Prenatal TCDD exposure predisposes for mammary cancer in rats

Abstract

Epidemiological data are conflicting in the link between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and breast cancer causation. We have hypothesized that timing of exposure to endocrine disruptors, such as TCDD, will alter breast cancer susceptibility. Using a carcinogen induced rat mammary cancer model, we have shown that prenatal exposure to TCDD alters mammary gland differentiation and increases susceptibility for mammary cancer. Investigations into imprinting via DNA methylation mechanisms showed that there were no changes in protein expression in DNA methyltransferases, ER-alpha, ER-beta, GST-pi, or MDGI. Using 2D gels and mass spectrometry, we have found seven proteins to be differentially regulated, including a decrease in superoxide dismutase 1 (SOD1). Down-regulation of SOD1 could provide an environment ill equipped to deal with subsequent free radical exposure. We conclude that prenatal TCDD can predispose for mammary cancer susceptibility in the adult offspring by altering the mammary proteome.

Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women

“…Enzyme activation by exposure to hormone receptor binding compounds can lead to increased hormone catabolism and compromise hormone signaling (6). Breast cancer risk has been directly linked to hormone receptor disruptors in animal models (7,8) and in occupational exposure studies (9,10). There is also evidence linking endocrine disruptors to breast cancer risk through regulation of microRNAs' expression (11), as well as through their involvement in the formation of reactive electrophiles such as reactive oxygen species and subsequent DNA adduct formation (12).…”

Impact of Environmental Contaminants on Breast Cancer / Wpływ Zanieczyszczenia Środowiska Na Raka Piersi

“…TCDD inhibited spontaneous and carcinogen-induced mammary tumour formation and growth in rodent models [55,56] and age-dependent formation of mammary tumours in female Sprague-Dawley rats [57]. Using a carcinogen induced rat mammary cancer model it was shown that prenatal exposure to TCDD alters mammary gland differentiation and increases susceptibility for mammary cancer [58]. Exposure during pregnancy severely impaired mice mammary gland differentiation, and severe defects in development, including stunted growth, decreased branching and poor formation of lobular alveolar structures, occurred [59].…”

Mitochondria as a Biosensor for Drug-induced Toxicity – Is It Really Relevant?

“…Reported data indicate that low doses of TCDD cause increased oxidative stress, including depletion of antioxidant enzymes, in mitochondria and microsomal fractions from rat testis, which can alter the mitochondrial ability to supply energy to male germ cells (Latchoumycandane, Chitra et al, 2002). Mitochondrial interactions of TCDD and the possible carcinogenesis associated with dioxin exposure (Knerr & Schrenk, 2006;Jenkins, Rowell et al, 2007) (although others disagree, (Cole, Trichopoulos et al, 2003)) were also demonstrated to be related since TCDD causes mitochondrial depolarization, stress signaling and tumor invasion, besides altering calcium homeostasis (Biswas, Srinivasan et al, 2008). Besides, TCDD directly targets mitochondrial transcription and causes a mitochondrial phenotype which is similar to what is observed in rho0 cells (Biswas, Srinivasan et al, 2008).…”