Journal of Toxicologic Pathology最新文献

This study investigated the effects on ovarian development in adult rats irradiated with γ-rays at fetal, neonatal, weaning, and early sexual maturation. Female Fischer-344 (F344) rats mated with male rats and their F1 offspring were irradiated with a single dose of 0.5 or 2 Gy of γ-rays on gestation day 15 or 19 (GD15 or 19), or postnatal day 5, 20, or 49 (PND5, 20, or 49). F1 females were reared until 27 weeks of age and necropsied. HE-stained specimens of the reproductive organs were prepared for histological examination (n=10-22 per group). The corpus luteum and follicle numbers were also counted in all ovaries. In addition, PCNA-stained specimens were used to count the primordial follicles. At 2 Gy, corpora lutea and follicle depletion was observed in the GD15, PND5, and PND20 irradiation groups. Instead of lost follicles consisting of granulosa cells, numerous tubular structures composed of Sertoli-like cells similar to those found in the testes were noted. In the GD19 group, the ovaries showed less sensitivity to γ-rays. In the PND49 irradiation group, the number of corpora lutea was normal; however, the number of follicles, including primordial follicles, decreased. At 0.5 Gy, the ovaries appeared histologically normal in all the groups; however, the number of follicles decreased in the GD15 and PND5 irradiation groups. In conclusion, we found that the timing of γ-ray irradiation significantly affected subsequent ovarian development, and the degree of change depended on the γ-ray dose.

In March 2024, a health hazard associated with the consumption of food products containing red yeast rice (beni-koji), which could lead to renal dysfunction, was reported in Japan. Puberulic acid (PA) was identified as an unintentional contaminant in these products; however, information on PA toxicity remains limited. The toxicological profile of PA was evaluated in a 28-day subacute toxicity study in rats. Synthesized PA was administrated by gavage to 6-week-old Crl:CD(SD) rats at 0, 1, 3, or 10 mg/kg/day (male) or 0, 0.3, 1, or 3 mg/kg/day (female) over 28 days, and satellite groups were used to evaluate the reversibility over a 14-day period. Male rats in the 10 mg/kg group exhibited increased urinary glucose and serum creatinine levels compared to controls. Histopathological examination revealed vacuolation, necrosis, and regeneration of proximal tubules in kidneys of all rats in the male 10 mg/kg and female 3 mg/kg groups. After the 14-day recovery period, focal interstitial fibrosis was observed in one male rats from the high-dose group, whereas no renal lesions were detected in the remaining rats of either sex. These results suggest that PA-induced nephrotoxicity is largely reversible under the conditions studied, although residual chronic lesions may occur in severe cases. Apoptosis/necrosis and diffuse hyperplasia of the glandular stomach mucosa were observed in male 3 and 10 mg/kg and female 3 mg/kg groups but were absent after the recovery period. These results indicate that, under the study conditions, the no-observed-adverse-effect level for PA was 1 mg/kg/day for both sexes.

In recent years, the development of Artificial Intelligence (AI) technology has led to the introduction and use of AI-based histopathological evaluation (AI pathology) by various companies and organizations. The AI Pathology Task Force of the Non-clinical Evaluation Expert Committee within the Drug Evaluation Committee of the Japan Pharmaceutical Manufacturers Association (JPMA) recognizes the importance of understanding the current use and needs surrounding AI pathology in Japan. This includes its role in non-clinical research fields, such as toxicity evaluation, drug efficacy evaluation, and basic research. In addition, assessing needs and challenges related to pathology image databases is essential. Between October and November 2023, with the cooperation of the Japanese Society of Toxicologic Pathology (JSTP), we conducted a questionnaire survey on non-clinical pathology image databases to explore these issues among JPMA-affiliated and JSTP-affiliated organizations. The questionnaire survey consisted of three items: (1) implementation and utilization of whole slide images, (2) use of AI pathology in non-clinical research fields, and (3) needs and feasibility of establishing a precompetitive pathology image database (repository) and AI pathology in the non-clinical pathology field. This report summarizes the survey results and serves as a foundation for guiding future directions in the use of AI pathology in non-clinical studies in Japan.

Lymphoblastic lymphoma (LBL) is an aggressive neoplasm characterized by the proliferation of undifferentiated lymphocytes. It primarily spreads to immune organs such as the thymus, spleen, lymph nodes, bone marrow, and liver. Although well-documented in humans, spontaneous LBL cases in laboratory animals are exceedingly rare. This study reports a case of T cell-derived LBL in a young adult ICR mouse, notably without bone marrow metastasis. This case provides valuable insights into the spontaneous occurrence of LBL in laboratory rodents by contributing to comparative oncology and preclinical research.

The use of artificial intelligence (AI) in non-clinical pathology is rapidly expanding. In this study, we conducted a literature survey of articles published after 2017 that used AI to analyze the histopathological images of experimental animals. We identified 44 articles that used AI for various purposes, including the detection of abnormal sites, determination and quantification of normal tissues, and classification of normal/abnormal images. AI systems or applications were either custom-built, commercially available, or a combination of both. Rats and mice were mainly used, and the liver was the most frequently analyzed organ. Our findings suggest that AI can be useful in non-clinical pathology and that collaboration between pharmaceutical companies or cooperation with IT experts can be a potential approach to further advance the utilization of AI in this field.

Intraepidermal nerve fiber (IENF) density is commonly evaluated to diagnose peripheral neuropathy. However, conventional two-dimensional (2D) analysis using rodent models shows high interstudy variability. Three-dimensional (3D) IENF analysis has been proposed for human skin biopsies because the spatial location of each nerve can be easily determined. However, no studies have compared 2D and 3D analyses of mouse cutaneous nerve fibers under the same conditions. We aimed to establish a more accurate analysis method for mouse cutaneous nerve fibers. We used the glabrous plantar metatarsal skin of male C57BL/6J mice. The middle area of the plantar skin was used for 2D and 3D analyses, and the marginal area was also investigated in the 3D analysis. Tissue transparency, nerve fiber-specific antibodies, confocal microscopy, and IMARIS software were used for the 3D analysis. The 3D analysis clearly defined branching points and continuity, allowing accurate IENF density measurement. Conversely, the 2D analysis could not accurately determine IENF density because it could not detect the continuity of the nerve from the dermis to epidermis. Thus, the actual IENF density from the 3D analysis was significantly less than that from the 2D analysis. In addition, the density and length of IENFs in the middle area were significantly higher than those in the marginal area. This 3D approach enables the precise capture of IENF trajectories with various parameters, establishing a standard method for evaluating peripheral neuropathy models. Furthermore, our findings indicate that comparative studies aiming to analyze mouse IENF need to consider the site of skin sampling.

Tobacco smoking is a major risk factor for human cancers including urinary bladder carcinoma. In a previous study, nicotine was shown to enhance rat urinary bladder carcinogenesis in a two-stage carcinogenesis model. In this study, we examined the progressive effects of nicotine on bladder carcinogenesis in F344 rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Nicotine, administered in drinking water for 52 weeks following 4 weeks of BBN treatment, significantly increased the incidence and multiplicity of invasive urothelial carcinoma in a dose-dependent manner. The Ki67 labeling index of bladder papillomas was significantly increased by nicotine in a dose-dependent manner. However, nicotine treatment did not affect the incidence or total number of tumors, and nicotine administration alone for 52 weeks did not result in any neoplastic lesions. These data suggest that while nicotine does not initiate carcinogenesis, it has the potential to promote invasive urinary cancers.

Histopathological, immunohistochemical, and ultrastructural characteristics of lymphocytic thyroiditis in an untreated four-year-old male beagle were described. Histopathologically, the thyroid glands were composed of two distinct cell types: round to oval cells with eosinophilic granular cytoplasm (Type A), which is consistent with the features of oncocytic oxyphils, and larger round cells with amphophilic or pale cytoplasm (Type B). These cell types extensively and diffusely infiltrated with a mixture of lymphocytes and plasma cells, destroying the follicular structure. Immunohistochemistry revealed that Type A cells were positive for thyroglobulin and cytochrome C, and that Type B cells were positive for calcitonin, synaptophysin, and cytochrome C. These results indicate that Type A and B cells stem from follicular and C cells, respectively. Ultrastructural investigation showed that microfollicles and microvilli were evident in the cytoplasm and along the luminal surface of Type A cells. Thus, the lymphocytic thyroiditis observed in the beagle exhibited a morphology similar to that of Hashimoto thyroiditis in humans, particularly in view of an oncocytic alteration of follicular cells.

Pulmonary emphysema is primarily attributable to prolonged exposure to cigarette smoke. Novel tobacco substitutes, such as heated tobacco products, have emerged as healthier alternatives to cigarettes. The effects of short-term inhalation of a heated tobacco product, Ploom TECH+ (PT+), on the lungs of mice were compared with those of 3R4F reference cigarettes. Male 10-week-old C57BL mice were exposed to clean air (control), 3R4F, or PT+ for 1 h/d, 5 d/week for two or four weeks. After four weeks of exposure, the number of inflammatory cells and proportion of neutrophils and lymphocytes in the bronchoalveolar lavage fluid and the number of macrophages in the lung tissue increased significantly in mice exposed to 3R4F but not in those exposed to PT+. Changes in the expression of genes related to inflammation-related factors were observed in the lung tissues of mice exposed to 3R4F for two and four weeks. Chemokine (C-C motif) ligand 17, resistin-like alpha, and lipocalin 2 were among the upregulated genes. In our previous short-term tobacco inhalation study, these genes were identified as useful markers of emphysema effects induced by exposure to cigarette smoke from Peace cigarettes, detectable before pulmonary histological changes appeared. These effects were not observed in the PT+-exposed mice. These data suggest that PT+ caused less damage to the lungs of mice than 3R4F, particularly regarding the induction of emphysema.

Rodents are widely used to study the toxicity of chemicals; however, differences between species indicate that the results from rodents are not always directly transferable to humans. The health of workers exposed to various chemicals and particulates at high doses or for long periods is at risk. Respiratory bronchioles and lobular structures, which are demarcated by interlobular septa, are key sites for occupational lung diseases such as pneumoconiosis; however, these structures vary among animal species. Understanding these differences is crucial for studying the pathology of human occupational lung diseases. However, there is a lack of reviews focusing on these structures in different species. This review explores the lung anatomy of various mammals and its functional importance in disease to connect animal studies with human occupational lung diseases. Our results indicate that artiodactyls, especially small pig breeds and goats, are ideal for research because their respiratory bronchioles and lobular structures are similar to those of humans. This review aims to enhance the use of experimental animal data and improve our understanding of human occupational lung diseases, thereby facilitating early disease detection, treatment, and prevention.