The Toxicology research being performed falls into two categories: (1) The causing of toxic responses by chemicals via nuclear receptors and (2) Chemoprevention.
Peroxisome proliferators (PPs) are a large group of chemicals which when fed to rodents result in a characteristic hepatomegaly, proliferation of peroxisomes in parenchymal cells, and an increase in peroxisomal β-oxidation of fatty acids. These chemicals have raised a health concern since there is a high likelihood of human exposure and an association between peroxisome proliferation and liver cancer in laboratory animals has been well documented. Throughout the 1970s and 1980s, much of the research on PPs focused on their biochemical effects in laboratory animals, such as alterations in lipid metabolism and enzyme induction. Upon the discovery of a nuclear hormone receptor that is activated by PPs in 1990 by I. Issemann, S. Green and colleagues the research has taken a dramatic turn toward molecular and cellular biology. The new era in peroxisome proliferator research focuses on this intracellular protein aptly named the peroxisome proliferator-activated receptor or PPAR. PPs are now considered to cause cancer in a manner similar to other steroid hormone receptor ligands such as estrogen, i.e. by altering gene expression and affecting the phenotype of the target cell. PPARs have been cloned in several species, including humans, which help explain the molecular events involved in PP-dependent gene regulation. The cloning of three distinct PPARs from xenopus, lead to the realization that a subfamily of these receptors existed. Currently, the subfamily has been defined as PPARα, PPARβ (also called PPARδ and NUC1) and PPARγ. The potency of various chemicals to activate PPARs is subtype specific and the expression of PPARα, β and γ varies widely from tissue-to-tissue. Thus each receptor has distinct ligands and has evolved to serve different biological role.
Several hypolipidemic drugs and industrial chemicals classified as PPAR ligands result in tumors in laboratory animals. Conversely, ligands for PPARγ have been associated with an inhibition of cancer of the colon, prostate and breast. A theory that has been gaining favor over recent years is that PPAR ligands affect the carcinogenic process by altering the expression of a particular subset of genes that in turn affects the rate of proliferation of cells. That PPARs are required for the effects of their ligands on cell proliferation has become apparent through the use of knockout animals. PPARα null mice do not respond to the tumor promoting effects of peroxisome proliferators and PPARβ null mice have altered response to mitogens. Taken together, this information indicates there is a direct link between peroxisome proliferators, PPAR, altered gene expression, and toxicity and/or therapeutic effects.
Example 1. Pancreatic Cancer (NIH Pending)
Although pancreatic cancer is a relatively uncommon tumor, the mortality rate is very high, making it the fourth leading cause of cancer death in the United States. Epidemiological and laboratory studies confirm that both the dietary fat content and the type of fat play a significant role in the risk for various cancers including that of the pancreas. Inflammation is a key contributor and all types of chronic pancreatitis have been linked to the subsequent development of tumors in this tissue. The primary hypothesis tested in the present proposal is omega 3 polyunsaturated fatty acids (ω3-PUFA) inhibit the development of pancreatic ductal cell adenomacarcinoma (PDA) by decreasing progression of pancreatic intraepithelial neoplasias (PanINs). A secondary but related hypothesis is that the mechanism by which ω3-PUFA exert this preventative effect is by decreasing inflammatory signaling in pancreatic cells and macrophages via activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Support for these studies comes from extensive preliminary data presented herein as well as recent research performed by the investigators. In Specific Aim 1, we will examine the effects of ω3-PUFA on the progression of pancreatic intraepithelial neoplasias (PanINs) in a mouse model of pathogenesis. A mouse genetic model (KRASG12D/Pdx1) that recapitulates human disease will be utilized. Mice will be fed high and low fat diets with varying ratios of ω3/ω6 PUFA and histological, biochemical and molecular markers of disease examined. Research in Specific Aim 2 will determine the mechanism by which ω3-PUFAs regulate PanIN progression, using human cell lines and a variety of cell and molecular biology techniques. The role of PPARβ/δ in PanIN progression and its contribution in the ω3-PUFA response will be examined in Specific Aim 3. This aim will integrate the studies performed in the first two aims by crossing the KRASG12D/Pdx1 and PPARβ/δ-/- mouse model systems. Taken together this research will aid in the identification of a nutritional means of prevention of pancreatic cancer, a disease with an alarmingly high mortality rate.
Example 2. Breast Cancer (AICR)
The basic premise that diet plays a major role in cancer etiology and prevention is no longer a matter of debate as this association has been proven in human clinical trials as well as animal and in vitro model systems. Nevertheless, many questions remain to be resolved, including exactly which specific dietary factors are most closely linked to cancer prevention and by what mechanisms food components exert their putative effects. Diets high in walnuts have a variety of beneficial effects including reduced cardiovascular risk factors. Of the complex mixture of components in walnut, ω-3 polyunsaturated fatty acids (ω3-PUFAs) have received the most attention as the reason for the health benefits in consuming walnuts. Interestingly, ω-3 PUFAs including alpha-linolenic acid (ALA), a fatty acid found in relatively high concentration in walnuts, are associated with reduced risk of a variety of cancers including breast cancer. Fatty acids affect the function of a variety of cells including tumor cells and fat cells and also modulate how they communicate with each other; this cell-cell communication between adipocytes and cancer cells is potentially a key step by which diet can modulate the cancer process. In these studies, we will examine the effects of walnut extracts as well as purified ω-3 PUFAs on breast cancer cells, adipocytes and there ability to modulates each other’s activity.