The long-term objective of this proposal is to test the hypothesis that dioxin, dioxin-like and nondioxin-like chemicals alone or in combination alter the expression and secretion of intestinal peptide hormones; and, to investigate the relationships between changes in gastrointestinal (GI) levels of peptide hormones, specific growth factors and oxidative stress with time, dose level, chemical, mixture and the toxic equivalency factor (TEF) of relevant chemicals. Dioxins are ubiquitous environmental contaminants with multiple, endocrine disruptive actions. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent congener of these halogenated, aromatic hydrocarbons. Previous studies indicate that dioxins have multiple adverse effects on the GI tract. TCDD exposure results in hypophagia, reduced growth, weight loss and the wasting syndrome. Because feeding behavior and weight gain are regulated, in part, by intestinal peptide hormones, TCDD-induced hypophagia may be due, in part, to TCDD-induced changes in intestinal hormone gene expression and secretion. There are limited data on the effects of dioxins (ie, TCDD), dioxin-like and nondioxin-like chemicals, singly and in mixtures on the GI tract. The working hypothesis for this research proposal is that dioxin, dioxin-like and nondioxin-like chemicals alter expression of GI peptide hormones involved in regulation of food intake (ie, TCDD, PeCDF, PCB126, PCB118, PCB153). Changes in GI hormone gene expression may be mechanistically due to chemically- induced changes in GI growth factor (IGF-1, EGF, TGF-alpha, TGF-beta) and EGF-receptor (EGF-R) gene expression and associated with chemical- induced intestinal oxidative stress.
The specific aim of this research project is to test the hypothesis that dioxin (TCDD), dioxin-like and nondioxin-like chemicals alone or in combination cause GI oxidative stress and increase gene expression and secretion of intestinal cholecystokinin and glucagon-like peptide-I. We intend to establish a relationship between intestinal changes in GI peptide hormones, growth factors and levels with treatment time, dose, chemicals/mixture and relevant TEF of these chemicals in order to assess their potential toxicological risks for human exposure.
| Lee, H M; He, Q; Englander, E W et al. (2000) Endocrine disruptive effects of polychlorinated aromatic hydrocarbons on intestinal cholecystokinin in rats. Endocrinology 141:2938-44 |
