Bracken fern carcinogenesis: multiple intravenous doses of activated ptaquiloside induce DNA adducts, monocytosis, increased TNF alpha levels, and mammary gland carcinoma in rats.
OBJECTIVE
(1) establish a rat model for investigating ptaquiloside (PT) carcinogenesis via intravenous dosing; (2) determine the role of activated PT (APT) in this model; and (3) monitor changes at molecular (DNA adducts, TNF alpha levels) and cellular (histopathology) levels.


METHODS
Sprague-Dawley rats were dosed with PT or APT intravenously for 10 consecutive weeks. One group of animals was sacrificed immediately for TNF alpha and DNA adduct analyses. A second group of animals was kept alive for 30 more weeks to allow for tumour formation. Tissues were collected at the end of the experiment for histopathological studies.


RESULTS
Rats dosed with PT or APT showed marked increase in monocyte and TNF alpha levels. These levels remained high even 30 weeks after the last dosing. Analysis of DNA showed the presence of DNA adducts in APT-treated animals in target organs. In addition, 40% of APT-treated rats developed mammary gland carcinomas.


CONCLUSIONS
This is the first study to demonstrate the potential of activated PT as a carcinogen in vivo. In addition, our findings suggest that PT exposure can be monitored using monocyte and TNF alpha levels.
Shahin
M
M
National Research Centre for Environmental Toxicology (NRCET), University of Queensland, Coopers Plains, Australia.
Smith
B L
BL
Worral
S
S
Moore
M R
MR
Seawright
A A
AA
Prakash
A S
AS
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000096:biosynthesis*; D004334:Drug Administration Schedule; D005260:Female; D007189:Indans; D007275:Injections, Intravenous; D007958:Leukocyte Count / Q000187:drug effects; D007964:Leukocytosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D010947:Plants, Toxic / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes; D013729:Terpenes / Q000378:metabolism / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D002273:Carcinogens; D018736:DNA Adducts; D007189:Indans; D012717:Sesquiterpenes; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; C043680:ptaquiloside