Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, Texas A&M University, College Station, Texas.
Department of Biology, Austin Community College, Austin, Texas.
Cancer Prev Res (Phila). 2017 Oct;10(10):553-562. doi: 10.1158/1940-6207.CAPR-17-0131. Epub 2017 Sep 13.
Obesity and alterations in metabolic programming from early diet exposures can affect the propensity to disease in later life. Through dietary manipulation, developing mouse pups were exposed to a hyperinsulinemic, hyperglycemic milieu during three developmental phases: gestation, lactation, and postweaning. Analyses showed that a postweaning high fat/high sugar (HF/HS) diet had the main negative effect on adult body weight, glucose tolerance, and insulin resistance. However, dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis revealed that animals born to a mother fed a HF/HS gestation diet, nursed by a mother on a mildly diet-restricted, low fat/low sugar diet (DR) and weaned onto a HF/HS diet (HF/DR/HF) had the highest mammary tumor incidence, while HF/HF/DR had the lowest tumor incidence. Cox proportional hazards analysis showed that a HF/HS postweaning diet doubled mammary cancer risk, and a HF/HS diet during gestation and postweaning increased risk 5.5 times. Exposure to a HF/HS diet during gestation, when combined with a postweaning DR diet, had a protective effect, reducing mammary tumor risk by 86% (HR = 0.142). Serum adipocytokine analysis revealed significant diet-dependent differences in leptin/adiponectin ratio and IGF-1. Flow cytometry analysis of cells isolated from mammary glands from a high tumor incidence group, DR/HF/HF, showed a significant increase in the size of the mammary stem cell compartment compared with a low tumor group, HF/HF/DR. These results indicate that dietary reprogramming induces an expansion of the mammary stem cell compartment during mammary development, increasing likely carcinogen targets and mammary cancer risk. .
肥胖和早期饮食暴露引起的代谢编程改变会影响晚年患病的倾向。通过饮食干预，发育中的小鼠幼仔在三个发育阶段（妊娠期、哺乳期和离乳后）暴露于高胰岛素血症、高血糖环境中。分析表明，离乳后高脂肪/高糖（HF/HS）饮食对成年体重、葡萄糖耐量和胰岛素抵抗有主要的负面影响。然而，二苯并[a]蒽（DMBA）诱导的致癌作用表明，出生于高脂肪/高糖妊娠期饮食喂养的母亲、哺乳期接受轻度饮食限制、低脂肪/低糖饮食（DR）喂养的母亲以及离乳后接受高脂肪/高糖饮食（HF/DR/HF）的动物具有最高的乳腺肿瘤发生率，而 HF/HF/DR 组的肿瘤发生率最低。Cox 比例风险分析表明，离乳后高脂肪/高糖饮食使乳腺癌风险增加一倍，妊娠期和离乳后高脂肪/高糖饮食使风险增加 5.5 倍。妊娠期暴露于高脂肪/高糖饮食，同时在离乳后接受 DR 饮食，具有保护作用，使乳腺肿瘤风险降低 86%（HR=0.142）。血清脂肪细胞因子分析显示，瘦素/脂联素比值和 IGF-1 存在显著的饮食依赖性差异。来自高肿瘤发生率组（DR/HF/HF）的乳腺细胞的流式细胞术分析显示，与低肿瘤发生率组（HF/HF/DR）相比，乳腺干细胞区室的大小显著增加。这些结果表明，饮食重编程在乳腺发育过程中诱导乳腺干细胞区室的扩张，增加了可能的致癌剂靶标和乳腺肿瘤风险。
