Carcinogenicity of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin in experimental models

Abstract

The contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a prototype compound of a whole class of halogenated aromatic hydrocarbons termed 'dioxinlike' contaminants present in food, human tissue, mothers milk, and environmental samples. Among the various adverse effects caused by TCDD in animal experiments, its carcinogenic effects caused particular concern. In rodents, long-term TCDD treatment leads to the development of tumors of the liver, thyroid, lung, skin, oral cavity and other sites. The occurrence of liver tumors mainly observed in female rats has been used as a basis for quantitative cancer risk assessment for TCDD. TCDD does not behave like a 'complete carcinogen', i. e. no DNA binding of the parent compound or metabolites thereof could be detected. However, enhanced oxidative damage of hepatic DNA was observed, probably resulting from a dramatic induction of cytochrome P450 enzymes, which are under the regulatory, transcriptional control of the TCDD-activated aryl hydrocarbon receptor. The marked enhancement of TCDD-related oxidative liver DNA damage in rats by estrogens warrants further mechanistic investigation. Furthermore, TCDD acts as a tumor promoter, i. e. it facilitates the growth of putative preneoplastic hepatic lesions after initiation with a complete carcinogen. The mechanisms underlying this effect may be related to altered intracellular signaling involving pronounced changes in the phosphorylation pattern of proteins regulating growth and apoptosis. These effects are thought to result in an enhanced survival of preneoplastic cells, some of which can undergo further steps on the way to malignancy. In summary, a better understanding of the mechanisms of the carcinogenicity of TCDD is mandatory to provide a rational basis for a better inter-species extrapolation. The final aim of these efforts is a more reliable risk assessment for the carcinogenic potency of the class of dioxinlike contaminants in humans.

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

“…TCDD (>99.5% pure) was obtained from Cambridge Isotope Laboratory (Andover, MA). [6, H]E 2 and [6,7-3 H]E 1 (specific activities of 51 and 58 Ci/ mmol, respectively) and [4][5][6][7][8][9][10][11][12][13][14] C]E 2 (specific activities of 55.1 mCi/mmol) were purchased from PerkinElmer Life Science Products (Boston, MA). All the organic solvents used in this study were of HPLC grade or better, and were obtained from Fisher Scientific (Atlanta, GA).…”

“…In comparison, the data from earlier animal studies were clearer and more intriguing. While chronic administration of TCDD to female rats enhanced the tumor incidence in liver and also many other organ sites, this treatment inhibited the formation of spontaneous tumors in the uterus, mammary gland, and pituitary [11][12][13], which are target tissues for endogenous estrogens.…”

“…These experiments were, in part, aimed to provide evidence for the hypothesis that beneficial alterations of the multiple metabolic pathways of endogenous estrogens are a significant factor contributing to the observed protective effect of TCDD against various estrogen-associated tumors in rodents [11][12][13]. It is of note that the caloric contribution of the fat component in the high-fat diet used in this study was 39% as opposed to 12% in the control diet.…”

“…TCDD is a developmental and reproductive toxicant and causes immunotoxicity, dermal and hepatic toxicity, and a plethora of endocrine-disrupting effects [3][4][5][6][7][8]. In addition, TCDD is also considered a carcinogen, increasing the incidence of a variety of cancers in humans as well as in laboratory animals [4,[9][10][11][12][13]. Tumors of the breast are common in humans, but at present epidemiological data are conflicting with respect to the link between TCDD exposure and the risk of breast cancer.…”

Sulforaphane inhibits CYP1A1 activity and promotes genotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vitro

“…Most of the studies revealed that TCDD lead to DNA damage by the induction of oxidative stress (Hung et al, 2006;IIavarasi et al, 2011;Knerr and Schrenk, 2006). However, the mechanism by which SFN elevated TCDD-induced DNA damage remains unclear.…”