- 著者
- Tetsuji Nagao Naomi Takada Noriko Onoda
- 出版者
- 日本環境変異原学会
- 雑誌
- Genes and Environment (ISSN:18807046)
- 巻号頁・発行日
- vol.33, no.2, pp.50-60, 2011 (Released:2011-05-25)
- 参考文献数
- 82
- 被引用文献数
- 1 2
Congenital malformations can be induced in the offspring of laboratory animals treated with the mutagens, ethylnitrosourea, methylnitrosourea, mitomycin C, triethylenemelamine or procarbazine before copulation. The spectra of malformations in the offspring classified as male-mediated malformations after exposure of paternal mice to mutagens showed no evidence of mutagen-specificity or germ-cell stage-dependent variations. Recently, we demonstrated the increased incidence of congenital malformations in the offspring of male mice exposed in utero to synthetic estrogens such as diethylstilbestrol (DES), 17β-estradiol (E2) or ethynyl estradiol (EE), and that the induction of male-mediated malformations by DES, E2 or EE showed a clear threshold effect. Developmental exposure to DES, E2 or EE caused partial atrophy and feminization in the genital tract. They also showed transgenerational effects when applied prenatally at a dose which caused histopathological changes in the testes. Germ-cell series in normal testis have mechanisms to select against spontaneously arising mutation; but these selection mechanisms may not function efficiently in chemically-damaged testes. Based on these results and considerations, we propose as a hypothesis that transgenerational teratogenesis by prenatal exposure to synthetic estrogens may occur as a consequence of testicular toxicity. Moreover, since DES has been reported to be non-genotoxic, epigenetic mechanisms such as DNA methylation may be involved in the transgenerational teratogenesis induced by estrogenic drugs. The expression patterns of DNA methyltransferases (Dnmts) mRNA, global DNA methylation levels in testicular cells of embryos exposed to estrogenic drugs or in epididymal sperm of mature male mice exposed prenatally to estrogenic drugs were different from those in the controls. Results shown in this review support the proposal that, when evaluating the toxicities of environmental chemicals including endocrine disruptors, epigenetic effects such as DNA methylation should be taken into account.