OBJECTIVE: This study evaluated the effects of long-term polystyrene microplastics (PS-MPs) exposure on hepatic lipid metabolism in vivo by lipidomics.
RESULTS: H&E staining showed long-term PS-MPs exposure could trigger the hepatic inflammatory cell infiltration and hepatic steatosis in SD rats, indicating long-term PS-MPs exposure caused hepatoxicity. Lipidomics revealed that the concentrations of 8 lipid metabolites in the liver were altered after exposure to PS-MPs for both 6 and 12 months, namely LdMePE (16:0), LPC (18:1), LPC (18:2), LPC (20:4), PC (17:0_20:4), PC (18:2_22:6), PC (22:6_13:0) and SM (d18:1_24:0), which were all statistically different from the control groups detected at both time points after PS-MPs exposure, suggesting the mainly metabolic pathway was glycerolipid metabolism.
CONCLUSIONS: This study showed chronic exposure to PS-MPs could cause hepatotoxicity and induce hepatic lipidomics alterations in vivo, which could provide an essential clue for the safety assessment of PS-MPs.

OBJECTIVE: The efficacy, safety, and liver toxicity of enfortumab vedotin (EV) for elderly advanced urothelial carcinoma (UC) patients and patients with a poor performance status (PS) are unclear.
METHODS: We retrospectively analyzed the efficacy, safety, and liver toxicity of EV in elderly patients and patients with a poor PS between December 2021 and August 2023.
RESULTS: Sixty-two patients (≥75 years old, n=22; PS≥2, n=10) were enrolled. Patients with PS≥2 had significantly lower albumin levels than those with PS<2 (p=0.023). The objective response and disease control rates did not differ significantly between patients <75 and ≥75 years old (p=0.598 and p=0.769, respectively) or between those with PS<2 and PS≥2 (p>0.99 and p=0.178, respectively). Progression-free survival (PFS) and overall survival (OS) were not significantly different in patients <75 years and ≥75 years (p=0984, 0.368). A significant difference in PFS (p=0.047) but not OS (p=0.086) was observed between the PS<2 and PS≥2 groups. The rates of any-grade and severe (grade ≥3) adverse events did not differ significantly between patients <75 and ≥75 years (p=0.471, p=0.136) or between PS<2 and PS≥2 groups (p>0.99, 0.99). Aspartate aminotransferase (AST) levels significantly increased, but alanine aminotransferase levels did not, following EV treatment (p<0.001). Multivariate analyses revealed that the albumin level was an independent prognostic factor (hazard ratio=0.159; p<0.001).
CONCLUSIONS: EV demonstrated similar efficacy and safety in elderly and younger patients with advanced UC. In patients with a poor PS, although the safety was similar, survival was significantly worse in terms of PFS, while the AST levels were significantly elevated.

UNASSIGNED: Paraphenylenediamine is the main component in many commercial hair dyes, and can produce severe local and systemic toxicity reactions after acute ingestion or dermal absorption. The aim of this study was to assess the factors contributing to morbidity and mortality in cases of acute paraphenylenediamine poisoning, with a focus on evaluating the resultant hepatic and cardiac toxicity.
UNASSIGNED: This observational study was conducted on patients with acute paraphenylenediamine poisoning presenting to Sohag University Hospitals, and included a retrospective part from February 2021 to January 2022 and a prospective part from February 2022 to July 2022. Clinical data were extracted and receiver operating characteristic curves created to identify prognostic markers.
UNASSIGNED: Among 50 eligible patients 39 (78 percent) recovered, and 11 (22 percent) died or had permanent complications. Angioedema and anuria were the most frequent features in complicated cases. By receiver operating characteristic analysis, either an increase in aspartate aminotransferase activity greater than 644 IU/L or alanine aminotransferase activity greater than 798 IU/L, a time delay to presentation of greater than 4.5 hours, and a pH of less than 7.32 were associated with a significant increase in morbidity and mortality. While cardiac enzyme activities, and concentrations of blood urea nitrogen and creatinine increased in most cases, they were not associated with mortality.
UNASSIGNED: Management of patients with paraphenylenediamine poisoning is mainly supportive, as there is no specific antidote. Respiratory failure and kidney failure are the most life threatening complications. Hepatoxicity and cardiotoxicity also occur. The ability to predict the events can help guide patient disposition and care.
UNASSIGNED: Elevated liver enzyme activities, increased time delay to admission, decreased pH, and the presence of angioedema and anuria can be used as predictors of morbidity and mortality in patients with acute paraphenylenediamine poisoning.

Toxicological studies have demonstrated the hepatic toxicity of several bisphenol analogs (BPs), a prevalent type of endocrine disruptor. The development of Adverse Outcome Pathway (AOP) has substantially contributed to the rapid risk assessment for human health. However, the lack of in vitro and in vivo data for the emerging BPs has limited the hazard assessment of these synthetic chemicals. Here, we aimed to develop a new strategy to rapidly predict BPs\' hepatotoxicity using network analysis coupled with machine learning models. Considering the structural and functional similarities shared by BPs with Bisphenol A (BPA), we first integrated hepatic disease related genes from multiple databases into BPA-Gene-Phenotype-hepatic toxicity network and subjected it to the computational AOP (cAOP). Through cAOP network and conventional machine learning approaches, we scored the hepatotoxicity of 20 emerging BPs and provided new insights into how BPs\' structure features contributed to biologic functions with limited experimental data. Additionally, we assessed the interactions between emerging BPs and ESR1 using molecular docking and proposed an AOP framework wherein ESR1 was a molecular initiating event. Overall, our study provides a computational approach to predict the hepatotoxicity of emerging BPs.

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

This case study session of the hepatobiliary system was held during the 42nd Annual Society of Toxicologic Pathology Symposium in Summerlin, Nevada. The case studies highlighed potential hepatic and biliary toxicity liabilities. This article comprises several of the case studies that were presented during the session which included copper-associated hepatitis in a dog, sinusoidal obstruction syndrome in non-human primates, hepatic cytoplasmic alteration in mice and rats, and Kupffer cell hyperplasia/granulomatous inflammation in rats. Presenters, when applicable, provided case signalment, anatomic/clinical pathology data, and diagnoses and discussed potential pathogeneses.

Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 μg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite documented human exposure there are almost no toxicity data available to inform risk assessment of PFMOAA. Here we exposed pregnant Sprague-Dawley rats to a range of PFMOAA doses (10-450 mg/kg/d) via oral gavage from gestation day (GD) 8 to postnatal day (PND) 2 and compared results to those we previously reported for perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). Newborn pups displayed reduced birthweight (≥30 mg/kg), depleted liver glycogen concentrations (all doses), hypoglycemia (≥125 mg/kg), and numerous significantly altered genes in the liver associated with fatty acid and glucose metabolism similar to gene changes produced by HFPO-DA. Pup survival was significantly reduced at ≥125 mg/kg, and at necropsy on PND2 both maternal and neonatal animals displayed increased liver weights, increased serum aspartate aminotransferase (AST), and reduced serum thyroid hormones at all doses (≥10 mg/kg). Pups also displayed highly elevated serum cholesterol at all doses. PFMOAA concentrations in serum and liver increased with maternal oral dose in both maternal and F1 animals and were similar to those we reported for PFOA but considerably higher than HFPO-DA. We calculated 10% effect levels (ED10 or EC10) and relative potency factors (RPF; PFOA = index chemical) among the three compounds based on maternal oral dose and maternal serum concentration (μM). Reduced pup liver glycogen, increased liver weights and reduced thyroid hormone levels (maternal and pup) were the most sensitive end points modeled. PFMOAA was ∼3-7-fold less potent than PFOA for most end points based on maternal serum RPFs, but slightly more potent for increased maternal and pup liver weights. PFMOAA is a maternal and developmental toxicant in the rat producing a constellation of adverse effects similar to PFOA and HFPO-DA.

BACKGROUND: Imatinib, a potent inhibitor of targeted protein tyrosine kinases, treats chronic myeloid leukaemia (CML). Data on imatinib-associated changes in hepatic and thyroid functions are limited and conflicting.
OBJECTIVE: To report the prevalence of hepatic and thyroid toxicity associated with the use of imatinib in CML patients.
METHODS: Articles for the systematic review were selected from electronic databases (PubMed, CINALH, Web of Science). Readily accessible peer-reviewed full articles in English published 1st January 2000 to 18th July 2023 were included. The search terms included combinations of: imatinib, CML, liver toxicity, hepatic toxicity, thyroid toxicity. Screening of titles, abstracts, full text articles was conducted independently by two reviewers. Inclusions and exclusions were recorded following PRISMA guidelines. Detailed reasons for exclusion were recorded. Included articles were critically appraised.
RESULTS: Ten thousand one hundred and twenty-three CML patients were reported in the 82 included studies corresponding to 21 case reports, 2 case series, 39 clinical trials and 20 observational studies were selected. Excluding case studies/reports, 1268 (12.6%; n = 1268/10046) hepatotoxicity adverse events were reported, of which 64.7% were rated as mild grade I & II adverse events, 363 (28.6%) as severe, grade III and IV adverse events; some led to treatment discontinuation, liver transplantation and fatal consequences. Twenty (35.1%) studies reported discontinuation of imatinib treatment due to the severity of hepatic toxicity. Fourteen (8.4%, n = 14/167) thyroid dysfunction adverse events were reported.
CONCLUSIONS: High frequency of mild and severe hepatotoxicity, associated with imatinib in CML patients, was reported in the published literature. Low numbers of mild and manageable thyroid toxicity events were reported.

Micro/nanoplastics (MNP) are ubiquitous in the environment and multiple living organisms. The toxicity of some common types of MNP, e.g., polyethersulfone (PES) MNP, remains poorly understood. Multi-omics approaches were used in this study to determine the effects of foodborne and airborne PES MNP on liver and lung, respectively. Foodborne MNP were capable of inducing gut microbial dysbiosis, gut and serum metabolic disruption, and liver transcriptomic dysregulation, and affecting serum antioxidant activity and liver function, resulting in liver injury. As for the airborne MNP, they were found to induce nasal and lung microbial dysbiosis, serum and lung metabolic disruption, and liver transcriptome disturbance, and cause disrupted serum antioxidant activity and lung injury. Foodborne and airborne PES NP were found to respectively induce greater liver and lung toxicity than MP, which could be associated with the differences between NP and MP exposures. The relevant results suggest that foodborne PES MNP could disrupt the \"gut microbiota-gut-liver\" axis and induce hepatic injury, while airborne PES MNP could affect the \"airborne microbiota-lung\" axis and cause lung injury. The findings could benefit the diagnoses of liver and lung injury respectively induced by foodborne and airborne PES MNP, as well as the proper use of PES in human living environment.

Diclofenac (DIC) is one of the most commonly prescribed non-steroidal anti-inflammatory drugs and has been shown to cause oxidative stress and liver injury. The current study investigated protective effects of metformin against DIC-induced hepatic toxicity in both in vitro and in vivo models. For the in vitro study, HepG2 cells were exposed to DIC in the presence or absence of metformin. The effect of metformin on cell viability was evaluated by MTT assay. Oxidative stress parameters (malondialdehyde (MDA), total thiol molecules (TTM), and total antioxidant capacity (TAC)) were assessed. For the in vivo study, thirty-six male Wistar rats were randomly divided into 6 groups. These groups were normal saline, metformin (200 mg/kg), DIC (50 mg/kg/day), DIC + metformin (50, 100, and 200 mg/kg/day). Histopathological studies and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), albumin, direct and total bilirubin were measured. Also, oxidative stress parameters were assessed in liver tissue. Furthermore, expression of glutathione peroxidase (GPX)-1, -3, and -4, catalase (CAT), superoxide dismutase (SOD)-1, and -3 was examined using the real-time PCR method in hepatic tissue. In the in vitro study, metformin significantly prevented DIC-induced loss in cell viability in HepG2 cells. Metformin markedly reduced DIC-induced elevation of MDA levels and increased the TAC and TTM levels. In the in vivo study, metformin significantly prevented DIC-induced changes in hematological and histological markers. Administration of metformin significantly improved oxidative stress parameters in liver tissue. In addition, metformin increased the expression of antioxidant enzymes. Our results suggest that metformin exerts a significant protective effect against DIC-induced hepatic toxicity.