Archives of Toxicology最新文献

Clinical chemistry retains its position as a cornerstone of toxicological assessment, yet inter-laboratory variability in baseline values remains a challenge for the integration and interpretation of multisite datasets. This study leveraged a publicly available clinical chemistry database to assess the impact of inter-laboratory variability in response to hydrazine-induced steatosis. Seventeen clinical chemistry and physico-chemical parameters were evaluated in response to a single dose of hydrazine (at 30 mg/kg or 90 mg/kg) administered to Sprague-Dawley rats (n = 83) across five different pharmaceutical companies and compared with sham-dosed control animals. Hydrazine exposure produced a distinct and consistent biochemical signature at 48 h post-dose across the combined sample set from all laboratory sites, characterised by increased serum bilirubin and BUN and decreased serum protein concentrations, alongside atypical reductions in ALT and AST due to transaminase inhibition. Despite sizable inter-laboratory differences in response when considering single assays, multivariate analysis of the complete dataset was able to extract a core pathological response signature. Early changes at 24 h post-dose in AST, ALT, total protein, and calcium demonstrated strong predictive value for 48-h toxicity profiles (AUROC 0.98), underscoring the translational potential of early biomarkers. This study highlights both the robustness and contextual limitations of clinical chemistry data in toxicological studies. It underscores the importance of matched-control designs and multivariate approaches for multisite studies and advocates for the integration of early predictive modelling to optimise study design and align with the principles of the Replace, Reduce, and Refine initiative.

Cigarette smoking induces cytochrome P450 (CYP) enzymes, causing significant drug interactions. To evaluate such interactions prior to clinical studies, an in vitro model was developed by Lenich and Ruez  (2025) in primary human hepatocytes. Because smoking affects patients worldwide with diverse genetic and environmental backgrounds, it is essential that this model can reflect population variability. This study aimed to apply the smoke induction model to 24 hepatocyte donors from various backgrounds, to validate the model´s reproducibility and enhance its clinical relevance. mRNA expression of CYP1A1, CYP1A2, CYP2C8, CYP2B6, and CYP3A4, along with CYP1A1 and CYP1A enzyme activity, was measured. CYP enzymes were induced (concentration-dependent increase ≥ 2-fold) in all donors, exhibiting a consistent induction pattern, with CYP1A1 mRNA expression and enzyme activity showing the highest response (10-225-fold and 12-334-fold, respectively). CYP1A2 mRNA expression was induced in all donors, CYP1A enzyme activity in 14 donors, CYP2C8 mRNA in 10 donors, CYP2B6 mRNA in 18 donors and CYP3A4 mRNA in 15 donors. Induction capacity was correlated to donor characteristics, including supplier, gender, ethnicity, smoking status, alcohol and drug abuse. No significant correlations were identified with demographic or lifestyle factors. However, a significant difference in CYP1A2 mRNA induction was observed between suppliers, with BioIVT donors exhibiting higher responses. In conclusion, CSE consistently induced CYP enzymes across 24 donors, demonstrating the robustness of the smoke induction model and its suitability to reflect patient variability in clinical studies.

Global fertility rates have exhibited a concerning decline, paralleling the public health challenges posed by fine particulate matter 2.5 (PM_2.5) pollution. This comprehensive review synthesizes current evidence on the multiple impacts of PM_2.5 exposure on male reproductive health, including epidemiological findings, mechanistic insights, and potential mitigation strategies, which have not been thoroughly evaluated in previous literature. Epidemiological evidence indicates a significant association between PM_2.5 exposure and adverse male reproductive outcomes, including reduced fertility and adverse semen quality. The detrimental effects of PM_2.5 are mediated through multiple biological pathways, particularly oxidative stress induction, disruption of mitochondrial and endoplasmic reticulum homeostasis, interference with endocrine signaling especially testosterone synthesis, and the promotion of harmful epigenetic modifications. These molecular and cellular alterations collectively impair spermatogenesis and overall reproductive function. Furthermore, this review discusses promising intervention approaches aimed at reducing the reproductive risks associated with PM_2.5 exposure. By integrating epidemiological, experimental, and mechanistic evidence, the review underscores the critical connection between ambient air pollution and male reproductive dysfunction, highlighting the urgent need to enhance public awareness of the adverse effects of PM_2.5 on male fertility and to promote effective protective measures.

The cannabidiol (CBD)-based drug, Epidiolex, received approval from the U.S. Food and Drug Administration (FDA) for treating seizures in certain childhood-onset epileptic disorders. CBD-associated liver toxicity is a serious side effect listed on the drug label. Our previous studies demonstrated cytotoxicity in primary human hepatocytes and HepG2 cells induced by CBD, 7-hydroxy-CBD, and 7-carboxy-CBD, with cell cycle disturbances, endoplasmic reticulum (ER) stress, and apoptosis identified as the underlying mechanisms. In this study, using a transcriptomic approach with mRNA-sequencing analysis, we found that downregulation of genes associated with oxidative phosphorylation and upregulation of genes associated with mitochondrial dysfunction, autophagy, and ER stress were among the top 10 canonical pathways consistently affected across different CBD concentrations. Direct measurement of the activity of the mitochondrial respiratory complexes that compose the oxidative phosphorylation process, demonstrated that CBD strongly inhibited Complexes IV and V and moderately inhibited Complexes II and III. CBD-induced mitochondrial dysfunction was indicated by a classic glucose-galactose assay, and the loss of mitochondrial membrane potential was confirmed by a JC-1 assay. Additionally, CBD induced autophagy, as evidenced by autophagosome formation and enhanced autophagic flux. Similar to CBD, 7-hydroxy-CBD induced a strong inhibition of Complexes IV and V, mitochondrial dysfunction, and autophagy, while 7-carboxy-CBD induced autophagy, with marginal inhibition on the respiratory complexes and no identified mitochondrial dysfunction. In summary, autophagy emerges as the common mechanism underlying CBD-, 7-hydroxy-CBD-, and 7-carboxy-CBD-induced cytotoxicity. Inhibition of mitochondrial respiratory complexes and mitochondrial dysfunction were observed with CBD and 7-hydroxy-CBD, but not with 7-carboxy-CBD.

The genes belonging to vascular endothelial growth factor (VEGF) family played critical roles in tumor angiogenesis and the activation of signaling pathways associated with cancer promotion. However, it remains unclear whether genetic variants within VEGF gene family could influence the development of colorectal cancer. Here, we utilized the genotyping data from 1150 colorectal cancer patients and 1342 healthy controls to evaluate the associations between single nucleotide polymorphisms (SNPs) within VEGF gene family and the risk of colorectal cancer. Notably, the C allele of VEGFA rs6899540 was significantly associated with an increased colorectal cancer risk after false discovery rate (FDR) adjustment [odds ratio (OR) = 1.61, 95% confidence interval (CI): 1.25-2.06, P = 1.80 × 10^-4; P_FDR = 0.015]. Furthermore, rs6899540 (A > C) could enhance VEGFA expression and exacerbate malignant phenotypes in colorectal cancer cells, as demonstrated through multiple biological experiments. Intriguingly, an integrated analysis using weighted gene co-expression network analysis (WGCNA) indicated that increased VEGFA expression may influence metabolic pathways, thereby increasing the risk of developing colorectal cancer. In conclusion, our findings demonstrated that genetic variants in VEGF family significantly contributed to susceptibility to colorectal cancer, which could provide new mechanistic insights into the molecular pathogenesis of colorectal cancer.