Fundamental Toxicological Sciences

2022 - Vol. 9 No. 5

2022 - Vol. 9

Data Report
Comet assay of thyroid gland in rats treated with ethyl methanesulfonate Vol.9, No.5, p.163-166
Naho Tsuji , Soichiro Hagio , Kazuya Takeuchi , Satoshi Furukawa
Released: October 12, 2022
Abstract Full Text PDF[700K]

In vivo comet assays are often used to evaluate genotoxicity. The advantage of an in vivo comet assay is that it can be applied to a variety of organs. In general, the liver and stomach are used in an in vivo comet assay. However, there have also been some reports on the in vivo comet assay of the thyroid gland, which is a common target organ for carcinogens in rodents. Ethyl methanesulfonate (EMS) is listed as a compound likely to be the positive control compound of choice in an in vivo comet assay, since it is known to cause DNA damage in a variety of tissues, including the liver, stomach, kidneys, and bone marrow. In contrast, there have been no reports on in vivo comet assays of the thyroid gland in rats treated with EMS. In the present study, we examined whether EMS also exhibits DNA damage in the in vivo comet assay of the thyroid gland in rats. EMS was administered orally at a dose of 200 mg/kg. The results showed a significant increase in mean % tail DNA in the thyroid gland, the extent of which was similar to that in the liver. Since histopathological examination of the thyroid gland revealed no histological findings, the increase in mean % tail DNA was most likely due to DNA damage rather than tissue damage. These results suggest that EMS can be used as a positive control compound in the in vivo comet assay of the thyroid gland in rats.

Toxicomics Report
Deubiquitinase USP54 attenuates methylmercury toxicity in human embryonic kidney 293 cells Vol.9, No.5, p.159-162
Jin-Yong Lee , Jong-Mu Kim , Takuya Noguchi , Atsushi Matsuzawa , Akira Naganuma , Gi-Wook Hwang
Released: October 07, 2022
Abstract Full Text PDF[885K]

Deubiquitinases are an important regulator of ubiquitin-mediated signaling pathways because of their ability to cleave the isopeptide bond that connects the ubiquitin chain to the target protein. We previously reported that the expression of many proteins involved in methylmercury toxicity is regulated by the ubiquitin-proteasome system. In this study, double-stranded siRNAs against mRNAs of approximately 60 deubiquitinases were transfected into human embryonic kidney (HEK) 293 cells, and ubiquitin-specific protease 54 (USP54) was identified as a deubiquitinase that increases the sensitivity of HEK293 cells to methylmercury by RNA interference.

Original Article
Bifunctional activity of tangeretin (5,6,7,8,4'-pentamethoxyflavone) in suppression of cell growth and gene expression of the superoxide-generating system-related proteins in U937 cells Vol.9, No.5, p.151-157
Hidehiko Kikuchi , Kaori Harata , Sumiko Akiyoshi , Takefumi Sagara , Harishkumar Madhyastha , Hitomi Mimuro , Futoshi Kuribayashi
Released: October 07, 2022
Abstract Full Text PDF[949K]

Polymethoxyflavones in which all hydroxyl groups are capped by methyl residues show high membrane permeability, metabolic resistance, and diverse biological activities such as cell growth inhibitory effects responsible for their anti-cancer activities. They are expected to be as biotherapeutic drugs for maintaining human health via contributing prevention and treatment of serious illnesses such as cancers, neurodegenerative diseases, inflammatory bowel diseases, lipid metabolism disorders, and so on. Human monoblastic leukemia U937 cell line has been used as an excellent in vitro cell model system for studying macrophage differentiation induced by various cell differentiation inducers such as all-trans retinoic acid (ATRA). In this study, we investigated the influences of two typical polymethoxyflavones, such as nobiletin and tangeretin, on the ATRA-induced superoxide anion (O2-)-generating ability of U937 cells. Nobiletin and tangeretin suppressed cell proliferation of U937 cells in a dose-dependent manner. At a concentration of 10 μM, tangeretin drastically brought about down-regulation of the ATRA-induced O2--generating ability (to ~15% of ATRA-treated cells) although nobiletin showed moderate inhibitory effects on the ATRA-induced O2--generating ability (to ~65% of ATRA-treated cells). Quantitative RT-PCR and immunoblotting revealed that tangeretin down-regulates the ATRA-induced O2--generating ability via suppressing gene exprerssion levels of gp91-phox (mRNA: to ~75%, protein: to ~70% of ATRA-treated cells) and p47-phox (mRNA: to ~75%, protein: to ~40% of ATRA-treated cells) genes. These findings demonstrated that tangeretin shows not only the inhibitory effects on cell growth but also the strong suppressing effects on the ATRA-induced O2--generating ability of U937 cells.

Original Article
The effects on growth and reproductive function by parabens in C. elegans Vol.9, No.5, p.145-150
Yuko Sakaguchi , Nana Hirota , Satoshi Fukushima , Nobuhiro Ichikawa , Koji Arizono
Released: September 13, 2022
Abstract Full Text PDF[1M]

In recent years, paraoxybenzoic acid esters (parabens) have been used in pharmaceuticals, cosmetics, and food additives. Parabens have been reported to have a weak estrogenic effect in in vitro test systems, and it is presumed that the longer the alkyl chain of the paraben, the greater its endocrine-disrupting and reproductive function effects. However, the effects of parabens on human health are still unclear. In this study, we evaluated the effects of six parabens (methyl p-hydroxybenzoate [MP], ethyl p-hydroxybenzoate [EP], propyl p-hydroxybenzoate [PP], isopropyl p-hydroxybenzoate [IPP], butyl p-hydroxybenzoate [BP], and isobutyl p-hydroxybenzoate [IBP]) on the reproductive function of the model organism Caenorhabditis elegans. We used 25, 50, and 100 µg/mL solutions of parabens in 0.1% dimethyl sulfoxide (DMSO). Bioassays (growth and maturation effect tests and reproduction effect tests) were performed on L1 larvae of wild-type C. elegans. In the growth effects test, all parabens were observed to have no effect. In the maturation effects test, there was a significant decrease in maturity at each concentration of five of the six parabens, with the exception being MP. In the reproduction effects test, a significant decrease in the number of lifetime offspring was observed at each concentration of five of the six parabens, with the exception being EP. This decrease was remarkable with PP, which has been reported to adversely affect reproductive function in rats. It is necessary to continue to focus on the estrogen-like action of parabens, including PP, and perform genetic analyses, such as RNA sequencing.