La Merrill Michele, Baston David S, Denison Michael S, Birnbaum Linda S, Pomp Daniel, Threadgill David W
Curriculum in Toxicology, Carolina Center for Genome Sciences, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA.
Am J Physiol Endocrinol Metab. 2009 Jan;296(1):E203-10. doi: 10.1152/ajpendo.90368.2008. Epub 2008 Oct 7.
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 microg/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.
高脂肪饮食与肥胖和代谢综合征易感性增加有关。高脂饮食（HFD）导致的脂肪组织增加会改变亲脂性毒物如2,3,7,8-四氯二苯并对二恶英（TCDD）的储存，这可能会进一步增加代谢综合征的易感性。由于TCDD和HFD都与乳腺癌风险增加有关，我们在三种乳腺癌小鼠模型中研究了它们对代谢综合征相关表型的影响：7,12-二甲基苯并[a]蒽（DMBA）、Tg(MMTV-Neu)202Mul/J（HER2）和TgN(MMTV-PyMT)634Mul/J（PyMT），均为FVB/N遗传背景。在妊娠第12.5天给予1微克/千克TCDD或赋形剂的怀孕小鼠在分娩时被置于高脂饮食或低脂饮食（LFD）中。纵向测量体重、体脂百分比和空腹血糖，并在研究结束时测量甘油三酯。在高脂饮食下，所有癌症模型都比FVB对照提前进入青春期生长突增期。在喂食高脂饮食的小鼠中，与PyMT和DMBA模型相比，HER2模型从青春期到成年期体重和脂肪组织增加得更多。然而，DMBA模型的空腹血糖水平始终高于PyMT和HER2模型。TCDD仅影响维持在高脂饮食下的PyMT模型中的血清甘油三酯。由于高脂饮食的雌激素活性比低脂饮食低三倍，不同的饮食雌激素活性并未驱动观察到的表型差异。相反，高脂饮食依赖性变化是癌症模型依赖性的。这些结果表明，癌症模型甚至在癌症发生之前就可能对代谢综合征相关表型产生不同的影响。
