Fundamental Toxicological Sciences

2015 - Vol. 2 No. 6

2015 - Vol. 2

Toxicomics Report
The enhancement effect of HIST1H4C knockdown on cadmium toxicity in human proximal tubular cells Vol.2, No.6, p.259-262
Jin-Yong Lee , Maki Tokumoto , Masahiko Satoh
Released: December 22, 2015
Abstract Full Text PDF[274K]

Cadmium (Cd) is a toxic heavy metal known to exert severe nephrotoxic effects. Mechanistically, Cd has been reported to disrupt gene expression in renal proximal tubular cells. In addition, alterations in DNA integrity have been reported to be associated with Cd toxicity. Histone proteins play important roles in maintaining DNA integrity, and are responsible for regulating gene transcription. In this study, we examined the involvement of HIST1H4C, a gene encoding the histone H4 protein, in Cd toxicity in HK-2 human proximal tubular cells. It was found that Cd significantly reduced the transcription level of HIST1H4C in HK-2 cells. In addition, HIST1H4C knockdown by siRNA transfection enhanced Cd toxicity in HK-2 cells. Our findings suggest that suppression of gene expression of HIST1H4C may be involved in the elevation of Cd toxicity in proximal tubular cells.

Original Article
Developmental changes in associative learning behavior in male rats Vol.2, No.6, p.249-258
Rieko Hojo , Yukie Yanagiba , Megumi Suda , Masao Tsuchiya
Released: December 22, 2015
Abstract Full Text PDF[380K]

To identify the developmental point of onset of learning and memory function under an operant task, performance of young rats was examined on postnatal days (PDs) 16, 19, 22, 25 and 28, and then compared with that of adult rats (PD60). Each group of Long-Evans male rats with difference days of age was assigned to a series of fixed ratio (FR) operant tasks, in which the number of lever-pressing was required for acquisition of food reward. FR rate started from 1, changed into 2, and finished with 20. Each session conducted once a day, 7 sessions per week, lasted 30 min. Response rate (the number of lever-pressing per minute) and the number of session until animal acquired the learning acquisition criterion were measured. In FR20 learning task, performance of animals at PD32 showed the same shape as those of adult rats, showing an increase of response rate and a decrease of the number of sessions. The results indicated that memory and learning function of rats required for FR20 task might be matured at PD32. Results in the present study implied that the higher brain function used for the operant FR tasks mainly depended on the hippocampal development.

Toxicomics Report
Knockdown of Acyl-CoA thioesterase 9 gene expression by siRNA confers resistance to arsenite in HEK293 cells Vol.2, No.6, p.245-247
Tsutomu Takahashi , Min-Seok Kim , Gi-Wook Hwang , Shusuke Kuge , Akira Naganuma
Released: December 21, 2015
Abstract Full Text PDF[295K]

Arsenic is a hazardous element that exists widely in the environment. To elucidate the molecular mechanism involved in the onset of arsenic toxicity, we comprehensively searched for genes affecting the sensitivity of HEK293 cells to arsenite by using a siRNA library targeting approximately 17,000 human genes. As a result, we identified ACOT9, one of the acyl-coenzyme A thioesterases, as the gene conferring arsenite resistance to cells by knockdown.

Methylmercury induces expression of interleukin-1β and interleukin-19 in mice brains Vol.2, No.6, p.239-243
Tsutomu Takahashi , Miyuki Iwai-Shimada , Yukina Syakushi , Min-Seok Kim , Gi-Wook Hwang , Nobuhiko Miura , Akira Naganuma
Released: December 21, 2015
Abstract Full Text PDF[471K]

We examined the effect of methylmercury administration on expression of interleukin genes in brain of mice. We found that gene expression of IL-1β and IL-19 was increased in the brain after the administration of methylmercury.

(–)-Xanthatin-mediated marked up-regulation of RhoB, a sensor for damaged DNA Vol.2, No.6, p.233-238
Shuso Takeda , Shunsuke Okajima , Hiroko Miyoshi , Kuniyoshi Koyachi , Kenji Matsumoto , Mitsuru Shindo , Hironori Aramaki
Released: December 12, 2015
Abstract Full Text PDF[396K]

Sesquiterpene lactones exhibit toxicity in humans and animals by non-selectively interacting with cellular macromolecules. Among the sesquiterpene lactones identified to date, (–)-xanthatin, which was obtained in an extract from Xanthium strumarium (the Cocklebur plant), is reportedly less toxic to animals. Although we have shown that (–)-xanthatin has anti-proliferative effects, coupled with the induction of DNA damage-inducible GADD45γ, on highly aggressive human MDA-MB-231 breast cancer cells, the molecular mechanisms of anti-proliferative activity have not yet been elucidated in detail. Furthermore, evidence for the involvement of DNA damage is currently not sufficient. In the present study, we chemically synthesized pure (–)-xanthatin, and attempted to obtain more concrete evidence for DNA damage caused by (–)-xanthatin, which leads to cell death. The results obtained revealed the marked up-regulation of RhoB, which is up-regulated by DNA damage. We summarized the anti-proliferative effects of (–)-xanthatin in combination with our previous findings.

Citrulline enhances methylmercury toxicity in HEK293 and C17.2 cells Vol.2, No.6, p.229-231
Takashi Toyama , Gi-Wook Hwang , Akira Naganuma
Released: December 11, 2015
Abstract Full Text PDF[530K]

We identified 3-phenylpropionic acid, citrulline, lactic acid, ornithine, proline, and betaalanine as low-molecular weight substances that are released from cells treated with methylmercury. In this study, we studied their effect on cellular sensitivity to methylmercury. Treating HEK293 and C17.2 cells with each of the six substances minimally affected the proliferation of both cell lines. Among these six substances, however, only citrulline slightly but significantly increased the sensitivity of C17.2 and HEK293 cells to low levels of methylmercury. Citrulline is thought to be a methylmercury toxicity-enhancing factor whose extracellular release is enhanced by methylmercury.