Influence of diet and maternal dioxin on endocrine disruption: puberty, metabolic syndrome, and breast cancer

Total lifetime estrogen (E2) exposure increases mammary cancer risk. TCDD indirectly affects E2 signaling and early life TCDD exposures are also implicated in breast cancer. E2 produced by adipose tissue is an underlying mechanism by which obesity contributes to early puberty, and if obesity and weight gain extend into adulthood, increased postmenopausal breast cancer risk. These observations are further complicated by greater TCDD stores in the adipose of obese- compared to lean- individuals. How several environmental exposures, maternal exposure to TCDD, lifelong exposure to high fat diet (HFD), and pubertal exposure to DMBA, modify the mammary gland was examined. It was expected that HFD and maternal exposure to TCDD would increase mammary cancer risk, through both structural remodeling of the pubertal gland and through molecular changes. Interactions of these exposures and phenotypes were examined using several mouse strains and mouse models of breast cancer, but objectives were primarily pursued using the DMBA mouse model of breast carcinogenesis. Growth trajectories, adiposity, blood glucose levels, and mammary gland development effects of HFD and maternal TCDD were examined as potential causal players in DMBA carcinogenesis. The growth trajectory, adiposity, and fasting blood glucose were increased in DMBA on HFD relative to low-fat diet (LFD). Maternal TCDD exposure increased blood glucose levels and depressed mammary gland growth at PND in DBA/2J mice fed HFD. Maternal TCDD exposure also increased blood glucose levels in DMBA transiently. Mammary lesion incidence was increased by HFD and maternal TCDD exposure. TCDD exposure increased the number of terminal end buds in DMBA on LFD, but decreased them at PND 35 in DMBA on HFD. Among DMBA on HFD, maternal TCDD increased epithelial Cyp1b1 and decreased Comt mRNA in PND 50 mammary glands. Maternal TCDD exposure also increased Cyp1b1 in mammary tumors of offspring. Thus increased steady state levels of E2 and its metabolites were likely associated with increased mammary tumor incidence in DMBA. The interactions of HFD and maternal TCDD exposure on type II diabetes risk, pubertal mammary morphology, mammary tumor incidence and estrogen pathway regulation should be further explored