Toxicologic Pathology最新文献

The 2023 annual scientific meeting of the French Society of Toxicologic Pathology (Société Française de Pathologie Toxicologique, SFPT), entitled "mRNA-based technologies: preclinical development and therapeutic applications," was held in Lyon (France) on May 25 to 26, 2023. The aim of the meeting was to discuss the biology, immunology, and preclinical development of messenger RNA (mRNA)-based vaccines and therapeutics, including immuno-oncology and rare diseases, as well as the regulatory aspect of the COVID-19 vaccines and an overview of the principles and applications of in situ hybridization techniques. This article presents the summary of five lectures along with selected figures, tables, and key literature references on this topic.

The second session of the 2024 European Society of Toxicologic Pathology (ESTP) Congress highlighted the significance of neural biomarkers and functional endpoints in nonclinical studies for detecting acute or delayed peripheral (PNS) and central nervous system (CNS) alterations and /or injury caused by drugs during development. The session emphasized the potential clinical translation of these biomarkers and endpoints and critical role of pathologists in correlating these biomarkers with the microscopic findings. Key neural biomarkers discussed included fluid-based biomarkers such as Neurofilament Light Chain (NF-L), Nonspecific Enolase (NSE), Tubulin Associated Unit (TAU), and Glial Fibrillar Associated Protein (GFAP) in blood and/or cerebrospinal fluid (CSF). These were evaluated in 15 in-vivo studies conducted with CNS and PNS toxicants. Safety pharmacology evaluation, such as the Irwin screen/the functional observation battery (FOB), were presented for detecting drug effects on behavior, motor and sensory functions in both rodents and nonrodent species, with or without histopathological correlate. Follow-up tests like nerve conduction velocity assessment were also highlighted. The session underscored the usefulness of noninvasive imaging modalities, including magnetic resonance imaging (MRI), nuclear imaging techniques, X-ray computed tomography, and ultrasound in preclinical studies. Overall, integrating neural biomarkers, safety pharmacology endpoints, advanced imaging modalities, and detailed histopathological analysis aids in better predicting neurotoxicity.

The last session of the 2024 European Society of Toxicologic Pathology Congress was dedicated to recent neuro concepts, encompassing various topics including artificial intelligence (AI) applied to toxicologic pathology, new technologies for visualization and/or analysis of tissues, as well as specific case reports. Four presentations detailed the role of AI and computational pathology for toxicologic pathologists, usage of cryofluorescent tomography in neuropathology, blood-brain barrier organoids in early drug screening, and spatial transcriptomics in toxicologic pathology. In addition, there were two short presentations about a spontaneous brain lesion in Beagle dogs as well as central nervous system lesions related to adeno-associated virus vectors administration in various preclinical species. This session underscored the current and prospective impact of emerging technologies on drug screening and development.

The fourth session of the 2024 European Society of Toxicologic Pathology (ESTP) Congress brought together lectures focused on the use of in vitro and in vivo models to investigate neurodegenerative diseases. Four presentations highlighted various aspects of neurodegenerative diseases including dementia, immune-mediated conditions, and neuromuscular disorders. The session began with an overview of animal models of dementia underscoring their critical role in understanding disease pathogenesis and supporting the development of effective therapeutic drugs. Subsequent presentations investigated immunological self-tolerance in autoimmune neurodegenerative diseases, such as multiple sclerosis and Guillain-Barré syndrome, and the application of in vitro models to study neuromuscular diseases such as amyotrophic lateral sclerosis. The final presentation examined cannabinoid-based therapeutic options for treating neurodegenerative diseases, highlighting their potential in neuroprotection and neurorepair. This session provided valuable insights into the latest research and advancements in neurodegenerative disease modeling and therapy, offering promising directions for improved modeling and therapeutic strategies.

The International Academy of Toxicologic Pathology (IATP) Satellite Symposium on "New Approach Methodologies (NAMs) for Neurotoxicity Assessment and Regulatory Perspectives," organized in Spain, addressed the growing need for improved assessment of neurotoxicity. Traditional neurotoxicity assessment using in vivo animal studies are impractical for testing the substantial number of environmental chemicals that currently lack data and in the early detection of neuro-related adverse reactions in drug discovery. The NAMs, including human in vitro assays and small model organisms, have been developed for faster and cost-effective assessment of neurotoxic potential. While NAMs offer improved practicality, utility, and valuable mechanistic insights, their integration into regulatory decision-making requires robust scientific validation and technical characterization. Confidence in and regulatory application of NAMs data can be supported by mapping cellular outcomes to neuropathological findings in mammals, including humans, through the Adverse Outcome Pathway (AOP) framework, and the Integrated Approach to Testing and Assessment (IATA). Case studies presented demonstrated the application of NAMs in chemical and drug safety evaluations, focusing on developmental neurotoxicity (DNT), Parkinson's disease, and drug-induced seizures. In conjunction with in vivo toxicology studies, NAMs represent a significant step toward advancing chemical and drug toxicity assessment via hazard identification and drug screening safety assessments.

Spatial transcriptomics (ST) is revolutionizing our understanding of the central nervous system (CNS) by providing spatially resolved gene expression data. This mini review explores the impact of ST on CNS research, particularly in neurodegenerative diseases like Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis. We describe two foundational ST methods: sequencing-based and imaging-based. Key studies are reviewed highlighting the power of ST data sets to map transcriptomes to disease-specific histomorphology, elucidate molecular mechanisms of regional and cellular vulnerability, integrate single-cell data with tissue mapping, and reveal receptor-ligand interactions. Despite current challenges like data interpretation and resolution limits, ST holds promise for identifying novel drug targets, evaluating their therapeutic potential, and bridging gaps between animal models and human studies to advance development of CNS-targeting compounds.

Hematoxylin and eosin (H&E) staining is a suitable approach for detecting substantial structural changes in neural tissues but is less sensitive for identifying subtle alterations to subcellular structures and various chemical constituents, including myelin. Neurohistological methods to better evaluate myelin integrity by light microscopy include acidophilic dyes (eg, eriochrome cyanine R, toluidine blue [used with hard plastic sections]); lipoprotein-binding dyes (eg, Luxol fast blue [LFB], Weil's iron hematoxylin); lipid impregnation with metals (eg, Marchi's, which uses osmium tetroxide for en bloc staining before embedding); and immunohistochemical (IHC) methods to highlight various antigens (eg, myelin basic protein [MBP] and peripheral myelin protein 22 [PMP22]). Some IHC methods reveal enhanced marker expression in damaged myelin (eg, matrix metalloproteinase-9 [MMP9], S100). In neuropathology investigations, H&E is the first-tier screening method, whereas myelin stains (often LFB alone or in combination with dyes that highlight other structural elements) are second-tier procedures performed in combination with other neurohistological procedures to examine neuroaxonal injury and/or glial responses. The choice of myelin method depends on such considerations as cost, institutional preference, the procedure (fixation and embedding medium), and the study objective.

Market authorization of a pesticide or biocide in Europe requires the hazard assessment of endocrine-disrupting properties, including the thyroid modality. Substances inducing thyroid histopathological and/or thyroid hormone effects in rodent studies need to be further investigated to rule out whether the substance can be considered as an endocrine disruptor for the thyroid pathway, including neurodevelopmental impact in pups and its relevance in humans. Histopathological assessment for identifying reliable biomarkers for assessing neurodevelopmental effects is an important aspect of this testing scheme in rats. Periventricular heterotopia in the corpus callosum and persistence of the external granular layer in the cerebellum have been proposed as potential histopathological biomarkers in the brain. The correlation in the cochlea for hearing impairment seen in rat pups derived from hypothyroid dams is another potential biomarker. Herein, we provide a brief overview of the histopathological endpoints. The technical challenges in correctly identifying these changes during brain development and their significance in detecting the impact of maternal hypothyroidism in rodents are discussed. This mini review is part of a scientific presentation by Dr Gangadharan during the developmental neurotoxicity (DNT) session at the 21st ESTP's Annual Congress (2024).

The 21st ESTP's (European Society of Toxicology Pathology) Annual Congress (2024) included a 3-hour scientific session on developmental neurotoxicity (DNT) as applied to chemical safety assessments. Key concepts of this session were to provide an introduction to public concerns around this endpoint, a status update on practical aspects of DNT studies, insights into the use of DNT studies within a regulatory context, as well as some pointers on how to evaluate specific parameters. Understanding the biological and technical variability in performing neuropathology examinations (such as morphometric evaluation) is critical during the course of DNT evaluation. Using thyroid hormone disruption as an example, challenges and pitfalls impacting data interpretation were discussed. Results from the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Thyroid Task Force regarding thyroid hormone-related neurodevelopmental toxicity in humans and rodents were presented. Histopathological findings in the brain and potential changes in the cochlea of pups associated with thyroid hormone imbalance in dams during pregnancy were shown. A case presentation from an Extended One-Generation Reproductive Toxicity Study (EOGRTS) showing histopathological findings in the absence of changes with morphometric endpoints was included. In conclusion, all session participants underscored the need for integrated data evaluation for DNT risk assessment.

Although blood triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels are useful for detecting antithyroid compounds in rodent toxicity studies, there are challenges with high variability due to sampling conditions. Here, we compared histopathological and immunohistochemical findings with blood hormone levels in rats treated with promoters of thyroid hormone metabolism to explore useful markers for hypothyroidism. Six-week-old male and female Sprague-Dawley rats (5/group) were administered phenobarbital sodium salt (NaPB) or nicardipine hydrochloride (NCD) by gavage for 28 days. Decreased serum T4 and increased TSH levels were detected at 100 mg/kg NaPB and 150 mg/kg NCD, whereas follicular cell hypertrophy occurred at lower doses of ≥ 30 mg/kg NaPB and ≥ 50 mg/kg NCD. There was no obvious change in T3 or T4 immunostaining in the thyroid unlike thyroid peroxidase (TPO) inhibitors, and uridine diphosphate-glucuronosyltransferase 1A6-positive area in the liver increased at doses lower than those affecting the serum T4 levels and generally the same as those at which hepatocellular hypertrophy and follicular cell hypertrophy were observed, indicating its usefulness in detecting thyroid hormone metabolism promoters. These results indicate that histopathology is useful for sensitive detection of hormone metabolism promoters and can be distinguished from TPO inhibitors by immunohistochemistry.