Co-mutagenic activity of arsenic and benzo[a]pyrene in mouse skin.
Exposure to inorganic arsenic in drinking water is linked to skin, lung and bladder cancer in humans. The mechanism of arsenic-induced cancer is not clear, but exposure to arsenic and polycyclic arylhydrocarbons (PAH) is more carcinogenic than exposure to either type of carcinogen alone. Arsenic can also generate reactive oxygen species, suggesting that oxidation of DNA may play a role in carcinogenesis. Oxidization of guanosines in polyG tracts is known to cause frameshift mutations, and such events can be detected in situ using the G11 placental alkaline phosphatase (PLAP) transgenic mouse model, which reports frameshift mutations in a run of 11 G:C basepairs by generating cells containing heat-resistant alkaline phosphatase activity. PAH can also induce frameshift mutations. In the study described here, FVB/N mice carrying the G11 PLAP transgene were crossed to C57Bl/6 mice. Half of the hybrid mice were given drinking water with sodium arsenite (10 mg/L) for 10 weeks. Half of the arsenic treated mice were also exposed to benzo[a]pyrene (BaP) by skin painting (500 nmol/week) for 8 weeks. Another group of mice was exposed to BaP but not arsenic. The effect on frameshift mutation was assessed by staining sections of skin tissue to detect cells with PLAP activity. Arsenic alone had no significant effect. On average, mice given BaP alone had approximately three times more PLAP-positive (PLAP+) cells. By contrast, mice exposed to both arsenic and BaP exhibited 10-fold more PLAP+ cells in the skin, and these cells were often arranged in large clusters, suggesting derivation from stem cells. Whereas combined treatment produced more PLAP+ cells, stable BaP adduct levels and arsenic burdens were not higher in mice exposed to both agents compared to mice exposed to either one agent or the other.
Fischer
Jared M
JM
University of Cincinnati, Department of Molecular Genetics, Biochemistry and Microbiology, 231 Albert Sabin Way, Cincinnati, OH 45267-0524, USA.
Robbins
Susan B
SB
Al-Zoughool
Mustafa
M
Kannamkumarath
Sasi S
SS
Stringer
Saundra L
SL
Larson
Jon Scott
JS
Caruso
Joseph A
JA
Talaska
Glenn
G
Stambrook
Peter J
PJ
Stringer
James R
JR
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001151:Arsenic; D018053:Arsenites / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D018736:DNA Adducts; D004357:Drug Synergism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009153:Mutagens / Q000633:toxicity*; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017670:Sodium Compounds / Q000633:toxicity*
D018053:Arsenites; D018736:DNA Adducts; D009153:Mutagens; D017670:Sodium Compounds; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; C017947:sodium arsenite; D000469:Alkaline Phosphatase; D001151:Arsenic