International Journal of Toxicology最新文献

Parkinson's disease (PD) is characterized by the abnormal aggregation of α-synuclein, which can originate in the gut and propagate to the brain. Recent evidence suggests a correlation between metabolic disorders, particularly diabetes, and PD pathogenesis through the gut-brain axis. Methylglyoxal (MGO), a glucose-derived metabolite produced by gut bacteria such as Proteus mirabilis, is implicated in protein misfolding and glycation. This study investigated whether MGO induced α-synuclein aggregation in intestinal enteroendocrine cells and explored the underlying mechanisms. Mouse enteroendocrine STC-1 cells were treated with MGO (0.01-1 mM) for 36 h, and changes in α-synuclein aggregation, neuronal markers, and relevant signaling pathways were assessed. MGO at 1 mM significantly reduced cell viability and neuronal marker expression, and concentrations of 0.1 and 1 mM increased α-synuclein aggregation. MGO also inhibited SIRT1 expression, leading to increased Hif-1α transcription and reduced expression of autophagy-related proteins Beclin1 and LC3B. These changes were accompanied by mitochondrial dysfunction, as evidenced by decreased Bcl2, increased cytochrome C expression, and reduced levels of the antioxidant factor HO-1. Our findings provide the first evidence that MGO directly induces α-synuclein aggregation in enteroendocrine cells via the SIRT1-Hif-1α-autophagy pathway dysregulation, establishing a potential mechanistic link between gut microbiome-derived metabolites and PD pathogenesis. These results suggest that intestinal glycation may be a critical target for preventing α-synuclein pathology originating in the gut.

The Tg.rasH2 mouse is a validated bioassay system for evaluation of carcinogenic potential, and it is confirmed to be sensitive to both genotoxic and nongenotoxic carcinogens. This is also one of the models specified in ICH S1B Guidance, enabling 6-month carcinogenicity studies as an alternative to traditional 2-year bioassays. We conducted a 26-week carcinogenicity study at our test facility on Tg.rasH2 mice sourced from CLEA Japan Inc., in a process to generate historical control database. Although historical control data have been published for these mice sourced from Taconic Biosciences Inc., USA, there is a dearth of published literature citing spontaneous incidence of neoplastic findings in Tg.rasH2 mice sourced from CLEA Japan. We have therefore presented the spontaneous tumor incidence in our study and compared it with the previously published tumor incidence for Tg.rasH2 mice sourced from Taconic, USA. The comparison reveals a similarity of tumor incidence between the mice from these two sources.

The rasH2^TM mouse model has become the primary alternative to a 2-year mouse carcinogenicity study in safety testing of human pharmaceuticals. In this publication, we present the neoplastic incidence for 2291 control males, 2191 control females, 575 MNU-treated males, 559 MNU-treated females, and 210 urethane-treated males and females in rasH2^TM carcinogenicity studies conducted from 2012 to 2024 as well as survival, body weights, and selected non-neoplastic microscopic findings for control and positive control mice. Inclusion of a positive control group is recommended to ensure regulatory acceptance. Survival of controls at the end of 26 weeks was approximately 96% with similar percentages of survivors in the 13-week urethane-treated positive controls in contrast to a survival percentage of approximately 17% in MNU-treated positive controls. Malignant neoplasms accounted for most early deaths in control and positive control mice. Major neoplasms in control mice included Harderian gland adenomas, bronchioloalveolar adenomas and carcinomas, and splenic hemangiosarcomas, while the predominant neoplasms in MNU-treated mice included squamous cell papillomas and carcinomas of the nonglandular stomach and malignant lymphomas. The percentage of urethane-treated mice developing bronchioloalveolar neoplasms was over 98% in both sexes. When compared to control mice, MNU-treated mice had lower mean body weights while urethane-treated mice had higher mean body weights. Major non-neoplastic findings in control mice were subcapsular cell hyperplasia (51.78% to 89.41%) and skeletal muscle myopathy (77.17% to 80.71%). Other non-neoplastic findings included retinal degeneration in MNU-treated mice (∼87% in both sexes) and bronchioloalveolar hyperplasia in urethane-treated mice (≥53% in both sexes).

Diabetes and hypertension often coexist and need complex pharmacological management. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used for glycemic control, and telmisartan, an angiotensin II receptor blocker, is the preferred treatment for hypertension. Thus, we have conducted a 1-month exploratory combination safety and toxicity study in male Wistar Han rats. Animals were administered 100 mg/kg/day of sitagliptin or telmisartan individually, or in combination by oral gavage. We have evaluated effects on body weight, feed intake, clinical chemistry, and hematology parameters, and microscopic examination of liver, kidney, adrenal glands, heart, lungs, lymphatic organs, and gastrointestinal tract. The combination showed a decrease in body weight gain, feed intake, hematocrit, reticulocytes, WBCs, serum triglycerides, AST, total protein, globulin, and heart weight, and increased serum levels of urea, phosphorous, magnesium, potassium, and kidney weight. Co-administration showed an additive effect on decrease in WBC counts, potentiating the effects on decreased serum triglycerides and increased phosphorous levels and kidney weights, and a synergistic effect on serum AST levels. Sitagliptin attenuated the changes caused by telmisartan on reticulocyte counts, serum creatinine levels, and liver and thymus weights. Administration of the individual compounds caused a reduction in spleen weight, though the combination had no effect. Sitagliptin, telmisartan, or combination dosing showed no significant organ toxicity upon histopathological examination. It appears that co-administration of telmisartan and sitagliptin is well tolerated in rats. Three-month toxicity studies, in both genders, with full toxicokinetic profiling and thorough tissue examination, will be necessary to support the combination's toxicity profile.

Although Bisphenol A (BPA) is still used in consumer products, concerns about its toxicity led to the adoption of structurally related replacement products such as Bisphenol F (BPF) and Bisphenol S (BPS). Unfortunately, comparing the biological responses to BPA and BPA substitutes in vivo can be challenging, as the available information is often derived from different studies using various animal strains and experimental protocols. To address this issue, we directly compared the impacts of BPA, BPF, and BPS in the same in vivo exposure study. Briefly, 8-week-old male Fischer rats were exposed to BPA, BPF, or BPS (at five different doses) and to 17α-ethinylestradiol (positive control for estrogenicity) by gavage for 28 consecutive days. Rat health, dietary intakes, and weight gains were monitored, 24-hour urine samples were collected, and blood and tissues were harvested at the terminal necropsy. The impacts of BPA, BPF, and BPS on rat weight gains, organ weights and histology, liver enzymatic activities, hematology, clinical chemistry, and serum hormone levels were relatively modest and mostly limited to the highest doses administered. However, bisphenol cross-contamination observed in urine samples from the vehicle control group may have interfered with the evaluation of their effects at lower doses. Although BPA, BPF, and BPS exposures all shared similarities with the 17α-ethinylestradiol positive control group, their impacts on serum hormone levels and endocrine-responsive tissues also presented noticeable differences. This suggests that BPA, BPF, and BPS may interfere with endocrine functions through slightly different molecular mechanisms.

Probiotics are living microorganisms that, when given in sufficient quantities, boost the host's health. Probiotics have been used more often in recent years as dietary supplement to prevent illnesses, including diarrhea, obesity, and constipation. The probiotic strain Bacillus subtilis BSP110 is being developed as a dietary supplement. In this work, we assessed the in vivo safety of the probiotic strain Bacillus subtilis BSP110 in rats as per OECD-423 and 407 guidelines. Female rats were given a single oral (gavage) dosage of 2000 mg/kg (4 × 10¹¹ CFU/g) to assess the maximum tolerated dose (MTD). This was followed by a 28-day sub-acute toxicity study in which Bacillus subtilis BSP110 was given orally (gavage) once daily to male and female rats at dose levels of 250, 500, and 1000 mg/kg/day. No effects of Bacillus subtilis BSP110 were noted at any of the dosage levels given over the course of 28 days. Between the control and test groups, there was no discernible difference in body weight, clinical symptoms, urinalysis, hematological tests, clinical biochemistry, gross pathology, or histopathological evaluation. Additionally, in vitro cytotoxicity was evaluated using the MTT assay with the VERO cell line, and Bacillus subtilis BSP110 was found to be non-cytotoxic at 4 × 10¹¹ CFU/kg. The single dose MTD was ≥2000 mg/kg, and the NOAEL was 1000 mg/kg/day.

The international cosmeceutical sector has experienced unprecedented expansion, compelling regulatory bodies to enhance and update systems to tackle consumer protection, product effectiveness, and ethical issues. This review critically evaluates and contrasts regulatory settings in key markets, such as the European Union, United States, Canada, Japan, China, India, and Brazil. The examination is concentrated on key features including product definitions, pre-market approval procedures, and ingredient regulation, labeling requirements, post-market surveillance, and integrating ethical and environmental considerations. The outcome shows significant advances in regulatory harmonization, especially in the area of ingredient safety and adverse event reporting; however, there are still considerable challenges. Pioneering among these are the lack of a standard definition for "cosmeceuticals," highly variable ingredient limitations, and uneven application practice across jurisdictions. The speedy growth of e-commerce and cross-border sales additionally complicates regulatory control, adding to the possibility of non-compliant or counterfeited products reaching consumers. The review also identifies a shortage of empirical evidence to document the actual impact of recent regulatory reforms in the real world, as well as on innovation and market access. The present study recommends the promotion of international harmonization of standards, enhancement of post-market surveillance, convergence of ethical and sustainability dimensions, and targeted support for small- and medium-sized enterprises. Henceforth, while important progress has been achieved, the future of the industry rests on creating nimble, science-informed, and internationally harmonized regulatory systems that can keep pace with changing technologies and consumers' and public health priorities, ensuring both consumer safety and industry innovation.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 24 silicate ingredients that are solid inorganic oxides, comprising, in part, silicon dioxide, which can be derived from naturally occurring minerals or can be produced synthetically. Reported functions in cosmetics include abrasives, absorbents, bulking agents, and deodorant agents. The Panel reviewed all relevant data and concluded that the silicate ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment when formulated to be non-irritating, with the exception that the available data are insufficient to make a determination of safety for the use of naturally sourced (i.e., mined) silicate ingredients in products that may be incidentally inhaled.