Fundamental Toxicological Sciences

2021 - Vol. 8 No. 5

2021 - Vol. 8

Original Article
Diverse unintended on-target mutations induced by zygote genome-editing using CRISPR/Cas9 system Vol.8, No.5, p.161-167
Toshime Igarashi , Yukuto Yasuhiko , Ryuichi Ono , Erika Tachihara , Miki Uchiyama , Atsuya Takagi , Yu Takahashi , Makiko Kuwagata , Satoshi Kitajima
Released: October 28, 2021
Abstract Full Text PDF[2M]

With the advent of the CRISPR/Cas9 system, genome editing in various fields is advancing. Unintended mutation in off-target regions is a major problem of genome editing using the CRISPR/Cas9 system, and it is being reviewed. However, we found a high frequency and various unintended mutations in the “on-target” region when we generated a “knock-in” mouse with point mutation using this technique to develop a supernumerary rib model. Additionally, an inserted sequence of unknown origin was observed. Furthermore, these mutations were transferred to the next generation, even if tandem knock-in or large deletions occurred. These strongly suggest that a proper selection that meets the purpose is essential when considering the safety of foods and medicines using the genome-editing technology.

Toxicomics Report
Knockdown of deubiquitinating enzyme Usp34 confers resistance to methylmercury in HEK293 cells Vol.8, No.5, p.157-160
Jong-Mu Kim , Jin-Yong Lee , Min-Seok Kim , Sawako Shindo , Takeshi Kumagai , Akira Naganuma , Gi-Wook Hwang
Released: October 20, 2021
Abstract Full Text PDF[907K]

We have previously reported that the ubiquitin–proteasome system, which is a selective proteolytic system, plays an important role in determining sensitivity to methylmercury in various cultured cells. Deubiquitinating enzyme is a negative regulator of protein degradation through the ubiquitin–proteasome system. In the present study, we searched for deubiquitinating enzymes that affect sensitivity to methylmercury by RNA interference, and identified ubiquitin-specific protease 34 (Usp34) as a deubiquitinating enzyme that confers methylmercury resistance to HEK293 cells by suppressing gene expression.

Original Article
Relationship between renal dysfunction and change in serum electrolyte levels in patients administered with liposomal amphotericin B Vol.8, No.5, p.147-155
Kaito Yamashiro , Atsushi Hirata , Ryosuke Ota , Fumihiko Ogata , Takehiro Nakamura , Naohito Kawasaki
Released: October 20, 2021
Abstract Full Text PDF[873K]

Liposomal amphotericin B (L-AMB) causes renal dysfunction and hypokalemia, but little is known about the relationship between serum electrolyte levels before or after administration and renal dysfunction. The changes in serum electrolyte levels before and after administration in patients with L-AMB-induced renal dysfunction were examined. This study included 87 patients administered L-AMB at Kindai University Nara Hospital. The number of patients with G1 (serum creatinine (Scr) levels (mg/dL) > 1.07–1.605 in male and > 0.79–1.185 in female) and G2 (Scr level > 1.605–3.21 in male and > 1.185–2.37 in female) was 25 (28.7%) and 14 (16.1%), respectively. Multivariable logistic regression analysis revealed the onset of G2 was significantly associated with baseline estimated glomerular filtration rate (eGFR), odds ratio (OR): 0.99, 95% confidential interval (95% CI): 0.95–1.02 and, baseline serum potassium levels, OR: 3.50, 95% CI: 1.16–12.06. Serum potassium levels were significantly higher in the G2 group than in the G0 group (Scr levels < 1.07 in male and < 0.79 in female) during the study period. These results indicated the changes in serum potassium levels are associated with renal dysfunction. Monitoring of serum potassium levels before and after administration may contribute to the evaluation of renal dysfunction in patients receiving L-AMB.

Original Article
Extract of Siraitia grosvenorii (Luo Han Guo) protects against hepatic fibrosis in mice on a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet without trans fatty acids Vol.8, No.5, p.135-145
Noriko Suzuki-Kemuriyama , Akari Abe , Sae Nakane , Kinuko Uno , Shuji Ogawa , Atsushi Watanabe , Ryuhei Sano , Megumi Yuki , Katsuhiro Miyajima , Dai Nakae
Released: October 20, 2021
Abstract Full Text PDF[4M]

Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease that presents with steatosis, inflammation, and fibrosis and can progress to cirrhosis and cancer. Thus, methods for controlling this lifestyle-related disease are urgently needed. An extract of Siraitia grosvenorii (Luo-Han-Guo) (luohanguo extract (LE)) is widely used as a sweetener; its major bioactive constituents, mogrosides, have shown anti-oxidative and anti-inflammatory properties, exerting multiple pharmacological effects in various disorders. In the present study, we investigated the effects of LE on NASH induced in mice fed a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet without trans fatty acids (CDAA-HF- T(−)). Mice were fed with CDAA-HF- T(−) and drinking water containing LE at concentrations of 0%, 0.2%, 0.6%, and 2% for 28 weeks. Our results showed that LE was not toxic under the experimental conditions evaluated. In the liver of mice fed CDAA-HF- T(−), LE did not affect steatosis or early phase events from macrophage recruitment to hepatocyte death but inhibited late phase events, the progression of inflammation, and fibrosis (mechanisms independent of transforming growth factor-β signaling). Sweeteners with beneficial biological functions, such as LE, may be useful for controlling lifestyle-related diseases, such as NASH, and promoting human health.