levels of aspartate aminotransferase and alanine aminotransferase, and hepatotoxicity. It is noteworthy that a considerable number of adverse events manifested within the inaugural month following the initiation of therapy with KRAS G12C inhibitors. Conclusion Although most adverse effects are reversible, vigilance is warranted particularly for nephrotoxicity and hepatotoxicity during the administration of KRAS G12C inhibitors.

The reproductive toxicity of silica nanoparticles (SiNPs) is well known, but the underlying mechanism is still not clear. To investigate the toxic mechanism of SiNPs on spermatogenic cells, 60 C57 male mice were randomly and equally divided into three groups (the control group, the saline control group, and the SiNPs group) with two observed time points (45 days and 75 days). The mice in the SiNPs group were administered with SiNPs 2 mg/kg diluted in normal saline, and the mice of the saline control group were given equivoluminal normal saline by tracheal perfusion every 3 days for 45 days (in total 15 times). The control group mice were bred without treatment. In each group, a half number of the mice were sacrificed on the 45th day after the first dose, and the remaining half were sacrificed on the 75th day. The results showed that SiNPs increased the malformation of sperms and decreased the motility and concentration of sperms in epididymis on the 45th day after the first dose. SiNPs induced oxidative stress in testis and led to apoptosis and necroptosis of the spermatogenic cells. Furthermore, SiNPs increased the expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3 and RIPK3/MLKL on the 45th day after the first dose. However, compared with the saline control group, the index of sperms and the expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3/RIPK3/MLKL showed no significant changes in the SiNPs group on the 75th day after the first dose. These data suggested that SiNPs could induce apoptosis and necroptosis in the spermatogenic cells by activating the RIPK1 pathway resulting from oxidative stress in male mice. SiNPs-induced damage recovered on the 75th day after the first dose, which suggested that SiNPs-induced toxicity is reversible.