Toxicologic Pathology最新文献

The 2025 annual Division of Translational Toxicology (DTT) Satellite Symposium, entitled ''Pathology Potpourri'' was held in Chicago, IL, at the Society of Toxicologic Pathology's (STP) 44th annual meeting. This year marked the 25th anniversary of the DTT Satellite Symposium. The goal of this symposium was to present and discuss challenging or interesting diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images and data that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included inflammatory lung lesions in rats due to inhalation of silica dust; excipient-related renal tubular vacuolation in rats; spheroids in the cerebellum of dogs associated with administration of an O-GlcNAc inhibitor; hyperplasia and papillomas in the bladder of mice treated with a fragrance component; hematology analyzer error flags related to increased numbers of large unstained cells (LUCs), as well as analyzer dysfunction in the measurement of the white blood cell (WBC) count and differential, paradoxical effect of cyclosporine in allergic lung inflammation in mice, and vertebral deformation and gas gland adenomas in killifish.

Digestive system development is a complex process, requiring precise molecular signaling interactions to produce various complex organs arising from a single primordium (the primitive gut tube). Abnormal development of this system is common in humans, leading to birth defects like structural anomalies (e.g., atresias, fistulas, stenosis) and/or functional deficits (e.g., dysautonomia, ileus), all of which impair digestion and passage of ingesta, thereby reducing nutrient uptake. Mouse models of disease (engineered and spontaneous) have provided many insights into the mammalian molecular mechanisms that are essential for guiding normal global and regional anatomic formation of the digestive system. Moreover, an understanding of normal development is an essential resource for identifying and characterizing aberrant phenotypes and toxic effects in embryonic and juvenile mice. This microscopic atlas details key developmental milestones for the upper and lower digestive tracts (including associated glands except liver) in a common wild-type mouse stock. This atlas uses a range of high-resolution, well-annotated color images to follow the evolving digestive system anatomy from initial formation of the primitive gut tube in utero (at embryonic day 7.5) through the appearance of adult-like features at weaning (postnatal day 21 in modern mouse colonies), including comparisons with similar features in humans.

The objective of the third session (Neurobiomarkers) in the 2025 Society of Toxicologic Pathology (STP) symposium was to provide an overview of different types of existing neural biomarkers, highlight the value of novel biomarkers to detect and/or predict nervous system changes in preclinical species, and provide perspectives on their translational potential. These biomarkers can also help evaluate the efficacy of new drugs, monitor neurological diseases, and better characterize neuropathology findings. The lectures in this session featured distinguished experts in their respective scientific disciplines such as electrophysiology, molecular pathology tools to characterize pathology lesions in the visual pathways, fluid-based biomarkers, the use of MRI imaging to visualize test article delivery to the CNS of monkeys, and quantifying DRG changes using techniques like stereology, micro-CT, and nano-CT. In this session, there was also a presentation about immunohistochemical stains performed to evaluate ketamine-induced neurotoxicity in neonatal Sprague Dawley rats as a model for pediatric anesthesia. The integration of neural biomarkers in nonclinical studies in conjunction with a dedicated histopathology evaluation provides the necessary scientific data to better predict and derisk neurotoxicity in clinical studies.

A majority of the human genome codes for genes that do not produce proteins. Many of these long non-coding RNA (lncRNA) transcripts have evolved at a faster rate than genes that code for proteins, have critical regulatory and structural roles, and have important roles in higher-level brain functioning and diseases. We have shown selective time and cell-type stability of RNA transcripts in human brain during the postmortem interval. Here, we have extended these studies to examine the stability of lncRNAs in a simulated human postmortem interval. We found that lncRNA stability is variable and cell-type specific. While some lncRNAs are stable for up to 24 hours, those expressed in neurons decline rapidly and those expressed in glial cells such as astrocytes and microglia increase dramatically during this same time interval. The lncRNAs are less stable than protein-coding RNAs, and microRNAs were highly unstable in the simulated postmortem interval. Knowing the stability of human brain protein-coding and non-coding genes in the postmortem interval is critical to interpret studies of all human brain disorders ranging from Alzheimer's disease to schizophrenia.

Ocular toxicity studies may encompass a variety of ocular routes of administration. Because the retina and optic nerve are an extension of the central nervous system, safety assessment of ocular compounds must include thorough examination of extraocular visual pathways, as ocular administration may result in primary toxicities in the nervous system due to its exposure to therapeutics via the retina and optic nerve, or changes that are secondary to primary ocular effects. Here we provide a practical guide to sampling extraocular visual pathway structures for commonly utilized ocular toxicology species (NHP, rabbit and rat) that is appropriate for implementation on the scale of preclinical ocular toxicity studies, highlighting examples of central nervous system toxicities following ocular administration of therapeutics. We discuss additional structures such as the ciliary ganglia, and oculomotor nerves, which may exhibit toxicities subsequent to administration of some ocular therapeutics and consider when these structures should be evaluated. Finally, we highlight special stains and molecular pathology tools, such as immunohistochemistry and in situ hybridization, and their utility in the investigation of primary (direct) or secondary toxicities present in extraocular visual pathways following ocular administration of a drug.

Chromogenic immunohistochemistry (IHC) is an important molecular localization assay in biomedical research and nonclinical drug development, enabling the visualization of specific epitopes within tissues. The methodology is widely used in drug target selection, risk assessment, understanding disease biology, and characterizing histopathological findings in nonclinical studies. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology formed a working group to compile essential information on chromogenic IHC assays not performed in compliance with Good Laboratory Practice (GLP) from nonclinical studies, using relevant literature and the Working Group members' collective expertise. In this "Points to Consider" article, emphasis is placed on factors influencing IHC data quality, including sample selection, general assay considerations, data generation and interpretation, and effective reporting. The Working Group members deliberated extensively on pertinent topics, aiming to provide specific and practical guidance for pathologists, histologists, and allied scientists engaged in chromogenic IHC assays. While refraining from an exhaustive exploration of the intricate technical details associated with chromogenic IHC, this article offers insights to enhance the accuracy, credibility, and reproducibility of chromogenic IHC, thereby facilitating informed decision-making in the nonclinical development of biomedical products.

This review investigates the incidences of decidual reactions and associated microscopic changes in Sprague-Dawley rats comparing dual-route (intravenous-IV + intraperitoneal-IP) to IV-only preclinical studies of nonimplant medical devices at Syngene International Ltd. Data from 132 rats in 14 dual-route studies and 120 rats in 12 IV-only studies were analyzed retrospectively. Sesame oil and normal saline were used as the vehicle for intraperitoneal and intravenous administration, respectively. The dual-route studies showed higher incidences of decidual reactions (9.8%) compared with IV-only studies (0.8%). Associated microscopic changes included increased mucification in the cervix (3.8% vs 0.8%) and vagina (6.1% vs 2.5%), and mammary gland hyperplasia (12.9% vs 4.2%), indicative of pseudopregnancy. The findings suggest that intraperitoneal administration of sesame oil, in presence of pseudopregnancy, significantly contributes to these effects. This review highlights the importance of understanding the potential effects of the vehicle and route of administration while interpreting the results in preclinical studies.

The 31st edition of the slide seminar "Classic Examples in Toxicologic Pathology" was held at the Department of Pathology at the University of Veterinary Medicine in Hannover, Germany, in March 2024. The meeting series is jointly organized with the ESTP (European Society of Toxicologic Pathology) and aims at presenting and discussing classical and novel cases of toxicologic and experimental pathology. This article reflects on 6 out of 10 presentations given at the seminar and includes images of representative lesions. They comprise cases of toxicologic pathology, induced directly or indirectly by a test item. We herein summarize findings with a progesterone receptor antagonist and its impact on uterine tumor development in rats; an example of hybridization-dependent off-target hepatotoxicity in rats administered a small interfering RNA (siRNA) conjugated to N-acetylgalactosamine (GalNAc) and the case of an orexin-1/-2 receptor antagonist with liver enzyme induction. We further include a case on reactive metabolites with associated liver findings, a study on findings induced by a GPR40 agonist and a presentation on dysgeusia and its translatability.

Streptozotocin (STZ) is known to induce renal tumors in rodents, but their similarity to human tumors remains poorly defined. We characterized and comparatively validated a mouse model of STZ-induced renal tumorigenesis by administering a single intraperitoneal dose of STZ (250 mg/kg) to female CBA/NSlc mice and maintaining them for 182 days. Renal tumors developed in 25 of 28 surviving mice (89%), with mean and median numbers of 3.4 and 2.5 tumors per animal, respectively. Histopathologically, the tumors were diagnosed as adenomas or adenocarcinomas and exhibited clear, eosinophilic, or mixed cytoplasm. Immunohistochemical analysis of four representative adenocarcinomas revealed positivity for CK AE1/AE3, CK7, PAX8, CD10, CD82, E-cadherin, CD117, and S100A1, and negativity for CK20 and vimentin. These morphological and immunohistochemical features resembled those of human chromophobe renal cell carcinoma (chRCC). Furthermore, the tumors expressed collecting duct markers (uromodulin, CD15, MUC1, and GLUT-1) but lacked proximal convoluted tubule markers (AQP1 and megalin), suggesting a collecting duct origin. Taken together, STZ-induced mouse renal tumors closely resemble human chRCC, providing a reproducible model for investigating the biology and potential therapeutic approaches for this tumor type.