Differential Effects of Arsenic in Drinking Water on Mouse Hepatic and Intestinal Heme Oxygenase-1 Expression

Abstract

Arsenic exposure has been associated with the risks of various diseases, including cancers and metabolic diseases. The aim of this study was to examine the effects of arsenic exposure via drinking water on the expression of heme oxygenase-1 (HO-1), a major responsive gene to arsenic-induced oxidative stress, in mouse intestinal epithelial cells which is the first site of exposure for ingested arsenic, and the liver, a known target of arsenic toxicity. The expression of HO-1 was determined at mRNA, protein, or enzymic activity levels in mice exposed to sodium arsenite through drinking water, at various doses (0, 2.5, 10, 25, 100 ppm), and for various time periods (1, 3, 7, or 28 days). HO-1 was significantly induced in the intestine, but not liver, at arsenic doses of 25 ppm or lower. The intestinal HO-1 induction was seen in both males and females, plateaued within 1–3 days of exposure, and was accompanied by increases in microsomal HO activity. In mice exposed to 25-ppm of arsenite for 7 days, total arsenic and As(III) levels in intestinal epithelial cells were significantly higher than in the liver. These findings identify intestinal epithelial cells as likely preferential targets for arsenic toxicity and support further studies on the functional consequences of intestinal HO-1 induction.

Tissue-, Region-, and Gene-Specific Induction of Microsomal Epoxide Hydrolase Expression and Activity in the Mouse Intestine by Arsenic in Drinking Water

“…DMA has been reported to lack the ability to induce HO-1 expression (a marker of Nrf2 activation) in mouse liver and kidney (Kenyon et al, 2005). Thus, a lower level of total arsenic and a more rapid metabolism of As III to DMA in the liver than the small intestine would lead to a weaker activation of Nrf2 and explain the need for a higher oral dose of arsenic to cause HO-1 induction (Li et al, 2022) and mEH induction (this study).…”

“…The lower sensitivity of the liver than the small intestine to drinking water arsenic exposure in the induction of mEH expression may be explained by tissue differences in arsenic levels and speciation. Our recent study on arsenic induced HO-1 expression in the liver and intestine showed that, in mice exposed to 25 ppm sodium arsenite in drinking water for 7 days, the levels of total arsenic and arsenite (As III ) were both higher (by 47% and 4.1 fold, respectively) in the intestinal epithelial cells than in the liver (Li et al, 2022). Furthermore, the proportion of As III in total arsenic, or the ratio of As III to the major arsenic metabolite dimethylarsinic acid (DMA), was much higher in the intestine than in liver (e.g., the As III :DMA ratio was 0.34 in the intestine vs 0.08 in the liver).…”

“…Levels of mEH protein in microsomes and sEH protein in S9 fractions were determined by immunoblot analysis as previously described (Li et al, 2022), using the following primary antibodies: anti-calnexin (1:1200, Abcam, Waltham, MA, USA, ab22595); anti-β-actin (1:1000, Invitrogen, MA1-140); anti-mEH (1:100, Santa Cruz Biotechnology, SC-135984); anti-sEH (1:100; Santa Cruz Biotechnology; SC-166961). Calnexin and β-actin served as loading controls for microsomes and S9 fractions, respectively.…”

“…Arsenic exposure has been reported to alter the expression of several antioxidant genes (Du et al, 2008;Pi et al, 2008;Li et al, 2022), as well as biotransformation genes, including those for several cytochrome P450 enzymes (Anwar-Mohamed et al, 2012;Anwar-Mohamed et al, 2013) and UDP glucuronosyltransferase 1A1 (Yang et al, 2023). A connection between arsenic exposure and epoxide hydrolases has also been reported.…”