Fundamental Toxicological Sciences

2019 - Vol. 6

2019 - Vol. 6

Toxicomics Report
Effects of lithium on developmental toxicity, teratogenicity and transcriptome in medaka embryos Vol.6, No.2, p.31-36
Nobuaki Tominaga , Seiya Shino , Masaya Uchida , Hiroshi Ishibashi , Midori Iida , Tadashi Okobira , Kayla Arizono , Noriaki Yoshida , Koji Arizono
Released: February 15, 2019
Abstract Full Text PDF[2M]

In this study, we assessed embryonic developmental toxicity and teratogenicity of lithium (Li) on medaka (Oryzias latipes) and predict the molecular mechanisms of their effects using a nanosecond pulsed electric field (nsPEF) technique and bioinformatics analysis. The microscopic observation revealed that the 1 mg/L LiCl treatment causes the most severe deformation effects, such as thrombus, heart hypertrophy, deformation of eyes, and growth retardation to embryos. The RNA-seq analysis identified 2,483 up- and down-regulated genes, such as histogenesis and organ growth related genes, in 2 day post-fertilization embryos after treatment with nsPEF and 1 mg/L LiCl. In addition, bioinformatic analyses showed that LiCl affects several aspects of gene ontology, such as molecular functions and cellular components, and some pathways, such as spliceosome, cell cycle, selenocompound metabolism, TGF-β signaling, and RNA degradation. The upregulation of GSK3B (signal transduction and cell growth), BAX (apoptosis), and MAP3K8 (cell death, arrest of cell cycle, and inflammation) genes were also observed in embryos exposed to LiCl. Our results suggest that the incorporation of Li compounds into medaka eggs using nsPEF shows adverse effects to the development and teratogenicity, and that these toxic effects may be affected by the alterations of certain gene expression in medaka embryos.

Letter
Protective effect of the Kampo formula “Juzen-taiho-to” on isoniazid- and rifampicin-induced hepatotoxicity in mice Vol.6, No.1, p.25-29
Hiroki Yoshioka , Shiori Fukaya , Sarah Tominaga , Akito Nagatsu , Nobuhiko Miura , Tohru Maeda
Released: February 06, 2019
Abstract Full Text PDF[1M]

The aim of this study was to investigate whether the Japanese herbal medicine Juzentaiho-to (JTX) showed attenuating effects on isoniazid- and rifampicin-induced liver injury. Seven-weekold male Institute of Cancer Research mice were orally administered JTX or saline once a day at 9:00 for 3 days. Additionally, the mice received a mixture of 80 mg/kg isoniazid and 160 mg/kg rifampicin (10 mL/kg) via intraperitoneal injection three times (at 19:30) per 24 hr period. Twenty-four hours after the last administration of isoniazid/rifampicin, the mice in each group were sacrificed and blood was removed to obtain the plasma and livers. Mice that had received isoniazid/rifampicin showed high plasma levels of alanine aminotransferase, aspartate aminotransferase, and interleukin-6. In addition, the mice injected with isoniazid/rifampicin displayed increased hepatic lipid peroxidation and receptor-interacting protein-1 and -3 levels. Treatment with JTX prevented an isoniazid/rifampicin-induced increase in levels of alanine aminotransferase and aspartate aminotransferase, lipid peroxidation, and receptor-interacting protein changes. Our results suggest that JTX protects against isoniazid/rifampicin-induced hepatic injury by modulating oxidative stress and inflammatory responses.

Original Article
Supplementation with lower doses of EGCg reduces liver injury markers of type 2 diabetic rats Vol.6, No.1, p.15-23
Kazuki Mochizuki , Yu Tan , Yumiko Uchiyama , Takuji Suzuki , Natsuyo Hariya , Toshinao Goda
Released: January 30, 2019
Abstract Full Text PDF[1M]

(-)-Epigallocatechin-3-gallate (EGCg), a major catechin in green tea, eliminates reactive oxygen species and development of lifestyle-related diseases. However, excessive EGCg intake could induce adverse effects, particularly liver injury. We examined whether optimal dietary doses of EGCg reduces the risk of liver injuries in non-obese type 2 diabetic Goto-Kakizaki (GK) rats by examining gene expression of the proinflammatory cytokines interleukin (IL)-1β, IL-18 and tumor necrosis factor-α (TNF-α) and fibrosis-related matrix metalloproteinases (MMPs) in the liver. GK rats at 9 weeks of age were fed a control high-fat diet or a high-fat diet containing 0.1%, 0.2% or 0.5% EGCg (w/w) for 25 weeks. Expression of mRNA and proteins related to inflammation were determined by qRT-PCR and western blot analysis, respectively. IL-1β and IL-18 mRNA in the liver were reduced by EGCg supplementation at concentrations of 0.1% and 0.1%-0.2%, respectively, but not at concentrations of 0.2% and 0.5% (IL-1β) or 0.5% (IL-18) EGCg. TNF-α mRNA in the liver was reduced by supplementation with EGCg at concentrations of 0.1%-0.5%. Expression of MMP2 in the liver was reduced by EGCg supplementation at a concentration of 0.2%, but not 0.1% or 0.5%. Importantly, IL-18 protein levels in the liver and serum were reduced by 0.1% EGCg, but not by 0.5%. EGCg supplementation at concentrations from 0.1% to 0.5% did not induce increases in the expression of liver injury marker genes, while low doses (0.1%–0.2%) of EGCg in GK rats reduced expression of injury-associated genes in the liver.

Letter
Investigation of DNA damage of glycidol and glycidol fatty acid esters using Fpg-modified comet assay Vol.6, No.1, p.9-14
Ryo Inagaki , Kohei Uchino , Yuko Shimamura , Shuichi Masuda
Released: January 18, 2019
Abstract Full Text PDF[2M]

Glycidol fatty acid esters (GEs) are food process contaminants detected in edible oils. It has been thought that glycidol is released from GEs by lipase in vivo, and shows genotoxicity. While DNA damage from glycidol has been reported, there is very little information on the DNA damaging potency of GEs in vivo. Therefore, we estimated DNA damage of glycidol and glycidyl oleate, which is one type of GEs, using the standard comet assay and a formamidopyrimidine glycosylase(Fpg)-modified comet assay. ICR male mice were orally administrated glycidol and glycidyl oleate (1.0 and 2.0 mmol/kg body weight) at 24 and 3 hr prior to dissection. In the standard comet assay, DNA damage (tail length and % tail DNA) in liver, kidney and blood samples of glycidol-treated groups were increased in a concentration-dependent manner. In Fpg-modified comet assay, glycidol showed DNA damage with higher sensitivity compared with the standard comet assay. DNA damage was not observed in the administration group of glycidyloleate in the standard comet assay. However, in Fpg-modified comet assay, glycidyl oleate showed significant DNA damage in the liver, kidney and blood samples compared with the standard comet assay. In this study, it was revealed that glycidol and glycidyl oleate induce DNA damage, such as oxidative and alkylation damage, recognized by Fpg protein.

Original Article
Thiamine supplementation modulates oxidative stress by inhibiting hepatic adenosine diphosphate (ADP)-ribosylation in obese diabetic rats Vol.6, No.1, p.1-8
Yuka Kohda , Junpei Ueda , Rie Azuma , Yuuka Nakatani , Hiroto Murase , Kanta Matsui , Yuka Takezoe , Eiko Nagata , Risa Matsui , Takao Tanaka , Hitoshi Matsumura
Released: January 16, 2019
Abstract Full Text PDF[2M]

Diabetic hyperglycemia is typically accompanied by various protein modifications, indicating hyperglycemic glucotoxicity. Overactivation of poly [adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP-1) has been implicated in the pathogenesis of oxidative stress-related diseases including diabetes and its complications. Furthermore, obesity and diabetes are known to be associated with a substantial risk of chronic liver disease. We have previously reported that thiamine supplementation prevented obesity and diabetes-related liver disease. As a step forward, in the present study, we focus on hepatic ADP-ribosylation that reflects PARP-1 activation and an increased oxidative stress condition. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were randomly divided into the following groups: thiamine-supplemented and unsupplemented control groups. The thiamine-supplemented group received 2 g of thiamine/L of drinking water for 33 weeks. ADP-ribosylated protein expression was analyzed in the livers of OLETF rats using Western blotting. Moreover, the fasting blood glucose level was measured in these rats. The obese diabetic OLETF rats exhibited high ADP-ribosylated protein expression in the liver. Interestingly, hepatic ADP-ribosylated protein expression and fasting blood glucose levels were lower in the thiamine-supplemented OLETF group than in the control OLETF group. These results suggest that thiamine supplementation attenuates oxidative stress by inhibiting hepatic ADP-ribosylation in OLETF rats. The beneficial effect of high-dose thiamine on oxidative stress-related diseases could be attributed to its inhibitory effect on PARP-1 activation, in addition to its role as a coenzyme. Furthermore, we found that thiamine supplementation prevented fasting hyperglycemia, suggesting that high-dose thiamine modifies the hepatic glucose metabolism and obesity-induced hepatic insulin resistance.