Induction of Hepatic 8-Oxo-deoxyguanosine Adducts by 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Sprague−Dawley Rats Is Female-Specific and Estrogen-Dependent

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a hepatocarcinogen that induces sex-specific hepatic neoplastic alterations in female, but not male, rats. It has been hypothesized that TCDD-induced alterations in estrogen metabolism lead to increased generation of reactive oxygen species. The resulting oxidative damage to DNA may contribute to TCDD-induced tumor promotion and hepatocarcinogenesis. This hypothesis is supported by previous observations of increased 8-oxo-deoxyguanosine (8-oxo-dG) adduct formation in the livers of intact, but not ovariectomized (OVX), rats following chronic exposure to TCDD. The aim of the current study was to more clearly define the roles of hormonal regulation, gender, dose-response, and exposure duration in TCDD induction of 8-oxo-dG adducts. Diethylnitrosamine (DEN)-initiated male and female (both intact and OVX) rats were exposed to TCDD in the presence or absence of 17 beta-estradiol. Following 30 weeks of exposure, hepatic 8-oxo-dG adduct levels were significantly higher in TCDD-treated intact female rats, and TCDD-treated OVX female rats receiving supplemental 17 beta-estradiol, when compared to respective corn oil vehicle controls. In DEN-initiated female rats exposed to a range of TCDD concentrations for 30 weeks, TCDD induced 8-oxo-dG adduct levels in a dose-dependent manner. However, 8-oxo-dG adduct levels were not altered in TCDD-treated male or OVX female rats following 30 weeks of exposure. In noninitiated female rats, the level of 8-oxo-dG adducts 4 days following a single dose of TCDD was not significantly different than in control rats. Additionally, 8-oxo-dG adduct formation was not affected by exposure to TCDD for 20 weeks in intact female rats. These data suggest that the induction of 8-oxo-dG adduct levels by TCDD is likely a response to chronic oxidative imbalance. These studies provide strong evidence that the induction of 8-oxo-dG by TCDD occurs via a chronic, sex-specific, estrogen-dependent mechanism.

Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

“…3, there was no trend in the numbers of M 1 dG DNA adducts in response to the different doses of TCDD or one of the PHAH mixtures (non-parametric Jonckheere-Terpstra exact test, p > 0.18). This result is consistent with the findings from other investigators who reported no significant changes in the numbers of 8-OHdG adducts after a single exposure to DLC [36,37]. In contrast, subchronic or chronic exposures to the chemicals resulted in an accumulation of 8-OH-dG adducts in animals [36,37].…”

“…Additionally, it has been proposed that DNA repair proteins can be impaired by mutations caused by the slow accumulation of DNA adducts over a long period of time [37]. This argument is supported by the findings from previous studies that reported sustained DNA adduct (i.e., 8-OH-dG) accumulation, toxicity, and carcinogenesis [12,36,37,41].…”

“…It has been hypothesized by a number of investigators [12,37] that DNA repair in healthy control animals is sufficient to repair DNA adducts formed by an acute exposure to PHAH. Unlike acute exposures, however, long-term exposures to PHAH may change the capacity of DNA repair by modifying the expression of proteins involved in DNA repair, analogous to how PHAH changes the expression of metabolic enzymes [38][39][40].…”

“…Unlike acute exposures, however, long-term exposures to PHAH may change the capacity of DNA repair by modifying the expression of proteins involved in DNA repair, analogous to how PHAH changes the expression of metabolic enzymes [38][39][40]. Additionally, it has been proposed that DNA repair proteins can be impaired by mutations caused by the slow accumulation of DNA adducts over a long period of time [37]. This argument is supported by the findings from previous studies that reported sustained DNA adduct (i.e., 8-OH-dG) accumulation, toxicity, and carcinogenesis [12,36,37,41].…”

DNA damage and cell cycle arrest induced by 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells

“…In contrast, the environmental pollutant TCDD, which is the most potent AhR agonist, induces CYP1A1 and modulates CYP1B1 expression in MCF-7 cells (Dohr et al, 1995), but is not directly genotoxic. It has been hypothesised that TCDDinduced alterations in estrogen metabolism may lead to increased generation of reactive oxygen species and consequent induction of DNA adducts (Wyde et al, 2001).…”