Genes and Environment
Online ISSN : 1880-7062
Print ISSN : 1880-7046
31 巻 , 3 号
選択された号の論文の4件中1~4を表示しています
REVIEW
  • Isao Yoshimura
    2009 年 31 巻 3 号 p. 57-63
    発行日: 2009年
    公開日: 2009/09/18
    ジャーナル フリー
    Toxicologists are accustomed to using methods of hypothesis testing in order to recognize the existence of target toxicity, on the basis of experimental data. However, in principle, it is impossible to identify the threshold via hypothesis testing in toxicological experiments since the probability of false-negative decisions cannot be determined in the context of hypothesis testing. When a mechanism for producing a threshold is hypothesized from a toxicological (or biological) perspective, and it is mathematically formulated as a dose-response relationship, statistics may be helpful in evaluating the existence (or non-existence) of the threshold, that is, in addressing the threshold identification problem. Consequently, it is important to select a model from a particular set of mathematical dose-response functions. Although the Akaike information criterion (AIC) or its modification is often used as a criterion index in the selection of the optimum model, their effectiveness in the threshold identification problem have not been validated. In these circumstances, the determination of a practical threshold using in vitro experiments may be an alternative to the identification of a “true” threshold, provided an appropriate in vitro assay affords a large scale experiment. Although quite difficult, it is important to maintain the homogeneity of experiments throughout the entire procedure. Only after establishing the experimental skills, the statistics may provide appropriate statistical methods that satisfy the requirements of toxicologists.
REGULAR ARTICLE
  • Mayumi Horinouchi, Sakae Arimoto-Kobayashi
    2009 年 31 巻 3 号 p. 64-68
    発行日: 2009年
    公開日: 2009/09/18
    ジャーナル フリー
    Blue rayon and blue chitin are potential absorbents of heterocyclic amines. However, in our preliminary research, no recovery (0%) of an activated form of Trp-P-2, 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole [Trp-P-2 (NHOH)] with blue rayon extraction was observed. We investigated whether copper phthalocyanine sulfonate on blue rayon may react with Trp-P-2(NHOH) and accelerate the degradation of Trp-P-2(NHOH) in concert with oxygen and photons. Both the disulfonate and tetrasulfonate of copper phthalocyanine inhibited the mutagenicity of Trp-P-2(NHOH). Copper phthalocyanine disulfonate (CuCYB) accelerated the disappearance of Trp-P-2(NHOH). The degradation of Trp-P-2(NHOH) with CuCYB was attenuated in the presence of glutathione, under dark conditions, and with helium bubbling. Therefore, the reaction mechanisms may involve the interaction of molecular oxygen with CuCYB, which accelerate the oxidative degradation of Trp-P-2(NHOH). Photodynamic activation of molecular oxygen might contribute, in a part, to the oxidative degradation of Trp-P-2(NHOH).
  • Masami Yamada, Keiko Matsui, Atsushi Katafuchi, Makiko Takamune, Takeh ...
    2009 年 31 巻 3 号 p. 69-79
    発行日: 2009年
    公開日: 2009/09/18
    ジャーナル フリー
    Oxidative DNA damage is a major cause of mutation and cell death in aerobic organisms. In addition to 8-hydroxyguanine, oxidized DNA pyrimidines play important roles in mutagenesis. Salmonella typhimurium TA1535, widely used in mutagenicity assays, carries a hisG46 missense mutation and efficiently detects mutations at G:C base pairs. To detect oxidative mutagens that selectively modify pyrimidines, we constructed a derivative of strain TA1535, termed YG3206, which lacks the Nei and Nth DNA glycosylases that excise oxidized pyrimidines from DNA. This novel strain easily detected the mutagenicity of L-cysteine, L-penicillamine, dopamine-HCl, and phenazine methosulfate, which are non-mutagenic or only weakly mutagenic in the TA1535 parent strain. A second strain that is equivalent to YG3206 but harbors the plasmid pKM101 which carries mucAB encoding DNA polymerase R1, termed YG3216, was significantly sensitive to phenazine ethosulfate. The compound was not mutagenic in either YG3206 or the Fapy-glycosylase-defective strain YG3001. Potassium bromate and methylene blue plus visible light with metabolic activation induced mutations in YG3001 but not YG3206 or YG3216. The number of spontaneous His+ revertants per plate was 82 ± 16 (YG3206, ΔnthΔnei), 19 ± 4 (YG3001, Δfpg), and 6 ± 2 (TA1535), suggesting a significant contribution to spontaneous mutagenesis by endogenous pyrimidine oxidation. In the absence of exogenous chemical treatment, exposure to fluorescent light enhanced the spontaneous mutation frequency by approximately two-fold (YG3206), 13-fold (YG3001), and 10-fold (TA1535). These results suggest that certain environmental chemicals may selectively introduce mutagenic damage at DNA pyrimidines, and that these changes can be monitored by the use of YG3206.
  • Wai-Ling Chu, Kazuhiro Shiizaki, Masanobu Kawanishi, Takashi Yagi
    2009 年 31 巻 3 号 p. 80-86
    発行日: 2009年
    公開日: 2009/09/18
    ジャーナル フリー
    We examined the agonistic and antagonistic activities of three categories of pharmaceuticals, including selective estrogen receptor modulators (SERM), tamoxifen (Tam), raloxifene (Ral) and clomiphene citrate (CC); a “pure” ER antagonist, ICI 182,780 (ICI); and a subtype (ERα)-selective agonist, propyl pyrazole triol (PPT), using our newly established reporter yeast strains (Saccharomyces cerevisiae), which express human ERα or ERβ. These strains also contain a reporter plasmid carrying one copy of estrogen responsive element (ERE) upstream of the β-galactosidase gene, and a plasmid expressing a steroid receptor coactivator, SRC-1e. In the ERα assay, none of the tested pharmaceuticals demonstrated antagonistic activity, whereas all showed weak agonistic activity at concentrations higher than 1×10-7 M. In the ERβ assay, Tam, CC and ICI showed antagonistic activity, whereas only Ral showed agonistic activity at concentrations higher than 1×10-8 M. The distinct estrogenic response in the ERα and ERβ assays was mainly due to their differences in ligand affinity and interaction with coactivators. PPT showed an agonistic effect in the ERα assay, but not in the ERβ assay. This study showed that our ERα and ERβ reporter yeasts have different responses to the test pharmaceuticals and are able to distinguish subtype-selective ligands. These reporter yeasts are applicable for exploring ER subtype-specific therapeutic agents and for detecting leaked pharmaceuticals that may act as environmental endocrine disruptors.
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