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ToxSci Advance Access published online on October 31, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl151
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Published by Oxford University Press 2006.
Received September 13, 2006
Accepted October 25, 2006

Carcinogenicity

Fetal Onset of Aberrant Gene Expression Relevant to Pulmonary Carcinogenesis in Lung Adenocarcinoma Development Induced by In Utero Arsenic Exposure

Jun Shen 1, Jie Liu 1, Yaxiong Xie 1, Bhalchandra A. Diwan 2, and Michael P. Waalkes 1 *

1 Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC , USA
2 Basic Research Program, Science Applications International Corp. (SAIC) at Frederick, National Cancer Institute, Frederick, MD, USA

* To whom correspondence should be addressed.
Michael P. Waalkes, E-mail: waalkes{at}niehs.nih.gov


  Abstract

Arsenic is a human pulmonary carcinogen. Our work indicates in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in the drinking water from day 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-{alpha} (ER-{alpha}) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2 and the steroid metabolism genes 17-{beta}-hydroxysteroid dehydrogenase-5 and aromatase. The IGF system, which can be influenced by ER and has been implicated in pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. In utero arsenic exposure also induced overexpression of {alpha}-fetoprotein, epidermal growth factor receptor, L-myc and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed wide-spread, intense nuclear ER-{alpha} expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-{alpha} expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-{alpha} activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programming in the lung leading eventually to lung tumor formation much later in adulthood.

Keywords: Inorganic arsenic; transplacental exposure; lung cancer; estrogen signaling.
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