APOB48 downregulation is the causing factor in mediating iAs-induced lipid accumulation in enterocytes

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ABSTRACT Early life exposure to arsenic during fetal and neonatal development is a prerequisite to accelerated toxicity and delayed health consequences. Humans ingest arsenic through contaminated drinking water and foods with the intestinal tract being the primary site for arsenic absorption. With whole life exposure to arsenic occurring worldwide, there is limited data available on arsenic’s effects on the intestinal tract, especially during the early developmental stage. Our laboratory has demonstrated that oral arsenic treatment induces oxidative stress in the intestinal tissues, altering significant overall gene expression. Most recently, we observed that oral administration of inorganic arsenic (iAs) to neonatal mice dramatically accelerates intestinal stem cell (ISC) proliferation and intestinal epithelial cell (IEC) differentiation. Histological examination and biochemical analysis have revealed that iAs exposure leads to drastic lipid accumulation in intestinal enterocytes. When we treated neonatal mice with oleic acid, which is abundant in breast milk, this treatment mimics what we observed with iAs-induced pathophysiological changes in the small intestine. Thus, it is likely that lipid accumulation from iAs exposure mediates iAs-induced intestinal effects. As the functionality of the digestive tract is determined primarily by the small intestine, through altering the epithelium function, early life iAs exposure may generate a myriad of health challenges that could predispose individuals to a greater disease vulnerability. Therefore, understanding how iAs impacts on intestinal lipid metabolism will be the focus of our studies. We have identified that apolipoprotein B48 (APOB48), the structural component of chylomicron synthesis and secretion, is dramatically downregulated following iAs exposure. We will test the hypothesis that downregulated APOB48 is the causing factor in mediating iAs-induced lipid accumulation in enterocytes. In this proposal, we will determine the functional outcomes of APOB48 downregulation by measuring lipid content in plasma samples, including lipid profiling, levels of fat-soluble vitamins, and essential fatty acids. We will determine the fat absorption capability in mice following iAs exposure (Aim 1). We will also determine if overexpression of the constitutive active APOB48 in intestinal tissue counters iAs induced enterocyte lipid accumulation by conducting experiments in transgenic mice carrying a villin-promoter driven human APOB cDNA (Aim 2). We contend that these experiments will lay the foundation for an understanding of the underlying mechanisms leading to iAs induced intestinal lipid accumulation in neonatal mice, an event that we predict may predispose mice to accelerated physiological changes and diseases later in life.