Mouse breast cancer model-dependent changes in metabolic syndrome-associated phenotypes caused by maternal dioxin exposure and dietary fat

• Published in: American journal of physiology: endocrinology and metabolism Vol. 296; no. 1; pp. E203 - E210
• Main Authors: La Merrill, Michele, Baston, David S, Denison, Michael S, Birnbaum, Linda S, Pomp, Daniel, Threadgill, David W
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.01.2009
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Composition - physiology; Body Weight - physiology; Breast cancer; Carcinogens; Dietary Fats - toxicity; Disease Models, Animal; Effects; Female; Genotype & phenotype; Longitudinal Studies; Male; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - metabolism; Maternal Exposure - adverse effects; Metabolic syndrome; Metabolic Syndrome - metabolism; Mice; Mice, Transgenic; Oils & fats; Phenotype; Polychlorinated Dibenzodioxins - toxicity; Pregnancy; Random Allocation; Receptors, Cytoplasmic and Nuclear - metabolism; Rodents
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.90368.2008

1 Curriculum in Toxicology, 2 Department of Genetics, 6 Departments of Nutrition and Cell and Molecular Physiology, and 3 Center for Environmental Health and Susceptibility, Clinical Nutrition Research Unit, Lineberger Cancer Center and Carolina Center for Genome Sciences, University of North Carolina Chapel Hill, Chapel Hill; 5 Experimental Toxicology Division, United States Environmental Protection Agency, Office of Research and Development/National Health Environmental Effects Research Laboratory, Research Triangle Park, North Carolina; 4 Department of Environmental Toxicology, University of California, Davis, California Submitted 15 April 2008 ; accepted in final form 6 October 2008 Diets high in fat are associated with increased susceptibility to obesity and metabolic syndrome. Increased adipose tissue that is caused by high-fat diets (HFD) results in altered storage of lipophilic toxicants like 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), which may further increase susceptibility to metabolic syndrome. Because both TCDD and HFD are associated with increased breast cancer risk, we examined their effects on metabolic syndrome-associated phenotypes in three mouse models of breast cancer: 7,12-dimethylbenz[a]anthracene (DMBA), Tg(MMTV-Neu)202Mul/J (HER2), and TgN(MMTV-PyMT)634Mul/J (PyMT), all on an FVB/N genetic background. Pregnant mice dosed with 1 µg/kg of TCDD or vehicle on gestational day 12.5 were placed on a HFD or low-fat diet (LFD) at parturition. Body weights, percent body fat, and fasting blood glucose were measured longitudinally, and triglycerides were measured at study termination. On HFD, all cancer models reached the pubertal growth spurt ahead of FVB controls. Among mice fed HFD, the HER2 model had a greater increase in body weight and adipose tissue from puberty through adulthood compared with the PyMT and DMBA models. However, the DMBA model consistently had higher fasting blood glucose levels than the PyMT and HER2 models. TCDD only impacted serum triglycerides in the PyMT model maintained on HFD. Because the estrogenic activity of the HFD was three times lower than that of the LFD, differential dietary estrogenic activities did not drive the observed phenotypic differences. Rather, the HFD-dependent changes were cancer model dependent. These results show that cancer models can have differential effects on metabolic syndrome-associated phenotypes even before cancers arise. obesity; metabolic syndrome; 2,3,7,8-tetrachlorodibenzo- p -dioxin; Tg(MMTV-Neu)202Mul/J; TgN(MMTV-PyMT)634Mul/J; dimethylbenz[a]anthracene Address for reprint requests and other correspondence: D. Threadgill, Dept. of Genetics, CB#7264, Univ. of North Carolina, Chapel Hill, NC 27599 (e-mail: dwt{at}med.unc.edu )