Fundamental Toxicological Sciences

2022 - Vol. 9 No. 3

2022 - Vol. 9

Original Article
Fecal microRNA223 as an indicator of recovery in chronic DSS colitis model in rats Vol.9, No.3, p.103-110
Terutaka Kodama , Yuko Togashi , Naomi Matsutani , Seiichiro Kurashige , Toyohiko Aoki , Yasuteru Otagiri
Released: July 06, 2022
Abstract Full Text PDF[1M]

Using a rat dextran sulfate sodium (DSS)-colitis model, we elucidated that the expression of miRNAs in colorectal tissues, plasma, and feces, particularly miR-31a-5p, miR-181b-5p, and miR-223-3p, could be used as noninvasive biomarkers to evaluate the reversibility of the model. We further investigated whether changes in miRNA levels were reproducible in chronic DSS-induced colitis in rats. Male SD rats were administered 5% DSS in drinking water for two cycles. Cycle 1 consisted of a 7-d dosing period and 14-d recovery period, followed by Cycle 2 consisting of a 5-d dosing period and 7-d recovery period. In-life parameters and the disease activity index (DAI) were respectively examined or calculated daily. Colon length and pathological changes were assessed postmortem in Cycle 2. A panel of nine miRNAs was also measured in colorectal tissues, plasma, and feces using digital PCR. The changes in DAI score and colon length were evident in Cycle 2. Erosive and inflammatory changes were observed in the colon and rectum following DSS treatment. At the end of the off-dose period of Cycle 2, the histological changes in the rectum worsened, while the colon changes showed recovery. The expression patterns of all miRNAs were almost the same in Cycle 2 when compared to those in a previous study (Kodama et al., 2021). Fecal miR-223-3p could be also a useful non-invasive indicator to evaluate the reversibility in chronic DSS-induced colitis in rats.

Original Article
Multigenerational effects of neonicotinoids (acetamiprid, clothianidin) on growth, fertility and motility of nematode C. elegans Vol.9, No.3, p.95-102
Yuko Sakaguchi , Saki Mikami , Naoko Ikoma , Sadahiro Kawazoe , Masaya Uchida , Nobuaki Tominaga , Koji Arizono , Nobuhiro Ichikawa
Released: July 06, 2022
Abstract Full Text PDF[2M]

Neonicotinoids are potent agonists of nicotinic acetylcholine receptors that exert insecticidal effects by causing abnormal excitation of the nervous system. Neonicotinoids and their metabolites effect in mammals, including humans, have become a concern. In the present study, we evaluated the effects of chronic exposure of two neonicotinoids, acetamiprid (ACE) and clothianidin (CTD), on Caenorhabditis elegans. We used 1, 10, 100, and 1000 µM solutions of nicotine, ACE, and CTD dissolved in 1% dimethyl sulfoxide (DMSO). Bioassays and motility tests, which are neurotoxicity assessments, were performed on the L1‒L2 larvae of wild-type C. elegans. To evaluate the effect of exposure over multiple generations and the correlation between concentrations and generations, the same study was conducted on the second and third generations of the exposed group. The bioassay results showed concentration-dependent adverse effects: body length, maturity rate, and lifetime number of pups decreased for both ACE and CTD for the first generation. In a multi-generation study, the effect intensified with the progression of generations, and the toxicity of both ACE and CTD was cumulative. This effect was more pronounced in breeding studies. The motility test results showed concentration-dependent adverse effects, such as a decrease in the number of behaviors for both ACE and CTD in both tests for the first generation. In a multi-generation study, the effect intensified with the progression of generations, and this effect was more pronounced with ACE exposure. Thus, the chronic exposure to ACE and CTD may cause cross-generational adverse effects, especially on C. elegans reproduction and motion.

Original Article
Occupational exposure of pharmacists to drugs during tablet crushing and its countermeasures Vol.9, No.3, p.85-93
Tsuyoshi Murahashi , Miho Arai , Kengo Ogata , Manami Matsumoto , Toshiyuki Higuchi
Released: May 24, 2022
Abstract Full Text PDF[1M]

To estimate the exposure of pharmacists to drugs during tablet crushing, we collected room dust in four pharmacies and a hospital and analyzed the concentrations of the drug ingredient. The ingredient concentrations in the room dust were detected in the range of 15–18000 µg/m3, and the median concentration was 320 µg/m3. The amount of exposure to pharmacists was estimated between 0.8–960 µg/crush, with a median of 17 µg/crush, when the respiratory volume of the pharmacist was 8 L/min. These maximum and median values were more than 10 times higher than those during the previously reported powder preparations, demonstrating that the working environment for pharmacists who crushed tablets posed more health hazards. As countermeasures, working on a bench with dust remover reduced the exposure by 99.0% compared to that on a normal bench, and wearing a medical mask reduced the exposure by 97%. The combined reduction rate of both measures was calculated to be over 99.9%. Moreover, we compared the estimated exposure by the crusher with the rotatory blade and that with two rotatory mortars and found that the estimated exposure using the latter was much less (lower than 1/1000) than that with the former. Thus, the above measures can be used to reduce the exposure of pharmacists to drugs during tablet crushing.

Original Article
Genotoxicity and subchronic toxicity of a kaempferol aglycone-rich product produced from horseradish leaves Vol.9, No.3, p.71-83
Hiroki Kimoto , Sakura Fujiwara , Noriyuki Koyama , Tohru Uesugi
Released: May 19, 2022
Abstract Full Text PDF[933K]

Kaempferol is a kind of natural flavonoid in many edible plants and reportedly has various physiological effects. In the present study, we conducted the genotoxicity (in vitro and in vivo) and 13-week subchronic toxicity studies of a new product, a kaempferol aglycone-rich food produced from enzyme-treated horseradish leaves, to evaluate its safety. In the bacterial reverse mutation test, the kaempferol aglycone-rich product showed positive results in some Salmonella typhimurium strains in the presence or absence of metabolic activation as well as other flavonoids. However, it did not increase micronucleated polychromatic erythrocytes taken from male Sprague−Dawley (SD) rats administered orally by gavage up to 4000 mg/kg for 2 consecutive days. In the 13-week subchronic toxicity study in SD rats, the kaempferol aglycone-rich product was orally administered by gavage once daily to SD rats for 13 weeks (91 days) at a dose of 500, 1000, or 2000 mg/kg/day. No toxic changes were observed at up to 2000 mg/kg/day. In conclusion, these findings indicated that the kaempferol aglycone-rich product was not genotoxic in vivo. The no-observed-adverse-effect level for both male and female rats was 2000 mg/kg/day, the highest dose tested, in the 13-week subchronic toxicity study in rats, suggesting it is safe for use as a food.