Fundamental Toxicological Sciences

2024 - Vol. 11 No. 4

2024 - Vol. 11

Data Report
A 90-day repeated oral dose toxicity study of p-cymene in rats Vol.11, No.4, p.169-181
Makiko Kuwagata , Yuko Doi , Hirokatsu Saito , Mariko Tsurumoto , Toshime Igarashi , Takuya Nishimura , Yuhji Taquahashi , Yoko Hirabayashi , Satoshi Kitajima
Released: July 09, 2024
Abstract Full Text PDF[1M]

p-Cymene, is a monocyclic monoterpene hydrocarbon, commonly used as a flavoring agent in food. A 90-day repeated oral toxicological study of p-cymene was conducted to examine the toxicological properties and determine the no-observed-adverse-effect level (NOAEL) of p-cymene in Crl:CD (SD) rats at the following doses: 0 (corn oil), 2.4, 12, and 60 mg/kg/day. No mortality or abnormal clinical signs were observed in the treatment groups. The body weight, food consumption, ophthalmoscopy, and gross pathology of the rats were also not affected by p-cymene treatment. However, in the 60 mg/kg group, certain parameters decreased in males, including hemoglobin and hematocrit, red blood cell count, triglyceride, total protein, and albumin. In females, urine volume and total potassium excretion increased, whereas specific gravity, and sodium, potassium, and chlorine concentrations decreased. Increased liver weight was observed in both males and females. Histopathological observations revealed centrilobular hepatocellular hypertrophy. In the 12 mg/kg group, no adverse effects of p-cymene treatment were observed in both sexes. In conclusion, the NOAEL of p-cymene was 12 mg/kg/day for both sexes under the present experimental conditions, considering the alterations in urinalysis, hematology, clinical biochemistry, and histopathology.

Original Article
Utility of urinary N-titin as a muscle atrophy biomarker in dexamethasone-induced muscle atrophy model mice Vol.11, No.4, p.159-168
Katsunori Ryoke , Kana Ishizuka , Yuzo Yasui , Kazuma Kondo , Noriko Suzuki-Kemuriyama , Tatsuya Maekawa , Katsuhiro Miyajima
Released: July 02, 2024
Abstract Full Text PDF[2M]

Titin is a giant protein that is specifically expressed in striated muscle and essential for the maintenance of sarcomere structure and function. Recently, the N-terminal fragment of the Titin (N-titin) has been reported to show high levels in human urine in patients with muscular diseases and is expected to serve as a diagnostic biomarker for these diseases. In this study, we examined the utility of N-titin as a biomarker to detect muscle atrophy in mice. Male BALB/c mice (6 weeks of age, n=5 per group) were given 10 mg/L dexamethasone (DEX) dissolved in drinking water for 4 weeks. The gastrocnemius muscle (GAS) weight was significantly decreased and mRNA levels of muscle atrophy-related genes (Atrogin-1 and MuRF-1) were increased in the GAS after 4 weeks of DEX treatment. Although there were no degenerative/necrotic changes in the histopathological examination, the muscle fiber cross-sectional area significantly decreased in the GAS. On the other hand, there were no DEX treatment-related changes in the muscle weights and the muscle fiber cross-sectional area in the soleus muscle. These results suggest that 4-week of DEX treatment preferentially caused atrophy of fast-dominant muscle. Under the condition of this study, urinary N-titin/CRN ratio markedly increased from Week 2 of the DEX treatment. From the above results, the urinary N-titin/CRN ratio could be a biomarker for monitoring skeletal muscle atrophy in mice.

Original Article
Evaluation of pharmaceutical concentrations and antimicrobial activity in river water from the Tone River system in Gunma Prefecture, Japan Vol.11, No.4, p.149-157
Tsuyoshi Murahashi , Jun-ichi Yamagishi , Taiju Igarashi , Mako Kawai , Seiji Yamasaki , Kunihiko Nishino , Toshiyuki Higuchi
Released: July 02, 2024
Abstract Full Text PDF[1M]

We investigated the characteristics of pharmaceutical concentrations and antimicrobial activities in river water from the Tone River system in Gunma Prefecture. The mean concentrations of diphenhydramine, clarithromycin, carbamazepine, and bezafibrate in the midstream of the Tone River were 8.6, 29, 3.8, and 8.1 ng/L, respectively. Their concentrations were nearly half of those in the midstream of the Ayase River, the main water source of which is wastewater. Seasonal variations in pharmaceutical concentrations were high in winter and low in late spring and autumn. This variation depended on the flow rate of the river water, which in turn depended on the rainfall in the upstream area. Except for bezafibrate, the pharmaceutical concentrations in river water did not change after 5 days of incubation at 30°C, indicating that biochemical degradation during the hot summer season was minimal. A comparison of the concentrations between the sampling locations revealed that the pharmaceutical load was proportional to basin population, and the annual fluxes of pharmaceuticals from Gunma Prefecture were estimated to be 98, 210, 28, and 53 kg/year, respectively. Disc diffusion assay of some samples of Tone River water extracts revealed inhibition zones owing to their antimicrobial activity. However, no relationship was observed between the diameter of the inhibition zone and clarithromycin concentration in the river water. These results suggest that the antimicrobial activities of the river samples were not dependent on clarithromycin. We are currently investigating the pollution and drug-resistant bacteria present in the Tone River in detail.