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Purpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined.Experimental Design: A/J C57BL6/J mice with wild-type Egfr (Egfrwt) or loss-of-function waved-2 Egfr (Egfrwa2) received azoxymethane followed by standard (5 fat) or western-style (20 fat) diet. As F1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and real-time PCR.Results:Egfrwt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfrwa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2 versus 36.7; P < 0.05) and cancer incidence (43.9 versus 16.7; P < 0.05) only in Egfrwt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfrwt mice. In tumors, dietary fat and Egfrwt upregulated transforming growth factor-, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfrwt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor- in normal colon.Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):67809)

Supplementary Data from Epidermal Growth Factor Receptor Is Required for Colonic Tumor Promotion by Dietary Fat in the Azoxymethane/Dextran Sulfate Sodium Model: Roles of Transforming Growth Factor- and PTGS2

Lead (Pb) poisoning is a major public health concern in environmental justice communities of the USA and in many developing countries. There is no identified safety threshold for lead in blood, as low-level Pb exposures can lead to severe toxicity in highly susceptible individuals and late onset of diseases from early-life exposure. However, identifying "susceptibility genes" or "early exposure biomarkers" remains challenging in human populations. There is a considerable variation in susceptibility to harmful effects from Pb exposure in the general population, likely due to the complex interplay of genetic and/or epigenetic factors. This systematic review summarizes current state of knowledge on the role of genetic and epigenetic factors in determining individual susceptibility in response to environmental Pb exposure in humans and rodents. Although a number of common genetic and epigenetic factors have been identified, the reviewed studies, which link these factors to various adverse health outcomes following Pb exposure, have provided somewhat inconsistent evidence of main health effects. Acknowledging the compelling need for new approaches could guide us to better characterize individual responses, predict potential adverse outcomes, and identify accurate and usable biomarkers for Pb exposure to improve mitigation therapies to reduce future adverse health outcomes of Pb exposure.

Background: Type 2 diabetes (T2D) is a high-risk factor for incident of cardiovascular diseases. Women at young ages show a reduced incidence of both T2D and cardiovascular diseases compared with men, but these disparities disappear in postmenopausal women versus age-matched men. Thus, ovaries and ovarian hormones, such as estrogen, are expected to protect from T2D and cardiovascular diseases. In this study, we aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism using the cardiac IRS (insulin receptor substrate) 1 and IRS2 double genes knockout mice that mimic cardiac insulin resistance. Methods: Control and heart-specific IRS1/2 double genes knockout mice were treated with placebo or 17β-estradiol (E 2 ) pellets, respectively, through subcutaneous implantation. Female mice were subjected to a bilateral ovariectomy surgery to remove endogenous E 2 . The cardiac function and energy metabolism were determined using echocardiography and indirect calorimeter, respectively. Results: All male heart-specific IRS1/2 double genes knockout mice died of heart failure at 6 to 8 weeks as we previously described (Qi et al), but all female heart-specific IRS1/2 double genes knockout mice survived >1 year. Removal of ovaries in heart-specific IRS1/2 double genes knockout female mice resulted in cardiac dysfunction, and ultimately animal death. However, E 2 supplementation prevented the dilated cardiomyopathy, improved cardiac function and energy metabolism, and enhanced lifespan in both male and ovariectomy female mice deficient for cardiac IRS1 and IRS2 genes, largely owing to the activation of Akt (protein kinase B)-Foxo1 (O1 class of forkhead/winged helix transcription factor) signaling cascades. Conclusions: These results show that estrogen protects mice from cardiac insulin resistance-induced diabetic cardiomyopathy. This may provide a fundamental mechanism for the gender difference for the incidence of both T2D and cardiovascular diseases. This study highlights that estrogen signaling could be a potential target for improving cardiac function and energy metabolism in humans with T2D.