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Oral arsenic exposure induces UGT1A1 expression in neonatal humanized UDP‐Glucuronosyltransferase‐1 mice through changes in cellular morphology associated cytotoxicity
Author(s) -
Konopnicki Camille,
Fujiwara Ryoichi,
Nguyen Nghia,
Tukey Robert H
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.850.13
Subject(s) - toxicant , oxidative stress , gene expression , arsenic , cytotoxicity , metallothionein , biology , carcinogen , arsenic toxicity , chemistry , toxicity , endocrinology , biochemistry , gene , in vitro , organic chemistry
Arsenic, which is commonly found in drinking water, is a human toxicant and carcinogen. Abnormal cell cycle regulation, as well as changes in cell morphology due to arsenic‐induced cytotoxicity, can lead to changes in cell signaling that ultimately affect gene expression patterns. In this study, we address the contribution of oral arsenic exposure on the induction of small intestinal UDP‐glucuronsyltransferase 1A1 expression in humanized UGT1 ( hUGT1 ) mice. Neonatal hUGT1 mice develop hyperbilirubinemia, which returns to normal as adults. When arsenic (10mg/kg) was administered to neonatal hUGT1 mice by oral gavage, intestinal UGT1A1 gene expression was induced followed by reduced levels of serum bilirubin. Induction of the Cyp2b10 gene and the oxidative stress marker, Gsta1 was also observed following exposure. Analysis of intestinal gene markers indicated that arsenic treatment led to intestinal proliferation and injury. Hematoxylin & eosin (H&E) and Periodic Acid Schiff (PAS) staining revealed abnormal vacuole formation of intestinal enterocytes and signs of cellular proliferation. Increased expression of proliferative gene markers was also seen in arsenic treated mice. We conclude that early intestinal damage by arsenic is linked to induction of intestinal xenobiotic metabolism. (Supported by grants GM086713 and ES010337)