title: Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism.
abstract: Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood.
authors.affiliation: Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709, USA. Liu6@niehs.nih.gov
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Yaxiong
authors.initials: Y
authors.lastname: Xie
authors.forename: Ryan
authors.initials: R
authors.lastname: Cooper
authors.forename: Danica M K
authors.initials: DM
authors.lastname: Ducharme
authors.forename: Raymond
authors.initials: R
authors.lastname: Tennant
authors.forename: Bhalchandra A
authors.initials: BA
authors.lastname: Diwan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*; D013256:Steroids / Q000378:metabolism*
chemical_list: D018053:Arsenites; D004967:Estrogens; D017670:Sodium Compounds; D013256:Steroids; C017947:sodium arsenite