Genotoxicity of the steroidal oestrogens oestrone and oestradiol: possible mechanism of uterine and mammary cancer development

Abstract

Oestrogens, including the natural hormones oestrone and oestradiol, induce various tumours in laboratory animals and have been recognized to be carcinogens in humans, raising the risk for breast and uterine cancer. As part of the search for the mechanism of hormone-induced carcinogenesis, various types of DNA damage have been detected which have been induced by oestrogens in cell-free systems, in cells in culture, or in vivo. Nevertheless, oestrogens have been postulated to act only as promoters of mammary carcinogenesis by receptor-mediated growth stimulation without consideration of their genotoxicity because these hormones failed to induce mutations in commonly used assays. More recently, oestradiol-induced numerical chromosomal changes (aneuploidy) and structural chromosomal aberrations have been detected in cells in culture and in hamster kidney, a target of oestrogen-induced cancer. In this animal model, oestradiol generates c-myc gene amplification and microsatellite instability. Mutations of the hprt gene have been induced by oestradiol in V79 cells and by catecholoestrogen metabolites in Syrian hamster embryo cells. Sequencing of this gene isolated from V79 mutant clones revealed point mutations and deletions. It is concluded that oestradiol plays a dual role as mutagen/carcinogen and as growth-stimulating hormone in the induction of tumours.

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

“…The presumption that estrogen mediates oxidative stress and carcinogenesis was confirmed in Syrian hamsters, which show 100% kidney tumor incidence following the administration of 17β-estradiol or estrone (Liehr, 1997). Likewise estradiol was also found to produce oxidative DNA damage in hamster tissues and other biological model systems (Han et al, 1995;Tritscher et al, 1996;Wyllie et al, 1997;Hodgson et al, 1998;Cavalieri et al, 2000;Liehr, 2001;Wyde et al, 2001b).…”

“…Rearrangement of estrone 3,4-quinone produces a strongly electrophilic carbonium cation that may undergo a Michael addition reaction with cellular sulfhydrals such as (i.e. glutathione, protein thiols) or by electrophilic addition to DNA purine bases resulting in depurinating adducts (Cavalieri et al, 2000), and ultimately procarcinogenic mutations ( Liehr, 2001;Embrechts et al, 2003). The relative contributions of redox cycling and electrophilic interactions in the oxidative stress response and toxicity have not been firmly established; however, limited evidence suggests that covalent sulfhydral modification by electrophiles is likely to be a greater cytotoxic hazard than transient quinone formation that facilitates disposal from the cell (Buffinton et al, 1989).…”

Understanding the human health effects of chemical mixtures.

“…Endogenous steroidal estrogens function not only as hormones but also as carcinogens [reviewed by Liehr (108,109)]. Estrogens have been proposed to induce carcinogenesis by multiple mechanisms including covalent modification of the estrogen receptor (110,111), induction of chromosomal abnormalities (112,113), an epigenotoxic mechanism (114), conversion of 17β-estradiol to catechol estrogens and redoxactive and adduct-forming estrogen quinones (108,115), and subsequent ROSmediated DNA damage (116,117).…”

Study on the in vivo Comet Assay Using Rat Uteri

“…I3C is reported to promote cancer in the uterus of rats under a particular condition, although, it is known to be an anti-carcinogen (22,23). As for the mechanism, it is believed that I3C induces CYP 1B1, followed by metabolism of 17-b-estradiol to 4-hydroxyestradiol which is considered to be a genotoxic compound that induces carcinogenesis (22,24). The absence of DNA damage observed in our study could be attributed to the lack of CYP 1B1 induction by singledose administration of I3C, and to the fact that I3C itself has no potential for in vivo genotoxicity.…”