Transplacental arsenic plus postnatal 12-O-teradecanoyl phorbol-13-acetate exposures associated with hepatocarcinogenesis induce similar aberrant gene expression patterns in male and female mouse liver.
Our prior work shows that in utero arsenic exposure alone is a complete transplacental carcinogen, producing hepatocellular carcinoma in adult male offspring but not in females. In a follow-up study to potentially promote arsenic-initiated tumors, mice were exposed to arsenic (85 ppm) from gestation day 8 to 18 and then exposed to 12-O-teradecanoyl phorbol-13-acetate (TPA), a well-known tumor promoter after weaning. The dermal application of TPA (2 mug/0.1 ml acetone, twice/week for 21 weeks) after transplacental arsenic did not further increase arsenic-induced liver tumor formation in adult males but significantly increased liver tumor formation in adult females. Thus, for comparison, liver tumors and normal liver samples taken from adult male and female mice at necropsy were analyzed for aberrant gene/protein expression by microarray, real-time RT-PCR and Western blot analysis. Arsenic/TPA treatment resulted in increased expression of alpha-fetoprotein, k-ras, c-myc, estrogen receptor-alpha, cyclin D1, cdk2na, plasminogen activator inhibitor-1, cytokeratin-8, cytokeratin-18, glutathione S-transferases and insulin-like growth factor binding proteins in liver and liver tumors from both male and female mice. Arsenic/TPA also decreased the expression of BRCA1, betaine-homocysteine methyltransferase, CYP7B1, CYP2F2 and insulin-like growth factor-1 in normal and cancerous livers. Alterations in these gene products were associated with arsenic/TPA-induced liver tumors, regardless of sex. Thus, transplacental arsenic plus postnatal TPA exposure induced similar aberrant gene expression patterns in male and female mouse liver, which are persistent and potentially important to the mechanism of arsenic initiation of hepatocarcinogenesis.
Liu
Jie
J
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
Xie
Yaxiong
Y
Merrick
B Alex
BA
Shen
Jun
J
Ducharme
Danica M K
DM
Collins
Jennifer
J
Diwan
Bhalchandra A
BA
Logsdon
Daniel
D
Waalkes
Michael P
MP
D000287:Administration, Topical; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000633:toxicity*
D001151:Arsenic; D013755:Tetradecanoylphorbol Acetate