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.