Rajapakse, Nissanka Ajitha; (2002) Biological effects of estrogenic agents: induction of DNA damage; receptor activation and joint action. Doctoral thesis (Ph.D.), University College London.

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Abstract

Breast and testicular cancer incidence continues to rise as does the number of reports of abnormal sexual development in Man and wildlife. A widely held belief is that estradiol and environmental contaminants capable of mimicking the hormones' actions may be implicated when the mechanisms are finally elucidated. I7β-Estradiol (E2) has been proposed as a carcinogen capable of tumour initiation by mutation. The ability of estradiol to induce DNA damage by undergoing metabolic activation to catechol estrogens in breast cancer cells was investigated. The hormone, at concentrations as low as 10 nM, caused DNA fragmentation in the Comet assay. The presence of 7,8-dihydro-8-oxo-guanine and oxidised purines was inferred from the observation that formamidopyrimidine glycosylase digestion of treated DNA led to increases in DNA damage. This suggests free-radical attack by redox cycling of catechol estrogen quinones. These quinones are believed to be involved in cell progression from the normal to the malignant state. The importance of assessing xenoestrogen (XE) mixtures is becoming more widely appreciated. Our goal was to test the hypothesis that, although XEs are considerably less potent than steroidal estrogens, they can significantly, impact on the effects of the hormones. We carried out extensive concentration-response analyses of E2 and XEs in a yeast reporter-gene assay with the α-human estrogen receptor. Two pharmacological models, concentration addition and independent action, were used to calculate effects for multiple-component mixtures. Observations confirmed decisively the additivity predictions and the impact of the XEs was significant. In a mixture with eleven XEs, mixed at ratios proportional to their EC01 values, before being combined with E2 at a mixture ratio of 1:25000 (E2:XE-poo1), the XEs, whose concentrations were below individual effect-thresholds, resulted in an 80% greater response than the hormone alone. By ignoring additive combination effects one might wrongly conclude that each XE presents no risk.

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